阅读说明：本技术 放置在床边处用于临时记录颅内eeg的成组设备的系统和方法 (System and method for a cluster device placed at the bedside for temporary recording of intracranial EEG ) 是由 艾伦·瓦兹瑞 罗纳德·埃默森 于 2020-03-29 设计创作，主要内容包括：本发明涵盖这样的系统和方法,其允许脑电图领域中的未培训的临床医生在床边处插入和功能化成组颅内电极阵列,通过特定的设计这些成组颅内电极阵列将接地和参考电极定位在电“安静”的位置,以记录持久、高保真的皮质内EEG。(The present invention encompasses systems and methods that allow untrained clinicians in the electroencephalogram field to insert and functionalize at the bedside into groups of intracranial electrode arrays that by specific design position the ground and reference electrodes in electrically "quiet" locations to record a durable, high fidelity, intra-cortical EEG.)

1. An intracranial electroencephalogram (EEG) apparatus, comprising:

a ground electrode;

a reference electrode; and

a cortical recording array comprising at least one recording element,

wherein each of the ground electrode, reference electrode and cortical recording array is secured to a support structure, an

Wherein, when the device is properly implanted in a subject's brain, the ground element and the reference element are positioned in a non-gray matter anatomical space and the cortical recording array is positioned to measure brain activity within a gray matter brain space of a subject located in the cerebral cortex.

2. The apparatus of claim 1, wherein the cortical recording array comprises 1 to 10 recording elements.

3. The apparatus of claim 1 or 2, wherein when the non-gray matter anatomical space is selected from:

the inferior aponeurosis gap;

subcortical white matter space;

gaps in skull fixation devices; or

The ventricular space.

4. The device of any one of claims 1 to 3, wherein the reference electrode and the ground electrode are positioned in different non-gray matter anatomical spaces.

5. The apparatus of claim 4, wherein:

(a) the reference electrode is in the subcortical space and the ground electrode is in the subcortical white matter space; or

(b) The ground electrode is in the subcortical white matter space and the reference electrode is in the subcortical white matter space; or

(c) The reference electrode is in the subcalotte gap and the ground electrode is in the ventricular gap; or

(d) The ground electrode is in the subcalotte gap and the reference electrode is in the ventricular gap; or

(e) The reference electrode is within the gap of the cranial fixation device and the ground electrode is in the subcortical white matter gap; or

(f) The ground electrode is within the gap of the cranial fixation device and the reference electrode is in the subcortical white matter gap; or

(g) The reference electrode is within the gap of the skull fixation device and the ground electrode is in the ventricular gap; or

(h) The ground electrode is within the gap of the skull fixation device and the reference electrode is in the ventricular gap.

6. The apparatus of any one of claims 3 to 5, wherein when the ground electrode is positioned in the subcalotte gap, it is fixed to the support structure at a distance of between 1.5cm and 10cm distal to the topmost recording element of the cortical recording array.

7. The apparatus of any one of claims 3 to 5, wherein when the ground electrode is positioned in the subcalotte gap, it is fixed to the support structure at a distance of about 3.5cm distal to the most superficial recording elements of the cortical recording array.

8. The apparatus according to any one of claims 3 to 5, wherein when the reference electrode is positioned in the subcalotte gap it is fixed to the support structure at a distance of between 1.5cm and 10cm distal to the topmost recording element of the cortical recording array.

9. The apparatus of any one of claims 3 to 5, wherein the reference electrode is fixed to the support structure at a distance of about 3cm distal to a most superficial recording element of the cortical recording array when it is positioned in the subcalotte gap.

10. The device of any one of claims 3 to 5, wherein when the ground electrode is positioned in the subcortical white matter, it is fixed to the support structure at a distance between 1.0cm and 3.0cm proximal to a deepest recording element of the cortical recording array.

11. The device of any one of claims 3 to 5, wherein when the ground electrode is positioned in the subcortical white matter, it is fixed to the support structure at a distance of about 2cm proximal to a deepest recording element of the cortical recording array.

12. The device of any one of claims 3 to 5, wherein when the reference electrode is positioned in the subcortical white matter it is fixed to the support structure at a distance between 1.0cm and 3.0cm proximal to a deepest recording element of the cortical recording array.

13. The device of any one of claims 3 to 5, wherein when the reference electrode is positioned in the subcortical white matter, it is fixed to the support structure at a distance of about 1.5cm proximal to a deepest recording element of the cortical recording array.

14. The device of any of claims 3 to 5, wherein when the ground electrode is positioned in the skull fixation device it is fixed to the support structure at a distance of between 1.0cm and 3.0cm distal to the most superficial recording element of the cortical recording array and within the skull fixation device.

15. The device of any of claims 3 to 5, wherein when the ground electrode is positioned in the skull fixation device it is fixed to the support structure at a distance of about 2cm distal to the most superficial recording element of the cortical recording array and within the skull fixation device.

16. The device of any of claims 3 to 5, wherein when the reference electrode is positioned in the skull fixation device it is fixed to the support structure at a distance of between 1.0cm and 3.0cm distal to the most superficial recording element of the cortical recording array and located within the skull fixation device.

17. The device of any of claims 3 to 5, wherein when the reference electrode is positioned in the skull fixation device it is fixed to the support structure at a distance of about 1.5cm distal to the most superficial recording element of the cortical recording array and within the skull fixation device.

18. The device of any one of claims 14 to 17, wherein the reference electrode and/or the ground electrode are in contact with a conductive element on an inner cavity of the skull fixation device that is electrically continuous with a further electrically isolated conductive element in contact with the skull.

19. The device of any one of claims 3 to 5, wherein when the ground electrode is positioned in the ventricle, it is fixed to the support structure at a distance between 3.5cm and 5.5cm proximal to a deepest recording element of the cortical recording array.

20. The device of any one of claims 3 to 5, wherein when the ground electrode is positioned in the ventricle, it is fixed to the support structure at a distance of about 5.5cm proximal to a deepest recording element of the cortical recording array.

21. The device of any one of claims 3 to 5, wherein when the reference electrode is positioned in the ventricle, it is fixed to the support structure at a distance between 3.5cm and 5.5cm proximal to a deepest recording element of the cortical recording array.

22. The device of any one of claims 3 to 5, wherein when the reference electrode is positioned in the ventricle, it is fixed to the support structure at a distance of about 4cm proximal to a deepest recording element of the cortical recording array.

23. The apparatus of claims 1-22, wherein the apparatus further comprises a ventricular cerebrospinal fluid drainage function.

24. The apparatus of any one of claims 1 to 23, wherein the cortical recording array is positioned within or near a gray matter brain space of the cerebral cortex.

25. The apparatus of any one of claims 1 to 24, wherein the apparatus further comprises a physiological sensor capable of measuring intracranial pressure, oxygen concentration, glucose level, blood flow or tissue perfusion, tissue temperature, electrolyte concentration, tissue osmolarity, parameters related to brain function and/or health, or any combination thereof.

26. The apparatus of any one of claims 1 to 25, wherein the ground electrode, the reference electrode and/or the recording element are made of metal, organic compound or other conductive material.

27. The apparatus of any one of claims 1-26, wherein the support structure is made of plastic or a biocompatible material.

28. The apparatus of any one of claims 1 to 27, wherein the support structure is flexible or rigid.

29. The apparatus of any one of claims 1 to 28, wherein the recording element, the reference electrode and the ground electrode are arranged circumferentially around the support structure.

30. The apparatus of any one of claims 1 to 29, wherein the support structure is cylindrical.

31. Apparatus according to any one of claims 1 to 30, wherein the width of the recording element, the reference electrode and/or the ground electrode is between 0.5mm and 4.0 mm.

32. The device of any one of claims 1-31, wherein the device further comprises an interface connected to a processor capable of processing brain activity.

33. The device of claim 32, wherein brain activity is measured by at least one parameter selected from the group consisting of:

(a) an average voltage level;

(b) a root mean square (rms) voltage level and/or a peak voltage level;

(c) derivatives of a Fast Fourier Transform (FFT) involving the recorded brain activity, including spectrogram, spectral edge, peak, phase spectrogram, power or power ratio; also included are variations of the calculated power, such as average power level, rms power level, and/or peak power level;

(d) metrics derived from spectral analysis, such as power spectral analysis, bispectrum analysis, density, coherence, signal correlation, and convolution;

(e) metrics derived from signal modeling such as linear predictive modeling or automatic compression modeling;

(f) integrating the amplitude;

(g) peak envelope or amplitude peak envelope;

(h) a periodic evolution;

(i) the inhibition ratio;

(j) coherence and phase delay;

(k) wavelet transformation of the recorded electrical signals including spectrogram, spectral edge, peak, phase spectrogram, power or power ratio of the measured brain activity;

(l) Wavelet atoms;

(m) bispectrum analysis, autocorrelation analysis, cross-bispectrum analysis, or cross-correlation analysis;

(n) data derived from a neural network, a recurrent neural network, or a deep learning technique; or

(o) detecting an identification of one or more recording elements of a local minimum or maximum of the parameter derived from (a-n).

34. The device according to claim 33, wherein the brain activity is measured by a categorical metric of a value selected from volts (V), hertz (Hz) and/or derivatives and/or ratios thereof.

35. The device of any one of claims 32 to 34, wherein the processor is capable of processing, filtering, amplifying, digitally converting, comparing, storing, compressing, displaying, and/or otherwise transmitting the brain activity detected by the cortical recording array.

36. The device of any one of claims 32 to 35, wherein the processor comprises hardware and/or software that analyzes, manipulates, displays, correlates, stores, and/or otherwise communicates brain electrical activity.

37. The device of any one of claims 32 to 36, wherein for the selected electrode configuration, the processor identifies the ground electrode, the reference electrode, and the cortical recording array in an automated manner.

38. The device of claim 37, wherein the processor performs common mode rejection of EEG signals recorded by the selected electrode configuration using the ground electrode selected in an automated manner.

39. The device of any one of claims 37 to 38, wherein the processor uses the reference electrode selected in an automatic manner to generate a reference EEG recording based on brain electrical signals detected by the cortical recording array.

40. The system of any one of claims 37 to 39, wherein the processor is further capable of performing a mathematical derivation of reference EEG recordings from individual recording elements of the cortical recording array to generate a synthetic EEG data channel.

41. The apparatus of any one of claims 32 to 40, wherein:

the device, the interface, and the processor are integrated with one another;

the processor and the interface are integrated with each other; or

The device and the interface are integrated with each other.

42. The device of any one of claims 32 to 41, wherein the interface is a physical interface.

43. The device of any one of claims 32 to 41, wherein the interface is a wireless interface.

44. The device of any one of claims 32 to 43, wherein the interface is implanted within the patient.

45. The device of any one of claims 32 to 44, wherein the interface is capable of filtering, amplifying, digitally converting, compressing and/or transmitting brain activity detected by the cortical recording array.

Technical Field

The present invention encompasses systems and methods that allow untrained clinicians in the electroencephalogram field to insert and functionalize at the bedside into groups of intracranial electrode arrays that by specific design position the ground and reference electrodes in electrically "quiet" locations to record a durable, high fidelity, intra-cortical EEG.

Background

Electroencephalography (EEG) is a technique for detecting the endogenous electrical activity of the brain by measuring the change in voltage between pairs of recorded electrodes. This brain activity is primarily generated by neurons located in the gray matter of the cerebral cortex.

EEG is very useful for monitoring brain health in patients suffering from various disorders leading to abnormalities in endogenous brain electrical activity. In addition to central roles in detecting epileptic activity, EEG has also proven to be of significant use as a real-time physiological monitor in other environments where brain health may be at risk due to potentially reversible causes such as reduced blood flow, reduced oxygen, or elevated intracranial pressure. This condition is common in patients with acute brain injury who are managed in intensive care settings. Therefore, the ability to perform EEG in a reliable and reproducible manner in an emergency or intensive care setting is of great value in the clinical management of patients suffering from acute brain injury. However, traditional EEG is difficult to perform in many clinical settings due to a range of technical and practical challenges.

First, conventional EEG relies on the temporary fixation of metal electrodes on the patient's scalp. Such metal scalp-based electrodes generally impart poor signal-to-noise characteristics due to the natural limitations of the metal-skin electrical interface, low signal amplitude of the electrical potentials recorded from the scalp due to distance from the cerebral cortex, presence of intervening tissues (e.g., skull, skin, etc.), and significant averaging effects of cortical-derived electrical signals, which collectively limit subsequent data interpretation.

Second, the application of long-term scalp arrays requires the availability of trained technicians skilled in the EEG field. This trained individual is particularly important in view of the technical requirements associated with processing the original brain-derived electrical signals into EEG signals. This process includes a hardware-based initial common-mode rejection of electrical artifacts using a ground electrode, and a subsequent step involving acquisition of a comparison signal from a recording electrode paired with a common reference electrode. The positioning and recording stability of the common reference and ground electrodes is central and critical to effective EEG recording-either poor signals (due to inaccurate electrical connections from the ground or reference electrodes to associated amplifier hardware, incorrect positioning of the ground and reference electrodes at specific points on the scalp, etc.) or discontinuous data (due to high impedance conditions between the metal electrodes and the skin, complete loss of electrode-to-skin contact, etc.) should be provided, the entire EEG recording may be considered spurious or uninterpretable. Thus, conventional scalp-based EEG requires a trained technician to place and maintain durable, high fidelity ground and reference electrodes.

Third, after placement of the conventional scalp electrodes, the wires associated with each electrode are individually connected to a specific input on the hardware amplifier element associated with the EEG recording system. If any of the electrode lines (especially those from a common ground or reference electrode) are incorrectly connected at an input on the hardware, EEG recording will be spurious, unexplainable or impossible.

Finally, conventional EEG software requires the user to specifically outline the "fit" of the electrodes in use (i.e. the particular anatomical "pattern" of electrodes spaced apart on the head) for a particular patient, requiring detailed knowledge of the connections between the ground electrode, reference electrode and recording electrode to obtain an accurate display of the recorded EEG. If any of the wired connections are incorrectly marked, the entire EEG recording may be interpreted in an incorrect or inappropriate manner, which poses a significant clinical risk.

For all of the aforementioned reasons, the performance of traditional EEG for brain monitoring in patients with severe nerve damage requires the continued availability of a trained technician for initial scalp electrode placement, connection of electrode wires to associated device hardware, assignment and connection of appropriate channels in the device hardware and software for a given electrode set-up, and subsequent maintenance of scalp electrodes.

However, it is vital that in the vast majority of clinical settings where patients suffering from nerve damage are treated, it is not practical or cost effective for trained technicians to be continuously available, which severely limits the use of EEG as a continuous monitoring tool in brain damage. Therefore, devices that allow untrained clinicians in the field to collect high fidelity EEG data simply, reproducibly, and reliably are of great value.

Patients with severe brain injury often experience insertion of monitoring or therapeutic devices into the skull and brain. Some such devices may detect physiological parameters such as pressure, tissue oxygen levels, blood flow rate, and the like. Other devices may function therapeutically by draining cerebrospinal fluid (CSF) to relieve intracranial pressure. More recently, devices designed to directly record EEG from the brain have been used for patients suffering from a range of brain injuries. Such devices that allow direct brain recordings have been shown to provide robust, durable, and high amplitude EEG data due to direct contact with "generators" of EEG signals (e.g., neurons present in the gray matter of the cerebral cortex). Notably, this method of using intracranial electrodes has previously used separate, independently connected scalp electrodes for reference and grounding in EEG recordings. However, since insertion of such devices into the brain typically occurs in an emergency environment outside of a formal operating room (such as an intensive care or emergency room), and is performed by an unskilled clinician in the EEG field, the ability to popularize such methods on a broad clinical basis is very limited.

Therefore, systems and methods that allow untrained clinicians in the EEG field to locate and functionalize electrode devices at the bedside for temporarily recording intracranial brain electrical activity are of significant value in the care of brain-injured patients.

Disclosure of Invention

According to a first aspect, there is provided an intracranial electroencephalographic (EEG) device comprising a ground electrode, a reference electrode, a cortical recording array comprising at least one recording element, wherein each of the ground electrode, reference electrode, and cortical recording array is fixed to a support structure, and wherein when the device is properly implanted in the brain of a subject, the ground electrode and reference electrode are positioned in a non-gray matter anatomical space, and the cortical recording array is positioned to measure brain activity within the gray matter cerebral space of the subject located in the cerebral cortex.

In one form, the cortical recording array includes 1 to 10 recording elements.

In one form, the non-gray matter anatomical space is selected from the group consisting of a sub-aponeurotic space (subcortical space), a sub-cortical white matter space (subcortical white matter space), a space within a cranial fixation device, or a ventricular space (ventricular space).

In one form, the reference electrode and the ground electrode are positioned in different non-gray matter anatomical spaces.

In one form, the reference electrode is in the subcortical space and the ground electrode is in the subcortical space, or the ground electrode is in the subcortical space and the reference electrode is in the subcortical space, or the reference electrode is in the subcortical space and the ground electrode is in the ventricular space, or the ground electrode is in the subcortical space and the reference electrode is in the ventricular space, or the reference electrode is in the skull fixation device space and the ground electrode is in the subcortical space, or the ground electrode is in the skull fixation device space and the reference electrode is in the subcortical space, or the reference electrode is in the skull fixation device space and the ground electrode is in the ventricular space, or the ground electrode is in the skull fixation device space and the reference electrode is in the ventricular space.

In one form, when the ground electrode is positioned in the sub-aponeurotic gap, it is fixed to the support structure at a distance between 1.5cm and 10cm distal to the topmost recording element of the cortical recording array.

In one form, when the ground electrode is positioned in the sub-tenon gap, it is fixed to the support structure at a distance of 3.5cm distal to the topmost recording element of the cortical recording array.

In one form, when the reference electrode is positioned in the sub-calotte gap, it is fixed to the support structure at a distance between 1.5cm and 10cm distal to the most superficial recording element of the cortical recording array.

In one form, when the reference electrode is positioned in the subcalotte gap, it is fixed to the support structure at a distance of 3.0cm distal to the topmost recording element of the cortical recording array.

In one form, when the ground electrode is positioned in subcortical white matter, it is fixed to the support structure at a distance between 1.0cm and 3.0cm proximal to the deepest recording element of the cortical recording array.

In one form, when the ground electrode is positioned in subcortical white matter, it is fixed to the support structure at a distance of 2.0cm proximal to the deepest recording element of the cortical recording array.

In one form, when the reference electrode is positioned in subcortical white matter, it is fixed to the support structure at a distance between 1.0cm and 3.0cm proximal to the deepest recording element of the cortical recording array.

In one form, when the reference electrode is positioned in subcortical white matter, it is fixed to the support structure at a distance of 1.5cm proximal to the deepest recording element of the cortical recording array.

In one form, when the ground electrode is positioned in the skull fixation device, it is fixed to the support structure at a distance between 1.0cm and 3.0cm distal to the most superficial recording element of the cortical recording array, and is located within the skull fixation device.

In one form, when the ground electrode is positioned in the skull fixation device, it is fixed to the support structure at a distance of 2.0cm distal to the most superficial recording element of the cortical recording array, and is located within the skull fixation device.

In one form, when the reference electrode is positioned in the skull fixation device, it is fixed to the support structure at a distance between 1.0cm and 3.0cm distal to the most superficial recording element of the cortical recording array, and is located within the skull fixation device.

In one form, when the reference electrode is positioned in the skull fixation device, it is fixed to the support structure at a distance of 1.5cm distal to the most superficial recording element of the cortical recording array, and is located within the skull fixation device.

In one form, the reference electrode and/or the ground electrode are in contact with a conductive element on the internal cavity of the skull fixation device that is electrically continuous with a further electrically isolated conductive element that is in contact with the skull.

In one form, when the ground electrode is positioned in the ventricle, it is fixed to the support structure at a distance between 3.5cm and 5.5cm proximal to the deepest recording element of the cortical recording array.

In one form, when the ground electrode is positioned in the ventricle, it is fixed to the support structure at a distance of 5.5cm proximal to the deepest recording element of the cortical recording array.

In one form, when the reference electrode is positioned in the ventricle, it is fixed to the support structure at a distance between 3.5cm and 5.5cm proximal to the deepest recording element of the cortical recording array.

In one form, when the reference electrode is positioned in the ventricle, it is fixed to the support structure at a distance of 4.0cm proximal to the deepest recording element of the cortical recording array.

In one form, the apparatus further comprises a ventricular cerebrospinal fluid drainage function.

In one form, the cortical recording array is positioned within or near the gray matter brain space of the cerebral cortex.

In one form, the device further comprises a physiological sensor capable of measuring intracranial pressure, oxygen concentration, glucose level, blood flow or tissue perfusion, tissue temperature, electrolyte concentration, tissue osmolarity, parameters related to brain function and/or health, or any combination thereof.

In one form, the ground electrode, reference electrode and/or recording element are made of metal, organic compound or other conductive material.

In one form, the support structure is made of plastic or a biocompatible material.

In one form, the support structure is flexible or rigid.

In one form, the recording element, the reference electrode and the ground electrode are arranged circumferentially around the support structure.

In one form, the support structure is cylindrical.

In one form the width of the recording element, reference electrode and/or ground electrode is between 0.5mm and 4.0 mm.

In one form, the device further comprises an interface connected to a processor capable of processing brain activity.

In one form, brain activity is measured by at least one parameter selected from the group consisting of:

(a) an average voltage level;

(b) a root mean square (rms) voltage level and/or a peak voltage level;

(c) derivatives of Fast Fourier Transform (FFT) involving recorded brain activity, including spectrogram, spectral edge, peak, phase spectrogram, power or power ratio; also included are variations of the calculated power, such as average power level, rms power level, and/or peak power level;

(d) metrics derived from spectral analysis, such as power spectral analysis, bispectrum analysis, density, coherence, signal correlation, and convolution;

(e) metrics derived from signal modeling such as linear predictive modeling or automatic compression modeling;

(f) integrating the amplitude;

(g) peak envelope or amplitude peak envelope;

(h) a periodic evolution;

(i) the inhibition ratio;

(j) coherence and phase delay;

(k) wavelet transformation of the recorded electrical signals including spectrogram, spectral edge, peak, phase spectrogram, power or power ratio of the measured brain activity;

(l) Wavelet atoms;

(m) bispectrum analysis, autocorrelation analysis, cross-bispectrum analysis, or cross-correlation analysis;

(n) data derived from a neural network, a recurrent neural network, or a deep learning technique; or (o) detecting the identity of the recording element(s) of the local minimum or maximum of the parameter derived from (a-n).

In one form, brain activity is measured by a categorical metric of a value selected from volts (V), hertz (Hz), and/or derivatives and/or ratios thereof.

In one form, the processor is capable of processing, filtering, amplifying, digitally converting, comparing, storing, compressing, displaying, and/or otherwise transmitting brain activity detected by the cortical recording array.

In one form, the processor includes hardware and/or software that analyzes, manipulates, displays, correlates, stores, and/or otherwise communicates brain electrical activity.

In one form, the processor identifies the ground electrode, the reference electrode, and the cortical recording array in an automated fashion for the selected electrode configuration.

In one form, the processor uses the ground electrode selected in an automatic manner to perform common mode rejection of EEG signals recorded by the selected electrode configuration.

In one form, a processor uses a reference electrode selected in an automated manner to generate a reference EEG recording based on brain electrical signals detected by a cortical recording array.

In one form, the processor may also perform mathematical derivation of reference EEG recordings from individual recording elements of the cortical recording array to generate a synthesized EEG data channel.

In one form, the device, the interface, and the processor are integrated with one another, the processor and the interface are integrated with one another, or the device and the interface are integrated with one another.

In one form, the interface is a physical interface.

In one form, the interface is a wireless interface.

In one form, the interface is implanted within the patient.

In one form, the interface is capable of filtering, amplifying, digitally converting, compressing and/or transmitting brain activity detected by the cortical recording array.

Drawings

Embodiments of the invention will be discussed with reference to the accompanying drawings, in which:

fig. 1 depicts an intracranial EEG device according to a first aspect;

fig. 2 depicts an intracranial EEG apparatus according to a second aspect;

fig. 3 depicts an intracranial EEG apparatus according to a third aspect;

fig. 4 depicts an intracranial EEG apparatus according to a fourth aspect;

figures 5 to 7 provide representative EEG data generated in an anaesthetised pig model using a series of electrode arrays with known inter-contact spacing;

fig. 8 depicts an intracranial EEG apparatus according to a fifth aspect; and

fig. 9 depicts an intracranial EEG apparatus according to a sixth aspect.

Detailed Description

As used herein, "reference electrode" refers to a contact (preferably also made of metal) designed to serve as a common member of a variable electrode pair as a control that allows comparison of brain activity detected by one or more recording elements on an implantable array. For example, a reference electrode may allow for comparison of brain activity detected by multiple recording elements.

As used herein, "ground electrode" refers to a recording element used to provide information about a globally recorded electrical signal derived from a non-physiological source (such as local electrical equipment) and thus allow for common mode rejection of such non-physiological signals.

As used herein, a "recording element" is a contact capable of detecting brain electrical activity.

As used herein, "sub-calophyllal space" refers to the anatomical compartment of the scalp that is located beneath the epidermis and the calophyllum (the fascia layer of the scalp) and the periosteum and bones of the skull. The cap-like inferior space is a naturally occurring avascular region that can be easily accessed and passed through using specialized tools without significant trauma, risk of bleeding, risk of intracranial infection or other major medical complications.

As used herein, "subcortical white matter space" refers to white matter located deep within the gray matter of the cerebral cortex within the cerebral hemisphere.

As used herein, "skull fixation device" refers to a hardware element designed to be implanted within or otherwise fixed to the skull that allows a separate hardware element (e.g., an electrode array) to pass through an opening in the skull and stabilize.

As used herein, "ventricular space" refers to an anatomical location within one of the cerebral cavities containing cerebrospinal fluid.

As used herein, "support structure" refers to (a) capable of housing a reference electrode, a ground electrode, and a recording element; (b) capable of transmitting electrical signals generated by the brain to an associated processor; and (c) a structure that can be inserted through the skin, optionally tunneled through the subtropical space of the cap, through a burr hole in the skull of the subject, and retained at least in part intracranially. The support structure may be designed as a separate piece of equipment that is tunneled through the sub-aponeurotic space and/or the skull, and/or the support structure itself may contain the necessary elements to allow independent passage.

As used herein, "circumferentially arranged" is defined as completely wrapped around the support structure such that geographically specific electrical signals (e.g., those originating only from one side of the array) may be recorded regardless of the rotational position of the array relative to the electrical signals. This therefore allows omni-directional recording with optimal tissue contact and/or eliminates the need for a specific orientation of the device.

As used herein, "proximal" and "distal" are used to refer to locations along the support structure where the proximal-most aspect of the device resides at the tip of the device within the brain (e.g., the deepest insertion point) and the distal-most aspect of the device resides at the farthest point from the tip of the device inserted into the brain (e.g., the end of the device that is not inserted into the brain).

As used herein, "deep" and "shallow" are used to describe the position of the device relative to the surface of the brain. For example, a "deeper" insertion refers to a location along the structure of the device that is inserted farther into the substance of the brain, while a "surface" refers to a location along the structure of the device that is farther from the tip of the device inserted within the brain.

Referring to fig. 1-4, four intracranial electroencephalographic (EEG) apparatuses 100, 200, 300, 400 for implantation in a subject's brain are shown. Each apparatus includes a ground element, a reference element, and a cortical recording array including at least one recording element, wherein each of the elements is fixed to a support structure.

When the device is properly implanted in the brain of a subject, the ground and reference elements are positioned in non-gray matter anatomical spaces and the cortical recording array is positioned to measure brain activity within the gray matter brain spaces of the subject located in the cerebral cortex.

The cortical recording array may include 1 to 10 recording elements organized and positioned at specific points along the length of the support structure to be placed within or in contact with the cerebral cortex to detect high amplitude brain electrical activity.

The ground and reference elements are placed at a specific distance from the recording elements along the support structure, which results in the ground and reference elements being positioned in non-gray matter, low amplitude tissue compartments (sometimes referred to as "quiet" areas) based on measured characteristics of the human brain and skull anatomy. As will be described in further detail below, these locations may be selected from the group consisting of the subaponeurotic space, the subcortical white matter space, the space within the cranial fixation device, or the ventricular space.

The device is connected, either with wires or wirelessly, to a hardware interface component that is preconfigured for known inputs from a particular electrode array. The hardware interface component is connected to a processor that allows the clinician to select a particular element configuration, whereby the processor then identifies the ground and reference elements for this particular device configuration in an automated manner.

Referring now to fig. 1, an intracranial EEG apparatus 100 according to a first aspect is shown. The device 100 is designed for placement through a burr hole 110 in the skull 120 and tunneled through the sub-calophyllum gap 130 and the scalp 140 at a distance from the insertion site. The cortical recording array 150 is located within the gray matter of the cerebral cortex 160, and the ground electrode 170 and the reference electrode 180 are positioned to reside in the sub-aponeurotic tissue compartment 130 (also known as the sub-aponeurotic space). The ground, reference and recording electrodes are connected to the hardware interface components by wires 190.

The ground electrode 170 may be secured to the support structure between 1.5cm and 10cm (and ideally 3.5cm) distal to the topmost recording element of the cortical recording array 150. The reference electrode 180 may be secured to the support structure between 1.5cm and 10cm (and ideally 3.0cm) distal to the topmost recording element of the cortical recording array 150.

With respect to the range of positioning of the ground or reference electrode within the sub-calotte gap (1.5 to 10.0cm distal to the most superficial contact in the cortical recording array), several anatomical measurements and practical applications specific to the claimed device were considered. Through clinical experience and measurements made by the inventors, the thickness of the human skull in the region of device insertion ranged from 1.0cm to 2.0 cm. By considering the device design and surgical procedures associated with device insertion, the device can tunnel through the sub-aponeurotic space and be brought out through the skin from the opening in the skull for device insertion, at a distance ranging from a minimum of 0.5cm to a maximum of 8.0 cm. Thus, in the case of the most "proximal" orientation position (i.e., 1.5cm) of the reference or ground contact, it is assumed that there is a minimum skull thickness of 1.0cm, and a distance of 0.5cm from the opening in the skull to the contact within the sub-calotte gap. With the most "distal" orientation position of the reference or ground contact (i.e., 10.0cm), it is assumed that there is a maximum skull thickness of 2.0cm and a distance of 8.0cm from the opening in the skull to the contact located within the sub-calophyllal gap.

Referring now to fig. 2, an intracranial EEG apparatus 200 according to a second aspect is shown. The device 200 is designed for placement through a burr hole 210 in the skull 220 and is tunneled out through the sub-calotte gap 230 and scalp 240 at a distance from the insertion site. Cortical recording array 250 is located within the gray matter of cerebral cortex 260, and ground electrode 270 and reference electrode 280 are positioned to reside in subcortical white matter compartment 290. The ground, reference and recording electrodes are connected to the hardware interface component by wires 295.

In this example, the ground electrode 270 may be secured to the support structure between 1cm and 3cm (and ideally 2cm) proximal to the deepest recording element of the cortical recording array 250. The reference electrode 280 may be fixed to the support structure between 1cm and 3cm (and ideally 1.5cm) proximal to the deepest recording element of the cortical recording array 250. The relative orientation of the reference electrode 280 with respect to the ground electrode 270 is not interdependent, but rather depends on the deepest recording element.

With respect to the range of positioning of the ground or reference electrode within the subcortical white matter compartment (1.0 to 3.0cm proximal to the deepest contact on the cortical recording array), several anatomical measurements specific to the claimed device and for optimized device function were considered. Through clinical experience and measurements made by the inventors, the border of subcortical white matter reliably begins approximately 1.0cm below the deep border of the gray matter of the cerebral cortex. The deep boundary of the subcortical white matter is located about 3.0cm from the deep boundary of the gray matter of the cerebral cortex and is limited by the CSF-containing lateral ventricles, since in some cases the lateral ventricles may be located within 3.5cm from the cortical surface. Thus, the most superficial white matter location of the reference or ground contact within the subcortical white matter may be located at 1.0cm from the deep boundary of the gray matter of the cerebral cortex, and the deepest white matter location of the reference or ground electrode may be located at 3.0cm from the deep boundary of the gray matter of the cerebral cortex.

Referring now to fig. 3, an intracranial EEG apparatus 300 according to a third aspect is shown. The device 300 is designed for placement through a skull fixation device 310 that passes through an opening in the skin 320 and is placed through a hole in the skull 330 and in direct contact with the bone of the skull 330. The cortical recording array 340 is located in the gray matter space of the cerebral cortex 350, and the ground electrode 360 and the reference electrode 370 are positioned within the cranial fixation device 310. The ground electrode 360 and reference electrode 370 are in contact with electrically isolated individual conductive elements 380 that make external individual electrical contact with the skull bone 330. The ground electrode, reference electrode and recording electrode are connected to the hardware interface component by wires 390.

In this configuration, the ground electrode 360 may be secured to the support structure between 1cm and 3cm (and ideally 2.0cm) distal to the topmost recording element of the cortical recording array 340. The reference electrode 370 may be secured to the support structure between 1cm and 3cm (and ideally 1.5cm) distal to the topmost recording element of the cortical recording array 340. Also, the relative orientations of the reference electrode 370 and the ground electrode 360 are not dependent on each other, but on the most superficial recording element.

With respect to the range of positioning of the ground or reference electrode within the cranial fixation device (1.0 to 3.0cm distal to the most superficial contact on the cortical recording array), several anatomical measurements and engineering aspects specific to the claimed device are considered. As mentioned above, the thickness of the human skull in the device insertion region ranges from 1.0cm to 2.0 cm. Furthermore, the typical height of the skull fixation device outside the associated opening of the skull is in the range from 1.0 to 3.0 cm. Given the requirements for the proposed device (which will produce electrical contacts on the internal cavity of the fixture that will interface with the reference or grounding element along the support structure of the claimed device), and assuming the necessary distance from the opening of the skull fixture on either side of the interface point, the minimum distance distal to the most superficial contact on the cortical recording array for the reference or grounding contact will be 1.0cm, and the maximum distance distal to the most superficial contact on the recording array for the reference or grounding contact will be 3.0 cm.

Referring now to fig. 4, an intracranial EEG apparatus 400 according to a fourth aspect is shown. The device 400 is designed for placement through a burr hole 410 in the skull 420 and tunneled out through the sub-calophyllum gap 430 and the scalp 440 at a distance from the insertion site. Cortical recording array 450 is located within the gray matter of cerebral cortex 460, and ground electrode 470 and reference electrode 480 are positioned to reside in ventricular compartment 490. The ground, reference and recording electrodes are connected to the hardware interface components by lines 495.

In this embodiment, the ground electrode 470 may be fixed to the support structure between 3.5cm and 5.5cm (and ideally 5.5cm) proximal to the deepest recording element of the cortical recording array 450. The reference electrode 480 may be fixed to the support structure between 3.5cm and 5.5cm (and ideally 4.0cm) proximal to the deepest recording element of the cortical recording array 450. As in the other embodiments, the relative positions of the reference electrode and the ground electrode depend on the position of the deepest recording element.

Referring now to fig. 8, an intracranial EEG apparatus 800 having a combined cerebrospinal fluid (CSF) drainage function 805 according to the fifth aspect is shown. The device 800 is hollow, has a central lumen designed for placement through a burr hole 810 in the skull 820, and is tunneled out through the sub-tenon gap 830 and the scalp 840 at a distance from the insertion site. The cortical recording array 850 is located within the gray matter of the cerebral cortex 860, and the reference electrode 870 and the ground electrode 880 are positioned to reside in the subgerminal gap 830. The ground, reference and recording electrodes are connected to an external hardware interface by wires 890.

In this embodiment, the ground electrode 880 may be secured to the support structure between 1.5cm and 10cm (and ideally 3.5cm) distal to the topmost recording element of the cortical recording array 850. The reference electrode 870 may be fixed to the support structure between 1.5cm and 10cm (and ideally 3cm) distal to the most superficial recording elements of the cortical recording array 150. A cerebrospinal fluid drainage function 805, consisting of a hole in the support structure for drainage through the hollow lumen of the device to an external collection system, is located at the deepest aspect of the support structure within the ventricle 895.

With respect to the range of positioning of the CSF-containing intracerebroventricular ground electrode and reference electrode (3.5 to 5.5cm distal to the deepest contact on the cortical recording array), several anatomical measurements involving elements for optimized device function and specific to the claimed device were considered. Through clinical experience and measurements made by the inventors, the boundaries of the lateral ventricles containing CSF range from a minimum of 3.0cm to a maximum of 4.0cm, with an average of 3.5cm from the deepest boundary of the gray matter of the cerebral cortex. The size of the lateral brain within which the intraventricular part of the device is located ranges from 1.5 to 2.5 cm. Thus, the range in which the reference or ground contact can be positioned along the support structure proximal to the cortical recording array will be 3.5 to 5.5cm, with the ideal iteration comprising a reference contact at 4.0cm proximal to the cortical recording array and a ground electrode at 5.5cm proximal to the cortical recording array.

The location of the recording element, ground electrode and reference electrode on the intracranial EEG device was determined by the inventors after placement of more than 50 individual electrodes in a human patient and confirmed using relevant experiments in a pig model. Considerations that are taken into account when determining the optimal location of the sensor on the intracranial EEG device include brain anatomy, observed patient-to-patient differences, and the type of data that is desired to be obtained from the intracranial EEG device.

It is to be understood that any of the above embodiments may further include a physiological sensor capable of measuring a parameter, such as intracranial pressure, oxygen concentration, glucose level, blood flow, tissue perfusion, tissue temperature, electrolyte concentration, tissue osmolarity, or any other parameter related to brain function and/or health.

According to a further aspect, there may be an intracranial EEG device, wherein the reference electrode and the ground electrode are positioned in different non-gray matter anatomical gaps, wherein the following configurations are possible:

a. the reference electrode is in the subcortical space and the ground electrode is in the subcortical white matter space; or

b. The ground electrode is in the subcortical space and the reference electrode is in the subcortical white matter space; or

c. The reference electrode is in the subcalotte gap and the ground electrode is in the ventricular gap; or

d. The ground electrode is in the subaponeurotic space and the reference electrode is in the ventricular space; or

e. The reference electrode is within the gap of the cranial fixation device and the ground electrode is in the subcortical white matter gap; or

f. The ground electrode is within the gap of the cranial fixation device and the reference electrode is in the subcortical white matter gap; or

g. The reference electrode is within the gap of the cranial fixation device and the ground electrode is in the ventricular gap; or

h. The ground electrode is within the gap of the skull fixation device and the reference electrode is in the ventricular gap.

Referring now to fig. 9, an intracranial EEG device 900 according to a sixth aspect is shown, wherein the ground and reference electrodes are located in different compartments. The device 900 is designed for placement through a burr hole 910 in the skull 920 and tunneled through the sub-calophyllal gap 930 and the scalp 940 at a distance from the insertion site. Cortical recording array 950 is located within the gray matter of cerebral cortex 960, and ground electrode 970 and reference electrode 980 are positioned to reside in subcutaneous tissue compartment 930 and white matter compartment 990, respectively. The ground, reference and recording electrodes are connected to the hardware interface component by wires 995.

The ground electrode 970 may be secured to the support structure between 1.5cm and 10cm (and desirably 3.5cm) distal to the topmost recording element of the cortical recording array 950. The reference electrode 980 may be fixed to the support structure between 1.0cm and 3.0cm (ideally 1.5cm) proximal to the cortical recording array 950 to be located within the white matter compartment 990.

Although the apparatus shown in the above embodiments features a cortical recording array positioned within the gray matter space of the cerebral cortex, it will be appreciated that the cortical recording array may also be positioned in direct contact with the gray matter surface of the cerebral cortex, as may be performed with an subdural electrode array.

It will be appreciated that the ground electrode, the reference electrode and/or the or each recording element may be made of a metal, an organic compound or any other suitable conductive material.

The support structure may be made of plastic or other suitable biocompatible material. The support structure may be flexible or rigid and may have a generally cylindrical form.

The or each recording element, reference electrode and ground electrode may be formed circumferentially around the support structure and may be between 0.5mm and 4mm in width.

All of the above devices will feature an interface for connection to a processor capable of processing brain activity measurable by a categorical metric of a value selected from volts (V), hertz (Hz) and/or derivatives and/or ratios thereof, wherein brain activity is measured by at least one parameter selected from:

a. an average voltage level;

b. a root mean square (rms) voltage level and/or a peak voltage level;

c. derivatives of Fast Fourier Transform (FFT) involving recorded brain activity, including spectrogram, spectral edge, peak, phase spectrogram, power or power ratio; also included are variations of the calculated power, such as average power level, rms power level, and/or peak power level;

d. metrics derived from spectral analysis, such as power spectral analysis, bispectrum analysis, density, coherence, signal correlation, and convolution;

e. metrics derived from signal modeling such as linear predictive modeling or automatic compression modeling;

f. integrating the amplitude;

g. peak envelope or amplitude peak envelope;

h. a periodic evolution;

i. the inhibition ratio;

j. coherence and phase delay;

k. wavelet transformation of the recorded electrical signals including spectrogram, spectral edge, peak, phase spectrogram, power or power ratio of the measured brain activity;

wavelet atoms;

bispectric analysis, autocorrelation analysis, cross-bispectric analysis, or cross-correlation analysis;

n. data derived from a neural network, a recurrent neural network, or a deep learning technique; or

Detecting the identity of the recording element(s) of the local minimum or maximum of the parameter derived from (a-n).

The processor may be capable of processing, filtering, amplifying, digitally converting, comparing, storing, compressing, displaying, and/or otherwise transmitting brain activity detected by the cortical recording array. The processor may include hardware and/or software to analyze, manipulate, display, associate, store, and/or otherwise communicate brain electrical activity. For the selected electrode configuration, the processor may identify the ground electrode, the reference electrode, and the cortical recording array in an automated manner. The processor may use the ground electrode selected in an automatic manner to perform common mode rejection on EEG signals recorded by the selected electrode configuration. The processor may use the automatically selected reference electrode to generate a reference EEG recording based on the brain electrical signals detected by the cortical recording array. The processor may also perform mathematical derivation of reference EEG recordings from individual recording elements of the cortical recording array to generate a synthesized EEG data channel.

In one form, the device, interface and processor may be integrated with each other. In another form the processor and the interface may be integrated with each other. In another form, the device and the interface may be integrated with each other. In one form, the interface may be a physical interface, and in another form it may be a wireless interface. In one form, the interface may be implanted in the subject. In one form, the interface may be capable of filtering, amplifying, digitally converting, compressing, and/or transmitting brain activity detected by the cortical recording array.

Referring now to fig. 5-7, these figures provide representative EEG data generated in a model of anesthetized pigs using a series of electrode arrays with known inter-contact spacing. After induction of general anesthesia, a borehole was formed in the right frontal lobe area and the recording electrode array (1.12mm contact, 2.2mm inter-contact spacing) was placed into the brain under direct vision until the last contact was just below the cortical surface. Notably, the measured variation in thickness of porcine and human cranium in this region ranged from 1.0cm to 2.0 cm. The measured variability in the distance from the cortical surface to the inner surface of the skull ranges from 0.5cm to 0.1cm in both porcine and human environments. The measured variability in thickness of cortical gray matter ranges from about 2.5mm to 5.0mm in both porcine and human systems.

In the experiment providing representative data for fig. 5, the distance from the cortical surface to the inner surface of the brain was measured to be at 0.5mm and the thickness of the skull was 1.5cm after placement of the recording electrode array. After insertion of the recording array, a separate electrode array (reference/ground array with 5mm inter-contact spacing) was tunneled laterally from the borehole through the subaponeurotic gap. This method brings the first contact on the reference/ground array (designated the reference electrode) 1.0cm from the borehole, resulting in a total distance of 3.0cm from the cortical surface, and the second contact (designated the ground electrode) 3.5cm from the cortical surface. Time on the x-axis is measured in seconds per bin. The contacts marked on the y-axis range from 1 (deepest) to 8 (shallowest) in the brain.

In the experiment providing representative data for fig. 6, after placement of the cortical recording array, a separate reference/ground electrode array (again with 5mm inter-contact spacing) was placed adjacent to the recording electrode array by a separate cortical method. Using the cortical thickness observed in the animals providing representative data, the deepest contact on the reference/ground array (designated the reference electrode) was located 2.0cm from the nearest contact on the recording array, and the last deep contact on the reference/ground array (designated the ground electrode) was located 1.5cm from the nearest contact on the recording array. Time on the x-axis is measured in seconds per bin. The contacts marked on the y-axis range from 1 (deepest) to 6 (shallowest) in the brain.

The data in fig. 7 represents a "synthetic" bipolar EEG trace mathematically generated from adjacent contacts recording reference EEG data in the experiment outlined in fig. 6. Time on the x-axis is measured in seconds per bin. The channels marked on the y-axis range from 1 (the deepest pair) to 5 (the shallowest pair) in the brain.

Throughout this specification and the claims which follow, unless the context requires otherwise, the words "comprise" and variations such as "comprises" and "comprising" will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment of any form of suggestion that such prior art forms part of the common general knowledge.

It will be appreciated by persons skilled in the art that the invention is not limited in its use to the particular applications described. The invention is also not limited to the preferred embodiments thereof with respect to the specific elements and/or features described or depicted herein. It should be understood that the invention is not limited to the embodiment(s) disclosed, but is capable of numerous rearrangements, modifications and substitutions without departing from the scope of the invention as set forth and defined by the following claims.

It is noted that the following claims are only provisional claims and are provided as examples of possible claims and are not intended to limit the scope of protection that may be claimed in any future patent application based on the present application. Integers may be added or omitted in the example claims at a later date to further define or redefine the invention.