Search

Mesial temporal lobe epilepsy (MTLE) is a syndromic disorder presenting with seizures and cognitive comorbidities. Although seizure etiology is increasingly understood, the pathophysiological mechanisms contributing to cognitive decline and epilepsy progression remain less recognized. We have previously shown that adult hippocampal neurogenesis dramatically declines in MTLE patients with increased disease duration. Here, we investigate when multiple cognitive domains become affected during epilepsy progression and how human neurogenesis levels contribute to it. We find that intelligence, verbal learning, and memory decline at a critical period of 20 years disease duration. In contrast to rodents, the number of human immature neurons positively associates with auditory verbal, rather than visuospatial, learning and memory. Moreover, this association does not apply to mature granule neurons. Our study provides cellular evidence of how adult neurogenesis corresponds with human cognition and signifies an opportunity to advance regenerative medicine for patients with MTLE and other cognitive disorders., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The hippocampus is crucial for forming new episodic memories. While the encoding of spatial and temporal information (where and when) in the hippocampus is well understood, the encoding of objects (what) remains less clear due to the high dimensions of object space. Rather than encoding each individual object separately, the hippocampus may instead encode categories of objects to reduce this dimensionality. In this study, we developed and applied a combined experimental-modeling approach to investigate how the hippocampus encodes visual memory categories in humans. We recorded spikes from hippocampal CA3 and CA1 neurons in 24 epilepsy patients performing a visual delayed match-to-sample (DMS) task involving five image categories. An ensemble multi-temporal-resolution classification model was employed to decode these visual memory categories from the hippocampal spiking activity with moderate numbers of trials. This model enables the identification of the spatio-temporal characteristics of hippocampal encoding through its interpretable representations. Using this model, we estimated the optimal temporal resolutions for decoding each visual memory category for each neuron in the ensemble. Results indicate that visual memory categories can be decoded from hippocampal spike patterns despite the short data length, supporting the presence of category-specific coding in the human hippocampus. We found that hippocampal neuron ensembles encode visual memory categories in a distributed manner, akin to a population code, while individual neurons use a temporal code. Additionally, CA3 and CA1 neurons exhibit similar and redundant information regarding visual memory categories, likely due to the strong and diffuse feedforward synaptic connections from the CA3 region to the CA1 region.

Objective: Here, we demonstrate the first successful use of static neural stimulation patterns for specific information content. These static patterns were derived by a model that was applied to a subject's own hippocampal spatiotemporal neural codes for memory., Approach: We constructed a new model of processes by which the hippocampus encodes specific memory items via spatiotemporal firing of neural ensembles that underlie the successful encoding of targeted content into short-term memory. A memory decoding model (MDM) of hippocampal CA3 and CA1 neural firing was computed which derives a stimulation pattern for CA1 and CA3 neurons to be applied during the encoding (sample) phase of a delayed match-to-sample (DMS) human short-term memory task., Main Results: MDM electrical stimulation delivered to the CA1 and CA3 locations in the hippocampus during the sample phase of DMS trials facilitated memory of images from the DMS task during a delayed recognition (DR) task that also included control images that were not from the DMS task. Across all subjects, the stimulated trials exhibited significant changes in performance in 22.4% of patient and category combinations. Changes in performance were a combination of both increased memory performance and decreased memory performance, with increases in performance occurring at almost 2 to 1 relative to decreases in performance. Across patients with impaired memory that received bilateral stimulation, significant changes in over 37.9% of patient and category combinations was seen with the changes in memory performance show a ratio of increased to decreased performance of over 4 to 1. Modification of memory performance was dependent on whether memory function was intact or impaired, and if stimulation was applied bilaterally or unilaterally, with nearly all increase in performance seen in subjects with impaired memory receiving bilateral stimulation., Significance: These results demonstrate that memory encoding in patients with impaired memory function can be facilitated for specific memory content, which offers a stimulation method for a future implantable neural prosthetic to improve human memory., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer SS declared a shared affiliation with the author XS to the handling editor at the time of review., (Copyright © 2024 Roeder, She, Dakos, Moore, Wicks, Witcher, Couture, Laxton, Clary, Popli, Liu, Lee, Heck, Nune, Gong, Shaw, Marmarelis, Berger, Deadwyler, Song and Hampson.)

Neurostimulation has diverse clinical applications and potential as a treatment for medically refractory movement disorders, epilepsy, and other neurological disorders. However, the parameters used to program electrodes-polarity, pulse width, amplitude, and frequency-and how they are adjusted have remained largely untouched since the 1970 s. This review summarizes the state-of-the-art in Deep Brain Stimulation (DBS) and highlights the need for further research to uncover the physiological mechanisms of neurostimulation. We focus on studies that reveal the potential for clinicians to use waveform parameters to selectively stimulate neural tissue for therapeutic benefit, while avoiding activating tissue associated with adverse effects. DBS uses cathodic monophasic rectangular pulses with passive recharging in clinical practice to treat neurological conditions such as Parkinson's Disease. However, research has shown that stimulation efficiency can be improved, and side effects reduced, through modulating parameters and adding novel waveform properties. These developments can prolong implantable pulse generator lifespan, reducing costs and surgery-associated risks. Waveform parameters can stimulate neurons based on axon orientation and intrinsic structural properties, providing clinicians with more precise targeting of neural pathways. These findings could expand the spectrum of diseases treatable with neuromodulation and improve patient outcomes., (Published by Elsevier B.V.)

Acute brain insults trigger diverse cellular and signaling responses and often precipitate epilepsy. The cellular, molecular and signaling events relevant to the emergence of the epileptic brain, however, remain poorly understood. These multiplex structural and functional alterations tend also to be opposing - some homeostatic and reparative while others disruptive; some associated with growth and proliferation while others, with cell death. To differentiate pathological from protective consequences, we compared seizure-induced changes in gene expression hours and days following kainic acid (KA)-induced status epilepticus (SE) in postnatal day (P) 30 and P15 rats by capitalizing on age-dependent differential physiologic responses to KA-SE; only mature rats, not immature rats, have been shown to develop spontaneous recurrent seizures after KA-SE. To correlate gene expression profiles in epileptic rats with epilepsy patients and demonstrate the clinical relevance of our findings, we performed gene analysis on four patient samples obtained from temporal lobectomy and compared to four control brains from NICHD Brain Bank. Pro-inflammatory gene expressions were at higher magnitudes and more sustained in P30. The inflammatory response was driven by the cytokines IL-1β, IL-6, and IL-18 in the acute period up to 72 h and by IL-18 in the subacute period through the 10-day time point. In addition, a panoply of other immune system genes was upregulated, including chemokines, glia markers and adhesion molecules. Genes associated with the mitogen activated protein kinase (MAPK) pathways comprised the largest functional group identified. Through the integration of multiple ontological databases, we analyzed genes belonging to 13 separate pathways linked to Classical MAPK ERK, as well as stress activated protein kinases (SAPKs) p38 and JNK. Interestingly, genes belonging to the Classical MAPK pathways were mostly transiently activated within the first 24 h, while genes in the SAPK pathways had divergent time courses of expression, showing sustained activation only in P30. Genes in P30 also had different regulatory functions than in P15: P30 animals showed marked increases in positive regulators of transcription, of signaling pathways as well as of MAPKKK cascades. Many of the same inflammation-related genes as in epileptic rats were significantly upregulated in human hippocampus, higher than in lateral temporal neocortex. They included glia-associated genes, cytokines, chemokines and adhesion molecules and MAPK pathway genes. Uniquely expressed in human hippocampus were adaptive immune system genes including immune receptors CDs and MHC II HLAs. In the brain, many immune molecules have additional roles in synaptic plasticity and the promotion of neurite outgrowth. We propose that persistent changes in inflammatory gene expression after SE leads not only to structural damage but also to aberrant synaptogenesis that may lead to epileptogenesis. Furthermore, the sustained pattern of inflammatory genes upregulated in the epileptic mature brain was distinct from that of the immature brain that show transient changes and are resistant to cell death and neuropathologic changes. Our data suggest that the epileptogenic process may be a result of failed cellular signaling mechanisms, where insults overwhelm the system beyond a homeostatic threshold., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Erisken, Nune, Chung, Kang and Koh.)

Rationale: Deep brain stimulation (DBS) of the hippocampus is proposed for enhancement of memory impaired by injury or disease. Many pre-clinical DBS paradigms can be addressed in epilepsy patients undergoing intracranial monitoring for seizure localization, since they already have electrodes implanted in brain areas of interest. Even though epilepsy is usually not a memory disorder targeted by DBS, the studies can nevertheless model other memory-impacting disorders, such as Traumatic Brain Injury (TBI)., Methods: Human patients undergoing Phase II invasive monitoring for intractable epilepsy were implanted with depth electrodes capable of recording neurophysiological signals. Subjects performed a delayed-match-to-sample (DMS) memory task while hippocampal ensembles from CA1 and CA3 cell layers were recorded to estimate a multi-input, multi-output (MIMO) model of CA3-to-CA1 neural encoding and a memory decoding model (MDM) to decode memory information from CA3 and CA1 neuronal signals. After model estimation, subjects again performed the DMS task while either MIMO-based or MDM-based patterned stimulation was delivered to CA1 electrode sites during the encoding phase of the DMS trials. Each subject was sorted ( post hoc ) by prior experience of repeated and/or mild-to-moderate brain injury (RMBI), TBI, or no history (control) and scored for percentage successful delayed recognition (DR) recall on stimulated vs. non-stimulated DMS trials. The subject's medical history was unknown to the experimenters until after individual subject memory retention results were scored., Results: When examined compared to control subjects, both TBI and RMBI subjects showed increased memory retention in response to both MIMO and MDM-based hippocampal stimulation. Furthermore, effects of stimulation were also greater in subjects who were evaluated as having pre-existing mild-to-moderate memory impairment., Conclusion: These results show that hippocampal stimulation for memory facilitation was more beneficial for subjects who had previously suffered a brain injury (other than epilepsy), compared to control (epilepsy) subjects who had not suffered a brain injury. This study demonstrates that the epilepsy/intracranial recording model can be extended to test the ability of DBS to restore memory function in subjects who previously suffered a brain injury other than epilepsy, and support further investigation into the beneficial effect of DBS in TBI patients., Competing Interests: RH discloses a current consulting and advisory relationship with Braingrade, Inc., a component of Engram (Holding), Inc., a Delaware C-Corporation. This relationship was not in effect at the time of the study. The remaining authors declare that the research was otherwise conducted in the absence of any other commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Roeder, Riley, She, Dakos, Robinson, Moore, Couture, Laxton, Popli, Clary, Sam, Heck, Nune, Lee, Liu, Shaw, Gong, Marmarelis, Berger, Deadwyler, Song and Hampson.)

Objective. This study aimed to characterize hippocampal neural signatures of uncertainty by measuring beta band power in the period prior to movement cue. Approach . Participants with epilepsy were implanted with hippocampal depth electrodes for stereo electroencephalographic (SEEG) monitoring. Hippocampal beta (13-30 Hz) power changes have been observed during motor tasks such as the direct reach (DR) and Go/No-Go (GNG) tasks. The primary difference between the tasks is the presence of uncertainty about whether movement should be executed. Previous research on cortical responses to uncertainty has found that baseline beta power changes with uncertainty. SEEG data were sampled throughout phases of the DR and GNG tasks. Beta-band power during the fixation phase was compared between the DR and GNG task using a Wilcoxon rank sum test. This unpaired test was also used to analyze response times from cue to task completion between tasks. Main results. Eight patients who performed both reaching tasks were analyzed in this study. Movement response times in the GNG task were on average 210 milliseconds slower than in the DR task. All patients exhibited a significantly increased response latency in the GNG task compared to the DR task (Wilcoxon rank-sum p-value < 0.001). Six out of eight patients demonstrated statistically significant differences in beta power in single hippocampal contacts between the fixation phases of the GNG and DR tasks. At the group level, baseline beta power was significantly lower in the GNG task than in the DR task (Wilcoxon rank-sum p-value < 0.001). Significance . This novel study found that, in the presence of task uncertainty, baseline beta power in the hippocampus is lower than in its absence. This finding implicates movement uncertainty as an important factor in baseline hippocampal beta power during movement preparation., (© 2022 IOP Publishing Ltd.)

The hippocampus is the most common seizure focus in people. In the hippocampus, aberrant neurogenesis plays a critical role in the initiation and progression of epilepsy in rodent models, but it is unknown whether this also holds true in humans. To address this question, we used immunofluorescence on control healthy hippocampus and surgical resections from mesial temporal lobe epilepsy (MTLE), plus neural stem-cell cultures and multi-electrode recordings of ex vivo hippocampal slices. We found that a longer duration of epilepsy is associated with a sharp decline in neuronal production and persistent numbers in astrogenesis. Further, immature neurons in MTLE are mostly inactive, and are not observed in cases with local epileptiform-like activity. However, immature astroglia are present in every MTLE case and their location and activity are dependent on epileptiform-like activity. Immature astroglia, rather than newborn neurons, therefore represent a potential target to continually modulate adult human neuronal hyperactivity., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objective . The human orbitofrontal cortex (OFC) is involved in automatic response inhibition and conflict processing, but the mechanism of frequency-specific power changes that control these functions is unknown. Theta and gamma activity have been independently observed in the OFC during conflict processing, while theta-gamma interactions in other brain areas have been noted primarily in studies of memory. Within the OFC, it is possible that theta-gamma phase amplitude coupling (PAC) drives conflict processing. This study aims to characterize the coupled relationship between theta and gamma frequency bands in the OFC during conflict processing using a modified Stroop task. Approach . Eight epilepsy patients implanted with OFC stereotactic electroencephalography electrodes participated in a color-word modified Stroop task. PAC between theta phase and gamma amplitude was assessed to determine the timing and magnitude of neural oscillatory changes. Group analysis was conducted using a non-parametric cluster-permutation t -test on coherence values. Main results. Theta-low gamma (LG) PAC significantly increased in five out of eight patients during successful trials of the incongruent condition compared with the congruent condition. Significant increases in theta-LG PAC were most prominent during cue processing 200-800 ms after cue presentation. On group analysis, trial-averaged mean theta-LG PAC was statistically significantly greater in the incongruent condition compared to the congruent condition ( p < 0.001, Cohen's d = 0.51). Significance. For the first time, we report that OFC theta phase and LG amplitude coupling increases during conflict resolution. Given the delayed onset after cue presentation, OFC theta-LG PAC may contribute to conflict processing after conflict detection and before motor response. This explanation follows the hypothesis that global theta waves modulate local gamma signals. Understanding this relationship within the OFC will help further elucidate the neural mechanisms of human conflict resolution., (© 2022 IOP Publishing Ltd.)

Introduction: The hippocampus is thought to be involved in movement, but its precise role in movement execution and inhibition has not been well studied. Previous work with direct neural recordings has found beta-band (13-30 Hz) modulation in both movement execution and inhibition throughout the motor system, but the role of beta-band modulation in the hippocampus during movement inhibition is not well understood. Here, we perform a Go/No-Go reaching task in ten patients with medically refractory epilepsy to study human hippocampal beta-power changes during movement., Materials and Methods: Ten epilepsy patients (5 female; ages 21-46) were implanted with intracranial depth electrodes for seizure monitoring and localization. Local field potentials were sampled at 2000 Hz during a Go/No-Go movement task. Comparison of beta-band power between Go and No-Go conditions was conducted using Wilcoxon signed-rank hypothesis testing for each patient. Sub-analyses were conducted to assess differences in the anterior vs posterior contacts, ipsilateral vs contralateral contacts, and male vs female beta-power values., Results: Eight out of ten patients showed significant beta-power decreases during the Go movement response (p < 0.05) compared to baseline. Eight out of ten patients also showed significant beta-power increases in the No-Go condition, occurring in the absence of movement. No significant differences were noted between ipsilateral vs contralateral contacts nor in anterior vs posterior hippocampal contacts. Female participants had a higher task success rate than males and had significantly greater beta-power increases in the No-Go condition (p < 0.001)., Conclusion: These findings indicate that increases in hippocampal beta power are associated with movement inhibition. To the best of our knowledge, this study is the first to report this phenomenon in the human hippocampus. The beta band may represent a state-change signal involved in motor processing. Future focus on the beta band in understanding human motor and impulse control will be vital., (Copyright © 2021 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

The amygdala is a medial temporal lobe structure known to be involved in processing emotional conflict. However, its role in processing non-emotional conflict is not well understood. Previous studies have utilized the Stroop Task to examine brain modulation of humans under the color-word conflict scenario, which is non-emotional conflict processing, and found hippocampal theta-band (4-7 Hz) modulation. This study aims to survey amygdaloid theta power changes during non-emotional conflict processing using intracranial depth electrodes in nine epileptic patients (3 female; age 20-62). All patients were asked to perform a modified Stroop task. During task performance, local field potential (LFP) data was recorded from macro contacts sampled at 2 K Hz and used for analysis. Mean theta power change from baseline was compared between the incongruent and congruent task condition groups using a paired sample t-test. Seven patients were available for analysis after artifact exclusion. In five out of seven patients, statistically significant increases in theta-band power from baseline were noted during the incongruent task condition (paired sample t-test p < 0.001), including one patient exhibiting theta power increases in both task conditions. Average response time was 1.07 s (failure trials) and 1.04 s (success trials). No speed-accuracy tradeoff was noted in this analysis. These findings indicate that human amygdaloid theta-band modulation may play a role in processing non-emotional conflict. It builds directly upon work suggesting that the amygdala processes emotional conflict and provides a neurophysiological mechanism for non-emotional conflict processing as well., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: Coherence between the hippocampus and other brain structures has been shown with the theta frequency (3-8 Hz). Cortical decreases in theta coherence are believed to reflect response accuracy efficiency. However, the role of theta coherence during conflict resolution is poorly understood in noncortical areas. In this study, coherence between the hippocampus and orbitofrontal cortex (OFC) was measured during a conflict resolution task. Although both brain areas have been previously implicated in the Stroop task, their interactions are not well understood., Methods: Nine patients were implanted with stereotactic electroencephalography contacts in the hippocampus and OFC. Local field potential data were sampled throughout discrete phases of a Stroop task. Coherence was calculated for hippocampal and OFC contact pairs, and coherence spectrograms were constructed for congruent and incongruent conditions. Coherence changes during cue processing were identified using a nonparametric cluster-permutation t test. Group analysis was conducted to compare overall theta coherence changes among conditions., Results: In 6 of 9 patients, decreased theta coherence was observed only during the incongruent condition (P < 0.05). Congruent theta coherence did not change from baseline. Group analysis showed lower theta coherence for the incongruent condition compared with the congruent condition (P < 0.05)., Conclusions: Theta coherence between the hippocampus and OFC decreased during conflict. This finding supports existing theories that theta coherence desynchronization contributes to improved response accuracy and processing efficiency during conflict resolution. The underlying theta coherence observed between the hippocampus and OFC during conflict may be distinct from its previously observed role in memory., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective . Identify the role of beta-band (13-30 Hz) power modulation in the human hippocampus during conflict processing. Approach . We investigated changes in the spectral power of the beta band (13-30 Hz) as measured by depth electrode leads in the hippocampus during a modified Stroop task in six patients with medically refractory epilepsy. Previous work done with direct electrophysiological recordings in humans has shown hippocampal theta-band (3-8 Hz) modulation during conflict processing. Local field potentials sampled at 2 k Hz were used for analysis and a non-parametric cluster-permutation t -test was used to identify the time period and frequency ranges of significant power change during cue processing (i.e. post-stimulus, pre-response). Main results . In five of the six patients, we observe a statistically significant increase in hippocampal beta-band power during successful conflict processing in the incongruent trial condition (cluster-based correction for multiple comparisons, p < 0.05). There was no significant beta-band power change observed during the cue-processing period of the congruent condition in the hippocampus of these patients. Significance . The beta-power changes during conflict processing represented here are consistent with previous studies suggesting that the hippocampus plays a role in conflict processing, but it is the first time that the beta band has been shown to be involved in humans with direct electrophysiological evidence. We propose that beta-band modulation plays a role in successful conflict detection and automatic response inhibition in the human hippocampus as studied during a conflict response task., (© 2020 IOP Publishing Ltd.)

Objective: Motor brain-computer interface (BCI) represents a new frontier in neurological surgery that could provide significant benefits for patients living with motor deficits. Both the primary motor cortex and posterior parietal cortex have successfully been used as a neural source for human motor BCI, leading to interest in exploring other brain areas involved in motor control. The amygdala is one area that has been shown to have functional connectivity to the motor system; however, its role in movement execution is not well studied. Gamma oscillations (30-200 Hz) are known to be prokinetic in the human cortex, but their role is poorly understood in subcortical structures. Here, the authors use direct electrophysiological recordings and the classic "center-out" direct-reach experiment to study amygdaloid gamma-band modulation in 8 patients with medically refractory epilepsy., Methods: The study population consisted of 8 epilepsy patients (2 men; age range 21-62 years) who underwent implantation of micro-macro depth electrodes for seizure localization and EEG monitoring. Data from the macro contacts sampled at 2000 Hz were used for analysis. The classic center-out direct-reach experiment was used, which consists of an intertrial interval phase, a fixation phase, and a response phase. The authors assessed the statistical significance of neural modulation by inspecting for nonoverlapping areas in the 95% confidence intervals of spectral power for the response and fixation phases., Results: In 5 of the 8 patients, power spectral analysis showed a statistically significant increase in power within regions of the gamma band during the response phase compared with the fixation phase. In these 5 patients, the 95% bootstrapped confidence intervals of trial-averaged power in contiguous frequencies of the gamma band during the response phase were above, and did not overlap with, the confidence intervals of trial-averaged power during the fixation phase., Conclusions: To the authors' knowledge, this is the first time that direct neural recordings have been used to show gamma-band modulation in the human amygdala during the execution of voluntary movement. This work indicates that gamma-band modulation in the amygdala could be a contributing source of neural signals for use in a motor BCI system.

Objective: Stimulation of the primary somatosensory cortex (S1) has been successful in evoking artificial somatosensation in both humans and animals, but much is unknown about the optimal stimulation parameters needed to generate robust percepts of somatosensation. In this study, the authors investigated frequency as an adjustable stimulation parameter for artificial somatosensation in a closed-loop brain-computer interface (BCI) system., Methods: Three epilepsy patients with subdural mini-electrocorticography grids over the hand area of S1 were asked to compare the percepts elicited with different stimulation frequencies. Amplitude, pulse width, and duration were held constant across all trials. In each trial, subjects experienced 2 stimuli and reported which they thought was given at a higher stimulation frequency. Two paradigms were used: first, 50 versus 100 Hz to establish the utility of comparing frequencies, and then 2, 5, 10, 20, 50, or 100 Hz were pseudorandomly compared., Results: As the magnitude of the stimulation frequency was increased, subjects described percepts that were "more intense" or "faster." Cumulatively, the participants achieved 98.0% accuracy when comparing stimulation at 50 and 100 Hz. In the second paradigm, the corresponding overall accuracy was 73.3%. If both tested frequencies were less than or equal to 10 Hz, accuracy was 41.7% and increased to 79.4% when one frequency was greater than 10 Hz (p = 0.01). When both stimulation frequencies were 20 Hz or less, accuracy was 40.7% compared with 91.7% when one frequency was greater than 20 Hz (p < 0.001). Accuracy was 85% in trials in which 50 Hz was the higher stimulation frequency. Therefore, the lower limit of detection occurred at 20 Hz, and accuracy decreased significantly when lower frequencies were tested. In trials testing 10 Hz versus 20 Hz, accuracy was 16.7% compared with 85.7% in trials testing 20 Hz versus 50 Hz (p < 0.05). Accuracy was greater than chance at frequency differences greater than or equal to 30 Hz., Conclusions: Frequencies greater than 20 Hz may be used as an adjustable parameter to elicit distinguishable percepts. These findings may be useful in informing the settings and the degrees of freedom achievable in future BCI systems.

Objectives: Describe changes in clinical seizure frequency and electrophysiological data recorded in patients with medically-intractable seizures and periventricular nodular heterotopias (PVNH) treated with the RNS® System (NeuroPace, Inc., Mountain View, CA)., Methods: Clinical seizures from eight patients (mean follow-up of 10.1 years) were analyzed pre- and post-treatment. Chronic ambulatory electrocorticograms (ECoGs) recorded from PVNHs, hippocampus and neocortex were evaluated to identify the earliest electrographic seizure onset type, pattern of spread, and interictal characteristics., Results: Mean reduction in disabling seizures was 85.7 % (n = 8); seven patients had >50% seizure reduction and two were seizure-free in the final year of analysis. Seizure rate showed a progressive reduction over the course of the study with the highest rate of improvement in the first two to three years after implantation. Four of seven patients with one PVNH lead and a second lead in the hippocampus or neocortex had some electrographic seizures first recorded at either lead location, suggesting two foci or seizure propagation patterns. Low voltage fast type activity was the prominent seizure onset pattern. Interictal ECoG power was lower in PVNH than hippocampus., Conclusions: RNS® System treatment substantially reduced clinical seizure frequency in patients with PVNH. Analysis of ictal ECoG records suggests PVNH may be involved in seizure generation., Significance: Chronic ECoG recordings suggest PVNH tissue can actively participate in epileptogenic networks. Direct brain-responsive neurostimulation is a safe and effective treatment option in such patients, progressively reducing seizure rate over a period of years., (Copyright © 2019 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Previous work in directional tuning for brain machine interfaces has primarily relied on algorithm sorted neuronal action potentials in primary motor cortex. However, local field potential has been utilized to show directional tuning in macaque studies, and inferior parietal cortex has shown increased neuronal activity in reaching tasks that relied on MRI imaging. In this study we utilized local field potential recordings from a human subject performing a delayed reach task and show that high frequency band (76-100 Hz) spectral power is directionally tuned to different reaching target locations during an active reach. We also show that during the delay phase of the task, directional tuning is present in areas of the inferior parietal cortex, in particular, the supramarginal gyrus., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Somatosensory feedback is the next step in brain computer interface (BCI). Here, we compare three cortical stimulating array modalities for generating somatosensory percepts in BCI. We compared human subjects with either a 64-channel "mini"-electrocorticography grid (mECoG; 1.2-mm diameter exposed contacts with 3-mm spacing, N = 1) over the hand area of primary somatosensory cortex (S1), or a standard grid (sECoG; 1.5-mm diameter exposed contacts with 1-cm spacing, N = 1), to generate artificial somatosensation through direct electrical cortical stimulation. Finally, we reference data in the literature from a patient implanted with microelectrode arrays (MEA) placed in the S1 hand area. We compare stimulation results to assess coverage and specificity of the artificial percepts in the hand. Using the mECoG array, hand mapping revealed coverage of 41.7% of the hand area versus 100% for the sECoG array, and 18.8% for the MEA. On average, stimulation of a single electrode corresponded to sensation reported in 4.42 boxes (range 1-11 boxes) for the mECoG array, 19.11 boxes (range 4-48 boxes) for the sECoG grid, and 2.3 boxes (range 1-5 boxes) for the MEA. Sensation in any box, on average, corresponded to stimulation from 2.65 electrodes (range 1-5 electrodes) for the mECoG grid, 3.58 electrodes for the sECoG grid (range 2-4 electrodes), and 11.22 electrodes (range 2-17 electrodes) for the MEA. Based on these findings, we conclude that mECoG grids provide an excellent balance between spatial cortical coverage of the hand area of S1 and high-density resolution., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: Restoration of somatosensory deficits in humans requires a clear understanding of the neural representations of percepts. To characterize the cortical response to naturalistic somatosensation, we examined field potentials in the primary somatosensory cortex of humans., Methods: Four patients with intractable epilepsy were implanted with subdural electrocorticography (ECoG) electrodes over the hand area of S1. Three types of stimuli were applied, soft-repetitive touch, light touch, and deep touch. Power in the alpha (8-15 Hz), beta (15-30 Hz), low-gamma (30-50 Hz), and high-gamma (50-125 Hz) frequency bands were evaluated for significance., Results: Seventy-seven percent of electrodes over the hand area of somatosensory cortex exhibited changes in these bands. High-gamma band power increased for all stimuli, with concurrent alpha and beta band power decreases. Earlier activity was seen in these bands in deep touch and light touch compared to soft touch., Conclusions: These findings are consistent with prior literature and suggest a widespread response to focal touch, and a different encoding of deeper pressure touch than soft touch.

Closed-loop brain-responsive neurostimulation via the RNS System is a treatment option for adults with medically refractory focal epilepsy. Using a novel technique, 2 RNS Systems (2 neurostimulators and 4 leads) were successfully implanted in a single patient with bilateral parietal epileptogenic zones. In patients with multiple epileptogenic zones, this technique allows for additional treatment options. Implantation can be done successfully, without telemetry interference, using proper surgical planning and neurostimulator positioning.Trajectories for the depth leads were planned using neuronavigation with CT and MR imaging. Stereotactic frames were used for coordinate targeting. Each neurostimulator was positioned with maximal spacing to avoid telemetry interference while minimizing patient discomfort. A separate J-shaped incision was used for each neurostimulator to allow for compartmentalization in case of infection. In order to minimize surgical time and risk of infection, the neurostimulators were implanted in 2 separate surgeries, approximately 3 weeks apart.The neurostimulators and leads were successfully implanted without adverse surgical outcomes. The patient recovered uneventfully, and the early therapy settings over several months resulted in preliminary decreases in aura and seizure frequency. Stimulation by one of the neurostimulators did not result in stimulation artifacts detected by the contralateral neurostimulator.

Opinion Statement: Neuromodulation devices are used in the treatment of medically refractory epilepsy. This has been defined as epilepsy with persistent seizures despite adequate trials of at least two anti-epileptic drugs (AEDs). In most cases of medically refractory partial epilepsy, the first choice of treatment is resective surgery if the seizure focus can be definitively localized and if surgery can be safely performed without causing intolerable neurologic deficits. Patients with medically refractory epilepsy who are not candidates for potentially curative surgery may benefit from the implantation of a neuromodulation device. While most of these devices require surgical implantation, they provide a significant added seizure reduction without typical medication side effects. Furthermore, the efficacy of these devices continues to improve over years. There are currently no head-to-head trials comparing the different neuromodulation devices but efficacy appears to be roughly similar. The choice of device therefore depends on the type of epilepsy, whether the seizure focus can be identified, and other clinical factors. Vagal Nerve Stimulation (VNS) does not require identification of the seizure focus and also carries an FDA indication for depression. While in the United States VNS is only approved for use in partial epilepsy, it is commonly used off-label to treat generalized seizures as well. VNS delivers stimulation on a scheduled basis, in response to patient activation, or in response to heart rate increases serving as a proxy for seizures. Responsive Neurostimulation (RNS) requires the identification of up to two seizure foci and delivers stimulation only in response to the detection of epileptiform activity. While it requires intracranial placement of electrodes, it allows for long-term monitoring of electrographic seizures and may be effective where VNS has not produced an optimal response. Deep brain stimulation of the anterior nucleus of the thalamus is not FDA approved at this time but is available in Europe and many other parts of the world. While it also carries an indication only for partial epilepsy, it does not require identification of the seizure focus and may be particularly helpful for temporal lobe epilepsy. It also appears effective in cases where VNS has not been sufficiently helpful. The Trigeminal Nerve Stimulation (TNS) system is another treatment modality which is not yet FDA approved but is available in Europe and other countries. Its mechanism of action is similar to the VNS system and it also appears to have anti-depression effects in addition to anti-epileptic benefits. However, the most compelling feature of TNS is that it is not implanted but rather applied to the skin with transdermal electrodes, typically at night.

Objective: The impact of epilepsy is manifest by effects related to seizures and side effects of therapy and comorbidities such as depression. This report describes the development of a brief patient-reported outcome (PRO) instrument, the Personal Impact of Epilepsy Scale (PIES), to measure the influence of epilepsy overall and in each of these domains., Methods: Instrument development followed standard procedures and an FDA Guidance. People with epilepsy were surveyed with open-ended questions to derive major themes of their concerns, resulting in 4 key areas: seizures, side effects, comorbidities, and overall quality of life (QOL). A preliminary set of 152 questions was based on these themes and completed by 50 patients, age 42.7 (range: 21-71) years, concurrent with comparator instruments, including the NH Seizure Severity Scale (NHSSS), the Liverpool Adverse Events Profile (LAEP), the Quality of Life in Epilepsy (QOLIE-31) scale, the Beck Depression Inventory, and the Epilepsy Foundation Depression: A Checklist. A multiple regression model indicated which PIES measures were associated with scores from the comparator instruments. Questions in each of the domains were selected for correlations and nonduplication. Test-retest consistency at a 3-day interval was completed by 38 subjects and a final set of questions constructed., Results: The final question set comprised 25 items: 9 about characteristics of seizures, 7 about medication side effects, 8 about comorbidities, and 1 about overall quality of life. All items had 5 response choices (0-4), with higher scores reflecting more negative status. A total of 46 subjects completed the 25 questions. Cronbach's alpha was 0.87, indicating good internal consistency. Each of the three domains correlated well with the overall QOL item. The questions pertaining to seizures correlated with the NHSSS, the side effect questions with the LAEP, and the comorbidity questions with the QOLIE-31., Conclusion: The PIES provides a simple, brief PRO measure as a profile of overall impact of seizures, medication side effects, comorbidities, and overall QOL for people with epilepsy. Further study will explore sensitivity to change quantification of the minimal clinically significant change., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Dual-sided subdural electrodes are used in the localization and lateralization of seizure-onset zones when the area of interest is within the interhemispheric fissure. We designed the current study to test the validity of the assumption that each side of the dual-sided electrodes records from the hemisphere it faces. We recorded with dual-sided strip and grid electrodes implanted in the occipital interhemispheric space in two patients with nonoccipital epilepsy during two visual stimulation tasks in which subjects were presented with visual stimuli in the ipsilateral or contralateral visual hemifields. Our findings show substantial contamination of recordings from the opposite hemisphere. Although, as expected, electrodes recording through the falx record faintly from the contralateral cortical surface, they unexpectedly pick up strong signals from the cortex behind them. Therefore, we conclude that these electrodes should not be used for lateralization of the origin of epileptic activity or evoked responses., (Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.)

Purpose: CNTF is a neuroprotective agent for retinal degenerations that can cause reduced electroretinogram (ERG) amplitudes. The goal of the present study was to determine the effects of intraocular delivery of CNTF on normal rat visual function., Methods: Full-field scotopic and photopic ERG amplitudes and spatial frequency thresholds of the optokinetic response (OKR) of adult Long-Evans rats were measured before and after intravitreous injection of CNTF or subretinal delivery of adenoassociated virus-vectored CNTF (AAV-CNTF) into one eye. Visual acuity was also measured by using the Visual Water Task in AAV-CNTF-injected animals. Multiunit luminance thresholds were recorded in the superior colliculus after CNTF injection, and the eyes were examined histologically., Results: In eyes injected with a high dose of CNTF, ERG amplitudes and OKR thresholds measured through CNTF-injected eyes were decreased by 45% to 70% within 6 days after injection. ERG amplitudes had begun to recover by 21 days, whereas OKR thresholds only began to recover after 56 days. Neither OKR thresholds nor ERG amplitudes fully recovered until 90 to 100 days. When measured in the superior colliculus at 2 weeks after CNTF injection, luminance thresholds were elevated by 0.35 log units. In AAV-CNTF-injected eyes, OKR thresholds, and visual acuity were reduced by approximately 50% for at least 6 months, and scotopic and photopic ERG b-waves were reduced by 30% to 50%. Photoreceptor loss occurred in the injected regions in some of the eyes. By contrast, comparison of dose-response analysis with a dose-response study of light damage strongly suggests that therapeutic doses of CNTF exist that do not suppress ERG responses., Conclusions: Intraocular delivery of CNTF, which preserves photoreceptors in animal models of retinal degeneration, impairs visual function in normal rats at very high doses, but not at lower doses that still provide protection from constant light damage.

Purpose: A prior study showed that brain-derived neurotrophic factor (BDNF) rescues photoreceptors from collateral retinal damage caused by photodynamic therapy (PDT). This study was conducted to determine whether ciliary neurotrophic factor (CNTF), a combination of BDNF and CNTF, or pigment epithelial cell-derived growth factor (PEDF) might protect photoreceptors and retinal function more effectively than BDNF. Also investigated was whether protection would be observed after a second round of PDT with adjunctive BDNF treatment., Methods: Normal rats received intravitreal injections of BDNF, CNTF, a combination of BDNF and CNTF, or PEDF in one eye and PBS in the other 2 days before PDT. Retinal function and photoreceptor survival were assessed with multifocal ERG (mfERG) and histology 1 week after PDT. Another group of rats received two courses of PDT 3 months apart, with injection of BDNF 2 days before each treatment., Results: All factors significantly increased photoreceptor survival. The combination of BDNF and CNTF rescued more photoreceptors than either factor alone. Only BDNF improved retinal function 1 week after PDT, with CNTF and the combination of BDNF and CNTF reducing mfERG responses. BDNF injection before a second round of PDT improved mfERG responses and retinal structure., Conclusions: BDNF is the most effective single factor among those tested for neuroprotection and improvement of retinal function after PDT, although a combination of BDNF and CNTF rescues more photoreceptors. Adjunctive treatment with BDNF also protects retinal structure and function through two rounds of PDT, suggesting its potential value for patients who require multiple treatments.

Transmission of visual signals at the first retinal synapse is associated with changes in calcium concentration in photoreceptors and bipolar cells. We investigated how loss of plasma membrane Ca2+ ATPase isoform 2 (PMCA2), the calcium transporter isoform with the highest affinity for Ca2+/calmodulin, affects transmission of rod- and cone-mediated responses. PMCA2 expression in the neuroblast layer was observed soon after birth; in the adult, PMCA2 was expressed in inner segments and synaptic terminals of rod photoreceptors, in rod bipolar cells, and in most inner retinal neurons but was absent from cones. To determine the role of PMCA2 in retinal signaling, we compared morphology and light responses of retinas from control mice and deafwaddler dfw2J mice, which lack functional PMCA2 protein. The cytoarchitecture of retinas from control and dfw2J mice was indistinguishable at the light microscope level. Suction electrode recordings revealed no difference in the sensitivity or amplitude of outer segment light responses of control and dfw2J rods. However, rod-mediated ERG b-wave responses in dfw2J mice were approximately 45% smaller and significantly slower than those of control mice. Furthermore, recordings from individual rod bipolar cells showed that the sensitivity of transmission at the rod output synapse was reduced by approximately 50%. No changes in the amplitude or timing of cone-mediated ERG responses were observed. These results suggest that PMCA2-mediated Ca2+ extrusion modulates the amplitude and timing of the high-sensitivity rod pathway to a much greater extent than that of the cone pathway.

Pantothenate kinase-associated neurodegeneration (PKAN, formerly known as Hallervorden-Spatz syndrome) is a rare but devastating neurodegenerative disorder, resulting from an inherited defect in coenzyme A biosynthesis. As pathology in the human condition is limited to the central nervous system, specifically the retina and globus pallidus, we have generated a mouse knock-out of the orthologous murine gene (Pank2) to enhance our understanding of the mechanisms of disease and to serve as a testing ground for therapies. Over time, the homozygous null mice manifest retinal degeneration, as evidenced by electroretinography, light microscopy and pupillometry response. Specifically, Pank2 mice show progressive photoreceptor decline, with significantly lower scotopic a- and b-wave amplitudes, decreased cell number and disruption of the outer segment and reduced pupillary constriction response when compared with those of wild-type littermates. Additionally, the homozygous male mutants are infertile due to azoospermia, a condition that was not appreciated in the human. Arrest occurs in spermiogenesis, with complete absence of elongated and mature spermatids. In contrast to the human, however, no changes were observed in the basal ganglia by MRI or by histological exam, nor were there signs of dystonia, even after following the mice for one year. Pank2 mice are 20% decreased in weight when compared with their wild-type littermates; however, dysphagia was not apparent. Immunohistochemistry shows staining consistent with localization of Pank2 to the mitochondria in both the retina and the spermatozoa.

Purpose: Verteporfin photodynamic therapy (PDT) is the most effective treatment for age-related macular degeneration, using laser activation of a photosensitizing dye to achieve closure of choroidal neovascularization. Although PDT preferentially affects pathologic vessels, it can also cause collateral damage to the overlying retina. In the current study, it was found that the neuroprotective agent brain-derived neurotrophic factor (BDNF) reduces this retinal damage., Methods: Normal adult rats received intravitreal BDNF in one eye and PBS or no injection in the other eye 2 days before PDT., Results: Control eyes exhibited choroidal hypofluorescence, moderate to severe photoreceptor loss, and depression of local retinal function measured using multifocal ERG in the laser-treated area. BDNF-injected eyes had more surviving photoreceptors and improved multifocal ERG responses 1 week after PDT. BDNF did not diminish the effect of PDT on the choroidal circulation as assessed by fluorescein angiography, and there was no evidence of retinal toxicity due to BDNF treatment., Conclusions: These results suggest that adjunctive neuroprotective therapy may reduce collateral damage to photoreceptors and improve visual outcome after PDT.