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.

Deep posteromedial cortical rhythm in dissociation.

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 layer 5 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 that rhythmic optogenetic activation of retrosplenial cortex layer 5 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 the molecular, cellular and physiological properties of a conserved deep posteromedial cortical rhythm that underlies states of dissociation.

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.

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.

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.

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.

Anticipation-induced delta phase reset improves human olfactory perception.

Anticipating an odor improves detection and perception, yet the underlying neural mechanisms of olfactory anticipation are not well understood. In this study, we used human intracranial electroencephalography (iEEG) to show that anticipation resets the phase of delta oscillations in piriform cortex prior to odor arrival. Anticipatory phase reset correlates with ensuing odor-evoked theta power and improvements in perceptual accuracy. These effects were consistently present in each individual subject and were not driven by potential confounds of pre-inhale motor preparation or power changes. Together, these findings suggest that states of anticipation enhance olfactory perception through phase resetting of delta oscillations in piriform cortex.

Intracranial Electroencephalography Reveals Selective Responses to Cognitive Stimuli in the Periventricular Heterotopias.

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 pathologic epileptic activity. Here, we aim to extend the scope of our work to epileptic periventricular heterotopias (PVH) and examine whether 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 (two females), 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 anatomic 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.

Pupillary Dynamics Link Spontaneous and Task-Evoked Activations Recorded Directly from Human Insula.

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 EEG 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 STATEMENT Most 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.

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.

Spatial and temporal heterogeneity of neural responses in human posteromedial cortex.

Neuroimaging evidence supports a role of the default mode network (DMN) in spontaneous thought and goal-driven internally oriented processes, such as recalling an autobiographical event, and has demonstrated its deactivation during focused, externally oriented attention. Recent work suggests that the DMN is not a homogeneous network but rather is composed of at least several subnetworks, which are engaged in distinct functions; however, it is still unclear if these different functions rely on the same neuronal populations. In this study, we used intracranial EEG to record from the posteromedial cortex (PMC), a core hub of the DMN, in 13 human subjects, during autobiographical memory retrieval (internally oriented), arithmetic processing (externally oriented), and cued rest (spontaneous thought), allowing us to measure activity from anatomically precise PMC sites with high temporal resolution. We observed a heterogeneous, yet spatially organized, pattern of activity across tasks. Many sites, primarily in the more ventral portion of PMC, were engaged during autobiographical recall and suppressed during arithmetic processing. Other more dorsal PMC sites were engaged during the cued-rest condition. Of these rest-active sites, some exhibited variable temporal dynamics across trials, possibly reflecting various forms of spontaneous thought, while others showed only transient activity at the beginning of cued-rest trials (i.e., after a switch from a task to cued rest), possibly involved in shifting the brain from a more focused to a more exploratory attentional state. These results suggest heterogeneity of function even within an individual node of the DMN.

Monitoring the Burden of Seizures and Highly Epileptiform Patterns in Critical Care with a Novel Machine Learning Method.

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 (Claritγ, 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 Claritγ, and various thresholds of seizure burden were tested (≥ 10% indicating ≥ 30 s of seizure activity in the last 5 min, ≥ 50% indicating ≥ 2.5 min of seizure activity, and ≥ 90% indicating ≥ 4.5 min of seizure activity and triggering a SE alert). The sensitivity and specificity of Claritγ'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: Claritγ 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. Claritγ'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.

Temporal Dynamics and Response Modulation across the Human Visual System in a Spatial Attention Task: An ECoG Study.

The selection of behaviorally relevant information from cluttered visual scenes (often referred to as "attention") is mediated by a cortical large-scale network consisting of areas in occipital, temporal, parietal, and frontal cortex that is organized into a functional hierarchy of feedforward and feedback pathways. In the human brain, little is known about the temporal dynamics of attentional processing from studies at the mesoscopic level of electrocorticography (ECoG), that combines millisecond temporal resolution with precise anatomical localization of recording sites. We analyzed high-frequency broadband responses (HFB) responses from 626 electrodes implanted in 8 epilepsy patients who performed a spatial attention task. Electrode locations were reconstructed using a probabilistic atlas of the human visual system. HFB responses showed high spatial selectivity and tuning, constituting ECoG response fields (RFs), within and outside the topographic visual system. In accordance with monkey physiology studies, both RF widths and onset latencies increased systematically across the visual processing hierarchy. We used the spatial specificity of HFB responses to quantitatively study spatial attention effects and their temporal dynamics to probe a hierarchical top-down model suggesting that feedback signals back propagate the visual processing hierarchy. Consistent with such a model, the strengths of attentional modulation were found to be greater and modulation latencies to be shorter in posterior parietal cortex, middle temporal cortex and ventral extrastriate cortex compared with early visual cortex. However, inconsistent with such a model, attention effects were weaker and more delayed in anterior parietal and frontal cortex.SIGNIFICANCE STATEMENT In the human brain, visual attention has been predominantly studied using methods with high spatial, but poor temporal resolution such as fMRI, or high temporal, but poor spatial resolution such as EEG/MEG. Here, we investigate temporal dynamics and attention effects across the human visual system at a mesoscopic level that combines precise spatial and temporal measurements by using electrocorticography in epilepsy patients performing a classical spatial attention task. Electrode locations were reconstructed using a probabilistic atlas of the human visual system, thereby relating them to topography and processing hierarchy. We demonstrate regional differences in temporal dynamics across the attention network. Our findings do not fully support a top-down model that promotes influences on visual cortex by reversing the processing hierarchy.

Evaluating the Clinical Impact of Rapid Response Electroencephalography: The DECIDE Multicenter Prospective Observational Clinical Study.

OBJECTIVES: To measure the diagnostic accuracy, timeliness, and ease of use of Ceribell rapid response electroencephalography. We assessed physicians' diagnostic assessments and treatment plans before and after rapid response electroencephalography assessment. Primary outcomes were changes in physicians' diagnostic and therapeutic decision making and their confidence in these decisions based on the use of the rapid response electroencephalography system. Secondary outcomes were time to electroencephalography, setup time, ease of use, and quality of electroencephalography data. DESIGN: Prospective multicenter nonrandomized observational study. SETTING: ICUs in five academic hospitals in the United States. SUBJECTS: Patients with encephalopathy suspected of having nonconvulsive seizures and physicians evaluating these patients. INTERVENTIONS: Physician bedside assessment of sonified electroencephalography (30 s from each hemisphere) and visual electroencephalography (60 s) using rapid response electroencephalography. MEASUREMENTS AND MAIN RESULTS: Physicians (29 fellows or residents, eight attending neurologists) evaluated 181 ICU patients; complete clinical and electroencephalography data were available in 164 patients (average 58.6 ± 18.7 yr old, 45% females). Relying on rapid response electroencephalography information at the bedside improved the sensitivity (95% CI) of physicians' seizure diagnosis from 77.8% (40.0%, 97.2%) to 100% (66.4%, 100%) and the specificity (95% CI) of their diagnosis from 63.9% (55.8%, 71.4%) to 89% (83.0%, 93.5%). Physicians' confidence in their own diagnosis and treatment plan were also improved. Time to electroencephalography (median [interquartile range]) was 5 minutes (4-10 min) with rapid response electroencephalography while the conventional electroencephalography was delayed by several hours (median [interquartile range] delay = 239 minutes [134-471 min] [p < 0.0001 using Wilcoxon signed rank test]). The device was rated as easy to use (mean ± SD: 4.7 ± 0.6 [1 = difficult, 5 = easy]) and was without serious adverse effects. CONCLUSIONS: Rapid response electroencephalography enabled timely and more accurate assessment of patients in the critical care setting. The use of rapid response electroencephalography may be clinically beneficial in the assessment of patients with high suspicion for nonconvulsive seizures and status epilepticus.

Neural repetition suppression effects in the human hippocampus.

Neurons in the temporal lobe cortex exhibit reduced responses when a stimulus or a stimulus feature is repeated. This phenomenon, termed "repetition suppression", is the basis for many functional imaging studies that have used Blood Oxygenation Level Dependent (BOLD) activity differences between novel and repeated items as an index of neural selectivity in hippocampal subfields. However, it is not clear how hippocampal neural activity changes across repeated exposure to a stimulus. Here, we used direct intracranial electroencephalography (iEEG) recordings of hippocampal activity to examine whether neural activity in the human hippocampus is modulated across successive repetitions of an item. Time-frequency analyses revealed that high-frequency activity, which is thought to include gamma oscillations and possible correlates of multi-unit activity, declined monotonically across successive presentations of an item. In contrast, low-frequency oscillations in the alpha and beta bands monotonically increased across successive presentations of an object. These results provide support for the assumption that, at least under some circumstances, repetition suppression (as measured by declines in high-frequency activity) can be observed in the hippocampus, and these effects are accompanied by increases in low-frequency oscillations as well.

Spatiotemporal dynamics of word retrieval in speech production revealed by cortical high-frequency band activity.

Word retrieval is core to language production and relies on complementary processes: the rapid activation of lexical and conceptual representations and word selection, which chooses the correct word among semantically related competitors. Lexical and conceptual activation is measured by semantic priming. In contrast, word selection is indexed by semantic interference and is hampered in semantically homogeneous (HOM) contexts. We examined the spatiotemporal dynamics of these complementary processes in a picture naming task with blocks of semantically heterogeneous (HET) or HOM stimuli. We used electrocorticography data obtained from frontal and temporal cortices, permitting detailed spatiotemporal analysis of word retrieval processes. A semantic interference effect was observed with naming latencies longer in HOM versus HET blocks. Cortical response strength as indexed by high-frequency band (HFB) activity (70-150 Hz) amplitude revealed effects linked to lexical-semantic activation and word selection observed in widespread regions of the cortical mantle. Depending on the subsecond timing and cortical region, HFB indexed semantic interference (i.e., more activity in HOM than HET blocks) or semantic priming effects (i.e., more activity in HET than HOM blocks). These effects overlapped in time and space in the left posterior inferior temporal gyrus and the left prefrontal cortex. The data do not support a modular view of word retrieval in speech production but rather support substantial overlap of lexical-semantic activation and word selection mechanisms in the brain.

Midline and Parasagittal Seizures are Rare in Adult Patients.

BACKGROUND: For decades, half of the electrodes used in traditional electroencephalography (EEG) have been dedicated to midline and parasagittal coverage. Recently, newer EEG devices have used fewer electrodes without direct coverage over the midline or parasagittal regions. However, no systematic study to date has explored the prevalence of midline parasagittal seizures, and as such the risk of missing such seizures with only ten electrodes remains unknown. METHODS: We reviewed retrospective EEG data from a cohort of 300 patients at Stanford University Medical Center and determined the frequency of seizures localized to the midline parasagittal regions. We then compiled previously reported EEG cohorts that reported the prevalence of midline parasagittal seizures to validate our findings. RESULTS: In our cohort, only two EEGs (0.66%) were identified with a midline or parasagittal seizure focus. In a subsequent study, we compiled literature evidence from 169510 EEGs and found that the prevalence of midline or parasagittal epileptic spikes/seizures was similarly less than 1%. CONCLUSIONS: Our study serves as the first to systematically explore the scope of EEG abnormalities captured exclusively by midline or parasagittal electrodes and document their very low prevalence.

Diagnostic Value of Electroencephalography with Ten Electrodes in Critically Ill Patients.

BACKGROUND: In critical care settings, electroencephalography (EEG) with reduced number of electrodes (reduced montage EEG, rm-EEG) might be a timely alternative to the conventional full montage EEG (fm-EEG). However, past studies have reported variable accuracies for detecting seizures using rm-EEG. We hypothesized that the past studies did not distinguish between differences in sensitivity from differences in classification of EEG patterns by different readers. The goal of the present study was to revisit the diagnostic value of rm-EEG when confounding issues are accounted for. METHODS: We retrospectively collected 212 adult EEGs recorded at Massachusetts General Hospital and reviewed by two epileptologists with access to clinical, trending, and video information. In Phase I of the study, we re-configured the first 4 h of the EEGs in lateral circumferential montage with ten electrodes and asked new readers to interpret the EEGs without access to any other ancillary information. We compared their rating to the reading of hospital clinicians with access to ancillary information. In Phase II, we measured the accuracy of the same raters reading representative samples of the discordant EEGs in full and reduced configurations presented randomly by comparing their performance to majority consensus as the gold standard. RESULTS: Of the 95 EEGs without seizures in the selected fm-EEG, readers of rm-EEG identified 92 cases (97%) as having no seizure activity. Of 117 EEGs with "seizures" identified in the selected fm-EEG, none of the cases was labeled as normal on rm-EEG. Readers of rm-EEG reported pathological activity in 100% of cases, but labeled them as seizures (N = 77), rhythmic or periodic patterns (N = 24), epileptiform spikes (N = 7), or burst suppression (N = 6). When the same raters read representative epochs of the discordant EEG cases (N = 43) in both fm-EEG and rm-EEG configurations, we found high concordance (95%) and intra-rater agreement (93%) between fm-EEG and rm-EEG diagnoses. CONCLUSIONS: Reduced EEG with ten electrodes in circumferential configuration preserves key features of the traditional EEG system. Discrepancies between rm-EEG and fm-EEG as reported in some of the past studies can be in part due to methodological factors such as choice of gold standard diagnosis, asymmetric access to ancillary clinical information, and inter-rater variability rather than detection failure of rm-EEG as a result of electrode reduction per se.