Focal cooling: An alternative treatment for drug-resistant epilepsy in a mesial temporal lobe epilepsy primate model-A preliminary study.

OBJECTIVE: Focal cooling is emerging as a relevant therapy for drug-resistant epilepsy (DRE). However, we lack data on its effectiveness in controlling seizures that originate in deep-seated areas like the hippocampus. We present a thermoelectric solution for focal brain cooling that specifically targets these brain structures. METHODS: A prototype implantable device was developed, including temperature sensors and a cannula for penicillin injection to create an epileptogenic zone (EZ) near the cooling tip in a non-human primate model of epilepsy. The mesial temporal lobe was targeted with repeated penicillin injections into the hippocampus. Signals were recorded from an sEEG (Stereoelectroencephalography) lead placed 2 mm from the EZ. Once the number of seizures had stabilized, focal cooling was applied, and temperature and electroclinical events were monitored using a customized detection algorithm. Tests were performed on two Macaca fascicularis monkeys at three temperatures. RESULTS: Hippocampal seizures were observed 40-120 min post-injection, their duration and frequency stabilized at around 120 min. Compared to the control condition, a reduction in the number of hippocampal seizures was observed with cooling to 21°C (Control: 4.34 seizures, SD 1.704 per 20 min vs Cooling to 21°C: 1.38 seizures, SD 1.004 per 20 min). The effect was more pronounced with cooling to 17°C, resulting in an almost 80% reduction in seizure frequency. Seizure duration and number of interictal discharges were unchanged following focal cooling. After several months of repeated penicillin injections, hippocampal sclerosis was observed, similar to that recorded in humans. In addition, seizures were identified by detecting temperature variations of 0.3°C in the EZ correlated with the start of the seizures. SIGNIFICANCE: In epilepsy therapy, the ultimate aim is total seizure control with minimal side effects. Focal cooling of the EZ could offer an alternative to surgery and to existing neuromodulation devices.

Long-term stability of the chronic epidural wireless recorder WIMAGINE in tetraplegic patients.

Objective.The evaluation of the long-term stability of ElectroCorticoGram (ECoG) signals is an important scientific question as new implantable recording devices can be used for medical purposes such as Brain-Computer Interface (BCI) or brain monitoring.Approach.The long-term clinical validation of wireless implantable multi-channel acquisition system for generic interface with neurons (WIMAGINE), a wireless 64-channel epidural ECoG recorder was investigated. The WIMAGINE device was implanted in two quadriplegic patients within the context of a BCI protocol. This study focused on the ECoG signal stability in two patients bilaterally implanted in June 2017 (P1) and in November 2019 (P2).Methods. The ECoG signal was recorded at rest prior to each BCI session resulting in a 32 month and in a 14 month follow-up for P1 and P2 respectively. State-of-the-art signal evaluation metrics such as root mean square (RMS), the band power (BP), the signal to noise ratio (SNR), the effective bandwidth (EBW) and the spectral edge frequency (SEF) were used to evaluate stability of signal over the implantation time course. The time-frequency maps obtained from task-related motor activations were also studied to investigate the long-term selectivity of the electrodes.Mainresults.Based on temporal linear regressions, we report a limited decrease of the signal average level (RMS), spectral distribution (BP) and SNR, and a remarkable steadiness of the EBW and SEF. Time-frequency maps obtained during motor imagery, showed a high level of discrimination 1 month after surgery and also after 2 years.Conclusions.The WIMAGINE epidural device showed high stability over time. The signal evaluation metrics of two quadriplegic patients during 32 months and 14 months respectively provide strong evidence that this wireless implant is well-suited for long-term ECoG recording.Significance.These findings are relevant for the future of implantable BCIs, and could benefit other patients with spinal cord injury, amyotrophic lateral sclerosis, neuromuscular diseases or drug-resistant epilepsy.

An exoskeleton controlled by an epidural wireless brain-machine interface in a tetraplegic patient: a proof-of-concept demonstration.

BACKGROUND: Approximately 20% of traumatic cervical spinal cord injuries result in tetraplegia. Neuroprosthetics are being developed to manage this condition and thus improve the lives of patients. We aimed to test the feasibility of a semi-invasive technique that uses brain signals to drive an exoskeleton. METHODS: We recruited two participants at Clinatec research centre, associated with Grenoble University Hospital, Grenoble, France, into our ongoing clinical trial. Inclusion criteria were age 18-45 years, stability of neurological deficits, a need for additional mobility expressed by the patient, ambulatory or hospitalised monitoring, registration in the French social security system, and signed informed consent. The exclusion criteria were previous brain surgery, anticoagulant treatments, neuropsychological sequelae, depression, substance dependence or misuse, and contraindications to magnetoencephalography (MEG), EEG, or MRI. One participant was excluded because of a technical problem with the implants. The remaining participant was a 28-year-old man, who had tetraplegia following a C4-C5 spinal cord injury. Two bilateral wireless epidural recorders, each with 64 electrodes, were implanted over the upper limb sensorimotor areas of the brain. Epidural electrocorticographic (ECoG) signals were processed online by an adaptive decoding algorithm to send commands to effectors (virtual avatar or exoskeleton). Throughout the 24 months of the study, the patient did various mental tasks to progressively increase the number of degrees of freedom. FINDINGS: Between June 12, 2017, and July 21, 2019, the patient cortically controlled a programme that simulated walking and made bimanual, multi-joint, upper-limb movements with eight degrees of freedom during various reach-and-touch tasks and wrist rotations, using a virtual avatar at home (64·0% [SD 5·1] success) or an exoskeleton in the laboratory (70·9% [11·6] success). Compared with microelectrodes, epidural ECoG is semi-invasive and has similar efficiency. The decoding models were reusable for up to approximately 7 weeks without recalibration. INTERPRETATION: These results showed long-term (24-month) activation of a four-limb neuroprosthetic exoskeleton by a complete brain-machine interface system using continuous, online epidural ECoG to decode brain activity in a tetraplegic patient. Up to eight degrees of freedom could be simultaneously controlled using a unique model, which was reusable without recalibration for up to about 7 weeks. FUNDING: French Atomic Energy Commission, French Ministry of Health, Edmond J Safra Philanthropic Foundation, Fondation Motrice, Fondation Nanosciences, Institut Carnot, Fonds de Dotation Clinatec.

A novel neural prosthesis providing long-term electrocorticography recording and cortical stimulation for epilepsy and brain-computer interface.

OBJECTIVE: Wireless technology is a novel tool for the transmission of cortical signals. Wireless electrocorticography (ECoG) aims to improve the safety and diagnostic gain of procedures requiring invasive localization of seizure foci and also to provide long-term recording of brain activity for brain-computer interfaces (BCIs). However, no wireless devices aimed at these clinical applications are currently available. The authors present the application of a fully implantable and externally rechargeable neural prosthesis providing wireless ECoG recording and direct cortical stimulation (DCS). Prolonged wireless ECoG monitoring was tested in nonhuman primates by using a custom-made device (the ECoG implantable wireless 16-electrode [ECOGIW-16E] device) containing a 16-contact subdural grid. This is a preliminary step toward large-scale, long-term wireless ECoG recording in humans. METHODS: The authors implanted the ECOGIW-16E device over the left sensorimotor cortex of a nonhuman primate (Macaca fascicularis), recording ECoG signals over a time span of 6 months. Daily electrode impedances were measured, aiming to maintain the impedance values below a threshold of 100 KΩ. Brain mapping was obtained through wireless cortical stimulation at fixed intervals (1, 3, and 6 months). After 6 months, the device was removed. The authors analyzed cortical tissues by using conventional histological and immunohistological investigation to assess whether there was evidence of damage after the long-term implantation of the grid. RESULTS: The implant was well tolerated; no neurological or behavioral consequences were reported in the monkey, which resumed his normal activities within a few hours of the procedure. The signal quality of wireless ECoG remained excellent over the 6-month observation period. Impedance values remained well below the threshold value; the average impedance per contact remains approximately 40 KΩ. Wireless cortical stimulation induced movements of the upper and lower limbs, and elicited fine movements of the digits as well. After the monkey was euthanized, the grid was found to be encapsulated by a newly formed dural sheet. The grid removal was performed easily, and no direct adhesions of the grid to the cortex were found. Conventional histological studies showed no cortical damage in the brain region covered by the grid, except for a single microscopic spot of cortical necrosis (not visible to the naked eye) in a region that had undergone repeated procedures of electrical stimulation. Immunohistological studies of the cortex underlying the grid showed a mild inflammatory process. CONCLUSIONS: This preliminary experience in a nonhuman primate shows that a wireless neuroprosthesis, with related long-term ECoG recording (up to 6 months) and multiple DCSs, was tolerated without sequelae. The authors predict that epilepsy surgery could realize great benefit from this novel prosthesis, providing an extended time span for ECoG recording.

Intracranial application of near-infrared light in a hemi-parkinsonian rat model: the impact on behavior and cell survival.

OBJECT The authors of this study used a newly developed intracranial optical fiber device to deliver near-infrared light (NIr) to the midbrain of 6-hydroxydopamine (6-OHDA)-lesioned rats, a model of Parkinson's disease. The authors explored whether NIr had any impact on apomorphine-induced turning behavior and whether it was neuroprotective. METHODS Two NIr powers (333 nW and 0.16 mW), modes of delivery (pulse and continuous), and total doses (634 mJ and 304 J) were tested, together with the feasibility of a midbrain implant site, one considered for later use in primates. Following a striatal 6-OHDA injection, the NIr optical fiber device was implanted surgically into the midline midbrain area of Wistar rats. Animals were tested for apomorphine-induced rotations, and then, 23 days later, their brains were aldehyde fixed for routine immunohistochemical analysis. RESULTS The results showed that there was no evidence of tissue toxicity by NIr in the midbrain. After 6-OHDA lesion, regardless of mode of delivery or total dose, NIr reduced apomorphine-induced rotations at the stronger, but not at the weaker, power. The authors found that neuroprotection, as assessed by tyrosine hydroxylase expression in midbrain dopaminergic cells, could account for some, but not all, of the observed behavioral improvements; the groups that were associated with fewer rotations did not all necessarily have a greater number of surviving cells. There may have been other "symptomatic" elements contributing to behavioral improvements in these rats. CONCLUSIONS In summary, when delivered at the appropriate power, delivery mode, and dosage, NIr treatment provided both improved behavior and neuroprotection in 6-OHDA-lesioned rats.

810nm near-infrared light offers neuroprotection and improves locomotor activity in MPTP-treated mice.

We explored whether 810nm near-infrared light (NIr) offered neuroprotection and/or improvement in locomotor activity in an acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mouse model of Parkinson's disease. Mice received MPTP and 810nm NIr treatments, or not, and were tested for locomotive activity in an open-field test. Thereafter, brains were aldehyde-fixed and processed for tyrosine hydroxylase immunohistochemistry. Our results showed that MPTP-treated mice that were irradiated with 810nm NIr had both greater locomotor activity (∼40%) and number of dopaminergic cells (∼20%) than those that were not. In summary, 810nm (as with 670nm) NIr offered neuroprotection and improved locomotor activity in MPTP-treated mice.