Causal Cortical and Thalamic Connections in the Human Brain.

The brain's functional architecture is intricately shaped by causal connections between its cortical and subcortical structures. Here, we studied 27 participants with 4864 electrodes implanted across the anterior, mediodorsal, and pulvinar thalamic regions, and the cortex. Using data from electrical stimulation procedures and a data-driven approach informed by neurophysiological standards, we dissociated three unique spectral patterns generated by the perturbation of a given brain area. Among these, a novel waveform emerged, marked by delayed-onset slow oscillations in both ipsilateral and contralateral cortices following thalamic stimulations, suggesting a mechanism by which a thalamic site can influence bilateral cortical activity. Moreover, cortical stimulations evoked earlier signals in the thalamus than in other connected cortical areas suggesting that the thalamus receives a copy of signals before they are exchanged across the cortex. Our causal connectivity data can be used to inform biologically-inspired computational models of the functional architecture of the brain.

Naturalistic acute pain states decoded from neural and facial dynamics.

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.

The Cost of After-Hour Electroencephalography.

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.

Spatiotemporal Dynamics of Successive Activations across the Human Brain during Simple Arithmetic Processing.

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 a precise anatomical source of 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 the intracranial electroencephalography. Our data revealed a remarkably distributed change of activity in almost half of the sampled sites. In each activated brain region, we found juxtaposed neuronal populations preferentially responsive to either the target or control conditions, arranged in an anatomically orderly manner. Notably, an orderly successive activation of a set of brain regions-anatomically consistent across subjects-was observed in individual brains. 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 the information is partially leaked or transformed along the processing chain. Our study complements 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.

Intracranial Recordings of the Human Orbitofrontal Cortical Activity during Self-Referential Episodic and Valenced Self-Judgments.

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 (SJs). We found significantly increased high-frequency activity (HFA) in ∼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 that 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 in the OFC during positive SJ trials among individuals with higher depression scores; responses during negative SJ 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 SJ 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.

Spatiotemporal dynamics of successive activations across the human brain during simple arithmetic processing.

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.

Subjective states induced by intracranial electrical stimulation matches the cytoarchitectonic organization of the human insula.

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.

Causal evidence for the processing of bodily self in the anterior precuneus.

To probe the causal importance of the human posteromedial cortex (PMC) in processing the sense of self, we studied a rare cohort of nine patients with electrodes implanted bilaterally in the precuneus, posterior cingulate, and retrosplenial regions with a combination of neuroimaging, intracranial recordings, and direct cortical stimulations. In all participants, the stimulation of specific sites within the anterior precuneus (aPCu) caused dissociative changes in physical and spatial domains. Using single-pulse electrical stimulations and neuroimaging, we present effective and resting-state connectivity of aPCu hot zone with the rest of the brain and show that they are located outside the boundaries of the default mode network (DMN) but connected reciprocally with it. We propose that the function of this subregion of the PMC is integral to a range of cognitive processes that require the self's physical point of reference, given its location within a spatial environment.

Multisite thalamic recordings to characterize seizure propagation in the human brain.

Neuromodulation of the anterior nuclei of the thalamus (ANT) has shown to be efficacious in a subset of patients with refractory focal epilepsy. One important uncertainty is to what extent thalamic subregions other than the ANT could be recruited more prominently in the propagation of focal onset seizures. We designed the current study to simultaneously monitor the engagement of the ANT, mediodorsal (MD) and pulvinar (PUL) nuclei during seizures in patients who could be candidates for thalamic neuromodulation. We studied 11 patients with clinical manifestations of presumed temporal lobe epilepsy (TLE) undergoing invasive stereo-encephalography (sEEG) monitoring to confirm the source of their seizures. We extended cortical electrodes to reach the ANT, MD and PUL nuclei of the thalamus. More than one thalamic subdivision was simultaneously interrogated in nine patients. We recorded seizures with implanted electrodes across various regions of the brain and documented seizure onset zones (SOZ) in each recorded seizure. We visually identified the first thalamic subregion to be involved in seizure propagation. Additionally, in eight patients, we applied repeated single pulse electrical stimulation in each SOZ and recorded the time and prominence of evoked responses across the implanted thalamic regions. Our approach for multisite thalamic sampling was safe and caused no adverse events. Intracranial EEG recordings confirmed SOZ in medial temporal lobe, insula, orbitofrontal and temporal neocortical sites, highlighting the importance of invasive monitoring for accurate localization of SOZs. In all patients, seizures with the same propagation network and originating from the same SOZ involved the same thalamic subregion, with a stereotyped thalamic EEG signature. Qualitative visual reviews of ictal EEGs were largely consistent with the quantitative analysis of the corticothalamic evoked potentials, and both documented that thalamic nuclei other than ANT could have the earliest participation in seizure propagation. Specifically, pulvinar nuclei were involved earlier and more prominently than ANT in more than half of the patients. However, which specific thalamic subregion first demonstrated ictal activity could not be reliably predicted based on clinical semiology or lobar localization of SOZs. Our findings document the feasibility and safety of bilateral multisite sampling from the human thalamus. This may allow more personalized thalamic targets to be identified for neuromodulation. Future studies are needed to determine if a personalized thalamic neuromodulation leads to greater improvements in clinical outcome.

Pre-stimulus gamma power in human posteromedial cortex shows supra-modal mechanisms in predicting the amplitude and latency of task-induced suppression.

Upon repetitively performing the same well-practiced task on identical bottom-up stimuli, our performance still varies. Although it has been well documented that elevated pre-stimulus baseline activity in the human default-mode network impairs the subsequent task performance, it remains unknown (i) the fine-grained temporal dynamics and (ii) whether the underlying neural dynamics are supra-modal or modality-specific. We utilized intracranial recordings in the human posteromedial cortex (PMC) during a simple visual and an auditory detection task. Our findings suggested that the pre-stimulus gamma power in PMC predicted the subsequent task performance. Critically, the higher the pre-stimulus gamma power, the longer it took for it to be suppressed, and the less suppressed it was during the task performance, which eventually resulted in deleterious effects on task performance, i.e. longer reaction times. These fine-grained temporal dynamics were consistent between the visual and auditory simple detection task. In addition, a direct comparison between the visual and auditory modality showed that the between-modality difference emerged during the recovery period from the maximal gamma suppression back to the baseline. Taken together, the present results contribute novel spatio-temporal mechanisms in human PMC on how simple detection performance varies across multiple repetitions, irrespective of the sensory modality involved.

Direct intracranial recordings in the human angular gyrus during arithmetic processing.

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.

Comparing Seizures Captured by Rapid Response EEG and Conventional EEG Recordings in a Multicenter Clinical Study.

Objective: A recent multicenter prospective study (DECIDE trial) examined the use of Ceribell Rapid Response EEG (Rapid-EEG) in the emergent evaluation and management of critically ill patients suspected to have non-convulsive seizures. We present a detailed, patient-level examination of seizures detected either on initial Rapid-EEG or subsequent conventional EEG within 24 h to investigate whether seizures were missed on Rapid-EEG due to the exclusion of midline/parasagittal coverage. Methods: We identified from 164 patients studied in the DECIDE trial those who had seizures detected on Rapid-EEG but not conventional EEG (n = 6), conventional EEG but not Rapid-EEG (n = 4), or both Rapid-EEG and conventional EEG (n = 9). We examined the electrographic characteristics of ictal and interictal findings on both devices, especially their detection in lateral or midline/parasagittal chains, and patient clinical histories to identify contributors toward discordant seizure detection. Results: Seizures detected on both EEG systems had similar electrographic appearance and laterality. Seizures detected only on conventional EEG (within 24 h following Rapid-EEG) were visible in the temporal chains, and external clinical factors (e.g., treatment with anti-seizure medications, sedation, and duration of recordings) explained the delayed presentation of seizures. Patients with seizures detected only by Rapid-EEG were treated with anti-seizure medications, and subsequent conventional EEG detected interictal highly epileptiform patterns with similar laterality. Conclusions: Our case series demonstrates that electrographic data obtained from initial Rapid-EEG and subsequent conventional EEG monitoring are largely concordant relative to morphology and laterality. These findings are valuable to inform future investigation of abbreviated EEG systems to optimize management of suspected non-convulsive seizures and status epilepticus. Future, larger studies could further investigate the value of Rapid-EEG findings for forecasting and predicting seizures in long-term EEG recordings.

Causal mapping of human brain function.

Mapping human brain function is a long-standing goal of neuroscience that promises to inform the development of new treatments for brain disorders. Early maps of human brain function were based on locations of brain damage or brain stimulation that caused a functional change. Over time, this approach was largely replaced by technologies such as functional neuroimaging, which identify brain regions in which activity is correlated with behaviours or symptoms. Despite their advantages, these technologies reveal correlations, not causation. This creates challenges for interpreting the data generated from these tools and using them to develop treatments for brain disorders. A return to causal mapping of human brain function based on brain lesions and brain stimulation is underway. New approaches can combine these causal sources of information with modern neuroimaging and electrophysiology techniques to gain new insights into the functions of specific brain areas. In this Review, we provide a definition of causality for translational research, propose a continuum along which to assess the relative strength of causal information from human brain mapping studies and discuss recent advances in causal brain mapping and their relevance for developing treatments.

Complex negative emotions induced by electrical stimulation of the human hypothalamus.

BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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). RESULTS: 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 structural connectivity. CONCLUSION: 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. The complexity of affective state induced by the stimulation of the hypothalamus and the profile of hypothalamic electrophysiological connectivity suggest that the hypothalamus and its connected structures ought to be seen as causally important for human affective experience.

Electrocorticographic evidence of a common neurocognitive sequence for mentalizing about the self and others.

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.

Temporal order of signal propagation within and across intrinsic brain networks.

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.

Overlapping Neuronal Population Responses in the Human Parietal Cortex during Visuospatial Attention and Arithmetic Processing.

Engagement of posterior parietal cortex (PPC) in visuospatial attention and arithmetic processing has been extensively documented using neuroimaging methods. Numerous studies have suggested a close connection between visuospatial attention and arithmetic processing. However, the extant evidence in humans stems from neuroimaging methods that have relied on group analyses without much knowledge about the profile of neurophysiological engagement within localized neuronal populations at the individual brain level. Hence, it has remained unclear if the overlap of two functions in the PPC is the product of averaging, or they truly stem from a common profile of activity within the same neuronal populations in the human PPC. In the current study, we leveraged the anatomical precision and high signal-to-noise ratio of intracranial electrocorticography and probed the engagement of discrete PPC neuronal populations in seven neurosurgical patients (n = 179 total PPC sites covered; 26 sites on average per individual participant). We aimed to study the extent of parietal activations within each individual brain during visuospatial attention versus arithmetic tasks and the profile of electrophysiological responses within a given recording site during these tasks. Our findings indicated that about 40% of PPC sites did not respond to either visuospatial attention or arithmetic stimuli-or episodic memory conditions that were used as an adjunct control condition. Of those that were activated during either visuospatial attention or arithmetic conditions, a large majority showed overlapping responses during both visuospatial attention and arithmetic conditions. Most interestingly, responses during arithmetic processing were greatest in sites along the intraparietal sulcus region showing preference to contralateral, instead of ipsilateral, visual probes in the visuospatial attention task. Our results provide novel data about the relationship between numerical and spatial orientation at the neuronal population level and shed light on the complex functional organization of the PPC that could not be attained with noninvasive methods.

Altered sense of self during seizures in the posteromedial cortex.

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.

Hippocampal ripples and their coordinated dialogue with the default mode network during recent and remote recollection.

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.