阅读说明：本技术 用于深部脑刺激的方法和装置 (Methods and devices for deep brain stimulation ) 是由 尼库尼·坎蒂拉尔·帕特尔 于 2020-09-21 设计创作，主要内容包括：公开了用于对受试者的脑执行治疗的装置,所述装置包括电极引线和控制器,所述电极引线被布置用于插入到所述受试者的脑中,所述电极引线的远端部分具有多个电极,所述多个电极被布置成将一个或多个神经调制信号施加至所述受试者的脑的外侧缰核和后连合,所述控制器被配置成生成由所述多个电极所施加的所述一个或多个神经调制信号。(An apparatus for performing therapy on a brain of a subject is disclosed, the apparatus comprising an electrode lead arranged for insertion into the brain of the subject, a distal portion of the electrode lead having a plurality of electrodes arranged to apply one or more neuromodulation signals to lateral reins and posterior commissures of the brain of the subject, and a controller configured to generate the one or more neuromodulation signals applied by the plurality of electrodes.)

1. An apparatus for performing therapy on a brain of a subject, the apparatus comprising: an electrode lead arranged for insertion into the brain of the subject, a distal portion of the electrode lead having a plurality of electrodes arranged to apply one or more neuromodulation signals to the lateral reins and posterior commissures of the brain of the subject; and

a controller configured to generate the one or more neuromodulation signals applied by the plurality of electrodes.

2. The apparatus of claim 1, wherein the plurality of electrodes are further arranged to apply one or more neuromodulation signals to one or more additional targets in the brain of the subject.

3. The device of claim 2, wherein the one or more additional targets comprise the thalamic dorsolateral nucleus and/or VL-PAG.

4. The apparatus of claim 1, wherein the plurality of electrodes span a length of 20mm to 25 mm.

5. The apparatus of claim 1, further comprising: a proximal electrode arranged to apply a neuromodulation signal to the anterior dorsal cingulum and/or the corpus callosum.

6. The apparatus of claim 5, wherein the proximal electrode comprises a proximal electrode disposed on the electrode lead.

7. The apparatus of claim 6, wherein a length of the proximal electrode disposed on the electrode lead is greater than a length of each of the plurality of electrodes.

8. The device of claim 7, wherein the proximal electrode disposed on the electrode lead is between 10mm and 30mm in length.

9. The apparatus of claim 1, further comprising: a catheter for insertion into the brain of the subject, the catheter comprising a hollow tube defining a longitudinal channel in which the electrode lead is receivable.

10. The apparatus of claim 9, wherein:

the proximal electrode comprises a proximal electrode disposed on the electrode lead; and is

The catheter includes a window formed in a sidewall of the hollow tube and arranged to expose the proximal electrode disposed on the electrode lead to an exterior of the hollow tube when the electrode lead is received in the longitudinal channel of the hollow tube.

11. The device of claim 10, wherein the window has a length that is shorter than a length of the proximal electrode disposed on the electrode lead.

12. The device of claim 10, wherein the window comprises two or more holes in the sidewall of the hollow tube.

13. The apparatus of claim 9, wherein:

the proximal electrode comprises a proximal electrode disposed on the electrode lead; and is

The proximal electrode comprises an outer electrode at the outer surface of the hollow tube and the outer electrode is arranged for electrical connection with the proximal electrode provided on the electrode lead when the electrode lead is received in the longitudinal channel of the hollow tube.

14. The apparatus of claim 9, further comprising: a proximal electrode arranged to apply neuromodulation signals to the anterior dorsal cingulum and/or the corpus callosum, wherein the proximal electrode comprises an outer electrode at the outer surface of the hollow tube and the outer electrode is electrically connected to the controller via a connecting lead extending through the hollow tube.

15. The apparatus of claim 9, wherein the catheter further comprises a cap that is securable to an aperture in the skull of the subject, and the cap comprises a passageway through which the hollow tube is insertable to insert the hollow tube into the brain of the subject.

16. The device of claim 15, further comprising a first limiter secured to a proximal end portion of the hollow tube and arranged to abut the cap when a predetermined length of the hollow tube is inserted through the passageway.

17. The device of claim 9, further comprising a second limiter secured to a proximal portion of the electrode lead and arranged to abut a proximal end of the catheter when a predetermined length of the electrode lead protrudes from the distal opening of the hollow tube.

18. The apparatus of claim 1, further comprising a sensor arranged to detect a physiological parameter of the subject and to generate an output signal related to the detected physiological parameter, wherein the controller is configured to adjust at least one of the one or more neuromodulation signals based on the output signal from the sensor.

19. The device of claim 1, further comprising one or more stimulation electrodes for applying one or more stimulation signals to carotid body and/or carotid baroreceptors in the subject.

20. A catheter for insertion into the brain of a subject, the catheter comprising a hollow tube defining a longitudinal channel in which an electrode lead can be housed;

wherein the catheter comprises a window formed in a side wall of the hollow tube and arranged to expose a proximal electrode on the electrode lead to the exterior of the hollow tube when the electrode lead is received in the longitudinal channel of the hollow tube.

21. The catheter of claim 20, wherein the window comprises two or more holes in the sidewall of the hollow tube.

22. A catheter for insertion into the brain of a subject, the catheter comprising a hollow tube defining a longitudinal channel in which an electrode lead can be housed;

wherein the catheter comprises an external electrode on the outer surface of the hollow tube.

23. The catheter of claim 22, further comprising a connecting lead extending through the hollow tube for connecting the outer electrode to a controller.

24. The catheter of claim 22, wherein the outer electrode is configured for electrical connection with a proximal electrode on the electrode lead when the electrode lead is received in the longitudinal channel of the hollow tube.

25. The catheter of claim 20, further comprising a cap that is securable to an aperture in the skull of the subject and that includes a passageway through which the hollow tube is insertable to insert the hollow tube into the brain of the subject.

26. The catheter of claim 25, further comprising a first limiter secured to a proximal end portion of the hollow tube and arranged to abut the cap when a predetermined length of the hollow tube is inserted through the passageway.

27. A method of performing therapy on a subject's brain, said method comprising the step of applying one or more neuromodulation signals to lateral reins and posterior commissures.

28. A method of performing therapy on a subject, the method comprising:

applying one or more neuromodulation signals to one or more targets in the brain of the subject; and

applying a stimulation signal to a carotid body and/or carotid baroreceptors in the subject.

29. A system, comprising:

means for applying one or more neuromodulation signals to one or more targets in the brain of the subject; and

a stimulation electrode for applying a stimulation signal to a carotid body and/or a carotid baroreceptor in the subject.

Technical Field

The present invention relates to methods and devices for Deep Brain Stimulation (DBS).

Background

Deep Brain Stimulation (DBS) is a neurosurgical approach introduced in 1987 that involves implanting electrodes at specific targets in the brain. Medical devices known as neurostimulators (sometimes referred to as "brain pacemakers") are used to apply neurostimulation signals in the form of electrical pulses through electrodes to targets in the brain, thereby altering the brain circuit for the treatment of motor and neuropsychiatric diseases.

This technique, which is currently used in the brain circuits directed to parkinson's disease, dystonia and tremor, has proven to be highly effective for controlling symptoms. Deep brain stimulation in selected brain regions also provides a therapeutic effect for other treatment resistant diseases, such as chronic pain, major depressive disorder, addiction, epilepsy, tourette's disease, and obsessive compulsive disorder.

Despite the long history of DBS, its underlying principles and mechanisms are still unclear. It is generally believed that electrical stimulation controls the excitability of neurons implanted in the vicinity of the electrodes. Stimulation frequencies are widely used to excite (e.g., less than 50 hertz) or suppress (e.g., greater than 100 hertz) neurons; the excitation amplitude and pulse width are used to provide control of the amount of charge applied to reach and empirically define the threshold. The threshold response is also determined by the physical proximity of the electrode contact to the brain target region of interest.

Typically, the electrodes for DBS are distributed along a lead in the form of circumferential (e.g., cylindrical) or directional contacts, which lead is connected to an Implantable Pulse Generator (IPG). This may enable a monopolar stimulation configuration (in the case of an IPG serving as the anode) or a bipolar stimulation configuration (between the contacts).

In US2016/0367809a1 (which is incorporated herein by reference), the present inventors disclose such a treatment: brain perfusion is increased by neurostimulating periaqueductal gray (PAG), thereby enabling the treatment of a range of diseases associated with impaired cerebral blood flow. US2016/0367809A1 also describes such a treatment: the method involves combined neural stimulation of the PAG and the dorsal medial nuclei of the thalamus.

Disclosure of Invention

The present invention is based on the work done by the present inventors in US2016/0367809a1 and is based on the following findings: combined neural stimulation of multiple targets in the brain can result in improved response to treatment. In particular, the present inventors have discovered that the response to neural stimulation of various targets in the brain can be improved by additional neural stimulation of the Lateral Halberella (LH) and postero-commissure (PC).

Thus, in its most general aspect, the invention provides a method of performing therapy on the brain of a subject, the method comprising applying one or more neuromodulation signals to LH and PC.

According to a first aspect of the present invention there is provided a method of performing therapy on the brain of a subject, the method comprising the step of applying one or more neuromodulation signals to the lateral reins (LH) and the Posterior Commissures (PC).

LH and PC can be stimulated by the same (single) neuromodulation signal. Alternatively, separate (different) neuromodulation signals may be applied to each of LH and PC, respectively.

Stimulation of LH and PC may affect the adjacent medial thalamus, and/or periventricular gray, and/or periaqueductal gray, and/or their respective processes (projections); and may affect the pineal gland and/or the contralateral hemispheric protrusion via LH and PC. Thus, applying one or more neuromodulation signals to LH and PC may include applying one or more neuromodulation signals directly or indirectly to one or more of adjacent medial thalamus, periventricular gray, periaqueductal gray, and their respective processes; and may include affecting one or both of the pineal gland and the contralateral hemispherical protrusion by LH and PC.

The neuromodulation signal may be an electrical signal applied to a target in the brain. For example, the neuromodulation signal may be a pulsed electrical signal. Parameters of the neuromodulation signal, such as frequency, pulse width, and pulse amplitude, may be adjusted according to the particular requirements of the therapy. The neuromodulation signal may be applied continuously, or in a string, or periodically.

The present inventors have found that neural stimulation of LH and PC in a subject can enhance cerebral blood flow. This may allow for the treatment of a variety of conditions associated with reduced cerebral blood flow.

The outer reins are part of the reins complex that includes the inner and outer reins. By extending the medullary groove, the medial reins receive fibers from the medial septal-diagonal ribbon complex. Medial reins also receive fibers from the periaqueductal gray, serotonin-containing (serotonergic) processes from the midbrain nucleus, and adrenergic innervation (adrenergicic innervation) from the upper cervical ganglion. The action of the medial reins is terminated only by the interapophyseal nucleus, which protrudes largely into the dorsal midline and the central superior nucleus. The lateral reins mainly receive the introduction of the nucleus of the diagonal zone, the lateral foresight-hypothalamus area, the innominate body and the medial pale segment; while the ventral tegmental area, the midbrain raphe nucleus and the ventral portion of the grey matter surrounding the aqueduct cause an ascending input of this nucleus. Efferent fibers from the lateral reins descend in the retroreflexogenic fascicles and terminate in various midbrain centers, including the substantia nigra pars compacta, the ventral portion of the periaqueductal gray, the dorsal and central superior raph, and the midbrain meshwork. Although the functional role of reins has not been fully elucidated, their fibrous connectivity suggests that they represent a treatment station for a variety of biological functions, including pain management, mood, reproduction, nutrition, stress, sleep arousal cycle, and learning.

The posterior commissure is a circular band of white fibers that passes through the midline on the dorsal side of the head of the cerebral aqueduct. Most of the fibers originate from the nucleus of the posterior commissure, which is located in the periaqueduct gray at the head of the cerebral aqueduct and in front of the oculomotor nucleus; other fibers are believed to originate from the posterior thalamus, superior colliculus, and medial longitudinal bundle. On the basis of clinical observations, the nucleus of the posterior commissure is suspected to be involved in the generation of upward eye movement and anterior movement control of the upper eyelid. The nucleus protrudes into the contralateral thalamus, inner capsule and midbrain locations. The nucleus has an interconnection with an adjacent midbrain central network that receives input from the cerebellar fascia nucleus, which when stimulated, is shown to be neuroprotective in stroke.

Ventral PC is closely related to the subentry nucleus, the posterior fasciculation (protruding into the midbrain), and the medial parathalamic nucleus. Thus, applying a neuromodulation signal to a PC may also include applying the neuromodulation signal directly or indirectly to one or more of the subentries, the flexor hallucis (toward the midbrain processes), and the lateral subthalamic nucleus.

The method may further comprise applying one or more neuromodulation signals to one or more additional targets in the brain of the subject. Thus, one or more neuromodulation signals may be applied to one or more additional targets and LH and PC in the brain of the subject. The present inventors have found that combining neurostimulation of brain targets with neurostimulation of LH and PC can result in improved response to the neurostimulation of the target.

The same (single) neuromodulation signal may be applied to each of LH and PC and one or more additional targets in the brain of the subject. Alternatively, different neuromodulation signals may be applied to each or a subset (group) of LH and PC and one or more additional targets in the brain of the subject.

The one or more additional targets may include the thalamus dorsolateral nucleus (DMN).

Thus, according to one embodiment, the method includes applying one or more neuromodulation signals to each of the DMN, LH and PC.

The inventors have found that by combining neurostimulation of DMN with neurostimulation of LH and PC, the subject's response to neurostimulation of DMN can be improved. Thus, the method of the first aspect may improve the subject's response to neural stimulation by the DMN, which may lead to improved results for treatments involving neural stimulation by the DMN.

DMN has a broad correlation with the prefrontal cortex and the limbic structures including the limbic cortex, hippocampus, and basolateral amygdala. DMNs are involved in higher cognitive functions, such as spatial working memory and emotional processes. DMN is also involved in managing pain. In schizophrenia, the volume and number of neurons in DMN are reduced. DMN also plays a major role in amygdala hippocampal seizures and controls limbic seizures. DMN's are closely related to the central bystander complex. DMN and the paraspinal complex are embedded in different basal ganglia-thalamocortical rings, which integrate the cognitive and emotional aspects of human behavior. Microcells of DMNs are involved in memory wake-up. The giant cell area in monkeys is essential for new learning; specific injuries in humans are associated with retrograde and antegrade forgetfulness. Acute isolated disorientation in time can occur with arteriolar disease of the thalamus that involves DMN.

Neural stimulation may be used, for example, to alter emotional responses and memory. For example, high frequency neural stimulation of DMN can be used to improve memory formation. Thus, neurostimulation of DMN's may enable treatment of a range of diseases (see Mavridis I, Human thalamus dorsalmedial nuclei as a Potential Target for Deep Brain Stimulation; Review of the characteristics and Anatomical Considerations, O A anatomy 1, 12 days 2014; 2(1) -1).

The one or more additional targets may include the posterior nucleus of the hypothalamus. Thus, according to one embodiment, the method comprises applying one or more neuromodulation signals to each of the hypothalamic nucleus, LH and PC (and optionally DMN). The inventors have found that stimulation of the posterior nuclei of the hypothalamus can lead to an increase in cerebral blood flow and cerebral blood volume, as well as a decrease in the mean transit time of blood through the brain. Stimulation of the posterior thalamic nucleus can be used to treat cluster headache.

The one or more neuromodulation signals may include a plurality of neuromodulation signals. For example, the one or more neuromodulation signals may include a first neuromodulation signal applied to the DMN, a second neuromodulation signal applied to the LH, and a third neuromodulation signal applied to the PC. In other cases, the same neuromodulation signal may be applied to multiple targets. For example, a first neuromodulation signal may be applied to DMN, while a second neuromodulation signal may be applied to LH and PC.

The neuromodulation signals may be applied to LH and PC and any additional targets in the brain through electrode leads implanted in the brain of the subject. The electrode lead may have a plurality of electrodes arranged to apply the neuromodulation signal to each of LH and PC and any additional targets (e.g., DMNs). For example, the electrode lead may include a first electrode arranged to apply a neuromodulation signal to the DMN, a second electrode arranged to apply a neuromodulation signal to the LH, and a third electrode arranged to apply a neuromodulation signal to the PC. The same or different neuromodulation signals may be applied to each of LH and PC as well as any additional targets in the brain. The electrode leads may be arranged such that a separate neuromodulation signal may be applied via each electrode. In this way, different targets can be stimulated separately. In some cases, multiple targets may be stimulated by the same electrode.

Different targets (e.g. LH, PC, DMN) can be stimulated simultaneously or sequentially.

In some embodiments, a first neuromodulation signal having a first frequency may be applied to the dorsolateral nucleus, and one or more second neuromodulation signals may be applied to the lateral reinsertia and the posterior commissure, wherein each of the one or more second neuromodulation signals has a lower frequency than the first frequency.

Higher frequency neuromodulation signals applied to the DMN's may be used to inhibit neurons in the DMN's, while lower frequency neuromodulation signals applied to the LH and PC's may be used to enhance the subject's response to the treatment. The first and second neuromodulation signals may be applied through different sets of electrodes on the electrode lead. The first neuromodulation signal may correspond to a first pulse sequence having a first frequency, and the second neuromodulation signal may correspond to a second pulse sequence having a second frequency.

The same second neuromodulation signal may be applied to LH and PC.

Alternatively, a different second neuromodulation signal having, for example, a different frequency may be applied to each of LH and PC, respectively.

The first neuromodulation signal applied to the DMN may have a frequency in the upper end of the gamma range (30Hz to 100Hz) or higher.

The second neuromodulation signal applied to LH may be in a range of theta (4Hz to 8Hz), alpha (8Hz to 14Hz), and beta (14Hz to 30Hz) frequencies. Stimulation of LH may also include the reinsertion of the pineal body commissures, while transmitting the stimulation to the pineal body. The stimulation of LH may be altered to calibrate and synchronize the circadian rhythm.

The second neuromodulation signal applied to the PC may be in a range of theta (4Hz to 8Hz) and alpha (8Hz to 14Hz) frequencies; and potentially up to 30Hz to 40 Hz.

In one example, the first frequency may be greater than 70Hz, and each of the one or more second neuromodulation signals may have a frequency between 450Hz and 50 Hz. In some examples, the same neuromodulation signal may be applied to LH and PC, while in other examples, separate/different neuromodulation signals may be applied to LH and PC.

The stimuli applied at different frequencies may be staggered, and when applied sequentially, the fluctuations may be programmed to provide stimuli at a burst frequency, or programmed with the appropriate on/off period. An algorithm that is deciphered from normal and disease state local field potentials and brain rhythm coherent mathematical decoding, as seen above the circadian rhythm.

In some embodiments, the one or more additional targets may include peri-abdominal lateral aqueduct gray matter (VL-PAG). Thus, according to one embodiment, the method includes applying one or more neuromodulation signals to each of LH, PC, and VL-PAG (and optionally DMN).

In this way, combined neural stimulation of DMN, VL-PAG, LH and PC may be performed. In US2016/0367809a1, the present inventors disclosed that combined neurostimulation of DMN and VL-PAG can be used to increase perfusion of hippocampus and other structures involved in cognition and memory. As a result, combined neurostimulation of DMN and VL-PAG can treat a variety of diseases, including alzheimer's disease, hypertension, and epilepsy. The inventors have further found that additionally applying a neural stimulation signal to LH and PC may improve the response of a subject to combined neural stimulation by DMN and VL-PAG.

The neuromodulation signal applied to the VL-PAG may be one of the one or more second neuromodulation signals described above. In this manner, a first higher frequency neuromodulation signal may be applied to the DMN, while a lower frequency neuromodulation signal may be applied to LH, PC, and VL-PAG. The neuromodulation signal applied to the VL-PAG may be the same as the neuromodulation signal applied to LH and/or PC, or may be different from the neuromodulation signal applied to LH and/or PC.

The neuromodulation signal applied to the VL-PAG may be in the theta (4Hz to 8Hz) and alpha (8Hz to 14Hz) frequency ranges; and potentially up to 30Hz to 40 Hz.

In one example, the neuromodulation signal applied to the VL-PAG may have a frequency of 5Hz to 50 Hz. Low frequency (e.g., 5Hz to 50Hz) stimulation of VL-PAGs can result in an overall increase in cerebral blood flow and cerebral blood volume, as well as a decrease in mean transit time of the blood.

Since 1977, periventricular gray matter (PVG) and periaqueductal gray matter (PAG) were considered targets for brain stimulation for the treatment of intractable pain. PAGs are present in the midbrain and their role in autonomic function has been extensively studied in animal models to find that the animal models are critically involved in mediating defensive responses to perceived or present danger. The perceived fear of evasion triggers a combat or escape response; conversely, a perceived fear of non-evasive (where it is advantageous to remain undetected) triggers the opposite freeze response pattern. Both reactions are mediated by PAGs, but by separate sites; the dorsal PAG produced a combat and escape response, while the ventral portion (VL-PAG) produced a freeze response.

The freezing response consists of hypotension, bradycardia and hyperventilation, and is usually associated with analgesia, and is mediated by VL-PAGs, which, in addition to participating in motor control and analgesia, have dense processes at known cardiovascular integration sites within the Central Nervous System (CNS), including the nucleus pulposus and the hypothalamic nucleus. VL-PAG also accepts protrusions from areas involved in somatosensory feedback and autonomic regulation, including forebrain cortical structures, limbic systems, spinal cord afferents, and hypothalamic nuclei.

In some embodiments, the method may further comprise: identifying a trajectory in the brain of a subject, said trajectory passing through said lateral reins and said posterior commissures connecting said dorsal-medial nucleus and said VL-PAG; and implanting an electrode lead in the brain of the subject along the identified trajectory, the electrode lead comprising a plurality of electrodes for applying the one or more neuromodulation signals. In this manner, the neuromodulation signals described above may be applied using a single electrode lead spanning the trace connecting DMN, LH, PC and VL-PAG. This may facilitate neurostimulation of DMN, LH, PC, and VL-PAG, and avoid having to use multiple electrode leads to stimulate these different targets. Additionally, having electrode leads that span such traces may enable different combinations of neuromodulation signals to be applied to one or more of DMN, LH, PC, and VL-PAG. This may enable the neural stimulation therapy to be adjusted to the needs of the subject. The trajectory may be trans-ventricular, i.e. the trajectory may pass through the lateral ventricle.

The expression "over the outside reins and posterior commissures" will mean that the trajectory passes from one side of the outside reins and posterior commissures through the other side of the outside reins and posterior commissures. Typically, this trajectory will be spaced from the lateral reins and posterior commissures, and will pass near the lateral reins and posterior commissures.

The trajectory may be identified prior to implantation of the electrode lead, for example, by obtaining an image of the subject's brain (e.g., by computed tomography and/or magnetic resonance imaging) and mapping the trajectory in the subject's brain. The electrode leads may be implanted into the brain of the subject along the identified trajectory, for example using a stereotactic frame and/or a stereotactic robot.

After implantation, the electrode lead may follow a substantially straight trajectory that passes through the lateral ventricle, into the DMN bypassing the third ventricle, adjacent to LH and PC, and into the VL-PAG. Preferably, the traces of the electrode leads pass adjacent to LH and PC without contacting LH or PC to avoid damage to LH and PC.

The trajectory may also encircle the anterior nucleus of the thalamus, so that neuromodulation signals may be applied to the anterior nucleus of the thalamus. Neurostimulation of the anterior thalamic nucleus can treat epilepsy.

The trajectory may also encircle the central midnucleus and/or the parabundle nuclei of the thalamus so that neuromodulation signals may be applied to these portions of the thalamus.

The plurality of electrodes on the electrode lead may be arranged such that, after implantation of the electrode lead, a neuromodulation signal may be applied to each of the DMN, LH, PC, and VL-PAG via an electrode of the plurality of electrodes. In some cases, each of the DMN, LH, PC, and VL-PAG may be stimulated by a respective electrode of the plurality of electrodes. The electrodes on the electrode leads may be isolated from each other so that each target may be individually excited.

The plurality of electrodes on the electrode lead may be regularly (evenly) spaced along the electrode lead spanning from the DMN to a portion of the VL-PAG. This may enable a neuromodulation signal to be applied to the target along the entire length of the trajectory between the DMN and VL-PAG. For example, the plurality of electrodes may span a length of 20mm to 30mm on the electrode lead, e.g., on the distal portion of the electrode lead. In one example, the plurality of electrodes may include eight electrodes, each electrode having a length of about 1.5mm with a spacing of 1.5mm between adjacent electrodes. In another example, the plurality of electrodes may include 12 electrodes, each having a length of about 1.5mm with a spacing of 0.5mm between adjacent electrodes.

The electrode leads may be implanted unilaterally into the hemisphere of the brain, preferably into the non-dominant hemisphere of the brain. The non-dominant hemisphere is generally the right side, opposite the side that primarily controls language processing. Unilateral implantation of an electrode lead in one hemisphere may minimize procedure time and risk of complications (e.g., bleeding). However, in some cases, clinical outcomes may be improved by applying neuromodulation signals to targets in both hemispheres. In this case, the electrode leads may be implanted into both hemispheres.

It has been shown that the right hemisphere and the pre-branched non-dominated hemisphere have greater laterality for cognitive and emotional processing and behavioral expression, and are preferred for targets and enable better responses. Thus, the electrode lead may be implanted unilaterally into the right hemisphere of the brain.

Implanting the electrode lead may involve first implanting a catheter into the brain of the user, and then inserting the electrode lead through the catheter.

The trace may be arranged so that the spacing between the electrode lead and the outside reins is less than 5mm, and/or the spacing between the electrode lead and the posterior commissure is less than 5 mm. A spacing of 5mm or less between the electrode leads and LH and PC may ensure reliable stimulation of LH and PC via the electrodes on the electrode leads. In particular, the electrodes for applying the neuromodulation signal to LH may be less than 5mm from LH, and the electrodes for applying the neuromodulation signal to PC may be less than 5mm from PC. The inventors have found that an interval of more than 5mm will prevent effective stimulation of LH and PC, which will reduce the overall effect of the treatment. For example, the spacing between the electrode lead and LH may preferably be 4mm, 3mm, 2mm, or 1mm, or less than any of these values. Similarly, the spacing between the electrode lead and the PC may preferably be 4mm, 3mm, 2mm or 1mm, or less than any of these values. Preferably, the spacing between the electrode lead and the outside reins is less than 2mm, and/or the spacing between the electrode lead and the posterior commissure is less than 2 mm.

In some embodiments, the method may further comprise applying neuromodulation signals to the anterior cingulate cortex (DACC) and/or Corpus Callosum (CC). The inventors have discovered that in some cases, the response to treatment can be improved by additional neural stimulation of DACC and/or CC. Thus, neurostimulation of one or more of DMN, LH, PC and VL-PAG may be enhanced by DACC and/or combined neurostimulation of CC. DACC and CC may be excited by the same or different electrodes.

The inventors have found that stimulation of DACC and/or CC in combination with LH and PC can further improve the patient's response to neural stimulation.

In one test subject, the inventors have found that bilateral stimulation of DACC in combination with LH, PC and VL-PAG produces a positive response in the subject to neural stimulation. In addition, applying a neuromodulation signal to the DMN may provide further stimulation of the edge circuit. Applying neuromodulation signals to the CC (e.g., unilaterally) may enable further commissural diffusion, which may enhance cerebral blood flow bilaterally.

The neuromodulation signals applied to the DACC and/or CC may have frequencies within the gamma band (e.g., 30Hz to 100 Hz).

The neuromodulation signals applied to the DACC and/or CC may have a high frequency, e.g., a frequency greater than 70 Hz.

In one approach, a single electrode lead may be used to apply neuromodulation signals to one or more of DACC, CC, DMN, LH, PC, and VL-PAG. In such a method, the trace may further pass through a location adjacent to the dorsal cingulate cortex and the electrode lead may include an electrode arranged to apply the neuromodulation signal to the dorsal cingulate cortex; and/or the trajectory may further pass through a location adjacent the corpus callosum, and the electrode lead may include an electrode arranged to apply the neuromodulation signal to the corpus callosum. With both DACC and CC excited, the trace may pass near the DACC and CC, and the same electrodes may be used to apply the neuromodulation signals to both DACC and CC. In some cases, separate electrodes may be used to stimulate DACC and CC. Using a single electrode lead to stimulate multiple targets can minimize surgical time and reduce the number of implants required by a subject. Preferably, the trace may pass 5mm or less from the DACC and/or CC to ensure that the DACC and CC may be effectively excited via the electrode leads.

In another approach, separate electrode leads may be used to stimulate the DACC and/or CC. Accordingly, the method may further comprise implanting a second electrode lead in the brain of the subject, the second electrode lead comprising an electrode arranged to apply neuromodulation signals to the dorsal cingulate cortex.

When it is felt that the transcranial track connecting the DMN, LH, PC and VL-PAG cannot safely bind DACC and/or CC, a separate electrode lead for DACC and/or CC may be used without affecting the intraventricular vascular structure or the sagittal sinus (sagittal sinus).

In one example, a separate electrode lead may have a single electrode (e.g., a cylindrical electrode) on the electrode lead that extends across the DACC and into the CC. Alternatively, a separate electrode lead having multiple electrodes arranged to excite the DACC and CC, respectively, may be used.

In some embodiments, the method may further include detecting a physiological parameter of the subject, and adjusting at least one of the one or more neuromodulation signals based on the detected physiological parameter. In this way, the physiological parameter may be used as feedback to adjust the neuromodulation signal. This may enable more accurate and efficient neural stimulation of the brain, as the neural modulation signal may be adjusted based on the subject's response to the signal.

For example, the physiological parameter may include one or more of blood pressure, blood flow, cerebral blood flow, and intracranial pressure of the subject.

The physiological parameter may be monitored by one or more sensors placed on or implanted in the subject.

When a neuromodulation signal is applied to VL-PAG, DACC, and/or CC, the neuromodulation signal applied to VL-PAG, DACC, and/or CC may be adjusted based on the detected physiological parameter.

Where one or more neuromodulation signals are applied in bursts (bursts), the neuromodulation signals may be based on measurements of the physiological parameter obtained between the strings of one or more neuromodulation signals.

Adjusting the neuromodulation signal may include adjusting one or more parameters of the neuromodulation signal, such as a frequency, a pulse width, and a pulse amplitude. In some cases, a set point may be associated with a physiological parameter, and the neuromodulation signal may be adjusted until it reaches the set point.

Where more than one neuromodulation signal is applied, one, more than one, or all of the neuromodulation signals may be adjusted based on the detected physiological parameter.

In some embodiments, the method may further comprise adjusting at least one of the one or more neuromodulation signals based on a circadian rhythm of the subject.

For example, one or more parameters (e.g., frequency, pulse width, and pulse amplitude) of one or more neuromodulation signals may be adjusted or modulated according to the time in the circadian rhythm of the subject.

In particular, one or more neuromodulation signals may be modulated to reflect a circadian rhythm with reduced nighttime activity. This may be used to ensure that the subject's circadian rhythm is not disrupted by the application of the neuromodulation signal. This may also be used to maintain and/or reestablish the circadian rhythm of the subject.

When the neuromodulation signal is applied to the VL-PAG, DACC, and/or CC, the neuromodulation signal applied to the VL-PAG, DACC, and/or CC may be modulated based on the circadian rhythm of the subject.

To reestablish the subject's circadian rhythm, the stimulation protocol (i.e., stimulation schedule) for one or more neuromodulation signals may be adjusted to reflect the circadian rhythm and to coincide with fluctuating tonic discharges (e.g., commonly seen in circuits and circadian neurons).

For example, in one embodiment, the method may comprise: low frequency stimulation (e.g., 5Hz to 50Hz) is applied to LH and PC during the day, followed by low frequency stimulation (e.g., 5Hz to 50Hz) and high frequency stimulation (e.g., frequencies greater than 70Hz) to LH and PC during the night. Alternatively, low frequency stimulation (e.g., 5Hz to 50Hz) is applied to LH and PC and high frequency stimulation (e.g., frequencies greater than 70Hz) is applied to DMN's during the day and night, but the current amplitude for applying high frequency stimulation to DMN's during the day is decreased and the current amplitude for applying high frequency stimulation to DMN's during the night is increased. Alternatively, low frequency stimulation (e.g., 5Hz to 50Hz) and high frequency stimulation are applied to LH and PC and to DMN during the day and night, but with reduced amplitude of high frequency stimulation (e.g., 50Hz to 70Hz) applied to DMN during the day and conversely with increased amplitude of high frequency stimulation (e.g., greater than 70Hz) applied to DMN during the night. Alternatively, during the night, a high frequency stimulation signal may be applied to the DMN and LH, and a low frequency stimulation signal may be applied to the PC.

Adjusting one or more neuromodulation signals based on the circadian rhythm of the subject may include monitoring physiological parameters of the subject (e.g., blood pressure, heart rate variability, pulse wave variability, muscle sympathetic nerve activity, body position changes, brain EEG, brain slow wave activity) to determine the circadian rhythm of the subject. One or more neuromodulation signals may then be adjusted based on the determined circadian rhythm. In fact, the subject's blood pressure and heart rate may vary with the circadian rhythm such that the blood pressure and heart rate are higher during the day and lower at night. In this way, the circadian rhythm of the subject may be determined by monitoring diurnal variations in blood pressure and/or heart rate.

In some cases, the method may involve detecting a perturbation in the biological rhythm of the subject, for example, by recording daily variations in a physiological parameter (e.g., blood pressure and/or heart rate) of the subject, and comparing the recorded daily variations to model variables corresponding to a non-interfering biological rhythm.

The method may also involve adjusting at least one of the one or more neuromodulation signals in an attempt to correct a disturbance detected in the circadian rhythm of the subject.

Perturbations in the circadian rhythm of the subject may be detected based on a correlation of the disturbed sleep/wake cycle of the subject with local field potentials recorded in one or more targets (e.g., one or more of LH, PC, DMN, VL-PAG, DACC, CC) in the brain of the subject.

The circadian rhythm of blood pressure is associated with a high span during wakefulness and a low span during sleep. Cardiovascular events may occur more frequently in the morning hours, when blood pressure and heart rate rise sharply. Patients with excessive morning blood pressure fluctuations and patients lacking normal nighttime pressure drops (so-called "non-scoopers") have been shown to have excessive incidence of stroke, heart failure and other cardiovascular events. Although there are many underlying abnormal physiological mechanisms in the 24-hour blood pressure curve, including abnormal and sympathetic nervous system activity, salt and volume balance, and activation of the renin angiotensin-aldosterone system, for many patients, the mechanisms remain unclear. The normal circadian rhythm of blood pressure has a 15% to 25% reduced nocturnal blood pressure compared to the wakefulness value. However, in 25% to 40% of hypertensive patients, there is a non-arytenotic blood pressure pattern. Clinical studies in patients with hypertension have found that a dull night-time reduction in BP occurs when adrenergic activity increases and vagal activity decreases during sleep.

Parameters of one or more neuromodulation signals may be determined, for example, by recording local field potentials across one or more targets (e.g., one or more of DMN, LH, PC, VL-PAG, DACC, CC) in the brain. Analysis of the recorded field potentials may then be performed to determine appropriate stimulation parameters, for example, to enhance brain perfusion and/or to reestablish a normal circadian rhythm. The neuromodulation signal may also be adjusted based on sensing of a disturbed rhythm (e.g., a circadian rhythm).

The local field potentials may be recorded with electrodes on electrode leads implanted into the brain of the subject.

The local field potentials at one or more targets in the brain can be recorded under normal and diseased conditions using animal models to generate computational and mathematical models. For example, in the anticipation of reestablishing normal circadian rhythms and rebalancing of autonomic imbalances, the local field potentials recorded in human disease states can be used to further improve the etiology and personalized stimulation parameters.

The method may further include applying a stimulation signal to the subject's carotid body and/or carotid baroreceptors. Such a method may be considered an independent aspect of the present invention. More generally, in such independent aspects, one or more neuromodulation signals may be applied to one or more targets in the brain of the subject, but are not necessarily limited to the targets discussed above. Accordingly, a separate aspect of the invention may provide a method of performing a treatment on a subject, the method comprising: applying one or more neuromodulation signals to one or more targets in the brain of the subject; and applying a stimulation signal to the subject's carotid body and/or carotid baroreceptors.

The present inventors have discovered that combining nerve stimulation of a target in a subject's brain with stimulation of carotid bodies and/or carotid baroreceptors in the subject can result in enhanced cerebral blood flow and can more accurately control cerebral blood flow. Indeed, when the carotid body and carotid baroreceptors are involved in regulating blood flow and blood pressure, combined stimulation of the target and/or carotid baroreceptors in the subject's brain and carotid body may play a synergistic role in enhancing and controlling brain perfusion. One or more targets for applying neuromodulation signals in the brain of the subject may be selected such that brain perfusion is increased.

Stimulation of carotid body and/or carotid baroreceptors and neural stimulation of targets in the brain may be performed simultaneously. This may enhance the response by retrograde peripheral reflex signals from the carotid body to the brain and anterograde from brain stimulation to the periphery. As a result, cerebral blood flow may be enhanced.

For example, as described above, one or more neuromodulation signals may be applied via an electrode lead implanted into the brain of a subject. Thus, the neuromodulation signal may be applied to LH and PC, optionally to VL-PAG and/or DMN, and optionally to DACC and/or CC. As described above, stimulation of these targets can lead to improved brain perfusion, thereby enabling the treatment of a variety of diseases.

In one embodiment, stimulation of the carotid body and/or carotid baroreceptors may be combined with neurostimulation of LH, PC, DMN and VL-PAG.

The stimulation signal may be applied to the carotid body and/or carotid baroreceptors via one or more stimulation electrodes implanted in and/or in contact with the subject. The stimulation signals may be applied to the carotid body and/or carotid baroreceptors according to the methods described in the inventor's earlier application US2015/0112359a1, which is incorporated herein by reference. For example, the stimulation signal may be a pulsed Radio Frequency (RF) electrical signal that is applied to the carotid body and/or carotid baroreceptors via electrodes implanted in the subject.

Electrical stimulation (e.g., with pulsed RF signals) can alter the function of one or more carotid bodies so that neural signals from these bodies can be attenuated or eliminated. The effect may be a decrease in mean arterial blood pressure within days, weeks or months after treatment.

Carotid baroreceptors are nerve endings located in the walls of the aortic arch and carotid sinus that detect changes in arterial pressure through the stretching of the vessel wall. Baroreceptors are stimulated by stretching and their rate of emission increases with pressure. Below an average pressure of about 60mmHg, the action potential frequency is minimized; above about 160mmHg, the baroreceptor reaches a maximum discharge rate, such that further increases in pressure do not result in an increase in discharge rate. Denervation of baroreceptors in the human body causes a long-term increase in mean arterial pressure and an increase in heart rate. In contrast, stimulating baroreceptors using an electrical pulse generator can reduce blood pressure over a long period of time.

Carotid baroreceptors may be located in the carotid sinus and aortic arch. Thus, for example, carotid baroreceptors may be stimulated by implanting stimulation electrodes proximate to the carotid sinus and/or aortic arch. The carotid body may be stimulated by implanting electrodes at or near the carotid body. In some cases, multiple stimulation electrodes may be used to enable stimulation of multiple targets.

The methods of the invention are useful for treating one or more of hypertension, traumatic brain injury, cerebral vasospasm, cerebral infarction, brain tumor, brain glioma, parkinson's disease, alzheimer's disease, vascular dementia, frontotemporal dementia, other dementias, amyotrophic lateral sclerosis, motor neuron disease, huntington's disease, multiple system atrophy, multiple sclerosis, addiction, depression, post-traumatic stress disorder, schizophrenia, obesity, renal failure, epilepsy, and attention deficit hyperactivity disorder. However, the methods of the invention may also or alternatively be used to treat other diseases, particularly those associated with reduced cerebral blood flow.

Neurostimulation for different conditions can be based on established computational mathematical models based on the recording of local field potentials along targets in the brain. The detection of one or more physiological parameters (as described above) may be combined with the simultaneous adjustment of one or more neuromodulation signals between one or more neuromodulation signal trains. The one or more neuromodulation signals may be adjusted based on one or more of transcranial brain activity, cerebral blood flow, and sympathetic monitoring, e.g., to optimize one or more neuromodulation signals in an expected reconstructed cerebral blood flow, circadian rhythm, and corrected autonomic imbalance.

The above-mentioned diseases may be associated with one or more of reduced cerebral blood flow, autonomic imbalance, circadian rhythm disruption, brain coherence changes, cortical diffuse depolarization, and brain rhythm desynchronization. The inventors have found that neural stimulation of LH and PC, optionally in combination with DMN and/or VL-PAG and optionally DACC and/or CC, can enhance cerebral blood flow, which can restore autonomic imbalance and reestablish circadian rhythm. As a result, the methods of the invention can be used to treat one or more of the above-mentioned diseases. The particular combination of neuromodulation signals used may be tailored to the subject and the disease being treated.

According to a second aspect of the present invention, there is provided an apparatus for performing therapy on a brain of a subject, the apparatus comprising: an electrode lead arranged to be inserted into the brain of the subject, a distal portion of the electrode lead having a plurality of electrodes arranged to apply one or more neuromodulation signals to the lateral reins and the posterior commissures; and a controller configured to generate the one or more neuromodulation signals applied by the plurality of electrodes.

The apparatus may be used to perform a method according to the first aspect of the invention. Thus, features of the first aspect of the invention may be shared with the second aspect of the invention.

The electrode lead may be inserted into the brain of the subject such that the neuromodulation signal is applied to the target in the brain of the subject via the plurality of electrodes on the distal portion of the electrode lead.

The plurality of electrodes may be disposed and arranged on the electrode lead so that each of LH and PC may be excited by the plurality of electrodes.

For example, the positions, and/or individual lengths, and/or spacings, and/or overall lengths of the plurality of electrodes may be configured such that each of LH and PC may be stimulated via the plurality of electrodes, e.g., such that one of the plurality of electrodes may be positioned in proximity to each of DMN, LH, and PC.

The plurality of electrodes may also be arranged to apply one or more neuromodulation signals to one or more additional targets in the brain of the subject. In this way, neural stimulation of LH and PC can be combined with neural stimulation of other targets in the brain.

The one or more additional targets may include the thalamus dorsolateral nucleus. In other words, the plurality of electrodes may be arranged to apply one or more neuromodulation signals to each of the DMN, LH and PC.

The plurality of electrodes may include two or more electrodes. For example, the plurality of electrodes may include a first electrode for stimulating DMN, a second electrode for stimulating LH, and a third electrode for stimulating PC. In some cases, LH and PC may be stimulated using a single electrode, e.g., where the electrode has sufficient length to apply neuromodulation signals to both targets. Each of the plurality of electrodes may be electrically isolated from each other so that different targets may be individually excited.

The one or more additional targets may include VL-PAGs. Thus, the plurality of electrodes may also be configured to apply a neuromodulation signal to the VL-PAG. In this way, a neuromodulation signal may be applied to each of LH and PC and optionally to VL-PAG and/or DMN. For example, the plurality of electrodes may include electrodes arranged (e.g., positioned and sized) to apply a neuromodulation signal to the VL-PAG.

The electrode lead may be sized for insertion into a user's brain. For example, the outer diameter of the electrode lead may be about 1.3mm or less. As described with respect to the first aspect of the invention, the electrode lead may be configured to be implanted along a straight line trajectory connecting the DMN and VL-PAG and spanning LH and PC.

The electrode lead may be in the form of an elongate cable having a generally cylindrical shape. The cable may include a set of wires extending through and connected to the plurality of electrodes such that electrical signals (e.g., neuromodulation signals) may be transmitted to the electrodes.

Each lead may be electrically coupled to the controller at a proximal end of the electrode lead such that the neuromodulation signals generated by the controller may be communicated to the electrodes via the leads.

The electrode lead may include an outer protective sheath configured to electrically insulate and protect the electrode lead from the environment.

A plurality of electrodes may be exposed on a surface of the electrode lead such that they may be in contact with brain tissue to apply neuromodulation signals to the brain tissue.

One of the plurality of electrodes may have an annular or cylindrical shape, i.e. it may extend around the circumference of the electrode lead. In this manner, the electrodes may apply the neuromodulation signals substantially uniformly about the longitudinal axis of the electrode lead.

Alternatively, one of the plurality of electrodes may be configured to apply a neuromodulation signal in a particular direction, e.g., the electrode may extend around only a portion of the circumference of the electrode lead.

The individual electrodes in the plurality of electrodes may all be the same, or they may have different shapes, sizes, and orientations (e.g., depending on the particular target they are to stimulate).

In one embodiment, a combination of directional electrodes (e.g., extending around only a portion of the circumference of the electrode lead) and non-directional electrodes (e.g., cylindrical electrodes) may be provided.

In other embodiments, all electrodes may be non-directional (e.g., cylindrical electrodes), or all electrodes may be directional (e.g., extending around only a portion of the circumference of the electrode lead).

The controller is configured to generate one or more neuromodulation signals applied by the plurality of electrodes. Accordingly, the controller may comprise suitable electronic circuitry for generating one or more neuromodulation signals. As described above, the plurality of electrodes may be connected to the controller via a set of wires in the electrode lead, the set of wires being arranged to transmit the neuromodulation signal to the electrodes.

The controller may be configured to apply different neuromodulation signals via different electrodes of the plurality of electrodes.

For example, the controller may be configured to apply a first neuromodulation signal having a first higher frequency (e.g., greater than 70Hz) to the DMN via the first electrode, and apply a second neuromodulation signal having a second lower frequency (e.g., between 5Hz and 50Hz) to LH and PC via the second and third electrodes.

The controller may be configured to apply the neuromodulation signal according to the method of the first aspect of the invention.

In some cases, two or more of the plurality of electrodes may be arranged in pairs, e.g., such that a first electrode of a pair may act as an anode and a second electrode of the pair may act as a cathode. This may enable bipolar stimulation of brain tissue located between a pair of electrodes.

In some cases, one or more of the plurality of electrodes may be arranged for monopolar stimulation. For example, the electrode on the electrode lead may serve as the cathode, while the housing of the catheter or controller serves as the anode.

The controller may be in the form of an Implantable Pulse Generator (IPG). The IPG may be arranged for implantation into the skull of a subject, for example into a pocket formed in the skull of a subject.

In some embodiments, the plurality of electrodes may be evenly spaced apart in the longitudinal direction along the length of the distal portion of the electrode lead. In other words, the plurality of electrodes may include a linear array of evenly spaced electrodes arranged along the length of the distal portion of the electrode lead. This may cause the target to be stimulated along substantially the entire length of the distal portion of the electrode lead. The distance between targets (e.g., DMN, LH, PC, VL-PAG) in the brain can vary from one subject to another. This variation can be accommodated by using a linear array of evenly spaced electrodes, as different electrodes in the linear array can be used to stimulate the target, depending on the specific location of the target in the subject's brain.

The number of evenly spaced electrodes and their spacing may be selected based on the target to be stimulated and the desired spatial resolution for applying the neuromodulation signal. For example, by selecting the electrode closest to the target, a larger number of closely spaced electrodes can achieve more accurate stimulation of the target.

The plurality of evenly spaced electrodes may span a length of 20mm to 25 mm. In this way, multiple electrodes may span the distance between the DMN and VL-PAG. This may enable the target located on the trajectory between the DMN and VL-PAG to be excited by the electrode. In particular, the processing of LH and PC may be accomplished when electrode leads are implanted along a linear trajectory connecting DMN and VL-PAG and crossing LH and PC.

As a first example, the plurality of evenly spaced electrodes may include eight electrodes, each electrode having a length of about 1.5mm, with a spacing between adjacent electrodes of about 1.5 mm. As a second example, the plurality of uniformly spaced electrodes may include twelve electrodes, each having a length of about 1.5mm, with a spacing between adjacent electrodes of about 0.5 mm. Of course, other examples with different numbers of electrodes and different sizes are possible. The second example can provide higher spatial resolution than the first example due to the increased number of electrodes per unit length.

The apparatus may also include a proximal electrode (which may also be referred to as another electrode) configured to apply a neuromodulation signal to the DACC and/or CC. In this manner, a neuromodulation signal may be applied to the DACC and/or CC.

The length and position of the proximal electrode may determine whether the electrode may apply a neuromodulation signal to one or both of DACC and CC.

In some embodiments, the proximal electrode may be provided separately from the electrode lead, e.g., the proximal electrode may be on another electrode lead or on a catheter of the device.

In some embodiments, the proximal electrode may be disposed on the electrode lead. In this manner, neuromodulation signals may be applied to the DACC and/or CC through the electrode leads. Thus, the electrode lead may enable combined neurostimulation of one or more of DMN, LH, PC, VL-PAG, DACC, and CC.

The proximal electrode may be similar to the electrodes in the plurality of electrodes described above, for example the proximal electrode may be annular (e.g., cylindrical), or the proximal electrode may be a directional electrode.

The proximal electrode may be spaced apart from the plurality of electrodes in the longitudinal direction, e.g., such that the proximal electrode may be positioned adjacent to the DACC and/or CC when the electrode lead is implanted in the brain of the subject. In particular, the proximal electrode may be closer to the proximal end of the electrode lead than the plurality of electrodes on the distal portion of the electrode lead.

The proximal electrode may be longitudinally spaced from the plurality of electrodes by a distance of about 5mm to 15 mm.

A spacer (e.g., made of an electrically insulating material) may be disposed between the proximal electrode and the plurality of electrodes.

The spacer may have a length of about 5mm to 15mm, i.e. the distance between the proximal electrode and the plurality of electrodes may be 5mm to 15 mm. The exact location and size of the proximal electrode may be set based on the location of the DACC and/or CC in the brain of the subject to ensure that the DACC and/or CC may be effectively stimulated.

Each of the plurality of electrodes may have a first length and the proximal electrode may have a second, longer length. Thus, the proximal electrode may be longer than the other electrodes. This may help apply neuromodulation signals to the DACC, as the inventors have found that the distance across the lateral ventricle between DACC and DMN will vary from subject to subject. Thus, having a longer proximal electrode may compensate for subject-to-subject positional changes of the DACC, so that the DACC and/or CC may be effectively stimulated with the proximal electrode.

The length of the electrodes of the plurality of electrodes, i.e. the first length, may preferably be about 1.5mm, as described above.

The second length may be between 10mm and 30 mm. A proximal electrode of such length may ensure that DACC and/or CC are effectively stimulated by the proximal electrode regardless of variations in the distance across the lateral ventricle between subjects. In particular, the inventors have found that the distance across the lateral ventricles may be between 9mm and 20mm for different subjects. Thus, by providing a proximal electrode having a length between 10mm and 30mm, DACC and/or CC may be stimulated in different subjects. Preferably, the second length may be 20mm to 30 mm.

In some embodiments, the device may further comprise a catheter for insertion into the brain of a patient, the catheter comprising a hollow tube defining a longitudinal channel in which the electrode lead may be received.

The length of the hollow tube may be arranged such that a distal end portion of the electrode lead protrudes from the distal opening of the hollow tube when the electrode lead is received in the longitudinal channel.

The catheter may be used to facilitate implantation of the electrode lead into the brain of a subject, as it may ensure that the electrode lead follows the correct trajectory during insertion. In particular, the catheter may facilitate transcranial implantation of the electrode lead, i.e. implantation of the electrode lead via the lateral ventricle.

The hollow tube may have a generally cylindrical shape with a longitudinal channel extending along the length of the hollow tube.

The longitudinal channel may be dimensioned to accommodate the electrode lead, e.g. the diameter of the longitudinal channel may be slightly larger than the outer diameter of the electrode lead.

The hollow tube may be made of any suitable insulating biocompatible material, such as a biocompatible plastic material (e.g., polycarbonate polyurethane). Preferably, the material of the hollow tube is rigid to facilitate insertion of the hollow tube into the brain of the subject and to prevent movement of the catheter after insertion of the catheter into the brain of the subject.

The catheter may be inserted into the brain of the subject by first introducing the guide rod into the brain of the subject along a desired trajectory and then sliding the hollow tube over the guide rod. The guide rod may then be withdrawn from the hollow tube, and the electrode lead may be inserted through the catheter into the brain of the subject to a desired depth, i.e., such that a distal portion of the electrode lead reaches a target location in the brain of the subject.

The guide rods may typically be made of radiopaque material to facilitate visualization of the guide rods in Computed Tomography (CT) or Magnetic Resonance Imaging (MRI).

The hollow tube may have a length shorter than a length of the electrode lead such that a distal end portion of the electrode lead protrudes from a distal opening of the hollow tube when the electrode lead is inserted into the catheter. In this manner, when the electrode lead is inserted into the catheter, the plurality of electrodes on the distal portion of the electrode lead may be exposed so that the plurality of electrodes may apply the neuromodulation signal to the target brain tissue.

The length of the hollow tube may be arranged to span the distance between the skull of the subject and slightly below the lateral ventricle (e.g., a few millimeters below the lateral ventricle). The hollow tube may be cut to a desired length prior to insertion into the patient's brain, for example, based on measurements of the subject's brain.

Where the electrode lead includes a proximal electrode, the catheter may be configured to be capable of transmitting a neuromodulation signal from the proximal electrode to the exterior of the hollow tube when the electrode lead is received in the longitudinal channel of the hollow tube.

When the electrode lead is received in the longitudinal channel, the proximal electrode may be located in the longitudinal channel. Thus, enabling the hollow tube to transmit a neuromodulation signal from the proximal electrode to the exterior of the hollow tube may enable the neuromodulation signal to be applied to the DACC and/or CC. In this way, the hollow tube does not need to be made shorter in order to expose the proximal electrode, as this would compromise the ability of the catheter to guide the electrode lead along the desired trajectory. Thus, the catheter may be used to accurately guide the electrode lead along a desired trajectory while enabling the DACC and/or CC to be excited via the proximal electrode on the electrode lead.

In some embodiments, the catheter may include a window formed in the sidewall of the hollow tube, the window being arranged to expose the proximal electrode to the exterior of the hollow tube when the electrode lead is received in the longitudinal channel of the hollow tube. Thus, a window in the sidewall of the hollow tube may transmit the neuromodulation signal from the proximal electrode to the exterior of the hollow tube.

When the electrode lead is inserted into the hollow tube, the proximal electrode may be exposed via the window so that the proximal electrode may be used to apply neuromodulation signals to the DACC and/or CC. Providing a window in the side wall of the hollow tube for the proximal electrode may expose the proximal electrode without having to shorten the length of the hollow tube. As a result, the catheter can be enabled to accurately place the distal portion of the electrode lead while exposing the proximal electrode via the window. The window may be arranged to expose all or a portion of the proximal electrode.

The length of the window in the sidewall of the hollow tube may be shorter than the length of the proximal electrode (e.g., the second length discussed above). As a result, only a portion of the proximal electrode may be exposed through the window. The length and location of the window may be determined based on the location of the DACC in the brain of the subject. As a result, the portion of the proximal electrode exposed via the window may be proximate to the DACC, such that a neuromodulation signal may be applied to the DACC and/or CC via the proximal electrode.

Since the proximal electrode may be relatively long (e.g., between 10mm and 25 mm), it would be beneficial to expose only a short portion of the proximal electrode in order to avoid stimulating an area away from the DACC with the proximal electrode.

The window in the side wall of the hollow tube may, for example, be cut (e.g., by a laser), or the window may be integrally formed (e.g., by a molding or 3D printing process) as part of the hollow tube.

For example, the window may have a length of 10mm to 25 mm.

The catheter may comprise indicia for indicating the direction the window is facing, i.e. indicia for indicating the orientation of the window.

The marker may be disposed on the catheter such that the marker is visible when the catheter is inserted into the brain of the subject.

The indicia may be used to inform a user (e.g., a surgeon) of the direction in which the window is facing so that the user may insert the catheter in the correct orientation, e.g., so that the window faces the DACC and/or CC. For example, the marker may be provided on a cap of the catheter so that the marker is visible to the user during insertion of the catheter into the user's brain.

The window may be arranged to face the DACC and/or CC when the catheter is inserted into the brain of the subject. This may be used to direct neuromodulation signals from the proximal electrode to the DACC to ensure effective stimulation of the DACC.

The window may be formed on one side of the hollow tube such that the window is arranged to face the DACC in use. In other words, the window may cover only a portion of the circumference of the hollow tube, i.e., the window does not extend all the way around the circumference of the hollow tube. For example, the window may have an opening angle of between 10 ° and 90 ° with respect to the longitudinal axis of the hollow tube.

In some examples, the window may include two or more apertures formed in the hollow tube. Forming the window as two or more holes (e.g., as opposed to a single larger hole) can be used to improve the rigidity of the hollow tube, which can facilitate insertion of the catheter into the brain of the subject. For example, the window may be formed by an array of longitudinally spaced holes in the side wall of the hollow tube.

In some embodiments, the catheter may include an external electrode located on the outer surface of the hollow tube. External electrodes may be used to apply neuromodulation signals to the targeted brain tissue. In this manner, neuromodulation signals may be applied to the target brain tissue via the external electrodes of the catheter. Thus, the neuromodulation signal may be applied via both the electrode lead and the catheter.

The outer electrode is disposed at the outer surface of the hollow tube such that the outer electrode can be in contact with the target brain tissue.

The outer electrode may be made of an electrically conductive material, for example, platinum-iridium.

The external electrode may be arranged to apply a neuromodulation signal to the DACC and/or CC.

As one example, the outer electrode may comprise a mesh electrode on the outer surface of the hollow tube. For example, the mesh electrode may be in the form of a mesh metal sleeve disposed on the outer surface of the hollow tube.

As another example, the external electrode may comprise an electrode embedded in a material (e.g., a plastic material) forming a sidewall of the hollow tube, the sidewall of the hollow tube including a window formed therein for exposing a portion of the electrode.

In some cases, the outer electrode may extend around the circumference of the catheter, e.g., the outer electrode may have a generally cylindrical shape. In other cases, the external electrode may be arranged to provide directional stimulation, for example where the external electrode is exposed via a window in the material forming the side wall of the hollow tube. In this case, the catheter may include an indicator for indicating the direction in which the outer electrode is facing, for example, the indicator may be on a cap of the catheter.

The outer electrode may be electrically connected to the controller via a connecting lead extending through the hollow tube. In this manner, the neuromodulation signals generated by the controller may be transmitted directly to the external electrodes on the catheter via the connecting wires. Therefore, it would not be necessary to provide a proximal electrode on the electrode lead. For example, the connecting leads may be in the form of thin wires embedded in the material forming the hollow tube. Alternatively, the connecting lead may be disposed within the longitudinal channel of the hollow tube.

Where the electrode lead comprises a proximal electrode, the outer electrode may be configured to electrically connect with the proximal electrode when the electrode lead is received in the longitudinal channel of the hollow tube. The proximal electrode on the electrode lead may then be electrically connected to the outer electrode on the catheter when the electrode lead is received in the longitudinal channel in the hollow tube. As a result, the neuromodulation signal applied to the proximal electrode may be communicated to the outer electrode such that the outer electrode may apply the neuromodulation signal to the surrounding target tissue, e.g., to the DACC. Thus, the external electrode may be used as a replacement for the window to apply neuromodulation signals to the DACC when the catheter is in use.

By providing an outer electrode on the catheter arranged in electrical connection with the proximal electrode, the length of the proximal electrode may be reduced, as the proximal electrode only needs to be long enough to provide a reliable connection with the outer electrode when the electrode lead is received within the longitudinal channel of the hollow tube.

When the electrode lead is received in the longitudinal channel of the hollow tube, various mechanisms can be used to electrically connect the outer electrode to the proximal electrode. For example, the connection portion of the outer electrode may be disposed (e.g., exposed) in the longitudinal channel such that the proximal electrode may contact the connection portion of the outer electrode when the electrode lead is received in the longitudinal channel.

The connecting portion of the outer electrode may be arranged to form a slidable electrical connection with the proximal electrode to enable insertion of the electrode through the longitudinal channel.

The outer electrode may be a ring electrode, i.e. the outer electrode may extend around the circumference of the hollow tube.

Alternatively, the outer electrode may be configured to apply the neuromodulation signal in a particular direction, e.g., the outer electrode may extend around only a portion of the circumference of the hollow tube. In particular, the external electrode may be arranged to face the DACC when it is inserted into the brain of the subject.

In this case, the catheter may include indicia (e.g., on the cap of the catheter) indicating the direction in which the outer electrode is facing. In this way, the user can ensure that the external electrode is properly oriented so as to be able to stimulate the DACC.

The conduit may include a cap that may be secured to a hole (e.g., a bore hole). Thus, the cap may be used to secure the catheter to the skull of the subject. For example, the cap may include a threaded outer surface so that it can be screwed into an aperture in the skull of a subject. This also facilitates subsequent removal of the catheter.

In some embodiments, a cap may be secured to the proximal end of the hollow tube. The cap may then include an inlet for inserting the electrode lead into the longitudinal channel of the hollow tube.

In other embodiments, the cap may be separate from the hollow tube. The cap may comprise a passage through which the hollow tube may be inserted, for example, through which the hollow tube may be slidably inserted. In other words, the cap may be movable relative to the hollow tube along the longitudinal direction of the hollow tube when the hollow tube is inserted into the passage in the cap.

In this manner, the hollow tube may be inserted into the brain of the subject through the passageway in the cap. The hollow tube may be adjusted with respect to the position of the cap, for example by inserting a desired length of the hollow tube through a passageway in the cap. This may enable the user to adjust the length of the hollow tube inserted into the brain of the subject.

The passage in the cap may be arranged to form a sliding seal around the hollow tube when inserted therethrough, so as to prevent leakage via the cap.

Where the hollow tube comprises a window or an external electrode, the ability to adjust the length of the hollow tube inserted through the channel in the cap would be particularly advantageous as this may enable a user (e.g. a surgeon) to ensure that the window or external electrode is at the appropriate depth in the subject's brain. In particular, it may enable a user to ensure that the window or external electrode is positioned to enable application of a neuromodulation signal to the DACC and/or CC.

The catheter may include an indicator for indicating that the length of the hollow tube has been inserted through the passageway in the cap, for example in the form of an index line along one side of the hollow tube. The indicator may be arranged to indicate a distance between the cap and the window or the outer electrode.

Additionally or alternatively, the hollow tube may include an indicator for indicating the orientation of the window or the outer electrode.

The catheter may further comprise a first limiter fixed to the proximal end portion of the hollow tube and arranged to abut the cap when the predetermined length of the hollow tube is inserted through the channel. The first limiter may be used to ensure that only a hollow tube of a predetermined length is passed through the passageway in the cap and inserted into the brain of the subject. In this way, it can be ensured that the hollow tube is inserted into the brain of the subject to a desired depth. The predetermined length may be determined by the position at which the first limiter is fixed to the proximal portion of the hollow tube. In use, the distal portion of the hollow tube may be inserted through the channel in the cap until the first limiter on the proximal portion of the hollow tube abuts the cap, thereby preventing further insertion of the hollow tube through the channel in the cap.

The position of the first limiter on the proximal portion of the hollow tube may be adjustable to set a predetermined length of the hollow tube. A first limiter and a catheter may be provided separately, i.e. the first limiter may be fixed to the proximal part of the hollow tube. In some cases, the first restrictor may be removably secured to the proximal portion of the hollow tube.

The device may further comprise a second limiter fixed to the proximal end portion of the electrode lead and arranged to abut the proximal end of the catheter when the predetermined length of the electrode lead protrudes from the distal opening of the hollow tube.

A second limiter may be used to ensure that only a predetermined length of the electrode lead protrudes from the distal opening of the hollow tube. In this manner, it may be ensured that the electrode lead is inserted into the brain of the subject to a desired depth, e.g., such that a distal portion of the electrode lead is properly positioned for application of one or more neuromodulation signals.

The predetermined length may be determined by the position at which the second limiter is fixed to the proximal end portion of the electrode lead.

In use, the distal end portion of the electrode lead may be inserted through the longitudinal channel of the hollow tube until the second limiter on the proximal end portion of the electrode lead abuts the cap, thereby preventing further insertion of the electrode lead through the hollow tube.

The position of the second restraint on the proximal portion of the electrode lead may be adjustable to set a predetermined length of the electrode lead. A first limiter and an electrode lead, respectively, may be provided, i.e. they may be fixed to the proximal portion of the hollow tube. In some cases, the first restrictor may be removably secured to the proximal portion of the hollow tube.

In some embodiments, the device may further comprise a sensor arranged to detect a physiological parameter of the subject and to generate an output signal related to the detected physiological parameter, wherein the controller is configured to adjust at least one of the one or more neuromodulation signals based on the output signal from the sensor.

In this way, the physiological parameter may be used as feedback to adjust the neuromodulation signal. This may enable more accurate and efficient neural stimulation of the brain, as the neural modulation signal may be adjusted based on the subject's response to the signal.

For example, the physiological parameter may include one or more of blood pressure, blood flow, cerebral blood flow, intracranial pressure of the subject.

When a neuromodulation signal is applied to VL-PAG, DACC, and/or CC, the neuromodulation signal applied to VL-PAG, DACC, and/or CC may be adjusted based on the detected physiological parameter.

Adjusting the neuromodulation signal may involve adjusting one or more parameters of the neuromodulation signal, such as a frequency, a pulse width, and a pulse amplitude. In some cases, a set point may be associated with a physiological parameter, and the neuromodulation signal may be adjusted until it reaches the set point.

Various types of sensors may be used to detect blood pressure and/or blood flow. Since the effect of neural stimulation of the brain of a subject can be used to enhance brain perfusion, changes in blood pressure and/or blood flow can be used as an indication of the effectiveness of the treatment.

For example, the sensor may comprise a wearable sensor configured to measure blood pressure and/or blood flow. The wearable sensor may be in the form of a sensor that can be worn on the wrist of the user (e.g., as a watch).

In some cases, the sensor may comprise an implantable sensor arranged to detect blood pressure and/or blood flow. For example, an implantable sensor may be arranged to be implanted on a carotid bifurcation, in a carotid sinus, or in an aortic arch.

Where the physiological parameter is intracranial pressure, the sensor may be in the form of a pressure sensor implantable beneath the skull of the subject.

In some cases, a pressure sensor may be incorporated into the electrode lead, or it may be incorporated into the catheter. This avoids having to implant the electrode lead and the catheter separately from the sensor. Like blood pressure and/or blood flow, intracranial pressure can be used as an indicator of the effectiveness of the treatment.

In some cases, the sensor may be incorporated into the generator. Accelerometers in devices commonly used to detect changes in an individual's position and motion may be optimized to sense changes in motion of the surrounding skull or lower dura mater secondary to the brain pulse and calibrated to cerebral blood flow and also to sense changes in heart rate.

The sensor may be communicatively coupled to the controller, for example by a wired or wireless connection, so that output signals from the sensor may be transmitted to the controller. Upon receiving the output signal from the sensor, the controller may compare the detected physiological parameter to a predetermined set point for the physiological parameter and adjust at least one of the one or more neuromodulation signals, e.g., attempt to change the detected physiological parameter to less than, equal to, or greater than the set point.

In some embodiments, the apparatus may further comprise an external power source comprising a transmitter for wirelessly transmitting power to the controller. In this manner, no wired connection is required between the external power source and the controller. Thus, during use, the external power source may be worn by the subject such that the external power source is proximate to the controller. Then, after use, the external power source can be easily removed. This may facilitate charging of the external power source and improve user comfort when the device is not in use, as the external power source may be removed. This would be particularly advantageous if the neural stimulation is performed only for a short time interval. The external power source may include a source of electrical power, such as a battery (e.g., a rechargeable battery).

Power may be transmitted from a transmitter of an external power source to the controller via an inductive coupling between the transmitter and the controller. For example, the transmitter may comprise a transmitter coil and the controller may comprise a receiver coil, the transmitter coil and the receiver coil being inductively coupleable such that power may be transferred from the transmitter to the controller.

The device may also include a wearable cover configured to hold the transmitter in proximity to the controller. In this way, the subject can wear the cover to hold the transmitter near the controller to power the controller.

The cover may comprise a pocket arranged to hold the emitter. The cover may be arranged to hold the transmitter above the controller, which may ensure efficient power transfer from the transmitter to the controller.

The device may also include one or more stimulation electrodes for applying one or more stimulation signals to the subject's carotid body and/or carotid baroreceptors.

Such an arrangement may be considered an independent aspect of the present invention. More generally, in this independent aspect, the apparatus may include an electrode lead for applying one or more neuromodulation signals to one or more targets in the brain of the subject, and need not be limited to the targets discussed above. Thus, an independent aspect of the invention may provide a system comprising means for applying one or more neuromodulation signals to one or more targets in the brain of a subject; and a stimulation electrode for applying a stimulation signal to the carotid body and/or carotid baroreceptors of the subject.

The one or more stimulation electrodes may be arranged to apply stimulation signals to one or more carotid bodies and/or carotid baroreceptors.

One or more stimulation electrodes may be provided on an implantable lead arranged for implantation into a subject, for example as described in US2015/0112359a 1. The stimulation signal applied via the stimulation electrodes may be a pulsed RF signal. The pulsed RF signal can be used to stimulate carotid bodies and/or carotid baroreceptors without heating the tissue to a temperature that inactivates it.

The controller may be configured to generate one or more stimulation signals applied by the one or more stimulation electrodes. In this manner, the controller may be configured to generate one or more neuromodulation signals applied by the plurality of electrodes on the electrode lead, and one or more stimulation signals applied by the one or more stimulation electrodes.

In this case, the one or more stimulation electrodes may be connected to the controller, e.g. via a connection line.

When the one or more electrodes are disposed on an implantable lead, the implantable lead may be connected to the controller such that the one or more stimulation signals may be transmitted to the one or more stimulation electrodes.

Generating both the neuromodulation signal and the stimulation signal with a single controller may facilitate the interoperability of applying the neuromodulation signal and the stimulation signal to their respective targets. This also reduces the number of components in the device.

Alternatively, a separate signal generator may be provided to generate the one or more stimulation signals. In this case, the controller and the signal generator may communicate with each other wiredly or wirelessly. This may enable the formation of applications that coordinate one or more neuromodulation signals and one or more stimulation signals.

The catheter described as part of the second aspect of the invention may form a separate aspect of the invention.

Thus, according to a third aspect of the present invention, there is provided a catheter for insertion into the brain of a subject, the catheter comprising a hollow tube defining a longitudinal channel in which an electrode lead may be housed; wherein the catheter comprises a window formed in a side wall of the hollow tube, the window being arranged to expose a proximal electrode on the electrode lead to the exterior of the hollow tube when the electrode lead is received in the longitudinal channel of the hollow tube.

Features of the catheter described in relation to the second aspect of the invention may be shared with the catheter of the third aspect of the invention and so will not be described again.

The catheter may include a window formed in the sidewall of the hollow tube arranged to expose the proximal electrode to the exterior of the hollow tube when the electrode lead is received in the longitudinal channel of the hollow tube.

The window may be shorter in length than the proximal electrode.

The catheter may include indicia for indicating the direction in which the window is facing.

The window may comprise two or more apertures in the side wall of the hollow tube.

According to a fourth aspect of the present invention there is provided a catheter for insertion into the brain of a subject, the catheter comprising a hollow tube defining a longitudinal channel in which an electrode lead may be received; wherein the catheter comprises an external electrode on the outer surface of the hollow tube.

Features of the catheter described in relation to the second aspect of the invention may be shared with the catheter of the third aspect of the invention and so will not be described again.

In some embodiments, the catheter may further include a connection lead extending through the hollow tube for connecting the external electrode to the controller.

In other embodiments, the outer electrode may be configured to electrically connect to the proximal electrode on the electrode lead when the electrode lead is received in the longitudinal channel of the hollow tube.

The catheter of the third or fourth aspects of the invention may further comprise a cap securable to an aperture in the skull of a subject, the cap comprising a passageway through which the hollow tube is insertable to enable the hollow tube to be inserted into the brain of the subject.

The catheter of the third or fourth aspect of the invention may further comprise a first limiter fixed to the proximal end portion of the hollow tube, the first limiter being arranged to abut the cap when a predetermined length of the hollow tube is inserted through the passage.

As used herein, the term "distal" may refer to a component (e.g., an electrode lead or catheter) that, in use, is located at an end or portion deeper in the brain of a subject. For example, the distal portion of the electrode lead may be a portion of the electrode lead that: the portion of the electrode lead is deepest in the brain of the subject after the electrode lead is implanted in the brain of the subject.

In this context, the term "proximal" may refer to a component (e.g. an electrode lead or catheter) which, in use, is closer to the controller, i.e. closer to the end or part of the skull of the user.

Herein, the "length" of a component (e.g., an electrode) may refer to the length of the component along the longitudinal direction of the hollow tube of the electrode lead or catheter.

Drawings

Embodiments of the invention are discussed below with reference to the accompanying drawings, in which:

FIG. 1 is a schematic illustration of an electrode lead that may form part of a device according to an embodiment of the present invention;

FIG. 2A is a schematic view of a catheter according to an embodiment of the present invention;

fig. 2B is a schematic view illustrating a configuration in which the electrode lead of fig. 1 is received in the catheter of fig. 2A;

FIG. 3A is a schematic view of a catheter according to an embodiment of the present invention;

FIG. 3B is a schematic diagram of an apparatus according to an embodiment of the invention;

FIG. 4A is a schematic view of a catheter according to an embodiment of the present invention;

FIG. 4B is an enlarged cross-sectional view of a portion of the catheter of FIG. 4A;

FIG. 5 is a schematic view of an apparatus according to an embodiment of the invention;

FIG. 6A is a schematic view of an apparatus according to an embodiment of the invention;

FIG. 6B is a cross-sectional view of a portion of the device of FIG. 6A;

FIG. 6C is a top view of a portion of the device of FIG. 6A;

FIG. 7A is a cross-sectional view of an apparatus according to an embodiment of the invention;

FIG. 7B is a schematic view of the device of FIG. 7A;

fig. 8 is a schematic diagram illustrating an apparatus for use on a subject in accordance with an embodiment of the present invention;

fig. 9 is a schematic diagram illustrating an apparatus for use on a subject in accordance with an embodiment of the present invention;

FIG. 10A is a cross-sectional view of a subject's head showing a device according to an embodiment of the invention in use on the subject;

FIG. 10B is a side view of the head of the subject indicating a section line corresponding to the section view shown in FIG. 10A;

fig. 11 is an image of a brain of a subject showing a trajectory for implanting an electrode lead into the brain of the subject, in accordance with an embodiment of the present invention;

fig. 12A and 12B are images of a catheter implanted into the brain of a subject along a preferred trajectory; and

fig. 13 is an image of a subject's brain showing the deviation of an implanted electrode lead from a preferred trajectory.

Detailed Description

Fig. 1 is a schematic diagram of an electrode lead 100 that may form part of a device according to an embodiment of the invention. Electrode lead 100 is arranged for insertion into the brain of a subject along a trajectory that connects the dorsomedial nucleus (DMN) and the ventrolateral periaqueductal gray (VL-PAG) throughout the lateral reins (LH) and the Posterior Commissure (PC). Electrode lead 100 is configured to apply one or more neuromodulation signals to a target along an implantation trajectory of the electrode lead, the trajectory including DMN, LH, PC, and VL-PAG. In addition, electrode lead 100 is configured to apply neuromodulation signals to anterior cingulate cortex (DACC) and/or Corpus Callosum (CC). A preferred implantation trajectory of the electrode lead 100 into the brain of a subject will be described below in conjunction with fig. 10-13.

The electrode lead 100 is in the form of an elongated cylindrical cable with a plurality of electrodes 102 at the distal portion of the electrode lead 100. The plurality of electrodes 102 includes seven evenly spaced electrodes. Each electrode 102 has a cylindrical shape and each electrode has a length of about 1.7mm with a spacing of about 1.7mm between adjacent electrodes. In this manner, the total length spanned by the plurality of electrodes 102 is approximately 23 mm. Thus, the plurality of electrodes 102 may enable the DMN and VL-PAG and the target located between the DMN and VL-PAG (e.g., LH and PC) to be excited via the electrodes 102. By providing a plurality of electrodes as a regularly spaced electrode array, variations in distance between targets of different subjects can be accommodated.

In other examples, the plurality of electrodes 102 may include a different number of electrodes, and the electrodes 102 may have different sizes, e.g., different sizes depending on the particular target to be treated. Typically, the plurality of electrodes 102 may span a length of 20mm to 30mm, as this may correspond to a typical distance between DMN and VL-PAG for most subjects.

The electrode lead 100 also includes a proximal electrode 104, the proximal electrode 104 being spaced apart from the plurality of electrodes 102. The proximal electrode 104 is spaced apart from the plurality of electrodes 102 by a distance of approximately 10mm such that the proximal electrode is closer to the proximal end of the electrode lead 100 than the plurality of electrodes 102.

In other examples, the proximal electrode 104 may be spaced apart from the plurality of electrodes 102 by a distance of about 5mm to 15 mm.

A spacer 106 may be provided between the proximal electrode 104 and the plurality of electrodes 102.

The proximal electrode 104 has a cylindrical shape and has a length of about 20 mm. In other examples, the proximal electrode 104 may have a length of 15mm to 30 mm.

The proximal electrode 104 is arranged to apply a neuromodulation signal to the DACC and/or CC. The length of the proximal electrode 104 may be used to compensate for positional variations of the DACC between subjects to ensure that neuromodulation signals may be applied to the DACC and/or CC.

The electrode lead 100 includes a plurality of wires 108, and the plurality of wires 108 extend within the electrode lead 100. Each of the plurality of electrodes 102 and the proximal electrode 104 are electrically connected to a respective one of a plurality of leads 108. In this manner, a neuromodulation signal may be applied to each of the electrodes 102 and the proximal electrode 104 via the respective leads. Each of the electrodes 102 and the proximal electrode may be electrically isolated from each other so that independent neuromodulation signals may be applied to each individual electrode. In this manner, multiple targets may be individually excited using the electrode lead 100.

Each of the electrodes 102 and the proximal electrode 104 are exposed on an outer surface of the electrode lead 100 such that the electrodes 102 and the proximal electrode 104 can contact the target brain tissue when the electrode lead 100 is inserted into the brain.

The plurality of wires 108 may be wound around the inner core 110 of the electrode lead 100 or carried by the inner core 110 of the electrode lead 100. The inner core 110 may be made of a rigid material to impart rigidity to the electrode lead 100 and to facilitate insertion of the electrode lead into the brain of the subject.

The proximal end of the electrode lead may be connected to a controller (not shown) configured to generate one or more neuromodulation signals to be applied by the plurality of electrodes 102 and the proximal electrode 104.

In particular, the lead 108 may be electrically connected to the controller such that the neuromodulation signals generated by the controller may be communicated to the electrode 102 and the proximal electrode 104 via the lead 108.

Each of the plurality of wires 108 may be connected to a respective channel in the controller so that independent neuromodulation signals may be applied via each of the plurality of electrodes 102 and the proximal electrode 104.

The controller may be in the form of an Implantable Pulse Generator (IPG), for example.

FIG. 2A shows a schematic view of a catheter (guide tube)200 according to an embodiment of the present invention. The catheter 200 may form part of a device according to an embodiment of the invention.

The catheter 200 includes a hollow tube 204 defining a longitudinal channel extending therethrough, and an electrode lead (e.g., electrode lead 100) may be received in the hollow tube 204. The catheter 200 includes a cap 204, the cap 204 being disposed at the proximal end of the hollow tube 202.

A cap 204 may be secured to the proximal end of the hollow tube 202.

The cap 204 includes an inlet for inserting an electrode lead into a longitudinal channel in the hollow tube 202. Thus, the electrode lead 100 may be inserted into the brain of the subject via the catheter 200. The hollow tube 202 may be used to guide the electrode lead 100 along a desired trajectory in the brain of the subject to facilitate implantation of the electrode lead 100.

The cap 204 also includes a threaded outer surface 206 so that the cap 204 can be screwed into an insertion aperture (hole) (e.g., a burr hole) formed in the skull of a subject. In this way, the catheter 200 may be inserted into the brain of a subject through an insertion aperture in the skull and secured to the skull via the threaded outer surface 206. The hollow tube 202 may be made of a rigid plastic material to facilitate insertion of the hollow tube 202 into the brain of a subject.

The length of the hollow tube 202 (shown as X in fig. 2A) is arranged such that when the electrode lead 100 is inserted into the longitudinal channel in the hollow tube 202, the distal end portion of the electrode lead comprising the plurality of electrodes 102 protrudes from the distal opening 208 of the hollow tube 202. In this manner, when the electrode lead 100 is received in the longitudinal channel of the hollow tube 202, the plurality of electrodes 102 on the electrode lead 100 are exposed so that neuromodulation signals may be applied to the surrounding brain tissue via the plurality of electrodes 102.

The hollow tube 202 may be cut to an appropriate length prior to insertion of the hollow tube 202 into the brain of the subject, for example based on the measured dimensions of the brain of the subject. In particular, the length X of the hollow tube 202 may correspond to a distance between the skull of the subject and a few millimeters below the lateral ventricle. Facilitating transcranial implantation of the electrode lead. For example, the length X may be 45mm to 65 mm.

The catheter 200 includes a window 210, the window 210 being formed in the sidewall of the hollow tube 202. The window 210 is arranged such that a portion of the proximal electrode 104 is exposed via the window 210 when the electrode lead 100 is received in the longitudinal channel in the hollow tube.

The length of the window 210 (shown as Z in fig. 2A) is shorter than the length of the proximal electrode 104, such that the portion of the proximal electrode 104 exposed through the window 210 is shorter than the length of the proximal electrode 104. Thus, in the example of fig. 1, where the proximal electrode has a length of about 20mm, the window 210 may have a length of less than 20mm, for example, less than 10mm or less than 5 mm. By making the window 210 shorter than the proximal electrode 104, it may be ensured that the proximal electrode 104 only applies the neuromodulation signal to the brain tissue in the target region around the window 210, rather than along the entire length of the proximal electrode 104. This avoids stimulating brain tissue far from the target area.

As described above, the window 210 may have a length of, for example, 10mm to 25 mm.

The window 210 in the hollow tube 202 is positioned such that when the catheter is inserted into the brain of the subject, the window 210 is aligned with the DACC. In this manner, the portion of the proximal electrode 104 exposed via the window 210 may be used to apply neuromodulation signals to the DACC and/or CC.

Specifically, the distance between the cap 204 and the window 210 (shown as Y in fig. 2A) may be set such that the window 210 is located near the DACC. To account for anatomical variations between subjects, catheters with different Y values may be provided.

For example, the distance between the cap 204 and the window 210 (shown as Y in fig. 2A) may be 20mm to 35 mm.

The window 210 is formed in the sidewall of the hollow tube 202 such that the window 210 faces in the radial direction. In this manner, when the electrode lead 100 is disposed in the longitudinal channel in the hollow tube 202, the orientation of the hollow tube 202 relative to the electrode lead 100 may determine the direction in which the proximal electrode 104 may apply the neuromodulation signal. The cap 204 of the catheter 200 includes indicia 212 (or indicators) in the form of arrows to indicate the direction in which the window 210 is facing. In this way, a user (e.g., a surgeon) can ensure that the window is oriented in the correct direction when inserting the catheter 200 into the brain of the subject. In particular, the marker 212 may be used to ensure that the window 210 faces the DACC when the catheter is inserted into the brain of the subject.

Fig. 2B shows such a configuration: the electrode lead 100 is received in a longitudinal channel in a hollow tube 202 of the catheter 200. As can be seen in fig. 2B, in this configuration, the distal portion of the electrode lead 100, including the plurality of electrodes 102, protrudes from the distal opening 208 of the hollow tube 202. Further, a portion of the proximal electrode 104 is exposed via a window 210 in the sidewall of the hollow tube 202. The proximal end of the electrode lead 100 extends through an inlet in the cap 204 of the catheter 200 so that the electrode lead 100 can be connected to a controller (not shown).

Fig. 3A shows a schematic view of a catheter 300 according to another embodiment of the invention. The catheter 300 may form part of a device according to an embodiment of the invention. Catheter 300 is similar to catheter 200 described above, but the configuration of the windows is different. Accordingly, features of catheter 300 corresponding to those described with respect to catheter 200 are identified in fig. 3A using the same reference numerals as in fig. 2A and will not be described again.

The catheter 300 includes a window 310, the window 310 being formed in the sidewall of the hollow tube 202. The window 310 includes three apertures 312, 314, 316, the apertures 312, 314, 316 being formed in the side wall of the hollow tube 202. The holes 312, 314, 316 are evenly spaced in the longitudinal direction of the hollow tube 202. The three holes together span a length Z similar to the length Z of the window 210 of the catheter 200. The window 310 is arranged such that portions of the proximal electrode 104 are exposed via the apertures 312, 314, 316 when the electrode lead 100 is received in the longitudinal channel of the hollow tube 202. Thus, window 310 performs a similar function as window 210 of catheter 200.

The inventors have found that by forming the window 310 as a series of smaller holes, the rigidity of the hollow tube 202 may be increased, which may facilitate insertion of the hollow tube 202 into the brain of a patient. In the example shown, window 310 includes three apertures. However, in other examples, a different number of apertures may be used, for example two, four, five or six apertures may be used, and the size and/or spacing of the apertures may be different than discussed above.

Fig. 3B is a schematic diagram illustrating an apparatus according to an embodiment of the present invention, which includes a catheter 300 and an electrode lead 100. Fig. 3B shows such a configuration: the electrode lead 100 is received in a longitudinal channel in the hollow tube 202 of the catheter 300. As can be seen in fig. 3B, in this configuration, the distal portion of the electrode lead 100, including the plurality of electrodes 102, protrudes from the distal opening 208 of the hollow tube 202. Further, a portion of the proximal electrode 104 is exposed through the apertures 312, 314, 316 of the window 310. The proximal end of the electrode lead 100 extends through an inlet in the cap 204 of the catheter 200 and is connected to a controller 318 in the form of an IPG. The controller is configured to generate a neuromodulation signal applied by the proximal electrode 104 and the plurality of electrodes 102.

Fig. 4A shows a schematic view of a catheter 400 according to another embodiment of the invention. The catheter 400 may form part of a device according to an embodiment of the invention. The catheter 400 is similar to the catheter 200 described above, but the catheter 400 does not include a window. Accordingly, features of catheter 400 corresponding to those described with respect to catheter 200 are identified in fig. 4A using the same reference numerals as in fig. 2A and will not be described again. In the example shown in fig. 4A, the electrode lead 100 is received in a hollow channel in the hollow tube 202 of the catheter 400.

The catheter 400 includes an outer electrode 402, the outer electrode 402 being exposed on the outer surface of the hollow tube 202 of the catheter 400. The outer electrode 402 has a generally cylindrical shape and forms a portion of the sidewall of the hollow tube 202. The outer electrode 402 is made of a conductive material, such as platinum-iridium. The outer electrode 402 is configured such that when the electrode lead is received in the longitudinal channel of the hollow tube 202, the outer electrode 402 is electrically connected to a proximal electrode on the electrode lead, such as the proximal electrode 104 on the electrode lead 100. Fig. 4B shows an enlarged cross-sectional view of the hollow tube 202 along section a-a shown in fig. 4A, with the electrode lead 100 received in the longitudinal channel of the hollow tube 202.

The outer electrode 402 includes a recess 404 formed therein and is arranged to contact the proximal electrode 104 when the electrode lead is received in the longitudinal channel of the hollow tube 202. In particular, the recess 404 passes through the sidewall of the hollow tube 202 so as to contact the proximal electrode 104 disposed within the hollow tube 202. The recess 404 is arranged to form a sliding contact with the proximal electrode 104 to enable the electrode lead 100 to be inserted through the longitudinal channel in the hollow tube 202. Thus, when the electrode lead 100 is received in the longitudinal channel of the hollow tube 202, the outer electrode 402 is electrically connected to the proximal electrode 104 via the recess 404 in the outer electrode 402. In this manner, the neuromodulation signal applied to the proximal electrode 104 may be transmitted to the outer electrode 402, which, in turn, the outer electrode 402 may apply the neuromodulation signal to the surrounding target tissue.

The recess 404 may also be referred to as a protrusion that protrudes into the hollow tube 202 to contact the proximal electrode 104.

Mechanisms other than the recess 404 may be used to electrically connect the outer electrode 402 to the proximal electrode 104. For example, instead of the recess 404, a connector may be provided that extends through the side wall of the hollow tube between the outer electrode 402 and a longitudinal channel in the hollow tube 202.

The external electrode 402 is positioned to enable neurostimulation of the DACC and/or CC. Accordingly, the outer electrode 402 may provide an alternative to the window 210 and window 310 discussed above for applying neuromodulation signals to the DACC and/or CC via the proximal electrode 104. For example, the distance Y (as shown in fig. 4A) between the cap 204 and the outer electrode 402 may correspond to the distance between the skull of the subject and the DACC. Catheters with different distances Y may be provided to accommodate variations in anatomy between subjects.

The hollow tube 202 of the catheter 400 may be generally made of a plastic material such as polycarbonate urethane (polycarbonate urethane). One method of forming the hollow tube 202 of the catheter 400 involves forming two thin-walled (e.g., 0.2mm) concentrically extruded tubes of suitable diameter. A window may then be formed in the inner tube for receiving the recess 404 (or connector). The outer electrode 402 and the outer tube may then be mounted on the inner tube and the plastic used to form the tube may be reflowed on the mandrel at high temperature to form a bond between the inner and outer tubes and to form a contact that does not introduce an adhesive.

Fig. 5 shows an apparatus 500 according to an embodiment of the invention. The device includes an electrode lead 502, the electrode lead 502 having a similar configuration as the electrode lead 100 described above. In particular, the electrode lead includes a plurality of electrodes 504, the plurality of electrodes 504 being on a distal portion of the electrode lead 502. However, unlike the electrode lead 100, the electrode lead 502 does not have a proximal electrode. The proximal ends of the electrode leads 502 are connected to a controller 506, the controller 506 being configured to generate neuromodulation signals applied by the plurality of electrodes 504.

The device 500 also includes a catheter 508. The conduit 508 is similar to the conduit 200 described above, but the conduit 508 does not include a window. Accordingly, features of the catheter 508 that correspond to those described with respect to the catheter 200 are identified in fig. 5 using the same reference numerals as in fig. 2A and will not be described again.

In the example shown in fig. 5, the electrode lead 502 is received in a hollow channel in the hollow tube 202 of the catheter 508. The proximal end of the electrode lead 502 protrudes from an entrance in the cap 204 of the catheter 508 so that the electrode lead 502 can be connected to the controller 506. The distal end portions of the electrode leads 502 protrude from the distal opening 208 of the hollow tube 202, exposing the plurality of electrodes 504.

The catheter 508 includes an outer electrode in the form of a mesh electrode 510 disposed on the outer surface of the hollow tube 202. The mesh electrode 510 is formed from a metal mesh material that is affixed or otherwise bonded to the outer surface of the hollow tube 202.

The mesh electrode 510 is electrically connected to the controller 506 via a connecting lead 512, the connecting lead 512 extending from the cap 204 of the catheter 508. Within the hollow tube 202, the connecting lead 512 is in the form of a thin connecting wire that extends between the cap 204 and the mesh electrode 510. The thin connecting wires may be disposed within a longitudinal channel in the hollow tube 202 or may be embedded in the material forming the hollow tube 202. In this manner, the neuromodulation signals generated by the controller 506 may be communicated to the mesh electrode 510, which in turn may apply the neuromodulation signals to the surrounding brain tissue by the mesh electrode 510.

Mesh electrode 510 is positioned to apply neuromodulation signals to DACC and/or CC. For example, the distance between the cap 204 and the mesh electrode 508 may correspond to the distance between the skull and the DACC. In this manner, neuromodulation signals may be applied to the DACC and/or CC via the mesh electrodes without including a proximal electrode on the electrode lead 504.

Of course, in other embodiments, a different form of electrode may be used in place of mesh electrode 510. For example, a cylindrical electrode may be used instead of mesh electrode 510.

Fig. 6A, 6B, and 6C illustrate an apparatus 600 according to an embodiment of the invention. The device 600 includes the electrode lead 100 described above. The proximal end of the electrode lead 100 may be connected to a controller (not shown) for generating neuromodulation signals applied by the plurality of electrodes 102 and the proximal electrode 104. The device 600 also includes a catheter 602. The catheter 602 includes a hollow tube 604, the hollow tube 604 defining a longitudinal channel in which the electrode lead 100 may be received. The hollow tube 604 includes a window 606, the window 606 being in the form of three holes in the sidewall of the hollow tube 604. When the electrode lead 100 is received in the hollow tube 604, the window 606 serves to expose the proximal electrode 104 of the electrode lead 100 to the outside of the hollow tube 604.

The catheter 602 also includes a cap 608. The cap 608 may be secured in an aperture in the skull of the subject via a threaded outer surface 610 on the cap 608. The cap 608 includes a passageway 612 (see fig. 6B) through which the hollow tube 604 may be inserted, thereby inserting the hollow tube 604 into the brain of the subject. Thus, when the cap 608 is secured in the aperture in the subject's aperture, the hollow tube 604 may be inserted into the subject's brain via the passageway 612 in the cap 608. The cap 608 is separate from the hollow tube 604, i.e., the cap 608 is not fixed relative to the hollow tube 604, so that the position of the hollow tube 604 relative to the cap 608 can be adjusted. The passage 612 in the cap may be arranged to form a sliding seal around the hollow tube 604 to prevent leakage through the cap 608.

The hollow tube 604 includes tick marks 614, the tick marks 614 indicating the orientation of the window 606, i.e., the direction in which the window 606 is facing. The tick marks 614 also include distance markings that indicate the distance between the cap 608 and the window 606 when the hollow tube 604 is inserted through the passage 612 in the cap 608. In this way, the user can ensure that the window 606 is inserted into the subject's brain at the correct depth and orientation.

A hollow tube 604 may be provided vertically to facilitate insertion of the hollow tube through the passage 612 in the cap. Prior to insertion, the distal end 616 of the hollow tube 604 may be cut to an appropriate length, for example, such that after insertion, the distal end 616 of the hollow tube 604 may extend a few millimeters below the lateral ventricle.

Catheter 602 includes a first limiter 618, first limiter 618 being fixed near proximal end 617 of hollow tube 604, first limiter 618 being arranged to abut a dome (dome)620 of the cap when a predetermined length of hollow tube 604 is inserted through the passageway.

The first limiter 618 may be positioned on the proximal portion of the hollow tube 604 such that when the first limiter 618 abuts the dome 620 of the cap 608, the window 606 and the distal end 616 of the hollow tube 604 are at a desired depth. In particular, the predetermined length may be set such that the window 606 is adjacent to the DACC (such that a neuromodulation signal may be applied to the DACC and/or CC through the proximal electrode), and such that the distal end 616 of the hollow tube is a few millimeters below the lateral ventricle. The ability to adjust the position of the hollow tube 604 relative to the cap 608 may enable the catheter 602 to be adapted to the particular anatomy of the subject.

The position of the first limiter 618 on the proximal portion of the hollow tube 604 may be set, for example, based on markings on the tick marks 614.

First restraint 618 can be secured to hollow tube 604 using any suitable means, such as using sutures, adhesives, or a clamping mechanism.

The proximal end 617 of the hollow tube 604 may be cut to ensure a sufficient length for securing the first restraint 618 to the hollow tube 604.

In practice, the hollow tube 604 may be introduced into the subject's brain via the passageway 612 in the cap 608 over a vertical guide rod aligned along a desired trajectory, for example, using a stereotactic frame or stereotactic robot. Once the hollow tube is inserted to the correct depth, i.e., when the first limiter 618 abuts the dome 620 of the cap 608, the guide rod may be withdrawn. The electrode lead 100 may then be inserted into the subject's brain via the longitudinal channel in the hollow tube 604 and into the channel formed in the subject's brain by the guide rod.

The second limiter 622 is fixed to the proximal end portion of the electrode lead 100. The second limiter 622 is located on the electrode lead 100 such that when a predetermined length of the electrode lead 100 protrudes through the opening at the distal end 616 of the hollow tube 604, the second limiter 622 abuts the proximal end 617 of the hollow tube 604.

In this way, it may be ensured that the distal portion of the electrode lead comprising the plurality of electrodes 102 is inserted to a suitable depth in the brain of the subject. This may also be used to ensure that the proximal electrode 104 on the electrode lead 100 is properly aligned with the window 606. The second limiter 622 may be secured to the electrode lead 100 using any suitable means, such as using sutures, adhesives, or a clamping mechanism.

After inserting the electrode lead 100 into the hollow tube 604, the proximal end portion of the hollow tube 604 and the electrode lead 100 protruding from the cap 608 may be bent at an angle of approximately 90 degrees. First limiter 618 is then secured to the subject's skull via a fixture 624 (e.g., a miniature bone plate), which can be screwed onto the subject's skull using bone screws (not shown). Such a configuration is shown in fig. 6A, 6B, and 6C.

The hollow tube 604 may be made of a thermoplastic material to facilitate bending the hollow tube 604 through an angle of approximately 90 degrees, for example, the thermoplastic material may be heated to enable the hollow tube 604 to bend and then harden the hollow tube when it is cooled.

First limiter 618 includes a recess formed in an outer surface thereof for receiving a retainer 624. The engagement between the groove and retainer 624 may ensure that first limiter 618 is securely held in place by retainer 624. When the first limiter 618 is secured to the hollow tube 604, the fixture 624 may prevent the hollow tube 604 from moving relative to the skull.

Fig. 6B shows a cross-sectional view of device 600 taken along section a-a shown in fig. 6C. The apparatus 600 is mounted on the skull 630 of a subject. The cap 608 is secured in an aperture formed in the skull 630 of the subject, and the hollow tube 604 is inserted into the brain 632 of the subject via a passageway 612 in the cap 608. Hollow tube 604 is fixed to the subject's skull 630 via fixture 624, fixture 624 engages in a groove of first limiter 618, and fixture 624 is threaded to the subject's skull 630. Fig. 6C shows a top view of the apparatus 600 mounted on the skull 630 of a subject.

Fig. 7A and 7B show a device 701 according to an embodiment of the invention, the device 701 comprising a catheter 700 (which is also an embodiment of the invention). The catheter 700 is similar to the catheter 602 described above, but the catheter 700 does not include a window for exposing the proximal electrode. Accordingly, features of the catheter 700 that correspond to features described with respect to the catheter 604 are indicated in fig. 7A and 7B with the same reference numerals as features in fig. 6A, 6B and 6C and will not be described again. The device 701 also includes an electrode lead 702.

Fig. 7A shows a cross-sectional view of a portion of the hollow tube 604 of the catheter 700. In the example shown, the electrode lead 702 is received in a longitudinal channel in the hollow tube 604. The electrode lead 702 has a similar structure to the electrode lead 100 described above. In particular, the electrode lead 702 includes a distal portion having a plurality of electrodes 704 thereon, and a proximal electrode 706 spaced apart from the plurality of electrodes 704.

The hollow tube 604 of the catheter 700 includes a cylindrical conductor 708, the cylindrical conductor 708 being embedded in the plastic material forming the hollow tube 604. The inner surface of the cylindrical conductor 708 forms part of the longitudinal channel in the hollow tube 604. In this manner, the proximal electrode 706 may be in contact with the cylindrical conductor 708 when the electrode lead 702 is received in the longitudinal channel in the hollow tube 604, as shown in fig. 7A.

A window 710 is formed in the plastic material of the hollow tube 604, the window 710 exposing a portion of the cylindrical conductor 708. Thus, the exposed portion of the cylindrical conductor 708 constitutes an outer electrode exposed at the outer surface of the hollow tube 604. In this manner, the neuromodulation signal applied to the proximal electrode 706 of the electrode lead 702 may be transmitted to the cylindrical conductor 708, which in turn may apply the neuromodulation signal to the target tissue via the window 710. The window 710 may be sized to enable application of directional neural stimulation to the DACC and/or CC. Since the proximal electrode 706 of the electrode lead 702 is not used to apply neuromodulation signals directly to the DACC, the length of the proximal electrode 706 may be reduced.

Similar to the catheter 602, the hollow tube 604 of the catheter 700 may be inserted through a passageway in the cap 608, such that the length of the hollow tube 604 inserted into the brain of the subject may be adjusted. A first limiter 618 on the proximal portion of the hollow tube 604 may be positioned and secured to ensure that the window 710 is located at a desired depth in the brain of the subject. The hollow tube 604 of the catheter 700 includes a tick mark 712 indicating the orientation of the window 710, i.e., the direction in which the window 606 is facing. The tick marks 712 also include distance markings that indicate the distance between the cap 608 and the window 710 when the hollow tube 604 is inserted through the passageway in the cap 608.

In the example shown in fig. 7B, the hollow tube 604 and the electrode lead 702 are in a vertical configuration, i.e., the hollow tube 604 and the electrode lead 702 are in a vertical configuration (discussed above in connection with fig. 6A, 6B, and 6C) prior to bending of the hollow tube 604 and the electrode lead 702 and attachment of the first limiter to the skull of the subject. As shown in fig. 7B, the electrode lead 702 includes a second limiter 714, the second limiter 714 being secured to the proximal end of the electrode lead to ensure a desired length of the electrode lead protrudes from the opening at the distal end 616 of the hollow tube 604.

In practice, the relative positions of the distal end 616 of the hollow tube, the window 710, and the cap 608 may be determined by selecting appropriate values for the dimensions X and Y shown in fig. 7B. The dimension X corresponding to the distance between the distal end 616 of the hollow tube 604 and the window 710 may be adjusted by cutting the distal end 616 of the hollow tube 604. The dimension Y corresponding to the distance between the cap 608 and the window 710 may be adjusted by sliding the cap 608 relative to the hollow tube 604. The proximal portion of the hollow tube 604 protruding from the cap 608 may be cut to an appropriate length (shown as Z in fig. 7B) for receiving the first limiter 618. Similar principles may be applied to adjust the various dimensions of the conduit 602 described above.

Fig. 8 is a schematic diagram illustrating an apparatus 800 according to an embodiment of the present invention. In the example shown, the apparatus is used on a subject 801. The device includes an electrode lead 802, the electrode lead 802 being implanted into the brain of the subject via a catheter 804. The electrode lead 802 may correspond to, for example, the electrode lead 100 described above, while the catheter 804 may correspond to the catheter 200 or the catheter 300 described above. Any of the electrode leads and catheters described above may be used as part of the device 800. The catheter 804 is inserted into the brain of the subject via a bore in the skull of the subject, and the cap of the catheter 804 is secured to the skull of the subject. The electrode lead 802 is implanted into the brain of the subject along a linear trajectory, and the linear trajectory passes through the DMN, adjacent to the DACC, adjacent to LH and PC, and into the VL-PAG. In this manner, neuromodulation signals may be applied to DACC and/or CC via the proximal electrodes, while DMN, LH, PC, and VL-PAG may be stimulated via the plurality of electrodes on electrode lead 802.

The electrode leads 802 are connected to a controller 806 in the form of an IPG. The controller 806 is implanted in a pocket formed in the skull of the subject. The controller 806 is configured to generate a neuromodulation signal applied by the electrodes on the electrode lead 802.

The apparatus 800 includes a plurality of sensors communicatively coupled to the controller and arranged to detect various physiological parameters of the subject 801. The apparatus 800 comprises an intracranial pressure (ICP) sensor 808, the ICP sensor 808 being arranged to detect ICP of the subject 801. In the example shown, the ICP sensor 808 is implanted below the skull of the subject via a second bore in the skull of the subject. The ICP sensor 808 is communicatively coupled to the controller 806 via a wire such that the ICP sensor 808 can transmit a signal related to the ICP of the subject to the controller 806. Additionally or alternatively, an ICP sensor may be incorporated into the catheter 804 and/or the electrode lead 802. Incorporating an ICP sensor into the catheter 804 and/or the electrode lead 802 may avoid having to form a second bore in the skull of the subject.

The device 800 further includes an internal sensor 810, the internal sensor 810 being used to detect blood flow and/or blood pressure. In the example shown, the internal sensor 810 is implanted on the carotid bifurcation. The internal sensor 810 is communicatively coupled to the controller 806 via a wire such that the internal sensor 810 can transmit signals related to the blood flow and/or blood pressure of the subject to the controller 806. The device may also include a wearable sensor, for example in the form of a wrist-wearable sensor 812. Wrist-wearable sensor 812 may, for example, be configured to detect blood pressure, heart rate, or blood flow. Wrist-wearable sensor 812 may be communicatively coupled to controller via a wireless connection between controller 806 and sensor 812, such that sensor 812 may transmit signals related to the measured physiological parameter to controller 806. Different embodiments may include different types of sensors arranged to detect different physiological parameters of the subject and to communicate signals related to the detected physiological parameters to the controller 806.

The controller 806 is configured to adjust one or more neuromodulation signals applied via the electrode lead 802 based on the physiological parameters detected by the sensors (e.g., the ICP sensor 808 and/or the wrist-mountable sensor 812). In this way, control of the neuromodulation signal may be based on feedback provided by the physiological parameter of the subject. The controller 806 may be configured to adjust one or more neuromodulation signals applied via the electrode lead 802 to achieve a set point associated with one of the physiological parameters.

The controller 806 may also be configured to detect a circadian rhythm of the subject 801. This may be accomplished by monitoring a physiological parameter of the subject (e.g., blood pressure and/or heart rate), which varies circadian in accordance with the circadian rhythm of the subject. Similarly, the controller 806 may be configured to detect a disturbance in the circadian rhythm of the subject, for example, by comparing the measured circadian variation in the physiological parameter with a model circadian variation corresponding to a non-disturbed circadian rhythm. The controller 806 may then adjust one or more neuromodulation signals based on the circadian rhythm, and/or reestablish a normal circadian rhythm in the subject 801.

Figure 8 shows the location of carotid baroreceptors and carotid body. The ascending aorta 820 feeds the carotid aorta 822. The bifurcation of the internal carotid artery 824 and the external carotid artery 826 forms a saddle in which the carotid body 828 is located. Aortic arch baroreceptors 816 feed the vagus nerve, the medulla of the vagus pathway. Carotid baroreceptors are located in the internal carotid artery 824 and carotid sinus 814. The carotid body and carotid baroreceptors supply the Herring's (Herring) sinus nerve, which connects to the glossopharyngeal nerve, before reaching the medulla.

In some embodiments, device 800 may also include one or more stimulation electrodes for applying one or more analog signals to the carotid body and/or carotid baroreceptors in subject 801. For example, the internal sensor 810 may include a stimulation electrode arranged to apply a stimulation signal to baroreceptors in the carotid sinus 814 and/or the carotid body 828. Alternatively, a separate stimulation electrode may be provided for applying stimulation signals to baroreceptors in the carotid sinus 814. Separate stimulation electrodes for applying stimulation signals to baroreceptors in the aortic arch 816 may also be provided.

The one or more stimulation electrodes may form part of an implantable lead that is implanted in the subject. The implantable lead may be similar to the leads described in US2015/0112359a 1. For example, the implantable lead may include a semi-circular hook that may enable the implantable lead to be placed on the bifurcation of the internal carotid artery 824 and the external carotid artery 826. The semicircular hook may comprise a stimulation electrode arranged such that the stimulation electrode is held proximate to a carotid body and/or proximate to carotid baroreceptors in a carotid sinus. The implantable lead may be implanted into the subject 801 with a catheter or needle.

The stimulation signals applied by the one or more stimulation electrodes may be generated by the controller 806, in which case a wired connection may be provided between the controller 806 and the stimulation electrodes. Alternatively, a separate controller (not shown) may be provided to generate the stimulation signals applied by the one or more stimulation electrodes.

The stimulation signals applied by the one or more stimulation electrodes may be in the form of pulsed RF electrical signals. The pulse duration of the stimulation signal may be 2ms to 10ms, or preferably 5ms to 8ms, each pulse consisting of a number of cycles of the RF waveform of 200kHz to 600kHz, or preferably 250kHz to 500 kHz. The pulses may be repeated at 2Hz to 8Hz, preferably at 5Hz, with an interval between each pulse of about 120ms to 500 ms. Generally, the amplitude of the pulsed RF signal may be 25V to 100V or 10V to 140V is employed. Such pulsed RF signals may avoid heat build-up at the stimulation electrode or electrodes, thereby avoiding tissue inactivation that would result in long-term damage to the nerve or carotid body. Such stimulation signals may be applied intermittently to the carotid body.

Alternatively, the stimulation signal applied to the carotid baroreceptors may have a pulse amplitude typically between 5mA and 10mA, a pulse width typically between 45ms and 210ms, and a pulse frequency typically between 40Hz and 80 Hz. Such stimulation signals have been shown to produce a blood pressure response. Such a stimulation signal may be continuously applied to the carotid baroreceptors, for example by a suitable cyclic or clustered discharge (bursting).

Fig. 9 is a schematic diagram illustrating an apparatus 900 according to an embodiment of the present invention. In the example shown, the apparatus 900 is mounted on the skull 901 of a subject. The apparatus 900 comprises a controller 902 in the form of an IPG, the controller 902 being implanted in a pocket (pocket) formed in the skull 901 of the subject. The controller 902 is electrically connected to an electrode lead 904, the electrode lead 904 being implanted into the brain of the subject via an aperture in the skull 901 of the subject. The electrode lead may be similar in configuration to the electrode lead 100 described above, for example. The electrode lead 904 is secured to the skull of the subject via a fixation member (e.g., a micro bone plate) 906.

The controller 902 is powered by an external power source that includes a transmitter coil 908, the transmitter coil 908 being arranged to be located on the scalp of the subject. The transmitter coil 908 is configured to deliver power to the controller 902 via inductive coupling between the transmitter coil 908 and the controller (e.g., a receiver coil in the controller). In this manner, power may be wirelessly transmitted from an external power source to the controller 902. This may avoid having to include an internal power supply in the controller 906 and facilitate coupling the controller 902 to an external power supply. The external power source may be configured to deliver power in bursts (bursts), for example, continuously or at programmed times. The apparatus 900 may also include a cover (not shown) arranged to hold the transmitter coil 908 in place over the controller 906.

Fig. 10A and 10B illustrate placement of electrode leads in a subject's brain along a preferred trajectory to achieve treatment according to embodiments of the present invention.

In the example shown in fig. 10A, the electrode lead 100 is implanted into the brain of the subject via the catheter 200 described above. However, other electrode leads and catheters described herein may also be implanted along the trajectory shown in fig. 10A. Fig. 10B shows a side view of the subject's head, and depicts section line 51 (a-a). Fig. 10A shows a cross-sectional view of the subject's head along cross-sectional line 51.

The cap 204 of the catheter 200 is secured to an aperture in the skull 49 of the subject. Hollow tube 202 of catheter 200 is implanted into the brain of the subject along a linear trajectory that traverses DACC 53 and corpus callosum 50, and further traverses DMN 57, adjacent to LH 58 and PC 59, and into VL-PAG 60. The hollow tube 202 passes through the lateral ventricle 56 with the distal opening 208 of the hollow tube 202 located a few millimeters below the lateral ventricle 56. The electrode lead 100 is implanted into the brain of the subject along a straight trajectory by a catheter 200.

The distal portion of the electrode lead, including the plurality of electrodes 102, protrudes from the distal opening 208 of the catheter such that it passes through DMN 57, adjacent to LH 58 and PC 59, and into VL-PAG 60.

The window 210 in the hollow tube 210 is positioned adjacent to the DACC 53 and corpus callosum 50. A portion of the proximal electrode 104 on the electrode lead 100 is exposed through a window 210 in the hollow tube. In this manner, a neuromodulation signal may be applied to the DACC 53 and CC 50 via the proximal electrode 104. Further, the plurality of electrodes 102 on the distal portion of the electrode lead 100 may be used to apply neuromodulation signals to one or more of DMN 57, LH 58, PC 59, and VL-PAG 60. A controller 48 in the form of an IPG is implanted in a pocket formed in the skull 49 of the subject. The controller 48 is configured to generate the neuromodulation signals applied by the plurality of electrodes 102 and the proximal electrode 104.

Fig. 11 is a picture of a subject's brain showing a preferred trajectory 21 for implanting an electrode lead according to the method of the present invention. The trajectory 21 is a straight trajectory: extends transverse to DACC 22 and CC 24, traverses DMN 23, extends adjacent to LH 25, bypasses third ventricle 28, extends adjacent to PC 26, and terminates at VL-PAG 27. Thus, if the electrode lead is implanted into the brain of the subject along trajectory 21, one or more of DACC, CC, DMN, LH, PC, and VL-PAG may be stimulated.

Fig. 12A and 12B show images of a catheter 31, which catheter 31 was implanted into the brain of a subject along the trajectory 21 shown in fig. 11, prior to insertion of an electrode lead. Fig. 12A corresponds to the front-rear projection of the track 21, and fig. 12B corresponds to the side view of the track 21. A guide rod 32 made of a radio opaque material is used to implant the catheter along the correct trajectory, for example using a stereotactic frame or stereotactic robotic implant catheter.

Fig. 13 is an image of a subject's brain showing an electrode lead 11 implanted into the subject's brain. The image shows the distance between the implanted electrode lead 11 and LH 12. As shown in fig. 13, the distance is in this case greater than 5mm, between 5mm and 7 mm. The inventors found that in the case where an electrode lead was implanted along a trajectory more than 5mm before LH and PC, such as shown in fig. 13, the subject did not respond to the combined stimulation of DMN and VL-PAG. This is because the electrode leads are too far from LH and PC so that the neuromodulation signal cannot be effectively applied to LH and PC.

In subjects in one study, the electrode leads are shown in figure 13, and the subjects did not respond to combined stimulation by DMN and/or VL-PAG. The inventors have found that by modifying the trajectory to extend closer to LH and PC (i.e. less than 5mm from LH and PC), a positive response can be obtained by stimulating DMN and VL-PAG and LH and PC in combination.

This allows the inventors to recognize that by applying neuromodulation signals to LH and PC, the subject's response to neurostimulation by DMN and/or VL-PAG may be enhanced. It may be preferred that the electrode lead trace distances LH and PC traversed be less than 5mm to ensure that the neuromodulation signal can be effectively applied to LH and PC.

According to the present invention, a higher frequency neuromodulation signal may be applied to the DMN, while a lower frequency neuromodulation signal may be applied to LH and PC. When a neuromodulation signal is also applied to VL-PAG, a neuromodulation signal having a lower frequency may also be applied to VL-PAG.

The higher frequency neuromodulation signal applied to the DMN may be, for example, a pulse train having a forward pulse width of 25 microseconds to 350 microseconds, more preferably 60 microseconds to 90 microseconds, at a repetition frequency of greater than 70Hz, more preferably in the range of 100Hz to 200Hz, or 130Hz or 150 Hz. Positive (negative) going pulses are delivered with a current controlled output, typically of magnitude 1mA, or 2mA to 3mA, or 5mA, or with a voltage controlled output, typically of magnitude 1V to 3V, with balanced reverse charge, at the same or lower intensity. Higher frequency neuromodulation signals may be used to inhibit neurons in structures such as the dorsolateral nucleus, the pronuclei, and the central mid/parafascial complex.

The lower neuromodulation signal applied to one or more of LH, PC, and VL-PAG may comprise a train of forward pulse widths of 50 microseconds to 450 microseconds with a repetition frequency of 5Hz, or 10Hz to 40Hz, or 50Hz, typically 90 microseconds to 180 microseconds with a current controlled output amplitude of 1mA, or 2mA to 3mA, or 5mA, or a voltage controlled output amplitude of 1V to 5V. Balancing the reverse charge may be required. Preferably, the repetition frequency is 5Hz to 10Hz or 20Hz, however, in some cases, the response may be maximized at 40 Hz. This lower frequency neuromodulation signal may be used to stimulate neuronal activity in the stimulated target. A lower frequency neuromodulation signal may be used to excite neurons in a structure (e.g., the pineal gland).

Table 1 below summarizes a series of tests performed on test subjects, which shows the effect of various neurostimulation methods according to embodiments of the present invention. Applying a neuromodulation signal to each test subject to treat hypertension in the test subject.

The left column of table 1 represents the test subjects on which the test was performed. The column labeled "stimulation targets" provides an indication of the various targets in the brain of the subject to which the neuromodulation signals were applied during each test. References to "bilateral", "left", "right" provide an indication of whether the neuromodulation signal is applied to a target in both hemispheres of the brain or in either the left or right hemisphere. The column labeled "stimulation on/off" provides an indication of when a measurement is taken during application of the neuromodulation signal ("on") or when the neuromodulation signal is turned off ("off"). The last three columns provide an indication of the values measured during the test. The column labeled "CBF" provides an indication of cerebral blood flow. The column labeled "CB V" provides an indication of cerebral blood volume. The column labeled "MTT" provides an indication of the average transit time of blood through the brain (i.e., the amount of time spent in the brain between the time of entry and exit from the brain).

CBV is measured in milliliters of blood per 100g of brain and is defined as the volume of flowing blood for a given volume of brain. MTT is measured in seconds and is defined as the average amount of time it takes for blood to pass through a given volume of brain. CBF is measured in milliliters of blood per minute per 100g of brain tissue and is defined as the volume of flowing blood that flows through a given volume of brain over a specified amount of time.

As can be seen from table 1, the overall effect of applying neuromodulation signals to targets in the brain is to increase cerebral blood flow and cerebral blood volume. In many cases, the mean transit time of blood through the brain also decreases.

Table 1: summary of test results

We provide a brief discussion of several diseases that can be treated using the methods of the present invention.

Hypertension disease

Hypertension (hypertension)Disease and illnessIs one of the most important challenges in public health systems. The prevalence of drug-resistant hypertension indicates that existing pharmacological interventions fail for many patients. The combination of the fact that some drugs are not tolerated by patients and are accompanied by associated non-sticking properties indicates the need for improved medical treatments. In the case of pharmacological intervention with three or more antihypertensive drugs, including diuretics, the commonly accepted diagnostic method for treatment of drug-resistant hypertensive disorders is official blood pressure measurement of over 140/90 mm hg.

Arterial blood pressure usually shows physiological daily fluctuations with higher levels during the day and lower levels during the night. Patients with hypertension whose pressure remains high during the night (non-arytenotic) have been reported in some studies to exhibit more target organ damage than patients exhibiting normal graphics (arytenotic). Typically during sleep, blood pressure drops (falls) by more than 10% from daytime baseline blood pressure. In addition, non-scooping (non-scooping) may be a risk factor for cardiovascular mortality in the general population, is not related to total blood pressure over a 24 hour period, and has been shown to be associated with cardiac hypertrophy and remodeling.

Non-arytenotic forms have been shown to be present in about 40% of untreated hypertension and over 50% of treated hypertension. It is possible that the non-arytenoid form is an early change in the blood pressure pattern of a person, and the loss of a nocturnal blood pressure reduction may precede the onset of clinical hypertension.

The antihypertensive effect of VL-PAG DBS has been observed in patients receiving neuropathic pain treatment, who are also diagnosed with hypertensive disease (Green, 2005) (Patel, 2011). By stimulating the dorsal PAG or the ventral PAG, respectively, one patient's blood pressure can be dramatically increased or decreased during surgery. Chronic DBS of VL-PAG causes a decrease in arterial pressure and analgesia that is associated with changes in heart rate variability indicating inhibition of sympathetic vasomotor rotation and an increase in parasympathetic cardiac activity (Pereira, 2010), which led the inventors to describe "methods and devices for modulating blood pressure" (WO 0702007058). The patient's muscle sympathetic activity decreased during acute ventral PAG DBS (svernis Dottir, 2014).

The inventors have observed a significant response of blood pressure reduction after DBS of VL-PAG, and acute complete normalization of chronic hypertension does not usually last for days to a week. Using a robot to stereotactically position the electrodes and confirm the position of the pre-inserted catheter and guide rod based on visual images (Renishaw PLC) (Patel 2007), the inventors reliably and accurately targeted VL-PAG. In 2011 (Neurology, 2011), the inventors reported a first case study in which stimulation of VL-PAG alleviated neuropathic pain and occasionally produced sustained (more than three years) arterial pressure normalization, and was not secondary to pain relief, as the patient's pain level returned to the anterior ventral PAG stimulation level after four months; in 2017 (Hypertension, 2017) recently, the present inventors reported a first case study in which chronic and deep brain stimulation could reduce blood pressure and sympathetic nerve activity in drug and device resistant severely hypertensive patients.

In addition, oxford tissue found that the hypotensive and bradycardia effects of acute VL-PAG DBS were associated with an increase in baroreflex sensitivity, however in these cases, the beneficial blood pressure effect was generally considered to be a secondary response to relief of chronic pain.

In the inventors' experience, and consistent with spontaneous hypertensive murine studies in which VL-PAG is stereoscopically targeted, stimulation of VL-PAG by itself was insufficient to elicit a sustained hypertensive response. Of the 5 patients who had received hypertensive therapy, 2 had no relief. Careful examination of the implanted lead position and trajectory revealed that the non-responder's trajectory did not pass along the lateral reins and posterior commissures, but rather was 5mm to 7mm forward (see figure 13). The distal electrodes of both chronic non-responders were located at VL-PAG and both showed an acute response, possibly associated with an impact and swelling extending to the lateral reins and posterior commissures, leading to a loss of response after remission.

Vascular dementia

Damage to the cerebral blood vessels can be caused by a number of diseases, including hypertension, heart disease, high cholesterol and diabetes. Vascular dementia can be caused by events occurring in the cerebral vessels, firstly stroke, and secondly small vessel disease. Vascular dementia caused by stroke is classified as either a single infarction or multiple infarctions and depends on whether it is caused by one or multiple strokes. Small vascular disease is caused by damage to blood vessels located in subcortical, deep and periventricular white matter, as well as blood vessels in the central gray matter (including thalamus and basal ganglia) lacunae. Small vessel disease will occur without any cognitive impairment and with varying degrees of cognitive impairment ranging from mild cognitive impairment to dementia.

There are a number of experimental data that suggest that vascular dementia is caused by small vessel disease, which is often continuous rather than progressive. In a study of patients with vascular dementia, a 4.5MMSE point reduction was found each year. Vascular dementia is associated with increased mortality, especially in the case of white matter lesions and lacunar stroke. The presence of white matter lesions in patients with lacunar stroke is also a predictive factor for functional disability. Further studies on patients with dementia associated with small vessel disease and mild cognitive impairment showed that survival was 70% after 2.6 years and 50% after 4.3 years; patients dropped 3.9 points on the shortened MMSE scale. (Bennet H P and Corbeta A J in 2002) subcortical vascular disease and functional decline (subclinical vascular disease and functional decline) A six year prospective study, Journal of the American Society of aged medical sciences, 50 th, 1969 to 1977, Mild cognitive impairment of subcortical vascular characteristics in Frison G B et al, clinical features and results (Mild cognitive impairment with subcortical vascular characteristics and clinical records), Ballard C et al, cognitive impairment and dementia in 2001 and lean body, vascular dementia and Alzheimer's disease progression (the cognitive impairment of vascular dementia and Alzheimer's disease, Journal of the world, 3 to 14316 th, Journal of the Society of senile medical sciences and clinical findings), Journal of clinical diagnosis and clinical findings, and Alzheimer's disease progression (Journal of clinical findings, 2 to 14316).

In the North Bristol NHS Trust foundation (North Bristol NHS Trust), two patients with post-stroke pain due to hypertension were implanted with deep brain stimulation leads. Patient 1 had a prior history of up to 6 TIAs, eventually leading to more severe right internal capsule, ventral lateral thalamus and islet lobe damage; and Medtronic 3387 leads (4mm x 1.5mm contacts, 1.5mm apart) implanted in VL-PAG. In a further examination, the inventors found that the proximal contact was located near the posterior commissure and the lateral reins and extended into the dorsal-medial nucleus of the thalamus. Under stimulation, the patient only achieved a pain response lasting three months, however his blood pressure remained controllable within two years (Patel et al, Neurology, 2011).

Patient 2 had as many as 10 stroke episodes resulting in hospitalization. He implanted Boston scientific 8 contact lead (8 mm. times.1.5 mm contact, 0.5mm apart) at the dorsal medial nucleus, lateral reins, and posterior commissure of the thalamus. With low frequency stimulation across VL-PAG, LH and PC and high frequency stimulation across DMN, both pain and blood pressure in patient 2 were controlled.

Patient 1 and patient 2 did not have a recurrence of stroke events after 12 and 5 years of surgery. Patient 1 received implantation of bilateral dorsal anterior cingulate cortical leads in 2011 due to failure of pain control; on the surgical plan he had the pre-existing lead removed and magnetic resonance imaging performed, which, in contrast to the 2006 image, precluded the development of any small vessel disease, white matter lesions and lacunar stroke. Patient 2 also exhibited stability to the 5 year stimulated neuropsychiatric test after stimulation and implantation, and did not exhibit significant degradation after brief stimulation cessation.

Epilepsy

Seizures are caused by hypersynchronization and uncontrolled cortical neuro-electroencephalogram activity, accounting for about 1% of the world's population, and can be controlled by drugs in only about 70% of cases. In the remaining 30% of cases, surgical treatment is necessary and neuromodulation techniques are becoming emerging treatment options, particularly when their effect is reversible, unlike invasive techniques, while they are able to alter brain activity in a controlled manner.

Bilateral thalamic pronuclear high-frequency deep brain electrical stimulation has been shown to gradually reduce the frequency and severity of seizures, especially in generalized tonic clonic seizures without the target of surgical treatment. This has been shown in a portion of the SANTE and MORE studies conducted by Medtronic Inc. In patients with partial and secondary generalized epilepsy, which is refractory to medication, nuclei can reduce seizures by more than 70% within 7 years before bilateral stimulation (SANTE test).

In both cases where the deep brain stimulation system is implanted for hypertension, both patients have a long-standing history of associated seizures. The deep brain stimulation system was implanted with VL-PAG across the right medial thalamus. Low frequency stimulation across the periabdominal grey matter, periventricular grey matter, posterior commissure, and the reins, combined with high frequency stimulation of the parafascial and dorsolateral thalamic nuclei (along the top extent of the lead), both patients had fully remitted epileptic activity. As shown by CT perfusion, a cerebral blood flow study performed in the second patient found a 39.5% increase in cerebral blood flow, a 16.7% increase in cerebral blood volume, and a 12.5% decrease in mean transit time.

Cerebral vasoconstriction and a decrease in cerebral blood flow are considered to be prodromal events of seizures or seizure activity, and studies have found that cerebral blood flow is generally increased after a seizure in the intended recovery of cerebral blood flow; seizure hypotension is well recognized in epileptic patients, is a cause of cardiovascular failure, and may lead to sudden epileptic death (SUDEP), which is noted to be more common during the night, consistent with the loss of circadian rhythm common in chronic hypertension.

DBS, which extends the electrode span from the anterior thalamic nucleus down to the periabdominal grey matter around the lateral aqueduct, is implanted by trans-ventricular track and avoids properly the vasculature collision. The contact extending from the anterior nucleus of the thalamus crosses the dorsal medial nucleus of the thalamus, the paradenal nucleus of the thalamus adjacent to the lateral reins, the periventricular gray adjacent to the posterior commissure, and into the periventral aqueduct gray.

Although the pre-thalamic nucleus has been identified for the treatment of generalized epilepsy, it is also effective to stimulate the bilateral central mesencephalon-parafascial nucleus. Stimulation of periaqueductal gray matter has been shown in animal models to eliminate cortical rhythm dyssynchrony and to contribute to brain rhythm stabilization and seizure control as an auxiliary candidate.

Brain glioma disease

Iodine-123 labeled hydroxy-iodo-propyl-diamine (HIPDM) is a diffusible indicator with an extraction fraction of 85% to 90% and stable in the brain for more than 2 hours, and HIPDM distribution has been shown to occur in proportion to local cerebral blood flow by SPECT (single photon emission computed tomography) scanning. In the distribution of the artery ligation in the middle brain, accumulation of HIPDM and calculated cerebral blood flow decreased in agreement with the distribution of cerebral infarction. Interestingly, patients with glioma disease have been shown to have reduced accumulation of HIPDM due to reduced cerebral blood flow in the tumor area, and are also associated with peripheral areas where vasogenic edema is present, and within the overlying gray matter.

Enhancing cerebral blood flow may help fight the pathology through the body's own immune system and fight this diffuse disease by enhancing chemotherapy and immunotherapy by enhancing immunoglobulins and leukocytes. Thus, the neurostimulation techniques described herein can be used to enhance cerebral blood flow to treat brain glioma disorders.

Psychosis, depression and schizophrenia

Reins dysfunction is associated with psychosis, including depression, schizophrenia, and drug-induced psychosis (Sandyk, 1991-Scheibel, 1997). In the depressed mouse model, the local glucose metabolism of the lateral reins is more stable than any other brain region (Caldecott-Hazard et al, 1988). Due to the precursor substance of plasma tryptophan (5-hydroxytryptamine (5-HT), transient depressive relapses in volunteers are associated with an associated increase in the dorsal activity of the reins and midribs, because of the increased rate of depressed mood (Morris et al, 1999).

In chronic schizophrenia patients, reins calcification occurs at a higher frequency than in age-matched controls (Sandyk, 1992; Caputo et al, 1998). Influenza viruses, which if previously experienced increased the risk of schizophrenia, selectively damage the reins upon entry into the brain via the olfactory bulb (Mori et al, 1999). Refractory schizophrenia remains an unsolved major clinical problem, with 10% to 30% of patients not responding to standard treatment regimens. Similarly, in Southmead hospital, a 70 year old was diagnosed with late psychosis two years ago and now diagnosed as central lymphoma affecting reins.

The inventors have found that high amplitude low frequency stimulation of the reins of a patient results in enhanced auditory and visual illusions. The latter was associated with a 58 year old female who developed trigeminal anesthesia pain after surgery and received right deep brain stimulation leads implanted in the periabdominal grey matter and parafascial nuclei of the lateral aqueduct in 2010 (age 49). Stimulation of the peri-thalamic ventral portion of the aqueduct, combined with high frequency stimulation of the medial thalamus (dorsal medial nucleus), has resulted in confusion between thinking and conversation long since 2012 to 2017, with auditory and sometimes visual hallucinations. Stimulation was stopped for 4 days, with complete relief from confusion and hallucinations, and severe exacerbation of pain. Reprogramming (amplitude reduction) with stimulation of the left medial thalamus, combined with high frequency stimulation of the proximal ventral lateral PAG lead across the lateral reins, resulted in complete relief of the visual illusion and reduced confusion and auditory illusion by 50%, while her facial pain was maintained at the level as previously controlled. Thus, the combination of high frequency stimulation of DMN's with low frequency stimulation of VL-PAG's leads to cognitive impairment and hallucinations, possibly as a result of inhibition of lateral reins. The combination of high frequency stimulation of DMN with low frequency stimulation of LH leads to an improvement of cognitive disorders and psychosis. Further amplitude reduction within the DMN results in cumulative improvement in cognitive and psychiatric disorders, while reducing pain control. Combining high frequency stimulation of DMN with low frequency stimulation spanning from LH to VL-PAG can optimize pain, mood, cognitive and psychiatric control.

Renal failure

Consistent with dorsal PAG causing a fight or escape response and VL-PAG causing a freeze response, stimulation of dorsal PAG can result in a significant reduction in Glomerular Filtration Rate (GFR), sustained action may trigger acute renal failure, while stimulation of VL-PAG improves GFR and helps alleviate acute renal failure.

The inventors have found that when combining low frequency stimulation into VL-PAG across the lateral reins with high frequency stimulation of DMN and/or DACC, the gradual normalization of GFR can be affected and prevented from worsening; this may be the result of autonomous imbalance reversal. This therefore facilitates the use of stimulation to treat renal failure, especially in pre-dialysis patients, and this combined mode of stimulation can be used to minimize the process, potentially promote healing, and prevent the need for dialysis.

Automatic regulation of cerebral blood flow

Automatic regulation of cerebral blood flow is the ability of the brain to maintain a relatively constant blood flow under varying perfusion pressures. Autoregulation exists in many vascular beds, but develops particularly well in the brain, probably because of the need for a continuous blood supply and water homeostasis. In normotensive adults, cerebral perfusion pressures range from 60mmHg (millimeters of mercury) to 160mmHg, and cerebral blood flow is maintained at around 50 milliliters per minute per 100 grams of brain tissue. Above or below this limit autoregulation function is lost and cerebral blood flow depends in a linear fashion on mean arterial pressure. Cerebral ischemia ensues when the cerebral perfusion pressure falls below the lower limit of autoregulation. The reduction in cerebral blood flow can be compensated by increasing the oxygen extracted from the blood.

The purpose of brain autoregulation is to stabilize blood flow to the brain when perfusion pressure changes, thereby protecting the brain from the risk of systemic hypotension and hypertension. This important mechanism is severely impaired in transgenic mouse models of alzheimer's disease that produce large amounts of β -amyloid β peptides 1 to 42. Experiments have shown that total Cerebral Blood Flow in Alzheimer's Disease is 20% lower in Alzheimer's patients compared to age-matched non-dementia controls (Roher a E et al, Cerebral Blood Flow in Alzheimer's Disease, Vascular Health and Risk Management), 2012, volume 8, pages 599 to 611. The presence of small vessel disease, lacunar infarction and stroke may contribute to the pathogenesis of dementia or exacerbate the clinical course of alzheimer's disease, clearly indicating that insufficient cerebral blood flow is one of the global pathogenesis of cognitive decline. In the elderly, chronic hypoperfusion due to low cardiac output is associated with high white matter signaling and abnormal brain aging. In alzheimer's disease, the systolic and pulse pressures of the patient are reduced. Ideally, the reduction in blood flow in the brain needs to be compensated by an increase in cardiac output which raises systolic blood pressure to maintain adequate brain perfusion, however, in chronic progressive disease, hypotension changes.

Cerebrovascular disease and alzheimer's disease in the elderly may have a variety of causal relationships. The relationship between thromboembolic and multiple infarcts or vascular dementia and alzheimer's disease has been recognized. The destruction of the pia mater arteries and the smooth muscle cells of the internal arteries of cerebral amyloid angiopathy patients may not only lead to cerebral hemorrhage, but also may have an effect on cerebral blood flow and autoregulation. Cerebral amyloid angiopathy prevents the discharge of interstitial fluid and peptides (such as soluble amyloid beta (Abeta)) from the brain; therefore, strategies that promote Abeta drainage along perivascular pathways may be of great benefit to future therapeutic interventions in alzheimer's patients. In particular, measures to increase cerebral blood flow, combined with drugs and molecules to enhance fibrinolysis and Abeta solubility, may be very beneficial for the treatment of alzheimer's disease.

In the elderly with normal cognition, white matter high signals (WMD) are widely recognized as markers of cerebrovascular and Small Vascular Disease (SVD). SVD is caused by exposure to systemic vascular injury processes associated with vascular risk factors such as hypertension, high cholesterol and diabetes. However, brain amyloid accumulation is also prevalent in this population and is associated with the development of WMH. It can be seen that higher amyloid burden and history of hypertension are independently associated with larger WMH volumes.

In patients with severe cerebral artery disease, autoregulation may or may not be impaired; in addition, autoregulation may be partially or completely lost, with alzheimer's disease, vascular dementia, multiple small vessel disease or infarction of the brain, progressive multiple sclerosis, traumatic encephalopathy and vasospastic disease following subarachnoid hemorrhage.

In subjects with minimal perceptual state, arterial spin labeling has identified a global decrease in serum blood flow, and a selective decrease in serum blood flow in the medial prefrontal and prefrontal cortical areas and in the gray matter (Liu et al, Neurology, 2011, vol 77, stage 16, pages 1518-1523).

The neurostimulation techniques described herein may be used to enhance and regulate cerebral blood flow, to treat diseases associated with autoregulation disorders, or to reduce cerebral blood flow. In particular, by using one or more physiological parameters of the subject (e.g., cerebral blood flow, intracranial pressure, blood pressure, etc.) as feedback for controlling the neural stimulation, the cerebral blood flow of the subject can be precisely regulated and controlled.

Diseases that register a reduction in cerebral blood flow and dysregulation include antihypertensive, ischemic stroke, hemorrhagic stroke, traumatic brain injury, vasospasm, subarachnoid hemorrhage, minimal consciousness state, vascular dementia, alzheimer's disease, multiple sclerosis, depression, schizophrenia, and migraine with aura.

Autonomous spiritMenstrual dysfunction

Diseases associated with autonomic dysfunction include alcoholism, amyloidosis, cerebral infarction, diabetes mellitus, Huntington's disease, multiple sclerosis, multiple system atrophy, Parkinson's disease, Alzheimer's disease, toxic neuropathy, brain tumors.

Among diseases associated with autonomic nerve dysfunction, there is autonomic nerve dysfunction or imbalance having increased sympathetic nerve activity and decreased parasympathetic nerve activity. Deep brain stimulation, through properly prescribed combined neural stimulation of targets in the brain, can reverse this imbalance and restore normal autonomic function, which is essential for enhancing cerebral blood flow, reestablishing circadian rhythms, and treating disease.

Circadian rhythm and sleep:

many characteristics of human behavior and their underlying molecular biochemical processes are driven by circadian rhythms. Disturbances of circadian rhythms are increasingly associated with many clinical conditions and include metabolic syndrome and obesity, premature aging, diabetes, immunodeficiency, cardiac arrhythmias, cardiovascular disease, hypertension and cancer. Sleep and circadian rhythm disturbances are common features of alzheimer's disease, dementia and other neurodegenerative diseases, as well as psychiatric disorders such as schizophrenia, depression, and the like.

Emerging data suggest that restatement of circadian rhythms, sleep and biological horology will prove to be of great importance in the treatment of disease states. There is good evidence that sleep function is critical for memory consolidation and it is increasingly indicated that it also requires effective removal of waste products from the brain via the cerebral glycerol and lymphatic system and is of great interest in the treatment of alzheimer's disease, dementia and other neurodegenerative diseases.

Brain coherence and synchronization:

given that "communicating via coherence" is widely accepted today, anatomical communication may become effective or inefficient due to the presence or absence of rhythm synchronization, respectively. It is known that communication between selective brain structures, as well as oscillatory activity in these structures, can interfere with neurological disorders (e.g., epilepsy), neurodegenerative disorders (e.g., alzheimer's disease), and psychiatric disorders (e.g., schizophrenia) disorders. There is a great deal of evidence that the coupling between the phase of slow oscillations (especially in the theta frequency range of 4Hz to 12 Hz) and the amplitude of fast oscillations (gamma in the range of 30Hz to 100Hz) involves information processing, and that such disruption of theta and gamma rhythm coherence is observed in disease.

Clause and subclause

The invention is described in the following clauses:

1. a method of performing therapy on a subject's brain, said method comprising the step of applying one or more neuromodulation signals to lateral reins and posterior commissures.

2. The method of clause 1, further comprising: applying one or more neuromodulation signals to one or more additional targets in the brain of the subject.

3. The method of clause 2, wherein the one or more additional targets comprise the thalamocortical nucleus.

4. The method of clause 3, wherein a first neuromodulation signal having a first frequency is applied to the dorsal medial nucleus and one or more second neuromodulation signals are applied to the lateral reins and the posterior commissures, wherein each of the one or more second neuromodulation signals has a lower frequency than the first frequency.

5. The method of clause 4, wherein the first frequency is greater than 70Hz and each of the one or more second neuromodulation signals has a frequency of 4Hz to 50 Hz.

6. The method of clause 2-5, wherein the one or more additional targets comprise an extraabdominal periaqueduct grey matter VL-PAG.

7. The method of clause 6 depending from clause 4 or 5, wherein said one or more second neuromodulation signals are applied to said lateral reins, said posterior commissures, and said VL-PAG.

8. The method of any of the preceding clauses further comprising:

identifying a trajectory in the brain of said subject, said trajectory connecting said dorsal-medial nucleus and said VL-PAG through said lateral reins and said posterior commissures; and

implanting an electrode lead into the brain of the subject along the identified trajectory, the electrode lead comprising a plurality of electrodes for applying the one or more neuromodulation signals.

9. The method of clause 8, wherein the trajectory is such that the spacing between the electrode lead and the lateral reins is less than 5mm, and/or the spacing between the electrode lead and the posterior commissure is less than 5 mm.

10. The method of any of the preceding clauses further comprising: neuromodulation signals are applied to the anterior cingulate cortex and/or the corpus callosum.

11. The method of clause 10 depending from clause 8 or 9, wherein the trace further passes adjacent to the dorsal anterior cingulate cortex and the electrode lead comprises an electrode arranged to apply the neuromodulation signal to the dorsal anterior cingulate cortex; and/or the trajectory further passes through an adjacent corpus callosum, and the electrode lead comprises electrodes arranged to apply neuromodulation signals to the corpus callosum.

12. The method of clause 10 depending from clause 8 or 9, further comprising: implanting a second electrode lead into the brain of the subject, the second electrode lead comprising electrodes arranged to apply neuromodulation signals to the anterior cingulate cortex and/or the corpus callosum.

13. The method of any of the preceding clauses further comprising: detecting a physiological parameter of the subject, and adjusting at least one of the one or more neuromodulation signals based on the detected physiological parameter.

14. The method of any of the preceding clauses further comprising: adjusting at least one of the one or more neuromodulation signals based on the circadian rhythm of the subject.

15. The method of any of the preceding clauses further comprising: applying a stimulation signal to a carotid body and/or carotid baroreceptors of the subject.

16. The method of any of the preceding clauses, wherein the method is used to treat one or more of hypertension, traumatic brain injury, cerebral vasospasm, cerebral infarction, brain tumor, brain glioma, parkinson's disease, alzheimer's disease, vascular dementia, amyotrophic lateral sclerosis, huntington's disease, multiple system atrophy, multiple sclerosis, addiction, depression, schizophrenia, obesity, renal failure, epilepsy, and attention deficit hyperactivity disorder.

17. An apparatus for performing therapy on a brain of a subject, the apparatus comprising: an electrode lead arranged to be inserted into the brain of the subject, a distal portion of the electrode lead having a plurality of electrodes arranged to apply one or more neuromodulation signals to the lateral reins and posterior commissures of the brain of the subject; and

a controller configured to generate the one or more neuromodulation signals applied by the plurality of electrodes.

18. The apparatus of clause 17, wherein the plurality of electrodes are further arranged to apply one or more neuromodulation signals to one or more additional targets in the brain of the subject.

19. The device of clause 18, wherein the one or more additional targets comprise the thalamocortical nucleus.

20. The apparatus of clause 18 or 19, wherein the one or more additional targets comprise VL-PAGs.

21. The apparatus of any of clauses 17-20, wherein the plurality of electrodes are evenly spaced apart in a longitudinal direction along a length of the distal portion of the electrode lead.

22. The apparatus of clause 21, wherein the plurality of electrodes span a length of 20mm to 25 mm.

23. The device of any of clauses 17 to 22, further comprising a proximal electrode arranged to apply a neuromodulation signal to the anterior dorsal cingulate and/or the corpus callosum.

24. The apparatus of clause 23, wherein the proximal electrode comprises a proximal electrode disposed on the electrode lead.

25. The apparatus of clause 24, wherein the length of the proximal electrode disposed on the electrode lead is greater than the length of each of the plurality of electrodes.

26. The device of clause 25, wherein the proximal electrode disposed on the electrode lead has a length of 10mm to 30 mm.

27. The apparatus of any of clauses 17-26, further comprising a catheter for insertion into the brain of the subject, the catheter comprising a hollow tube defining a longitudinal channel in which the electrode lead may be received.

28. The device of clause 27 depending from any of clauses 24 to 26, wherein the catheter comprises a window formed in a sidewall of the hollow tube, the window arranged to expose the proximal electrode disposed on the electrode lead to the exterior of the hollow tube when the electrode lead is received in the longitudinal channel of the hollow tube.

29. The apparatus of clause 28, wherein the window has a length that is shorter than a length of the proximal electrode disposed on the electrode lead.

30. The apparatus of clause 28 or 29, wherein the conduit comprises indicia for indicating a direction in which the window faces.

31. The device of any of clauses 28-30, wherein the window comprises two or more apertures in a sidewall of the hollow tube.

32. The device according to clause 27 depending from any of clauses 24 to 26, wherein the proximal electrode comprises an outer electrode located at the outer surface of the hollow tube and arranged for electrical connection with a proximal electrode provided on the electrode lead when the electrode lead is received in the longitudinal channel of the hollow tube.

33. The device of clause 27 depending from clause 23, wherein the proximal electrode comprises an outer electrode at the outer surface of the hollow tube, the outer electrode being electrically connected with the controller via a connecting wire extending through the hollow tube.

34. The apparatus of any of clauses 27 to 33, wherein the catheter further comprises a cap that can be secured to an aperture in the skull of the subject, the cap comprising a passageway through which the hollow tube is insertable to insert the hollow tube into the brain of the subject.

35. The device of clause 34, further comprising a first limiter secured to a proximal end portion of the hollow tube, the first limiter being arranged to abut the cap when a predetermined length of the hollow tube is inserted through the channel.

36. The device of any of clauses 27-35, further comprising a second limiter secured to a proximal portion of the electrode lead and arranged to abut a proximal end of the catheter when a predetermined length of the electrode lead protrudes from the distal opening of the hollow tube.

37. The apparatus of any of clauses 17-36, further comprising a sensor configured to detect a physiological parameter of the subject and generate an output signal related to the detected physiological parameter, wherein the controller is configured to adjust at least one of the one or more neuromodulation signals based on the output signal from the sensor.

38. The apparatus of any of clauses 17 to 37, further comprising an external power source, wherein the external power source comprises a transmitter for wirelessly transmitting power to the controller.

39. The device of clause 38, further comprising a wearable cover configured to hold the transmitter in proximity to the controller.

40. The device of any of clauses 17-39, further comprising one or more stimulation electrodes for applying one or more stimulation signals to the subject's carotid body and/or carotid baroreceptors.

41. The apparatus of clause 40, wherein the controller is further configured to generate the stimulation signal.

42. A catheter for insertion into the brain of a subject, the catheter comprising a hollow tube defining a longitudinal channel in which an electrode lead can be housed;

wherein the catheter comprises a window formed in a side wall of the hollow tube and arranged to expose a proximal electrode on the electrode lead to the exterior of the hollow tube when the electrode lead is received in the longitudinal channel of the hollow tube.

43. The catheter of clause 42, wherein the catheter includes indicia for indicating a direction in which the window faces.

44. The catheter of clauses 42 or 43, wherein the window comprises two or more apertures in the sidewall of the hollow tube.

45. A catheter for insertion into the brain of a subject, the catheter comprising a hollow tube defining a longitudinal channel in which an electrode lead can be housed;

wherein the catheter comprises an external electrode on the outer surface of the hollow tube.

46. The catheter of clause 45, further comprising a connecting lead extending through the hollow tube for connecting the outer electrode to a controller.

47. The catheter of clause 45, wherein the outer electrode is configured for electrical connection with a proximal electrode on the electrode lead when the electrode lead is received in the longitudinal channel of the hollow tube.

48. The catheter of any of clauses 42-47, further comprising a cap that is capable of being secured to an aperture in the skull of the subject, and the cap comprises a passageway through which the hollow tube is insertable to insert the hollow tube into the brain of the subject.

49. The catheter of clause 48, further comprising a first limiter secured to a proximal end portion of the hollow tube, the first limiter being arranged to abut the cap when a predetermined length of the hollow tube is inserted through the channel.

50. A method of performing therapy on a subject, the method comprising:

applying one or more neuromodulation signals to one or more targets in the brain of the subject; and

applying a stimulation signal to a carotid body and/or carotid baroreceptors in the subject.

51. A system, comprising:

means for applying one or more neuromodulation signals to one or more targets in the brain of the subject; and

a stimulation electrode for applying a stimulation signal to a carotid body and/or a carotid baroreceptor in the subject.