@article {4564, title = {Circuit dynamics of approach-avoidance conflict in humans.}, journal = {bioRxiv}, year = {2025}, month = {2025 Jan 01}, abstract = {

Debilitating anxiety is pervasive in the modern world. Choices to approach or avoid are common in everyday life and excessive avoidance is a cardinal feature of all anxiety disorders. Here, we used intracranial EEG to define a distributed prefrontal-limbic circuit dynamics supporting approach and avoidance. Presurgical epilepsy patients (n=20) performed an approach-avoidance conflict decision-making task inspired by the arcade game Pac-Man, where participants trade-off real-time harvesting rewards with potential losses from attack. As patients approached increasing rewards and threats, we found evidence of a limbic circuit mediated by increased theta power in the hippocampus, amygdala, orbitofrontal cortex (OFC) and anterior cingulate cortex (ACC), which then drops rapidly during avoidance. Theta band connectivity between these regions increases during approach and falls during avoidance, with OFC serving as a connector in this circuit with high theta coherence across limbic regions, but also with regions outside of the limbic system, including the lateral prefrontal cortex. Importantly, the degree of OFC-driven connectivity predicts how long participants approach, with enhanced network synchronicity extending approach times. Finally, under ghost attack, the system dynamically switches to a sustained increase in high-frequency activity (70-150Hz) in the middle frontal gyrus (MFG), marking the retreat from the ghost. The results provide evidence for a distributed prefrontal-limbic circuit, mediated by theta oscillations, underlying approach-avoidance conflict.

}, issn = {2692-8205}, doi = {10.1101/2024.12.31.630927}, author = {Staveland, Brooke R and Oberschulte, Julia and Kim-McManus, Olivia and Willie, Jon T and Brunner, Peter and Dastjerdi, Mohammad and Lin, Jack J and Hsu, Ming and Knight, Robert T} } @article {4565, title = {The effect of transcutaneous auricular vagus nerve stimulation on cardiovascular function in subarachnoid hemorrhage patients: A randomized trial.}, journal = {Elife}, volume = {13}, year = {2025}, month = {2025 Jan 09}, abstract = {

BACKGROUND: Subarachnoid hemorrhage (SAH) is characterized by intense central inflammation, leading to substantial post-hemorrhagic complications such as vasospasm and delayed cerebral ischemia. Given the anti-inflammatory effect of transcutaneous auricular vagus nerve stimulation (taVNS) and its ability to promote brain plasticity, taVNS has emerged as a promising therapeutic option for SAH patients. However, the effects of taVNS on cardiovascular dynamics in critically ill patients, like those with SAH, have not yet been investigated. Given the association between cardiac complications and elevated risk of poor clinical outcomes after SAH, it is essential to characterize the cardiovascular effects of taVNS to ensure this approach is safe in this fragile population. Therefore, this study assessed the impact of both acute and repetitive taVNS on cardiovascular function.

METHODS: In this randomized clinical trial, 24 SAH patients were assigned to either a taVNS treatment or a sham treatment group. During their stay in the intensive care unit, we monitored patient electrocardiogram readings and vital signs. We compared long-term changes in heart rate, heart rate variability (HRV), QT interval, and blood pressure between the two groups. Additionally, we assessed the effects of acute taVNS by comparing cardiovascular metrics before, during, and after the intervention. We also explored acute cardiovascular biomarkers in patients exhibiting clinical improvement.

RESULTS: We found that repetitive taVNS did not significantly alter heart rate, QT interval, blood pressure, or intracranial pressure (ICP). However, repetitive taVNS increased overall HRV and parasympathetic activity compared to the sham treatment. The increase in parasympathetic activity was most pronounced from 2 to 4 days after initial treatment (Cohen{\textquoteright}s = 0.50). Acutely, taVNS increased heart rate, blood pressure, and peripheral perfusion index without affecting the corrected QT interval, ICP, or HRV. The acute post-treatment elevation in heart rate was more pronounced in patients who experienced a decrease of more than one point in their modified Rankin Score at the time of discharge.

CONCLUSIONS: Our study found that taVNS treatment did not induce adverse cardiovascular effects, such as bradycardia or QT prolongation, supporting its development as a safe immunomodulatory treatment approach for SAH patients. The observed acute increase in heart rate after taVNS treatment may serve as a biomarker for SAH patients who could derive greater benefit from this treatment.

FUNDING: The American Association of Neurological Surgeons (ALH), The Aneurysm and AVM Foundation (ALH), The National Institutes of Health R01-EB026439, P41-EB018783, U24-NS109103, R21-NS128307 (ECL, PB), McDonnell Center for Systems Neuroscience (ECL, PB), and Fondazione Neurone (PB).

CLINICAL TRIAL NUMBER: NCT04557618.

}, keywords = {Adult, Aged, Blood Pressure, Electrocardiography, Female, Heart Rate, Humans, Male, Middle Aged, Subarachnoid Hemorrhage, Transcutaneous Electric Nerve Stimulation, Vagus Nerve Stimulation}, issn = {2050-084X}, doi = {10.7554/eLife.100088}, author = {Tan, Gansheng and Huguenard, Anna L and Donovan, Kara M and Demarest, Phillip and Liu, Xiaoxuan and Li, Ziwei and Adamek, Markus and Lavine, Kory and Vellimana, Ananthv K and Kummer, Terrance T and Osbun, Joshua W and Zipfel, Gregory J and Brunner, Peter and Leuthardt, Eric C} } @article {4563, title = {A human single-neuron dataset for object recognition.}, journal = {Sci Data}, volume = {12}, year = {2025}, month = {2025 Jan 15}, pages = {79}, abstract = {

Object recognition is fundamental to how we interact with and interpret the world around us. The human amygdala and hippocampus play a key role in object recognition, contributing to both the encoding and retrieval of visual information. Here, we recorded single-neuron activity from the human amygdala and hippocampus when neurosurgical epilepsy patients performed a one-back task using naturalistic object stimuli. We employed two sets of naturalistic object images from leading datasets extensively used in primate neural recordings and computer vision models: we recorded 1204 neurons using the ImageNet stimuli, which included broader object categories (10 different images per category for 50 categories), and we recorded 512 neurons using the Microsoft COCO stimuli, which featured a higher number of images per category (50 different images per category for 10 categories). Together, our extensive dataset, offering the highest spatial and temporal resolution currently available in humans, will not only facilitate a comprehensive analysis of the neural correlates of object recognition but also provide valuable opportunities for training and validating computational models.

}, keywords = {Amygdala, Epilepsy, Hippocampus, Humans, Neurons, Pattern Recognition, Visual, Recognition, Psychology}, issn = {2052-4463}, doi = {10.1038/s41597-024-04265-1}, author = {Cao, Runnan and Brunner, Peter and Brandmeir, Nicholas J and Willie, Jon T and Wang, Shuo} } @article {4561, title = {Anatomical registration of intracranial electrodes. Robust model-based localization and deformable smooth brain-shift compensation methods}, journal = {Journal of Neuroscience Methods}, volume = {404}, year = {2024}, pages = {110056}, author = {Blenkmann, Alejandro Omar and Leske, Sabine Liliana and Llorens, Ana{\"\i}s and Lin, Jack J and Chang, Edward F and Brunner, Peter and Schalk, Gerwin and Ivanovic, Jugoslav and Larsson, P{\r a}l Gunnar and Knight, Robert Thomas and others} } @article {4584, title = {Anatomical registration of intracranial electrodes. Robust model-based localization and deformable smooth brain-shift compensation methods.}, journal = {J Neurosci Methods}, volume = {404}, year = {2024}, month = {2024 Apr}, pages = {110056}, abstract = {

BACKGROUND: Intracranial electrodes are typically localized from post-implantation CT artifacts. Automatic~algorithms localizing low signal-to-noise ratio artifacts and high-density electrode arrays are missing. Additionally, implantation of grids/strips introduces brain deformations, resulting in registration errors when fusing post-implantation CT and pre-implantation MR images. Brain-shift compensation methods project electrode coordinates to cortex, but either fail to produce smooth solutions or do not account for brain deformations.

NEW METHODS: We first introduce GridFit, a model-based fitting approach that simultaneously localizes all electrodes{\textquoteright} CT artifacts in grids, strips, or depth arrays. Second, we present CEPA, a brain-shift compensation algorithm combining orthogonal-based projections, spring-mesh models, and spatial regularization constraints.

RESULTS: We tested GridFit on \~{}6000 simulated scenarios. The localization of CT artifacts showed robust performance under difficult scenarios, such as noise, overlaps, and high-density implants (<1~mm errors). Validation with data from 20 challenging patients showed 99\% accurate localization of the electrodes (3160/3192). We tested CEPA brain-shift compensation with data from 15 patients. Projections accounted for simple mechanical deformation principles with <~0.4~mm errors. The inter-electrode distances smoothly changed across neighbor electrodes, while changes in inter-electrode distances linearly increased with projection distance.

COMPARISON WITH EXISTING METHODS: GridFit succeeded in difficult scenarios that challenged available methods and outperformed visual localization by preserving the inter-electrode distance. CEPA registration errors were smaller than those obtained for well-established alternatives. Additionally, modeling resting-state high-frequency activity in five patients further supported CEPA.

CONCLUSION: GridFit and CEPA are versatile tools for registering intracranial electrode coordinates, providing highly accurate results even in the most challenging implantation scenarios. The methods are implemented in the iElectrodes open-source toolbox.

}, keywords = {Brain, Cerebral Cortex, Electrodes, Electrodes, Implanted, Electroencephalography, Humans, Magnetic Resonance Imaging}, issn = {1872-678X}, doi = {10.1016/j.jneumeth.2024.110056}, author = {Blenkmann, Alejandro Omar and Leske, Sabine Liliana and Llorens, Ana{\"\i}s and Lin, Jack J and Chang, Edward F and Brunner, Peter and Schalk, Gerwin and Ivanovic, Jugoslav and Larsson, P{\r a}l Gunnar and Knight, Robert Thomas and Endestad, Tor and Solbakk, Anne-Kristin} } @article {4566, title = {The development of aperiodic neural activity in the human brain.}, journal = {bioRxiv}, year = {2024}, month = {2024 Nov 09}, abstract = {

The neurophysiological mechanisms supporting brain maturation are fundamental to attention and memory capacity across the lifespan. Human brain regions develop at different rates, with many regions developing into the third and fourth decades of life. Here, in this preregistered study (https://osf.io/gsru7), we analyzed intracranial EEG (iEEG) recordings from widespread brain regions in a large developmental cohort. Using task-based (i.e., attention to-be-remembered visual stimuli) and task-free (resting-state) data from 101 children and adults (5.93 - 54.00 years, 63 males; electrodes = 5691), we mapped aperiodic (1/{\textflorin}-like) activity, a proxy of excitation:inhibition (E:I) balance with steeper slopes indexing inhibition and flatter slopes indexing excitation. We reveal that aperiodic slopes flatten with age into young adulthood in both association and sensorimotor cortices, challenging models of early sensorimotor development based on brain structure. In prefrontal cortex (PFC), attentional state modulated age effects, revealing steeper task-based than task-free slopes in adults and the opposite in children, consistent with the development of cognitive control. Age-related differences in task-based slopes also explained age-related gains in memory performance, linking the development of PFC cognitive control to the development of memory. Last, with additional structural imaging measures, we reveal that age-related differences in gray matter volume are differentially associated with aperiodic slopes in association and sensorimotor cortices. Our findings establish developmental trajectories of aperiodic activity in localized brain regions and illuminate the development of PFC inhibitory control during adolescence in the development of attention and memory.

}, issn = {2692-8205}, doi = {10.1101/2024.11.08.622714}, author = {Cross, Zachariah R and Gray, Samantha M and Dede, Adam J O and Rivera, Yessenia M and Yin, Qin and Vahidi, Parisa and Rau, Elias M B and Cyr, Christopher and Holubecki, Ania M and Asano, Eishi and Lin, Jack J and McManus, Olivia Kim and Sattar, Shifteh and Saez, Ignacio and Girgis, Fady and King-Stephens, David and Weber, Peter B and Laxer, Kenneth D and Schuele, Stephan U and Rosenow, Joshua M and Wu, Joyce Y and Lam, Sandi K and Raskin, Jeffrey S and Chang, Edward F and Shaikhouni, Ammar and Brunner, Peter and Roland, Jarod L and Braga, Rodrigo M and Knight, Robert T and Ofen, Noa and Johnson, Elizabeth L} } @article {4577, title = {Does vibrotactile stimulation of the auricular vagus nerve enhance working memory? A behavioral and physiological investigation.}, journal = {Brain Stimul}, volume = {17}, year = {2024}, month = {2024 Mar-Apr}, pages = {460-468}, abstract = {

BACKGROUND: Working memory is essential to a wide range of cognitive functions and activities. Transcutaneous auricular vagus nerve stimulation (taVNS) is a promising method to improve working memory performance. However, the feasibility and scalability of electrical stimulation are constrained by several limitations, such as auricular discomfort and inconsistent electrical contact.

OBJECTIVE: We aimed to develop a novel and practical method, vibrotactile taVNS, to improve working memory. Further, we investigated its effects on arousal, measured by skin conductance and pupil diameter.

METHOD: This study included 20 healthy participants. Behavioral response, skin conductance, and eye tracking data were concurrently recorded while the participants performed N-back tasks under three conditions: vibrotactile taVNS delivered to the cymba concha, earlobe (sham control), and no stimulation (baseline control).

RESULTS: In 4-back tasks, which demand maximal working memory capacity, active vibrotactile taVNS significantly improved the performance metric d compared to the baseline but not to the sham. Moreover, we found that the reduction rate of d with increasing task difficulty was significantly smaller during vibrotactile taVNS sessions than in both baseline and sham conditions. Arousal, measured as skin conductance and pupil diameter, declined over the course of the tasks. Vibrotactile taVNS rescued this arousal decline, leading to arousal levels corresponding to optimal working memory levels. Moreover, pupil diameter and skin conductance level were higher during high-cognitive-load tasks when vibrotactile taVNS was delivered to the concha compared to baseline and sham.

CONCLUSION: Our findings suggest that vibrotactile taVNS modulates the arousal pathway and could be a potential intervention for enhancing working memory.

}, keywords = {Adult, Female, Galvanic Skin Response, Humans, Male, Memory, Short-Term, Pupil, Vagus Nerve, Vagus Nerve Stimulation, Vibration, Young Adult}, issn = {1876-4754}, doi = {10.1016/j.brs.2024.04.002}, author = {Tan, Gansheng and Adams, Josh and Donovan, Kara and Demarest, Phillip and Willie, Jon T and Brunner, Peter and Gorlewicz, Jenna L and Leuthardt, Eric C} } @article {4558, title = {Does vibrotactile stimulation of the auricular vagus nerve enhance working memory? A behavioral and physiological investigation}, journal = {Brain Stimulation}, volume = {17}, year = {2024}, pages = {460{\textendash}468}, author = {Tan, Gansheng and Adams, Josh and Donovan, Kara and Demarest, Phillip and Willie, Jon T and Brunner, Peter and Gorlewicz, Jenna L and Leuthardt, Eric C} } @article {4578, title = {Does Vibrotactile Stimulation of the Auricular Vagus Nerve Enhance Working Memory? A Behavioral and Physiological Investigation.}, journal = {bioRxiv}, year = {2024}, month = {2024 Mar 27}, abstract = {

BACKGROUND: Working memory is essential to a wide range of cognitive functions and activities. Transcutaneous auricular VNS (taVNS) is a promising method to improve working memory performance. However, the feasibility and scalability of electrical stimulation are constrained by several limitations, such as auricular discomfort and inconsistent electrical contact.

OBJECTIVE: We aimed to develop a novel and practical method, vibrotactile taVNS, to improve working memory. Further, we investigated its effects on arousal, measured by skin conductance and pupil diameter.

METHOD: This study included 20 healthy participants. Behavioral response, skin conductance, and eye tracking data were concurrently recorded while the participants performed N-back tasks under three conditions: vibrotactile taVNS delivered to the cymba concha, earlobe (sham control), and no stimulation (baseline control).

RESULTS: In 4-back tasks, which demand maximal working memory capacity, active vibrotactile taVNS significantly improved the performance metric {\textquoteright} compared to the baseline but not to the sham. Moreover, we found that the reduction rate of {\textquoteright} with increasing task difficulty was significantly smaller during vibrotactile taVNS sessions than in both baseline and sham conditions. Arousal, measured as skin conductance and pupil diameter, declined over the course of the tasks. Vibrotactile taVNS rescued this arousal decline, leading to arousal levels corresponding to optimal working memory levels. Moreover, pupil diameter and skin conductance level were higher during high-cognitive-load tasks when vibrotactile taVNS was delivered to the concha compared to baseline and sham.

CONCLUSION: Our findings suggest that vibrotactile taVNS modulates the arousal pathway and could be a potential intervention for enhancing working memory.

HIGHLIGHTS: Vibrotactile stimulation of the auricular vagus nerve increases general arousal.Vibrotactile stimulation of the auricular vagus nerve mitigates arousal decreases as subjects continuously perform working memory tasks.6 Hz Vibrotactile auricular vagus nerve stimulation is a potential intervention for enhancing working memory performance.

}, issn = {2692-8205}, doi = {10.1101/2024.03.24.586365}, author = {Tan, Gansheng and Adams, Josh and Donovan, Kara and Demarest, Phillip and Willie, Jon T and Brunner, Peter and Gorlewicz, Jenna L and Leuthardt, Eric C} } @article {4575, title = {The effect of transcutaneous auricular vagus nerve stimulation on cardiovascular function in subarachnoid hemorrhage patients: a safety study.}, journal = {medRxiv}, year = {2024}, month = {2024 Sep 08}, abstract = {

INTRODUCTION: Subarachnoid hemorrhage (SAH) is characterized by intense central inflammation, leading to substantial post-hemorrhagic complications such as vasospasm and delayed cerebral ischemia. Given the anti-inflammatory effect of transcutaneous auricular vagus nerve stimulation (taVNS) and its ability to promote brain plasticity, taVNS has emerged as a promising therapeutic option for SAH patients. However, the effects of taVNS on cardiovascular dynamics in critically ill patients, like those with SAH, have not yet been investigated. Given the association between cardiac complications and elevated risk of poor clinical outcomes after SAH, it is essential to characterize the cardiovascular effects of taVNS to ensure this approach is safe in this fragile population. Therefore, we assessed the impact of both acute taVNS and repetitive taVNS on cardiovascular function in this study.

METHODS: In this randomized clinical trial, 24 SAH patients were assigned to either a taVNS treatment or a Sham treatment group. During their stay in the intensive care unit, we monitored patient electrocardiogram (ECG) readings and vital signs. We compared long-term changes in heart rate, heart rate variability, QT interval, and blood pressure between the two groups. Additionally, we assessed the effects of acute taVNS by comparing cardiovascular metrics before, during, and after the intervention. We also explored acute cardiovascular biomarkers in patients exhibiting clinical improvement.

RESULTS: We found that repetitive taVNS did not significantly alter heart rate, QT interval, blood pressure, or intracranial pressure. However, taVNS increased overall heart rate variability and parasympathetic activity compared to the sham treatment. The increase in parasympathetic activity was most pronounced from 2-4 days after initial treatment (Cohen{\textquoteright}s d = 0.50). Acutely, taVNS increased heart rate, blood pressure, and peripheral perfusion index without affecting the corrected QT interval, intracranial pressure, or heart rate variability. The acute post-treatment elevation in heart rate was more pronounced in patients who experienced a decrease of more than one point in their Modified Rankin Score at the time of discharge.

CONCLUSIONS: Our study found that taVNS treatment did not induce adverse cardiovascular effects, such as bradycardia or QT prolongation, supporting its development as a safe immunomodulatory treatment approach for SAH patients. The observed acute increase in heart rate after taVNS treatment may serve as a biomarker for SAH patients who could derive greater benefit from this treatment.

TRIAL REGISTRATION: NCT04557618.

}, doi = {10.1101/2024.04.03.24304759}, author = {Tan, Gansheng and Huguenard, Anna L and Donovan, Kara M and Demarest, Phillip and Liu, Xiaoxuan and Li, Ziwei and Adamek, Markus and Lavine, Kory and Vellimana, Ananth K and Kummer, Terrance T and Osbun, Joshua W and Zipfel, Gregory J and Brunner, Peter and Leuthardt, Eric C} } @article {4574, title = {Graded decisions in the human brain.}, journal = {Nat Commun}, volume = {15}, year = {2024}, month = {2024 May 21}, pages = {4308}, abstract = {

Decision-makers objectively commit to a definitive choice, yet at the subjective level, human decisions appear to be associated with a degree of uncertainty. Whether decisions are definitive (i.e., concluding in all-or-none choices), or whether the underlying representations are graded, remains unclear. To answer this question, we recorded intracranial neural signals directly from the brain while human subjects made perceptual decisions. The recordings revealed that broadband gamma activity reflecting~each individual{\textquoteright}s decision-making process, ramped up gradually while being graded by the accumulated decision evidence. Crucially, this grading effect persisted throughout the decision process without ever reaching a definite bound at the time of choice. This effect was most prominent in the parietal cortex, a brain region traditionally implicated in decision-making. These results provide neural evidence for a graded decision process in humans and an analog framework for flexible choice behavior.

}, keywords = {Adult, Brain, Choice Behavior, Decision Making, Female, Humans, Male, Parietal Lobe, Uncertainty, Young Adult}, issn = {2041-1723}, doi = {10.1038/s41467-024-48342-w}, author = {Xie, Tao and Adamek, Markus and Cho, Hohyun and Adamo, Matthew A and Ritaccio, Anthony L and Willie, Jon T and Brunner, Peter and Kubanek, Jan} } @article {4555, title = {Graded decisions in the human brain}, journal = {Nature communications}, volume = {15}, year = {2024}, pages = {4308}, author = {Xie, Tao and Adamek, Markus and Cho, Hohyun and Adamo, Matthew A and Ritaccio, Anthony L and Willie, Jon T and Brunner, Peter and Kubanek, Jan} } @article {4585, title = {Neural mechanisms of face familiarity and learning in the human amygdala and hippocampus.}, journal = {Cell Rep}, volume = {43}, year = {2024}, month = {2024 Jan 23}, pages = {113520}, abstract = {

Recognizing familiar faces and learning new faces play an important role in social cognition. However, the underlying neural computational mechanisms remain unclear. Here, we record from single neurons in the human amygdala and hippocampus and find a greater neuronal representational distance between pairs of familiar faces than unfamiliar faces, suggesting that neural representations for familiar faces are more distinct. Representational distance increases with exposures to the same identity, suggesting that neural face representations are sharpened with learning and familiarization. Furthermore, representational distance is positively correlated with visual dissimilarity between faces, and exposure to visually similar faces increases representational distance, thus sharpening neural representations. Finally, we construct a computational model that demonstrates an increase in the representational distance of artificial units with training. Together, our results suggest that the neuronal population geometry, quantified by the representational distance, encodes face familiarity, similarity, and learning, forming the basis of face recognition and memory.

}, keywords = {Amygdala, Facial Recognition, Hippocampus, Humans, Learning, Pattern Recognition, Visual, Recognition, Psychology}, issn = {2211-1247}, doi = {10.1016/j.celrep.2023.113520}, author = {Cao, Runnan and Wang, Jinge and Brunner, Peter and Willie, Jon T and Li, Xin and Rutishauser, Ueli and Brandmeir, Nicholas J and Wang, Shuo} } @article {4556, title = {Neural mechanisms of face familiarity and learning in the human amygdala and hippocampus}, journal = {Cell reports}, volume = {43}, year = {2024}, author = {Cao, Runnan and Wang, Jinge and Brunner, Peter and Willie, Jon T and Li, Xin and Rutishauser, Ueli and Brandmeir, Nicholas J and Wang, Shuo} } @article {4559, title = {Neural populations in the language network differ in the size of their temporal receptive windows}, journal = {Nature Human Behaviour}, volume = {8}, year = {2024}, pages = {1924{\textendash}1942}, author = {Regev, Tamar I and Casto, Colton and Hosseini, Eghbal A and Adamek, Markus and Ritaccio, Anthony L and Willie, Jon T and Brunner, Peter and Fedorenko, Evelina} } @article {4571, title = {Non-invasive Auricular Vagus nerve stimulation for Subarachnoid Hemorrhage (NAVSaH): Protocol for a prospective, triple-blinded, randomized controlled trial.}, journal = {PLoS One}, volume = {19}, year = {2024}, month = {2024}, pages = {e0301154}, abstract = {

BACKGROUND: Inflammation has been implicated in driving the morbidity associated with subarachnoid hemorrhage (SAH). Despite understanding the important role of inflammation in morbidity following SAH, there is no current effective way to modulate this deleterious response. There is a critical need for a novel approach to immunomodulation that can be safely, rapidly, and effectively deployed in SAH patients. Vagus nerve stimulation (VNS) provides a non-pharmacologic approach to immunomodulation, with prior studies demonstrating VNS can reduce systemic inflammatory markers, and VNS has had early success treating inflammatory conditions such as arthritis, sepsis, and inflammatory bowel diseases. The aim of the Non-invasive Auricular Vagus nerve stimulation for Subarachnoid Hemorrhage (NAVSaH) trial is to translate the use of non-invasive transcutaneous auricular VNS (taVNS) to spontaneous SAH, with our central hypothesis being that implementing taVNS in the acute period following spontaneous SAH attenuates the expected inflammatory response to hemorrhage and curtails morbidity associated with inflammatory-mediated clinical endpoints.

MATERIALS AND METHODS: The overall objectives for the NAHSaH trial are to 1) Define the impact that taVNS has on SAH-induced inflammatory markers in the plasma and cerebrospinal fluid (CSF), 2) Determine whether taVNS following SAH reduces radiographic vasospasm, and 3) Determine whether taVNS following SAH reduces chronic hydrocephalus. Following presentation to a single enrollment site, enrolled SAH patients are randomly assigned twice daily treatment with either taVNS or sham stimulation for the duration of their intensive care unit stay. Blood and CSF are drawn before initiation of treatment sessions, and then every three days during a patient{\textquoteright}s hospital stay. Primary endpoints include change in the inflammatory cytokine TNF-α in plasma and cerebrospinal fluid between day 1 and day 13, rate of radiographic vasospasm, and rate of requirement for long-term CSF diversion via a ventricular shunt. Secondary outcomes include exploratory analyses of a panel of additional cytokines, number and type of hospitalized acquired infections, duration of external ventricular drain in days, interventions required for vasospasm, continuous physiology data before, during, and after treatment sessions, hospital length of stay, intensive care unit length of stay, and modified Rankin Scale score (mRS) at admission, discharge, and each at follow-up appointment for up to two years following SAH.

DISCUSSION: Inflammation plays a central role in morbidity following SAH. This NAVSaH trial is innovative because it diverges from the pharmacologic status quo by harnessing a novel non-invasive neuromodulatory approach and its known anti-inflammatory effects to alter the pathophysiology of SAH. The investigation of a new, effective, and rapidly deployable intervention in SAH offers a new route to improve outcomes following SAH.

TRIAL REGISTRATION: Clinical Trials Registered, NCT04557618. Registered on September 21, 2020, and the first patient was enrolled on January 4, 2021.

}, keywords = {Adult, Female, Humans, Inflammation, Male, Middle Aged, Prospective Studies, Randomized Controlled Trials as Topic, Subarachnoid Hemorrhage, Treatment Outcome, Vagus Nerve Stimulation}, issn = {1932-6203}, doi = {10.1371/journal.pone.0301154}, author = {Huguenard, Anna and Tan, Gansheng and Johnson, Gabrielle and Adamek, Markus and Coxon, Andrew and Kummer, Terrance and Osbun, Joshua and Vellimana, Ananth and Limbrick, David and Zipfel, Gregory and Brunner, Peter and Leuthardt, Eric} } @article {4580, title = {Non-invasive Auricular Vagus nerve stimulation for Subarachnoid Hemorrhage (NAVSaH): Protocol for a prospective, triple-blinded, randomized controlled trial.}, journal = {medRxiv}, year = {2024}, month = {2024 Mar 19}, abstract = {

BACKGROUND: Inflammation has been implicated in driving the morbidity associated with subarachnoid hemorrhage (SAH). Despite understanding the important role of inflammation in morbidity following SAH, there is no current effective way to modulate this deleterious response. There is a critical need for a novel approach to immunomodulation that can be safely, rapidly, and effectively deployed in SAH patients. Vagus nerve stimulation (VNS) provides a non-pharmacologic approach to immunomodulation, with prior studies demonstrating VNS can reduce systemic inflammatory markers, and VNS has had early success treating inflammatory conditions such as arthritis, sepsis, and inflammatory bowel diseases. The aim of the Non-invasive Auricular Vagus nerve stimulation for Subarachnoid Hemorrhage (NAVSaH) trial is to translate the use of non-invasive transcutaneous auricular VNS (taVNS) to spontaneous SAH, with our central hypothesis being that implementing taVNS in the acute period following spontaneous SAH attenuates the expected inflammatory response to hemorrhage and curtails morbidity associated with inflammatory-mediated clinical endpoints.

MATERIALS AND METHODS: The overall objectives for the NAHSaH trial are to 1) Define the impact that taVNS has on SAH-induced inflammatory markers in the plasma and cerebrospinal fluid (CSF), 2) Determine whether taVNS following SAH reduces radiographic vasospasm, and 3) Determine whether taVNS following SAH reduces chronic hydrocephalus. Following presentation to a single enrollment site, enrolled SAH patients are randomly assigned twice daily treatment with either taVNS or sham stimulation for the duration of their intensive care unit stay. Blood and CSF are drawn before initiation of treatment sessions, and then every three days during a patient{\textquoteright}s hospital stay. Primary endpoints include change in the inflammatory cytokine TNF-α in plasma and cerebrospinal fluid between day 1 and day 13, rate of radiographic vasospasm, and rate of requirement for long-term CSF diversion via a ventricular shunt. Secondary outcomes include exploratory analyses of a panel of additional cytokines, number and type of hospitalized acquired infections, duration of external ventricular drain in days, interventions required for vasospasm, continuous physiology data before, during, and after treatment sessions, hospital length of stay, intensive care unit length of stay, and modified Rankin Scale score (mRS) at admission, discharge, and each at follow-up appointment for up to two years following SAH.

DISCUSSION: Inflammation plays a central role in morbidity following SAH. This NAVSaH trial is innovative because it diverges from the pharmacologic status quo by harnessing a novel non-invasive neuromodulatory approach and its known anti-inflammatory effects to alter the pathophysiology of SAH. The investigation of a new, effective, and rapidly deployable intervention in SAH offers a new route to improve outcomes following SAH.

TRIAL REGISTRATION: Clinical Trials Registered, NCT04557618. Registered on September 21, 2020, and the first patient was enrolled on January 4, 2021.

}, doi = {10.1101/2024.03.18.24304239}, author = {Huguenard, Anna L and Tan, Gansheng and Johnson, Gabrielle W and Adamek, Markus and Coxon, Andrew T and Kummer, Terrance T and Osbun, Joshua W and Vellimana, Ananth K and Limbrick, David D and Zipfel, Gregory J and Brunner, Peter and Leuthardt, Eric C} } @article {4554, title = {Non-invasive Brain-Computer Interfaces: State of the Art and Trends}, journal = {IEEE Reviews in Biomedical Engineering}, year = {2024}, author = {Edelman, Bradley J and Zhang, Shuailei and Schalk, Gerwin and Brunner, Peter and M{\"u}ller-Putz, Gernot and Guan, Cuntai and He, Bin} } @article {4560, title = {Novel cyclic homogeneous oscillation detection method for high accuracy and specific characterization of neural dynamics}, journal = {Elife}, volume = {12}, year = {2024}, pages = {RP91605}, author = {Cho, Hohyun and Adamek, Markus and Willie, Jon T and Brunner, Peter} } @article {4568, title = {Novel cyclic homogeneous oscillation detection method for high accuracy and specific characterization of neural dynamics.}, journal = {Elife}, volume = {12}, year = {2024}, month = {2024 Sep 06}, abstract = {

Determining the presence and frequency of neural oscillations is essential to understanding dynamic brain function. Traditional methods that detect peaks over 1/ noise within the power spectrum fail to distinguish between the fundamental frequency and harmonics of often highly non-sinusoidal neural oscillations. To overcome this limitation, we define fundamental criteria that characterize neural oscillations and introduce the cyclic homogeneous oscillation (CHO) detection method. We implemented these criteria based on an autocorrelation approach to determine an oscillation{\textquoteright}s fundamental frequency. We evaluated CHO by verifying its performance on simulated non-sinusoidal oscillatory bursts and validated its ability to determine the fundamental frequency of neural oscillations in electrocorticographic (ECoG), electroencephalographic (EEG), and stereoelectroencephalographic (SEEG) signals recorded from 27 human subjects. Our results demonstrate that CHO outperforms conventional techniques in accurately detecting oscillations. In summary, CHO demonstrates high precision and specificity in detecting neural oscillations in time and frequency domains. The method{\textquoteright}s specificity enables the detailed study of non-sinusoidal characteristics of oscillations, such as the degree of asymmetry and waveform of an oscillation. Furthermore, CHO can be applied to identify how neural oscillations govern interactions throughout the brain and to determine oscillatory biomarkers that index abnormal brain function.

}, keywords = {Brain, Electrocorticography, Electroencephalography, Humans, Signal Processing, Computer-Assisted}, issn = {2050-084X}, doi = {10.7554/eLife.91605}, author = {Cho, Hohyun and Adamek, Markus and Willie, Jon T and Brunner, Peter} } @article {4581, title = {Novel Cyclic Homogeneous Oscillation Detection Method for High Accuracy and Specific Characterization of Neural Dynamics.}, journal = {bioRxiv}, year = {2024}, month = {2024 Mar 23}, abstract = {

Detecting temporal and spectral features of neural oscillations is essential to understanding dynamic brain function. Traditionally, the presence and frequency of neural oscillations are determined by identifying peaks over 1/f noise within the power spectrum. However, this approach solely operates within the frequency domain and thus cannot adequately distinguish between the fundamental frequency of a non-sinusoidal oscillation and its harmonics. Non-sinusoidal signals generate harmonics, significantly increasing the false-positive detection rate - a confounding factor in the analysis of neural oscillations. To overcome these limitations, we define the fundamental criteria that characterize a neural oscillation and introduce the Cyclic Homogeneous Oscillation (CHO) detection method that implements these criteria based on an auto-correlation approach that determines the oscillation{\textquoteright}s periodicity and fundamental frequency. We evaluated CHO by verifying its performance on simulated sinusoidal and non-sinusoidal oscillatory bursts convolved with 1/f noise. Our results demonstrate that CHO outperforms conventional techniques in accurately detecting oscillations. Specifically, we determined the sensitivity and specificity of CHO as a function of signal-to-noise ratio (SNR). We further assessed CHO by testing it on electrocorticographic (ECoG, 8 subjects) and electroencephalographic (EEG, 7 subjects) signals recorded during the pre-stimulus period of an auditory reaction time task and on electrocorticographic signals (6 SEEG subjects and 6 ECoG subjects) collected during resting state. In the reaction time task, the CHO method detected auditory alpha and pre-motor beta oscillations in ECoG signals and occipital alpha and pre-motor beta oscillations in EEG signals. Moreover, CHO determined the fundamental frequency of hippocampal oscillations in the human hippocampus during the resting state (6 SEEG subjects). In summary, CHO demonstrates high precision and specificity in detecting neural oscillations in time and frequency domains. The method{\textquoteright}s specificity enables the detailed study of non-sinusoidal characteristics of oscillations, such as the degree of asymmetry and waveform of an oscillation. Furthermore, CHO can be applied to identify how neural oscillations govern interactions throughout the brain and to determine oscillatory biomarkers that index abnormal brain function.

}, issn = {2692-8205}, doi = {10.1101/2023.10.04.560843}, author = {Cho, Hohyun and Adamek, Markus and Willie, Jon T and Brunner, Peter} } @article {4583, title = {A novel theta-controlled vibrotactile brain-computer interface to treat chronic pain: a pilot study.}, journal = {Sci Rep}, volume = {14}, year = {2024}, month = {2024 Feb 10}, pages = {3433}, abstract = {

Limitations in chronic pain therapies necessitate novel interventions that are effective, accessible, and safe. Brain-computer interfaces (BCIs) provide a promising modality for targeting neuropathology underlying chronic pain by converting recorded neural activity into perceivable outputs. Recent evidence suggests that increased frontal theta power (4-7~Hz) reflects pain relief from chronic and acute pain. Further studies have suggested that vibrotactile stimulation decreases pain intensity in experimental and clinical models. This longitudinal, non-randomized, open-label pilot study{\textquoteright}s objective was to reinforce frontal theta activity in six patients with chronic upper extremity pain using a novel vibrotactile neurofeedback BCI system. Patients increased their BCI performance, reflecting thought-driven control of neurofeedback, and showed a significant decrease in pain severity (1.29 {\textpm} 0.25 MAD, p = 0.03, q = 0.05) and pain interference (1.79 {\textpm} 1.10 MAD p = 0.03, q = 0.05) scores without any adverse events. Pain relief significantly correlated with frontal theta modulation. These findings highlight the potential of BCI-mediated cortico-sensory coupling of frontal theta with vibrotactile stimulation for alleviating chronic pain.

}, keywords = {brain-computer interfaces, Chronic Pain, Electroencephalography, Humans, Longitudinal Studies, Neurofeedback, Non-Randomized Controlled Trials as Topic, Pilot Projects}, issn = {2045-2322}, doi = {10.1038/s41598-024-53261-3}, author = {Demarest, Phillip and Rustamov, Nabi and Swift, James and Xie, Tao and Adamek, Markus and Cho, Hohyun and Wilson, Elizabeth and Han, Zhuangyu and Belsten, Alexander and Luczak, Nicholas and Brunner, Peter and Haroutounian, Simon and Leuthardt, Eric C} } @article {4481, title = {Characterization of High-Gamma Activity in Electrocorticographic signals}, journal = {Frontiers in Neuroscience}, volume = {17}, year = {2023}, month = {08/2023}, abstract = {Introduction: Electrocorticographic (ECoG) high-gamma activity (HGA) is a widely recognized and robust neural correlate of cognition and behavior. However, fundamental signal properties of HGA, such as the high-gamma frequency band or temporal dynamics of HGA, have never been systematically characterized. As a result, HGA estimators are often poorly adjusted, such that they miss valuable physiological information. Methods: To address these issues, we conducted a thorough qualitative and quantitative characterization of HGA in ECoG signals. Our study is based on ECoG signals recorded from 18 epilepsy patients while performing motor control, listening, and visual perception tasks. In this study, we first categorize HGA into HGA types based on the cognitive/behavioral task. For each HGA type, we then systematically quantify three fundamental signal properties of HGA: the high-gamma frequency band, the HGA bandwidth, and the temporal dynamics of HGA. Results: The high-gamma frequency band strongly varies across subjects and across cognitive/behavioral tasks. In addition, HGA time courses have lowpass character, with transients limited to 10 Hz. The task-related rise time and duration of these HGA time courses depend on the individual subject and cognitive/behavioral task. Task-related HGA amplitudes are comparable across the investigated tasks. Discussion: This study is of high practical relevance because it provides a systematic basis for optimizing experiment design, ECoG acquisition and processing, and HGA estimation. Our results reveal previously unknown characteristics of HGA, the physiological principles of which need to be investigated in further studies.}, issn = {1662-453X}, doi = {10.3389/fnins.2023.1206120}, url = {https://www.frontiersin.org/articles/10.3389/fnins.2023.1206120}, author = {Gruenwald, Johannes and Sieghartsleitner, Sebastian and Kapeller, Christoph and Scharinger, Josef and Kamada, Kyousuke and Brunner, Peter and Guger, Christoph} } @article {4462, title = {A motor association area in the depths of the central sulcus.}, journal = {Nat Neurosci}, volume = {26}, year = {2023}, month = {07/2023}, pages = {1165-1169}, abstract = {

Cells in the precentral gyrus directly send signals to the periphery to generate movement and are principally organized as a topological map of the body. We find that movement-induced electrophysiological responses from depth electrodes extend this map three-dimensionally throughout the gyrus. Unexpectedly, this organization is interrupted by a previously undescribed motor association area in the depths of the midlateral aspect of the central sulcus. This {\textquoteright}Rolandic motor association{\textquoteright} (RMA) area is active during movements of different body parts from both sides of the body and may be important for coordinating complex behaviors.

}, keywords = {Brain Mapping, Motor Cortex, Movement}, issn = {1546-1726}, doi = {10.1038/s41593-023-01346-z}, author = {Jensen, Michael A and Huang, Harvey and Valencia, Gabriela Ojeda and Klassen, Bryan T and van den Boom, Max A and Kaufmann, Timothy J and Schalk, Gerwin and Brunner, Peter and Worrell, Gregory A and Hermes, Dora and Miller, Kai J} } @article {4448, title = {Passive functional mapping of receptive language cortex during general anesthesia using electrocorticography.}, journal = {Clin Neurophysiol}, volume = {147}, year = {2023}, month = {03/2023}, pages = {31-44}, abstract = {

OBJECTIVE: To investigate the feasibility of passive functional mapping in the receptive language cortex during general anesthesia using electrocorticographic (ECoG) signals.

METHODS: We used subdurally placed ECoG grids to record cortical responses to speech stimuli during awake and anesthesia conditions. We identified the cortical areas with significant responses to the stimuli using the spectro-temporal consistency of the brain signal in the broadband gamma (BBG) frequency band (70-170~Hz).

RESULTS: We found that ECoG BBG responses during general anesthesia effectively identify cortical regions associated with receptive language function. Our analyses demonstrated that the ability to identify receptive language cortex varies across different states and depths of anesthesia. We confirmed these results by comparing them to receptive language areas identified during the awake condition. Quantification of these results demonstrated an average sensitivity and specificity of passive language mapping during general anesthesia to be 49{\textpm}7.7\% and 100\%, respectively.

CONCLUSION: Our results demonstrate that mapping receptive language cortex in patients during general anesthesia is feasible.

SIGNIFICANCE: Our proposed protocol could greatly expand the population of patients that can benefit from passive language mapping techniques, and could eliminate the risks associated with electrocortical stimulation during an awake craniotomy.

}, keywords = {Anesthesia, General, Brain, Brain Mapping, Cerebral Cortex, Electrocorticography, Humans, Language}, issn = {1872-8952}, doi = {10.1016/j.clinph.2022.11.021}, author = {Nourmohammadi, Amin and Swift, James R and de Pesters, Adriana and Guay, Christian S and Adamo, Matthew A and Dalfino, John C and Ritaccio, Anthony L and Schalk, Gerwin and Brunner, Peter} } @article {4459, title = {A somato-cognitive action network alternates with effector regions in motor cortex.}, journal = {Nature}, volume = {617}, year = {2023}, month = {05/2023}, pages = {351-359}, abstract = {

Motor cortex (M1) has been thought to form a continuous somatotopic homunculus extending down~the precentral gyrus from foot to face representations, despite evidence for concentric functional zones and maps of complex actions. Here, using precision functional magnetic resonance imaging (fMRI) methods, we find that the classic homunculus is interrupted by regions with distinct connectivity, structure and function, alternating with effector-specific (foot, hand and mouth) areas. These inter-effector regions exhibit decreased cortical thickness and strong functional connectivity to each other, as well as to the cingulo-opercular network (CON), critical for action and physiological control, arousal, errors and pain. This interdigitation of action control-linked and motor effector regions was verified in the three largest fMRI datasets. Macaque and pediatric (newborn, infant and child) precision fMRI suggested cross-species homologues and developmental precursors of the inter-effector system. A battery of motor and action fMRI tasks documented concentric effector somatotopies, separated by the CON-linked inter-effector regions. The inter-effectors lacked movement specificity and co-activated during action planning (coordination of hands and feet) and axial body movement (such as of the abdomen or eyebrows). These results, together with previous studies demonstrating stimulation-evoked complex actions and connectivity to internal organs such as the adrenal medulla, suggest that M1 is punctuated by a system for whole-body action planning, the somato-cognitive action network (SCAN). In M1, two parallel systems intertwine, forming an integrate-isolate pattern: effector-specific regions (foot, hand and mouth) for isolating fine motor control and the SCAN for integrating goals, physiology and body movement.

}, keywords = {Animals, Brain Mapping, Child, Cognition, Datasets as Topic, Foot, Hand, Humans, Infant, Infant, Newborn, Macaca, Magnetic Resonance Imaging, Motor Cortex, Mouth}, issn = {1476-4687}, doi = {10.1038/s41586-023-05964-2}, author = {Gordon, Evan M and Chauvin, Roselyne J and Van, Andrew N and Rajesh, Aishwarya and Nielsen, Ashley and Newbold, Dillan J and Lynch, Charles J and Seider, Nicole A and Krimmel, Samuel R and Scheidter, Kristen M and Monk, Julia and Miller, Ryland L and Metoki, Athanasia and Montez, David F and Zheng, Annie and Elbau, Immanuel and Madison, Thomas and Nishino, Tomoyuki and Myers, Michael J and Kaplan, Sydney and Badke D{\textquoteright}Andrea, Carolina and Demeter, Damion V and Feigelis, Matthew and Ramirez, Julian S B and Xu, Ting and Barch, Deanna M and Smyser, Christopher D and Rogers, Cynthia E and Zimmermann, Jan and Botteron, Kelly N and Pruett, John R and Willie, Jon T and Brunner, Peter and Shimony, Joshua S and Kay, Benjamin P and Marek, Scott and Norris, Scott A and Gratton, Caterina and Sylvester, Chad M and Power, Jonathan D and Liston, Conor and Greene, Deanna J and Roland, Jarod L and Petersen, Steven E and Raichle, Marcus E and Laumann, Timothy O and Fair, Damien A and Dosenbach, Nico U F} } @article {4447, title = {Toward a fully implantable ecosystem for adaptive neuromodulation in humans: Preliminary experience with the CorTec BrainInterchange device in a canine model.}, journal = {Front Neurosci}, volume = {16}, year = {2022}, month = {12/2022}, pages = {932782}, abstract = {

This article describes initial work toward an ecosystem for adaptive neuromodulation in humans by documenting the experience of implanting CorTec{\textquoteright}s BrainInterchange (BIC) device in a beagle canine and using the BCI2000 environment to interact with the BIC device. It begins with laying out the substantial opportunity presented by a useful, easy-to-use, and widely available hardware/software ecosystem in the current landscape of the field of adaptive neuromodulation, and then describes experience with implantation, software integration, and post-surgical validation of recording of brain signals and implant parameters. Initial experience suggests that the hardware capabilities of the BIC device are fully supported by BCI2000, and that the BIC/BCI2000 device can record and process brain signals during free behavior. With further development and validation, the BIC/BCI2000 ecosystem could become an important tool for research into new adaptive neuromodulation protocols in humans.

}, issn = {1662-4548}, doi = {10.3389/fnins.2022.932782}, author = {Schalk, Gerwin and Worrell, Samuel and Mivalt, Filip and Belsten, Alexander and Kim, Inyong and Morris, Jonathan M and Hermes, Dora and Klassen, Bryan T and Staff, Nathan P and Messina, Steven and Kaufmann, Timothy and Rickert, J{\"o}rn and Brunner, Peter and Worrell, Gregory A and Miller, Kai J} }