LBCN Select Publications

Abstract

Intracranial electroencephalography (iEEG) offers human neuroscientists a unique opportunity to collect brain data simultaneously from hundreds of discrete brain sites with high temporal resolution and anatomical precision at the single subject level. Although the number of iEEG studies keeps surging in the recent neuroscience literature, the practical details of this research platform often remain unclear to those not actively involved. This report offers insights from 15+ years of experience with iEEG practice to add clarity about the realities on the ground at a single medical center in the United States. We provide quantified details about the brain regions that are often covered for recordings, number of electrodes often utilized in each patient, and how neuroscience research is safely integrated with clinical monitoring and patient care. We document a clear shift from electrocorticography with subdural electrodes to stereoelectroencephalography with depth electrodes. We present our clinical results, emphasizing that iEEG offers a unique opportunity to expand our understanding of human brain function and achieve improved seizure control and long-term outcomes for millions of patients currently suffering from medication-resistant epilepsy. This report not only provides critical insights into the practical realities of iEEG research but also serves as a valuable resource for cognitive neuroscientists seeking to leverage this methodology for studying human brain function. By detailing the spatial and temporal characteristics of iEEG recordings, as well as the evolving trends in electrode implantation, this article helps bridge the gap between clinical practice and cognitive neuroscience applications.

View details for DOI 10.1162/JOCN.a.53

View details for Web of Science ID 001591200900018

View details for PubMedID 40392101

Abstract

The Papez circuit traditionally highlights the anterior nuclei of the thalamus (ANT) as the main relay of hippocampal (HPC) output to the cortex, a view that has shaped neuromodulation strategies in temporal lobe epilepsy (TLE). However, recent studies suggest that the medial subregion of the pulvinar (mPLV)- a thalamic nucleus that has undergone significant evolutionary expansion throughout the mammalian brain evolution- also forms functional connections with medial temporal lobe (MTL) structures, including the hippocampus (HPC). To date, however, there is a lack of causal evidence directly comparing the connectivity between the HPC and the two thalamic nuclei (mPLV and ANT) and between the two thalamic structures within the same brains. In this study, we investigated 41 patients with medial (mTLE, N=22) and non-medial temporal lobe epilepsy (non-mTLE, N=19) implanted with simultaneous depth electrodes in the HPC, ANT, and mPLV. Repeated single-pulse electrical stimulations were applied to compare the causal electrophysiological connectivity of these regions within the same individuals. Our intra-subject analysis revealed that anterior HPC stimulation evoked strong responses in both ANT and mPLV, with mPLV responses occurring significantly later than those in the ANT [linear mixed-effect model (LMM), Mean: 10.19ms, 95% CI [1.78, 18.59], (FDR corrected P = 0.040)]. In contrast, stimulation of the posterior HPC resulted in stronger (and a trend for earlier) responses in mPLV compared to ANT [LMM: Mean: 0.117, 95% CI [0.033, 0.201] (FDR corrected P = 0.012)]. This finding suggests anterio-posterior gradient of HPC connectivity. Furthermore, we found robust bilateral and bidirectional connectivity between ANT and mPLV. Stimulation of either elicited responses in the other, including contralateral thalamus. This represents clear evidence for both intra-thalamic and inter-thalamic connectivity within the human brain. Our findings offer new insights about the connectivity of human HPC with the thalamus and strong intra-thalamic exchange of electrophysiological activity within the human brain.

View details for DOI 10.1093/brain/awaf342

View details for PubMedID 41048168

View details for DOI 10.1073/pnas.2514623122

View details for PubMedID 40720667

Abstract

Emerging literature suggests that multi-lead thalamic DBS may be safe and therapeutically beneficial to patients with diffuse or poorly defined epileptic networks; however, more studies are needed to support such off-label methods. Here, in a single-center retrospective, non-controlled observational pilot study, we investigated the off-label use of a multinodal thalamic DBS system in patients with medically refractory and poorly localized epilepsies.Utilizing either a robotic or frame-based technique, we implanted four DBS leads (Boston Scientific, Marlborough, MA) into either bilateral (1) ANT and CM (n = 6 patients) or (2) ANT and PLV (n = 4 patients). In five patients, only bilateral ANT (n = 2) or CM (n = 3) stimulations were applied while in five other patients, bilateral ANT was supplemented with bilateral CM (n = 1) or PLV (n = 4) DBS. The thalamic targets were personalized in each patient based on available clinical or intracranial multi-site thalamic stereoencephalography or scalp EEG evidence. Primary outcomes were intraoperative and postoperative complications as well as changes in seizure frequency.DBS implantation was well tolerated with no intraoperative complications. Only one patient had a post-operative wound-related complication. Average follow-up was 12.4 months (range 3-21 months). Most patients (nine out of 10 patients) experienced a clinically noticeable reduction in seizure frequency, including a subset (two out of 10 patients) who were seizure free. Efficacy was similar in the two-lead and four-lead stimulation groups.This cohort provides early and preliminary data documenting the feasibility and safety (and clinical utility) of targeted multinodal thalamic DBS for medically refractory, poorly localized epilepsy. As this was not a controlled outcomes study, the clinical efficacy data must be interpreted cautiously. Our findings may motivate larger controlled studies to rigorously evaluate the clinical efficacy of personalized optimization of multinodal configuration in patients with diffuse or poorly defined epileptic networks.

View details for DOI 10.1002/epd2.70070

View details for PubMedID 40699906

Abstract

The pulvinar is increasingly recognized as a promising target for neuromodulation in drug-resistant epilepsy (DRE). Despite growing interest, empirical evidence substantiating the efficacy and mechanism of its deep brain stimulation (DBS) in patients with epilepsy remains scarce. This study endeavors to address this knowledge gap by investigating the electrophysiological properties of pulvinar.We enrolled 35 patients with DRE who underwent stereoelectroencephalography with electrodes extended to the pulvinar and analyzed the pulvinar's involvement in seizures originating from different brain lobes. Repeated single electrical pulse stimulation (RSEPS) was employed to map the connectivity of the pulvinar. We also evaluated the effect of pulvinar DBS on interictal epileptic discharges within the epileptogenic zone.We observed that greater involvement of the pulvinar exists in temporal lobe epilepsy, with the medial pulvinar (PuM) showing stronger engagement. Findings with RSEPS highlighted significant connections from the PuM to parietal, occipital, and temporal regions, as well as robust connections from the mesial temporal lobes to PuM. Lastly, we found high-frequency stimulation (140-150 Hz) of PuM significantly reduced interictal epileptic discharges.Our study supports emerging evidence for pulvinar involvement in seizure propagation. The data with RSEPS also map PuM causal connectivity in the human brain. Although the clinical utility of pulvinar neuromodulation in patients with DRE remains to be determined by prospective clinical trials, our findings provide a convincing link between PuM neuromodulation and the reduction of epileptic activity.

View details for DOI 10.1111/epi.18537

View details for PubMedID 40673605

View details for DOI 10.1038/s41593-025-02035-9

View details for Web of Science ID 001530804700001

View details for PubMedID 40670686

View details for PubMedCentralID 11044197

Abstract

The hippocampus is critical for encoding episodic memories, but how it interacts with cortical regions during this process remains unclear. In this study, 16 participants with implanted electrodes in the insula (217 sites) and hippocampus (131 sites) viewed emotionally valenced words and attempted to recall them. During encoding, one subset of insular neuronal populations showed changes in aperiodic activity that predicted successful recall. These insular changes followed hippocampal theta but preceded hippocampal ripples. Another subset of insular sites responded to word valence, unrelated to memory performance. Direct electrical stimulation of memory-related insular sites evoked early responses in the ipsilateral hippocampus, whereas stimulation of valence-related sites did not. Conversely, stimulating hippocampal sites produced slow, variable signals across all insular sites, suggesting asymmetric communication between the hippocampus and the insula. These findings provide a glimpse of mesoscale hippocampal interactions with functionally selective neuronal populations within a given cortical structure.

View details for DOI 10.1038/s41593-025-02005-1

View details for PubMedID 40659846

View details for PubMedCentralID 3172893

Abstract

INTRODUCTION: Prior findings on direct intracranial electrical stimulation (iES) of the human orbitofrontal cortex (OFC), which includes the orbital and ventromedial prefrontal regions, have been mixed, with several reports lacking replication. We aimed to clarify the effects of iES in the OFC.METHODS: We analyzed data from 608 stimulations across 277 OFC site pairs (352 sites total) in 49 patients collected over 17 years of our practice.RESULTS: We found 24.4% of sites as responsive to iES, with subjects reporting visual and olfactory sensations. However, post hoc analysis revealed that these responses largely originated from the stimulation of nearby non-OFC optic and olfactory structures. After applying quality controls, stimulation of only 0.6% of OFC sites (2 sites, 2 patients) produced changes in subjective domain, while 99.4% had no reportable effects. Contrary to earlier studies, we found no evidence of valence lateralization or functional organization within the OFC.CONCLUSIONS: Our findings suggest that the electrical perturbation of OFC is largely silent and does not lead to reportable change in the subjective state of the individual.SIGNIFICANCE: Orbitofrontal cortex is a higher transmodal cortical area. The variability and limited replicability of reported effects from prior publications and the inconsistencies in the extant literature about OFC stimulations can be attributed to methodological shortcomings.

View details for DOI 10.1097/WNP.0000000000001184

View details for PubMedID 40637402

View details for DOI 10.1038/s41467-025-60452-7

View details for PubMedID 40473622

Abstract

Attention samples visual space sequentially to enhance behaviorally relevant sensory representations. While traditionally conceptualized as a static continuous spotlight, contemporary models of attention highlight its discrete nature. But which neural mechanisms govern the temporally precise allocation of attention? Periodic brain activity as exemplified by neuronal oscillations as well as aperiodic temporal structure in the form of intrinsic neural timescales have been proposed to orchestrate the attentional sampling process in space and time. However, both mechanisms have been largely studied in isolation. To date, it remains unclear whether periodic and aperiodic temporal structure reflect distinct neural mechanisms. Here, we combined computational simulations with a multimodal approach encompassing five experiments, and three different variants of classic spatial attention paradigms, to differentiate aperiodic from oscillatory-based sampling. Converging evidence across behavior as well as scalp and intracranial electroencephalography (EEG) revealed that periodic and aperiodic temporal regularities can theoretically and experimentally be distinguished. Our results extend the rhythmic sampling framework of attention by demonstrating that aperiodic neural timescales predict behavior in a spatially-, context-, and demand-dependent manner. Aperiodic timescales increased from sensory to association cortex, decreased during sensory processing or action execution, and were prolonged with increasing behavioral demands. These results reveal that multiple, concurrent temporal regularities govern attentional sampling.

View details for DOI 10.1371/journal.pbio.3003232

View details for PubMedID 40577312

Abstract

The goal of this study was to investigate how the topographical map of human subjective experiences induced by intracranial electrical stimulation (iES) compares to the map of subjective auras experienced by patients during seizures involving the same cortical areas (here, the insular cortex).We recruited 14 patients with insular epilepsies confirmed with intracranial electroencephalography in the United States (N = 7) and France (N = 7). We identified insular regions involved early in seizures (i.e., presumed seizure-onset zones [SOZs]), and documented the auras reported by each patient. Data from subjective reports of auras were then compared with subjective reports during insular iES in 10 of the 14 patients with confirmed insular seizures and in 17 other patients with stimulation of normal insular sites (previously reported by our group).Epileptic auras reported by patients with seizures involving the insula were largely categorized as visceral, pain/temperature, or non-painful/non-temperature bodily sensations. We observed a striking similarity between the topographical maps of auras during insular seizures and the subjective states induced by the stimulation of the same insular regions (either identified as epileptic or not-epileptic).Our findings may guide informed clinical decision-making in patients with similar ictal semiology and insular lesions identified on magnetic resonance imaging. On the basis of our findings, we conclude that (1) electrically evoked and seizure-induced subjective symptoms are similar when the presumed SOZ involves the insula; (2) the topography of subjective experiences evoked by insular iES and seizures is largely anatomically consistent across subjects; and (3) stimulation of radiographically abnormal brain tissue seems to cause symptoms that are similar and reliable compared to the ones evoked by the stimulation of the same site in subjects without structural insular abnormalities. The extent to which these findings can be generalized to other cortical regions and networks remains to be determined.

View details for DOI 10.1111/epi.18433

View details for PubMedID 40357762

Abstract

Pain remains poorly understood in task-free contexts, limiting our understanding of its neurobehavioral basis in naturalistic settings. Here, we use a multimodal, data-driven approach with intracranial electroencephalography, pain self-reports, and facial expression analysis to study acute pain in twelve epilepsy patients under continuous neural and audiovisual monitoring. Using machine learning, we successfully decode individual participants' high versus low pain states from distributed neural activity, involving mesolimbic regions, striatum, and temporoparietal cortex. Neural representation of pain remains stable for hours and is modulated by pain onset and relief. Objective facial expressions also classify pain states, concordant with neural findings. Importantly, we identify transient periods of momentary pain as a distinct naturalistic acute pain measure, which can be reliably discriminated from affect-neutral periods using neural and facial features. These findings reveal reliable neurobehavioral markers of acute pain across naturalistic contexts, underscoring the potential for monitoring and personalizing pain interventions in real-world settings.

View details for DOI 10.1038/s41467-025-59756-5

View details for PubMedID 40350488

View details for PubMedCentralID 6146950

View details for DOI 10.1016/j.neucli.2025.103063

View details for PubMedID 40015234

Abstract

Deep brain stimulation (DBS) targeting the anterior nucleus of the thalamus (ANT) has been shown to be effective in treating some patients with medically refractory epilepsy. However, it remains unknown how seizures spread through the ANT relative to other thalamic nuclei. This study aimed to investigate, through simultaneous recordings from both ANT and pulvinar (PLV) nucleus, their roles in seizure propagation. Our goal was to determine whether the ANT is the primary site of seizure propagation in the human thalamus, especially for focal seizure originating in the medial temporal lobe.In a retrospective design, we studied EEGs and clinical notes of patients with refractory epilepsy who were implanted with stereo-EEG (sEEG) electrodes across cortical regions, some of which were extended to reach various sites of the thalamus (i.e., multisite thalamic recordings). We selected patients from the Stanford Comprehensive Epilepsy Center with both ANT and PLV electrodes and collected information about the timing and anatomy of seizure activity in the seizure onset zones, usually temporal, and the 2 thalamic sites.We recruited 17 (5 female, mean age 32 years) adult patients with simultaneous ipsilateral ANT and PLV recordings. In all patients, the procedure was safe without any complications. In 100% of patients, the thalamus was involved during seizures (in 88% both ANT and PLV and in 82% first the PLV). In patients with confirmed hippocampal or amygdalar onset seizures, 62% had initial involvement and 100% had subsequent involvement of the PLV nucleus. Only 31% showed initial propagation to ANT. All focal-to-bilateral tonic-clonic seizures and most of the focal impaired awareness seizures had early involvement of both ANT and PLV, with rapid spread to the contralateral nuclei.sEEG of thalamic nuclei simultaneously provides an opportunity to understand propagation patterns of seizures with respect to each thalamic subdivision at the individual level. The patterns of seizure propagation, as we report here, provide insights about the prominent involvement of the PLV nucleus during seizure propagation. This may motivate future prospective work in larger cohorts of patients to understand how thalamic propagation may predict response to resective/ablative surgery or whether personalization of DBS (for instance, PLV instead of, or together with, ANT) could improve clinical outcomes.

View details for DOI 10.1212/WNL.0000000000210039

View details for PubMedID 39531602

Abstract

The authors recently demonstrated the utility of a novel multinuclear thalamic stereotactic electroencephalography (sEEG) approach to identify personalized seizure propagation networks through the human thalamus. In this study, they detail their strategy to efficiently sample the thalamus.The authors previously showed that a multilead orthogonal transsylvian approach allows lateral-medial sampling of bilateral anterior nuclei of the thalamus (ANTs), mediodorsal (MD) nuclei, and pulvinar (PLV) nuclei, with simultaneous capture of the opercular and insular regions. They also described a novel trans-massa intermedia trajectory to sample bilateral MD nuclei with a single electrode. For a second approach to multinuclear thalamic sampling, they designed a novel long-axis trajectory for posterior-to-anterior sampling of the lateral PLV nucleus, lateral MD nucleus, and ANT with a single electrode. Superficially, this trajectory samples from the posterior inferior temporal gyrus and then the posterior hippocampus, known as seizure network nodes. Concurrent with this long-axis trajectory, the centromedian nucleus can also be targeted with the orthogonal approach, minimizing the number of electrodes required to sample all 8 of the most relevant nuclei (4 on each side).The multinuclear thalamic sampling approaches resulted in no complications in a series of 34 patients.This study provides a strategy and specific implementation details for these approaches to identify the thalamic seizure networks that are increasingly important in the surgical treatment of epilepsy.

View details for DOI 10.3171/2024.7.JNS24452

View details for PubMedID 39576976

Abstract

Pain is a complex experience that remains largely unexplored in naturalistic contexts, hindering our understanding of its neurobehavioral representation in ecologically valid settings. To address this, we employed a multimodal, data-driven approach integrating intracranial electroencephalography, pain self-reports, and facial expression quantification to characterize the neural and behavioral correlates of naturalistic acute pain in twelve epilepsy patients undergoing continuous monitoring with neural and audiovisual recordings. High self-reported pain states were associated with elevated blood pressure, increased pain medication use, and distinct facial muscle activations. Using machine learning, we successfully decoded individual participants' high versus low self-reported pain states from distributed neural activity patterns (mean AUC = 0.70), involving mesolimbic regions, striatum, and temporoparietal cortex. High self-reported pain states exhibited increased low-frequency activity in temporoparietal areas and decreased high-frequency activity in mesolimbic regions (hippocampus, cingulate, and orbitofrontal cortex) compared to low pain states. This neural pain representation remained stable for hours and was modulated by pain onset and relief. Objective facial expression changes also classified self-reported pain states, with results concordant with electrophysiological predictions. Importantly, we identified transient periods of momentary pain as a distinct naturalistic acute pain measure, which could be reliably differentiated from affect-neutral periods using intracranial and facial features, albeit with neural and facial patterns distinct from self-reported pain. These findings reveal reliable neurobehavioral markers of naturalistic acute pain across contexts and timescales, underscoring the potential for developing personalized pain interventions in real-world settings.

View details for DOI 10.1101/2024.05.10.593652

View details for PubMedID 38766098

View details for PubMedCentralID PMC11100805

Abstract

Background and Objectives: High costs associated with after-hour electroencephalography (EEG) constitute a barrier for financially constrained hospitals to provide this neurodiagnostic procedure outside regular working hours. Our study aims to deepen our understanding of the cost elements involved in delivering EEG services during after-hours.Methods: We accessed publicly available data sets and created a cost model depending on 3 most commonly seen staffing scenarios: (1) technologist on-site, (2) technologist on-call from home, and (3) a hybrid of the two.Results: Cost of EEG depends on the volume of testing and the staffing plan. Within the various cost elements, labor cost of EEG technologists is the predominant expenditure, which varies across geographic regions and urban areas.Discussion: We provide a model to explain why access to EEGs during after-hours has a substantial expense. This model provides a cost calculator tool (made available as part of this publication in eAppendix 1, links.lww.com/CPJ/A513) to estimate the cost of EEG platform based on site-specific staffing scenarios and annual volume.

View details for DOI 10.1212/CPJ.0000000000200264

View details for PubMedID 38585440

Abstract

Previous neuroimaging studies have offered unique insights about the spatial organization of activations and deactivations across the brain, however these were not powered to explore the exact timing of events at the subsecond scale combined with precise anatomical source information at the level of individual brains. As a result, we know little about the order of engagement across different brain regions during a given cognitive task. Using experimental arithmetic tasks as a prototype for human-unique symbolic processing, we recorded directly across 10,076 brain sites in 85 human subjects (52% female) using intracranial electroencephalography (iEEG). Our data revealed a remarkably distributed change of activity in almost half of the sampled sites. Notably, an orderly successive activation of a set of brain regions - anatomically consistent across subjects- was observed in individual brains. Furthermore, the temporal order of activations across these sites was replicable across subjects and trials. Moreover, the degree of functional connectivity between the sites decreased as a function of temporal distance between regions, suggesting that information is partially leaked or transformed along the processing chain. Furthermore, in each activated region, distinct neuronal populations with opposite activity patterns during target and control conditions were juxtaposed in an anatomically orderly manner. Our study complements the prior imaging studies by providing hitherto unknown information about the timing of events in the brain during arithmetic processing. Such findings can be a basis for developing mechanistic computational models of human-specific cognitive symbolic systems.Significance statement Our study elucidates the spatiotemporal dynamics and anatomical specificity of brain activations across >10,000 sites during arithmetic tasks, as captured by intracranial EEG. We discovered an orderly, successive activation of brain regions, consistent across individuals, and a decrease in functional connectivity as a function of temporal distance between regions. Our findings provide unprecedented insights into the sequence of cognitive processing and regional interactions, offering a novel perspective for enhancing computational models of cognitive symbolic systems.

View details for DOI 10.1523/JNEUROSCI.2118-22.2024

View details for PubMedID 38485257

Abstract

We recorded directly from the orbital (oPFC) and ventromedial (vmPFC) subregions of the orbitofrontal cortex (OFC) in 22 (9 female, 13 male) epilepsy patients undergoing intracranial electroencephalography (iEEG) monitoring during an experimental task in which the participants judged the accuracy of self-referential autobiographical statements as well as valenced self-judgments. We found significantly increased high-frequency activity (HFA) in about 13% of oPFC sites (10/18 subjects) and 16% of vmPFC sites (4/12 subjects) during both of these self-referential thought processes, with the HFA power being modulated by the content of self-referential stimuli. The location of these activated sites corresponded with the location of fMRI-identified limbic network. Furthermore, the onset of HFA in the vmPFC was significantly earlier than in the oPFC in all patients with simultaneous recordings in both regions. In 11 patients with available depression scores from comprehensive neuropsychological assessments, we documented diminished HFA activity in the OFC during positive self-judgment trials among individuals with higher depression scores; responses during negative self-judgment trials were not related to the patients' depression scores. Our findings provide new temporal and anatomical information about the mode of engagement in two important subregions of the OFC during autobiographical memory and self-judgment conditions. Our findings from the OFC support the hypothesis that diminished brain activity during positive self-evaluations, rather than heightened activity during negative self-evaluations, plays a key role in the pathophysiology of depression.Significance Statement In direct recordings from the human brain, we observed significant responses characterized by high-frequency activity, aka high gamma, in distinct populations of the orbital (oPFC) and ventromedial (vmPFC) regions of the orbitofrontal cortex (OFC) - corresponding to the location of the resting state limbic network and to a lesser extent default mode network - when human subjects were engaged in self-referential episodic memory retrieval and self-trait judgments. Notably, simultaneous recordings across the two OFC regions in the same individuals revealed earlier activations in vmPFC than oPFC, indicating that the two subregions are involved in different stages of self-referential thought processes. Lastly, in individuals with high depressive symptoms, the OFC responses were significantly reduced during positive self-judgments but not heightened during negative self-evaluations.

View details for DOI 10.1523/JNEUROSCI.1634-23.2024

View details for PubMedID 38316564

Abstract

Overall stereoelectroencephalography (SEEG) has a favorable risk profile, patient tolerability, and superior investigative capability of individualized 3-dimensional seizure onset activity over subdural electrodes. Further, our recent surgical approach to safely enable multinuclear thalamic propagation mapping can only be performed with SEEG. For these reasons, SEEG has become the gold standard of phase II monitoring at our institution, and believe the ability to develop precision network-centric approaches to therapy will be critical to enhance our ability to care for medically refractory, and importantly, even complex multifocal, generalized, or surgically refractory epilepsy patients.

View details for DOI 10.1016/j.nec.2023.08.003

View details for PubMedID 38000844

View details for Web of Science ID 001131541101056

Abstract

Functions of the human insula have been explored extensively with neuroimaging methods and intracranial electrical stimulation studies that have highlighted a functional segregation across its subregions. A recently developed cytoarchitectonic map of the human insula has also segregated this brain region into various areas. Our knowledge of the functional organization of this brain region at the level of these fine-parceled microstructural areas remains only partially understood. We address this gap of knowledge by applying a multimodal approach linking direct electrical stimulation and task-evoked intracranial EEG recordings with microstructural subdivisions of the human insular cortex. In 17 neurosurgical patients with 142 implanted electrodes, stimulation of 40 % of the sites induced a reportable change in the conscious experience of the subjects in visceral/autonomic, anxiety, taste/olfactory, pain/temperature as well as somatosensory domains. These subjective responses showed a topographical allocation to microstructural areas defined by probabilistic cytoarchitectonic parcellation maps of the human insula. We found the pain and thermal responses to be located in areas lg2/ld2, while non-painful/non-thermal somatosensory responses corresponded to area ld3 and visceroceptive responses to area Id6. Lastly, the stimulation of area Id7 in the dorsal anterior insula, failed to induce reportable changes to subjective experience even though intracranial EEG recordings from this region captured significant time-locked high-frequency activity (HFA. Our results provide a multimodal map of functional subdivisions within the human insular cortex at the individual brain basis and characterize their anatomical association with fine-grained cytoarchitectonic parcellations of this brain structure.

View details for DOI 10.1016/j.brs.2023.11.001

View details for PubMedID 37949296

View details for DOI 10.1007/s12028-023-01797-z

View details for PubMedID 37523108

Abstract

The role of angular gyrus (AG) in arithmetic processing remains a subject of debate. In the present study, we recorded from the AG, supramarginal gyrus (SMG), intraparietal sulcus (IPS), and superior parietal lobule (SPL) across 467 sites in 30 subjects performing addition or multiplication with digits or number words. We measured the power of high-frequency-broadband (HFB) signal, a surrogate marker for regional cortical engagement, and used single-subject anatomical boundaries to define the location of each recording site. Our recordings revealed the lowest proportion of sites with activation or deactivation within the AG compared to other subregions of the inferior parietal cortex during arithmetic processing. The few activated AG sites were mostly located at the border zones between AG and IPS, or AG and SMG. Additionally, we found that AG sites were more deactivated in trials with fast compared to slow response times. The increase or decrease of HFB within specific AG sites was the same when arithmetic trials were presented with number words versus digits and during multiplication as well as addition trials. Based on our findings, we conclude that the prior neuroimaging findings of so-called activations in the AG during arithmetic processing could have been due to group-based analyses that might have blurred the individual anatomical boundaries of AG or the subtractive nature of the neuroimaging methods in which lesser deactivations compared to the control condition have been interpreted as "activations". Our findings offer a new perspective with electrophysiological data about the engagement of AG during arithmetic processing.

View details for DOI 10.1007/s00429-022-02540-8

View details for PubMedID 35907987

Abstract

Stimulation of the ventromedial hypothalamic region in animals has been reported to cause attack behavior labeled as sham-rage without offering information about the internal affective state of the animal being stimulated.To examine the causal effect of electrical stimulation near the ventromedial region of the human hypothalamus on the human subjective experience and map the electrophysiological connectivity of the hypothalamus with other brain regions.We examined a patient (Subject S20_150) with intracranial electrodes implanted across 170 brain regions, including the hypothalamus. We combined direct electrical stimulation with tractography, cortico-cortical evoked potentials (CCEP), and functional connectivity using resting state intracranial electroencephalography (EEG).Recordings in the hypothalamus did not reveal any epileptic abnormalities. Electrical stimulations near the ventromedial hypothalamus induced profound shame, sadness, and fear but not rage or anger. When repeated single-pulse stimulations were delivered to the hypothalamus, significant responses were evoked in the amygdala, hippocampus, ventromedial-prefrontal and orbitofrontal cortices, anterior cingulate, as well as ventral-anterior and dorsal-posterior insula. The time to first peak of these evoked responses varied and earliest propagations correlated best with the measures of resting-state EEG connectivity and tractography.This patient's case offers details about the affective state induced by the stimulation of the human hypothalamus and provides causal evidence relevant to current theories of emotion and the importance of subcortical structures in processing emotions. The complexity of affective state induced by the stimulation of the hypothalamus and the profile of hypothalamic electrophysiological connectivity suggest that the hypothalamus ought to be seen as a causally important functional unit, within a broader human telencephalon, for our human subjective experience.

View details for DOI 10.1016/j.brs.2022.04.008

View details for PubMedID 35413481

Abstract

Neuroimaging studies of mentalizing (i.e., theory of mind) consistently implicate the default mode network (DMN). Nevertheless, the social cognitive functions of individual DMN regions remain unclear, perhaps due to limited spatiotemporal resolution in neuroimaging. Here we use electrocorticography (ECoG) to directly record neuronal population activity while 16 human participants judge the psychological traits of themselves and others. Self- and other-mentalizing recruit near-identical cortical sites in a common spatiotemporal sequence. Activations begin in the visual cortex, followed by temporoparietal DMN regions, then finally in medial prefrontal regions. Moreover, regions with later activations exhibit stronger functional specificity for mentalizing, stronger associations with behavioral responses, and stronger self/other differentiation. Specifically, other-mentalizing evokes slower and longer activations than self-mentalizing across successive DMN regions, implying lengthier processing at higher levels of representation. Our results suggest a common neurocognitive pathway for self- and other-mentalizing that follows a complex spatiotemporal gradient of functional specialization across DMN and beyond.

View details for DOI 10.1038/s41467-022-29510-2

View details for PubMedID 35395826

Abstract

We studied the temporal dynamics of activity within and across functional MRI (fMRI)-derived nodes of intrinsic resting-state networks of the human brain using intracranial electroencephalography (iEEG) and repeated single-pulse electrical stimulation (SPES) in neurosurgical subjects implanted with intracranial electrodes. We stimulated and recorded from 2,133 and 2,372 sites, respectively, in 29 subjects. We found that N1 and N2 segments of the evoked responses are associated with intra- and internetwork communications, respectively. In a separate cognitive experiment, evoked electrophysiological responses to visual target stimuli occurred with less temporal separation across pairs of electrodes that were located within the same fMRI-defined resting-state networks compared with those located across different resting-state networks. Our results suggest intranetwork prior to internetwork information processing at the subsecond timescale.

View details for DOI 10.1073/pnas.2105031118

View details for PubMedID 34819365

View details for DOI 10.1162/jocn_a_01775

View details for Web of Science ID 000731690600009

Abstract

The posteromedial cortex (PMC) is known to be a core node of the default mode network. Given its anatomical location and blood supply pattern, the effects of targeted disruption of this part of the brain are largely unknown. Here, we report a rare case of a patient (S19_137) with confirmed seizures originating within the PMC. Intracranial recordings confirmed the onset of seizures in the right dorsal posterior cingulate cortex, adjacent to the marginal sulcus, likely corresponding to Brodmann area 31. Upon the onset of seizures, the patient reported a reproducible sense of self-dissociation-a condition he described as a distorted awareness of the position of his body in space and feeling as if he had temporarily become an outside observer to his own thoughts, his "me" having become a separate entity that was listening to different parts of his brain speak to each other. Importantly, 50-Hz electrical stimulation of the seizure zone and a homotopical region within the contralateral PMC induced a subjectively similar state, reproducibly. We supplement our clinical findings with the definition of the patient's network anatomy at sites of interest using cortico-cortical-evoked potentials, experimental and resting-state electrophysiological connectivity, and individual-level functional imaging. This rare case of patient S19_137 highlights the potential causal importance of the PMC for integrating self-referential information and provides clues for future mechanistic studies of self-dissociation in neuropsychiatric populations.

View details for DOI 10.1073/pnas.2100522118

View details for PubMedID 34272280

Abstract

Hippocampal ripples are prominent synchronization events generated by hippocampal neuronal assemblies. To date, ripples have been primarily associated with navigational memory in rodents and short-term episodic recollections in humans. Here, we uncover different profiles of ripple activity in the human hippocampus during the retrieval of recent and remote autobiographical events and semantic facts. We found that the ripple rate increased significantly before reported recall compared to control conditions. Patterns of ripple activity across multiple hippocampal sites demonstrated remarkable specificity for memory type. Intriguingly, these ripple patterns revealed a semantization dimension, in which patterns associated with autobiographical contents become similar to those of semantic memory as a function of memory age. Finally, widely distributed sites across the neocortex exhibited ripple-coupled activations during recollection, with the strongest activation found within the default mode network. Our results thus reveal a key role for hippocampal ripples in orchestrating hippocampal-cortical communication across large-scale networks involved in conscious recollection.

View details for DOI 10.1016/j.neuron.2021.06.020

View details for PubMedID 34297916

Abstract

Our recent work suggests that non-lesional epileptic brain tissue is capable of generating normal neurophysiological responses during cognitive tasks, which are then seized by ongoing pathological epileptic activity. Here, we aim to extend the scope of our work to epileptic periventricular heterotopias (PVH) and examine if the PVH tissue also exhibits normal neurophysiological responses and network-level integration with other non-lesional cortical regions. As part of routine clinical assessment, three adult patients with PVH underwent implantation of intracranial electrodes and participated in experimental cognitive tasks. We obtained simultaneous recordings from PVH and remote cortical sites during rest as well as controlled experimental conditions. In all three subjects (2 female), cognitive experimental conditions evoked significant electrophysiological responses in discrete locations within the PVH tissue that were correlated with responses seen in non-epileptic cortical sites. Moreover, the responsive PVH sites exhibited correlated electrophysiological activity with responsive, non-lesional cortical sites during rest conditions. Taken together, our work clearly demonstrates that the PVH tissue may be functionally organized and it may be functionally integrated within cognitively engaged cortical networks despite its anatomical displacement during neurodevelopment.SIGNIFICANCE STATEMENT:Periventricular heterotopias (PVH) are developmentally abnormal brain tissues that frequently cause epileptic seizures. In a rare opportunity to obtain direct electrophysiological recordings from PVH, we were able to show that, contrary to common assumptions, PVH functional activity is similar to healthy cortical sites during a well-established cognitive task and exhibits clear resting state connectivity with the responsive cortical regions.

View details for DOI 10.1523/JNEUROSCI.2785-20.2021

View details for PubMedID 33727335

Abstract

BACKGROUND: Brain stimulation, both invasive and non-invasive, is increasingly being used to modulate mood and other aspects of subjective experience in various neuropsychiatric conditions. Because this enterprise is deeply dependent on first-person reports provided by patients, sham stimulation is routinely employed to control for demand characteristics and placebo effects. However, a general empirical assessment of the fidelity of this control is missing.OBJECTIVE: To provide an empirical exploration of the fidelity of first-person reports following intracranial electrical stimulation (iES) in neurosurgical patients.METHODS: We assessed Type I (false positive) error rate following 159 sham stimulations administered to 44 adult epilepsy patients implanted with intracranial electrodes and undergoing iES as part of routine clinical procedures at the Stanford Medical Center.RESULTS: The majority of our patients (75%) never committed a single Type I error, and 93% of our sham stimulations (n = 148) yielded true negative reports. False positives were restricted to only 11 patients, and no patient committed more than a single Type I error, even after multiple sham stimulations.CONCLUSION: Neurosurgical patients are highly resilient to Type I errors following sham intracranial brain stimulation. Our findings support the validity of prior research exploring first-person experiences elicited by electrical stimulation of the human brain. More broadly, our data are relevant to emerging efforts to use brain stimulation to modulate mood and other aspects of human subjective experience.

View details for DOI 10.1016/j.brs.2020.10.015

View details for PubMedID 33130019

Abstract

INTRODUCTION: Current electroencephalography (EEG) practice relies on interpretation by expert neurologists, which introduces diagnostic and therapeutic delays that can impact patients' clinical outcomes. As EEG practice expands, these experts are becoming increasingly limited resources. A highly sensitive and specific automated seizure detection system would streamline practice and expedite appropriate management for patients with possible nonconvulsive seizures. We aimed to test the performance of a recently FDA-cleared machine learning method (Claritgamma, Ceribell Inc.) that measures the burden of seizure activity in real time and generates bedside alerts for possible status epilepticus (SE).METHODS: We retrospectively identified adult patients (n=353) who underwent evaluation of possible seizures with Rapid Response EEG system (Rapid-EEG, Ceribell Inc.). Automated detection of seizure activity and seizure burden throughout a recording (calculated as the percentage of ten-second epochs with seizure activity in any 5-min EEG segment) was performed with Claritgamma, and various thresholds of seizure burden were tested (≥10% indicating≥30s of seizure activity in the last 5min,≥50% indicating≥2.5min of seizure activity, and≥90% indicating≥4.5min of seizure activity and triggering a SE alert). The sensitivity and specificity of Claritgamma's real-time seizure burden measurements and SE alerts were compared to the majority consensus of at least two expert neurologists.RESULTS: Majority consensus of neurologists labeled the 353 EEGs as normal or slow activity (n=249), highly epileptiform patterns (HEP, n=87), or seizures [n=17, nine longer than 5 min (e.g., SE), and eight shorter than 5 min]. The algorithm generated a SE alert (≥90% seizure burden) with 100% sensitivity and 93% specificity. The sensitivity and specificity of various thresholds for seizure burden during EEG recordings for detecting patients with seizures were 100% and 82% for≥50% seizure burden and 88% and 60% for≥10% seizure burden. Of the 179 EEG recordings in which the algorithm detected no seizures, seizures were identified by the expert reviewers in only two cases, indicating a negative predictive value of 99%.DISCUSSION: Claritgamma detected SE events with high sensitivity and specificity, and it demonstrated a high negative predictive value for distinguishing nonepileptiform activity from seizure and highly epileptiform activity.CONCLUSIONS: Ruling out seizures accurately in a large proportion of cases can help prevent unnecessary or aggressive over-treatment in critical care settings, where empiric treatment with antiseizure medications is currently prevalent. Claritgamma's high sensitivity for SE and high negative predictive value for cases without epileptiform activity make it a useful tool for triaging treatment and the need for urgent neurological consultation.

View details for DOI 10.1007/s12028-020-01120-0

View details for PubMedID 33025543

Abstract

Advanced imaging methods now allow cell-type-specific recording of neural activity across the mammalian brain, potentially enabling the exploration of how brain-wide dynamical patterns give rise to complex behavioural states1-12. Dissociation is an altered behavioural state in which the integrity of experience is disrupted, resulting in reproducible cognitive phenomena including the dissociation of stimulus detection from stimulus-related affective responses. Dissociation can occur as a result of trauma, epilepsy or dissociative drug use13,14, but despite its substantial basic and clinical importance, the underlying neurophysiology of this state is unknown. Here we establish such a dissociation-like state in mice, induced by precisely-dosed administration of ketamine or phencyclidine. Large-scale imaging of neural activity revealed that these dissociative agents elicited a 1-3-Hz rhythm in layer5 neurons of the retrosplenial cortex. Electrophysiological recording with four simultaneously deployed high-density probes revealed rhythmic coupling of the retrosplenial cortex with anatomically connected components of thalamus circuitry, but uncoupling from most other brain regions was observed-including a notable inverse correlation with frontally projecting thalamic nuclei. In testing for causal significance, we found thatrhythmic optogenetic activation of retrosplenial cortex layer5 neurons recapitulated dissociation-like behavioural effects. Local retrosplenial hyperpolarization-activated cyclic-nucleotide-gated potassium channel 1 (HCN1) pacemakers were required for systemic ketamine to induce this rhythm and to elicit dissociation-like behavioural effects. In a patient with focal epilepsy, simultaneous intracranial stereoencephalography recordings from across the brain revealed a similarly localized rhythm in the homologous deep posteromedial cortex that was temporally correlated with pre-seizure self-reported dissociation, and local brief electrical stimulation of this region elicited dissociative experiences. These results identify themolecular, cellular and physiological properties of a conserved deep posteromedial cortical rhythm that underlies states of dissociation.

View details for DOI 10.1038/s41586-020-2731-9

View details for PubMedID 32939091

Abstract

Spontaneous activations within neuronal populations can emerge similarly to "task-evoked" activations elicited during cognitive performance or sensory stimulation. We hypothesized that spontaneous activations within a given brain region have comparable functional and physiological properties to task-evoked activations. Using human intracranial electroencephalography with concurrent pupillometry in 3 subjects (2 males, 1 female), we localized neuronal populations in the dorsal anterior insular cortex that showed task-evoked activations correlating positively with the magnitude of pupil dilation during a continuous performance task. The pupillary response peaks lagged behind insular activations by several hundreds of milliseconds. We then detected spontaneous activations, within the same neuronal populations of insular cortex, that emerged intermittently during a wakeful "resting state" and that had comparable electrophysiological properties (magnitude, duration, and spectral signature) to task-evoked activations. Critically, similar to task-evoked activations, spontaneous activations systematically preceded phasic pupil dilations with a strikingly similar temporal profile. Our findings suggest similar neurophysiological profiles between spontaneous and task evoked activations in the human insula and support a clear link between these activations and autonomic functions measured by dynamics of pupillary dilation.Significance StatementMost of our knowledge about activations in the human brain is derived from studies of responses to external events and experimental conditions (i.e., "task-evoked" activations). We obtained direct neural recordings from electrodes implanted in human subjects and showed that activations emerge spontaneously and have strong similarities to task-evoked activations (e.g. magnitude, temporal profile) within the same populations of neurons. Within the dorsal anterior insula, a brain region implicated in salience processing and alertness, activations that are either spontaneous or task-evoked are coupled with brief dilations of the pupil. Our findings underscore how spontaneous brain activity-a major current focus of human neuroimaging studies aimed at developing biomarkers of disease- is relevant to ongoing physiological and possibly self-generated mental processes.

View details for DOI 10.1523/JNEUROSCI.0435-20.2020

View details for PubMedID 32631937

Abstract

We measured the fast temporal dynamics of face processing simultaneously across the human temporal cortex (TC) using intracranial recordings in eight participants. We found sites with selective responses to faces clustered in the ventral TC, which responded increasingly strongly to marine animal, bird, mammal, and human faces. Both face-selective and face-active but non-selective sites showed a posterior to anterior gradient in response time and selectivity. A sparse model focusing on information from the human face-selective sites performed as well as, or better than, anatomically distributed models when discriminating faces from non-faces stimuli. Additionally, we identified the posterior fusiform site (pFUS) as causally the most relevant node for inducing distortion of conscious face processing by direct electrical stimulation. These findings support anatomically discrete but temporally distributed response profiles in the human brain and provide a new common ground for unifying the seemingly contradictory modular and distributed modes of face processing.

View details for DOI 10.1038/s41467-020-14432-8

View details for PubMedID 32005819