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.

Alpha-2a adrenergic receptor activation in genetic absence epilepsy: An absence status model?

OBJECTIVE: The objective of the study was to propose a candidate animal model of absence status epilepticus induced by specific alpha-2a adrenergic receptor (α2AR) activation. We also aim to investigate the responsiveness of this model to classical anti-status or anti-absence medications. METHODS: An α2AR agonist, dexmedetomidine (DEX), was injected intracerebroventricularly into adult rats with genetic absence epilepsy, and their electroencephalography (EEG) was recorded. The total duration, number, and mean duration of each spike-and-wave discharges (SWDs) were evaluated. The blocks of absence status events were classified as the initial and second sets of absence statuses. Ethosuximide (ETX) was administered as a pretreatment to another group of rats and later injected with 2.5 µg DEX. In addition, ETX, valproic acid (VPA), diazepam (DIAZ), and atipamezole (ATI) were administered after induced status-like events following DEX administration. Power spectral characteristics and coherence analysis were performed on the EEG to assess the absence status events and sleep. RESULTS: The 2.5 µg dose of DEX increased the total SWD duration and induced continuous SWDs up to 26 min. Following the initial absence status event, sleep was induced; then, the second period of absence status-like activities were initiated. ETX pretreatment blocked the occurrence of absence status-like activities. Power spectral density analyses revealed that DEX-induced post-sleep activities had higher power in delta frequency band (1-4 Hz) and attenuated power of 7 Hz harmonics (14 and 21 Hz) than the pre-injection seizure. The mean duration of SWDs were decreased in all the groups, but occasional prolonged activities were seen in ETX or VPA-injected rats but not with DIAZ or ATI. SIGNIFICANCE: This study presents an absence status epilepticus animal model that is activated by α2AR activation to investigate the pathophysiological role of absence status. Unlike other agents ATI switched off the second set of absence statuses to normal SWDs, without sedation or lethargy, can show it may preferentially block absence status-like activity. THE PLAIN LANGUAGE SUMMARY: This study proposes a rat model for prolonged seizures, resembling absence status epilepticus. Activating the brain's alpha-2a adrenergic receptor with dexmedetomidine induced seizures lasting up to 26 minutes. Ethosuximide pretreatment and post-treatment with valproic acid, diazepam, and atipamezole decreased induced seizures. The findings suggest this model is valuable for studying absence status epilepticus. In addition, atipamezole normalized abnormal seizures without sedation, hinting at its potential for targeted treatment and further research.

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.

Dexmedetomidine, an alpha 2A receptor agonist, triggers seizures unilaterally in GAERS during the pre-epileptic phase: does the onset of spike-and-wave discharges occur in a focal manner?

Introduction: The genetic absence epilepsy rat from Strasbourg (GAERS) is a rat model for infantile absence epilepsy with spike-and-wave discharges (SWDs). This study aimed to investigate the potential of alpha 2A agonism to induce seizures during the pre-epileptic period in GAERS rats. Methods: Stereotaxic surgery was performed on male pups and adult GAERS rats to implant recording electrodes in the frontoparietal cortices (right/left) under anesthesia (PN23-26). Following the recovery period, pup GAERS rats were subjected to electroencephalography (EEG) recordings for 2 h. Before the injections, pup epileptiform activity was examined using baseline EEG data. Dexmedetomidine was acutely administered at 0.6 mg/kg to pup GAERS rats 2-3 days after the surgery and once during the post-natal (PN) days 25-29. Epileptiform activities before injections triggered unilateral SWDs and induced sleep durations, and power spectral density was evaluated based on EEG traces. Results: The most prominent finding of this study is that unilateral SWD-like activities were induced in 47% of the animals with the intraperitoneal dexmedetomidine injection. The baseline EEGs of pup GAERS rats had no SWDs as expected since they are in the pre-epileptic period but showed low-amplitude non-rhythmic epileptiform activity. There was no difference in the duration of epileptiform activities between the basal EEG groups and DEX-injected unilateral SWD-like-exhibiting and non-SWD-like activities groups; however, the sleep duration of the unilateral SWD-like-exhibiting group was shorter. Power spectrum density (PSD) results revealed that the 1.75-Hz power in the left hemisphere peaks significantly higher than in the right. Discussion: As anticipated, pup GAERS rats in the pre-epileptic stage showed no SWDs. Nevertheless, they exhibited sporadic epileptiform activities. Specifically, dexmedetomidine induced SWD-like activities solely within the left hemisphere. These observations imply that absence seizures might originate unilaterally in the left cortex due to α2AAR agonism. Additional research is necessary to explore the precise cortical focal point of this activity.

Joint, distributed and hierarchically organized encoding of linguistic features in the human auditory cortex.

The precise role of the human auditory cortex in representing speech sounds and transforming them to meaning is not yet fully understood. Here we used intracranial recordings from the auditory cortex of neurosurgical patients as they listened to natural speech. We found an explicit, temporally ordered and anatomically distributed neural encoding of multiple linguistic features, including phonetic, prelexical phonotactics, word frequency, and lexical-phonological and lexical-semantic information. Grouping neural sites on the basis of their encoded linguistic features revealed a hierarchical pattern, with distinct representations of prelexical and postlexical features distributed across various auditory areas. While sites with longer response latencies and greater distance from the primary auditory cortex encoded higher-level linguistic features, the encoding of lower-level features was preserved and not discarded. Our study reveals a cumulative mapping of sound to meaning and provides empirical evidence for validating neurolinguistic and psycholinguistic models of spoken word recognition that preserve the acoustic variations in speech.

A Wolf in Hiding: Epilepsy and Post-ictal Psychosis As Unrecognized Presenting Features of Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that affects multiple organ systems. Many patients present with neurological and psychiatric signs and symptoms at some point in the course of the disease. Here, we present a patient with neuropsychiatric SLE (NPSLE) who presented with long-standing and difficult-to-control epileptic seizures and post-ictal psychotic symptoms prior to the diagnosis of SLE. A 39-year-old patient with a ten-year history of uncontrolled epileptic seizures despite multiple medications and recent diagnosis of chronic kidney disease presented to the emergency department following multiple witnessed seizures. Her seizures were controlled following initial interventions and the patient was admitted to the hospital to control metabolic acidosis and hyperkalemia. Later, the patient developed psychosis with auditory hallucinations, combative behavior, and agitation which were controlled with restraints and sedatives. Initial serological and urinary studies revealed disturbances of multiple systems and triggered broad workup resulting in positive serological SLE markers. The patient was then started on immunosuppressive medications with prompt control of post-ictal psychosis. The patient was discharged with immunosuppressive regimen and control of her seizures. This case highlights that signs and symptoms of NPSLE may appear before the onset of SLE diagnosis. Additionally, our patient had long-standing epilepsy with post-ictal psychosis, which has not been reported in the literature before. We believe this case highlights the challenges in the diagnosis of NPSLE, the rapid control of seizures and/or psychosis with SLE treatment, and the necessity to broaden the differential diagnosis in atypical presentation of seizures and/or psychosis.

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.

European trends in epilepsy surgery.

OBJECTIVE: Resective surgery is effective in treating drug-resistant focal epilepsy, but it remains unclear whether improved diagnostics influence postsurgical outcomes. Here, we compared practice and outcomes over 2 periods 15 years apart. METHODS: Sixteen European centers retrospectively identified 2 cohorts of children and adults who underwent epilepsy surgery in the period of 1997 to 1998 (n = 562) or 2012 to 2013 (n = 736). Data collected included patient (sex, age) and disease (duration, localization and diagnosis) characteristics, type of surgery, histopathology, Engel postsurgical outcome, and complications, as well as imaging and electrophysiologic tests performed for each case. Postsurgical outcome predictors were included in a multivariate logistic regression to assess the strength of date of surgery as an independent predictor. RESULTS: Over time, the number of operated cases per center increased from a median of 31 to 50 per 2-year period (p = 0.02). Mean disease duration at surgery decreased by 5.2 years (p < 0.001). Overall seizure freedom (Engel class 1) increased from 66.7% to 70.9% (adjusted p = 0.04), despite an increase in complex surgeries (extratemporal and/or MRI negative). Surgeries performed during the later period were 1.34 times (adjusted odds ratio; 95% confidence interval 1.02-1.77) more likely to yield a favorable outcome (Engel class I) than earlier surgeries, and improvement was more marked in extratemporal and MRI-negative temporal epilepsy. The rate of persistent neurologic complications remained stable (4.6%-5.3%, p = 0.7). CONCLUSION: Improvements in European epilepsy surgery over time are modest but significant, including higher surgical volume, shorter disease duration, and improved postsurgical seizure outcomes. Early referral for evaluation is required to continue on this encouraging trend.

Seizure Outcome of Patients with Magnetic Resonance Imaging-Negative Epilepsies: Still An Ongoing Debate.

BACKGROUND: Surgical results regarding MRI-negative epilepsy were presented and related clinical and histopathological parameters were discussed. METHODS: Thirty-six MRI-negative epilepsy patients were retrospectively analyzed. Histopathological specimens were re-reviewed by 2 blind neuropathologists and re-classified based on the current classifications. RESULTS: The mean age at surgery and seizure onset was 24.5 years and 9.3 years, respectively. Eight patients were younger than 18 years. Mean duration of seizures was 15.3 years. All but 2 underwent invasive monitorization. Eighteen patients had hypometabolism on FDG-PET with temporal lobe involvement in majority (66.7%). Hypometabolism was found in all patients with hippocampal sclerosis (HS), which was present in 50% and 66.7% of focal cortical dysplasia (FCD) type I and II patients, respectively. The frontal lobe resection was the most frequent type of operation followed by resections in temporal, parietal and occipital lobes. In 7 patients, multilobar resection was performed. Histopathological diagnosis was FCD type I, II, III, HS, and gliosis in 14, 12, 2, 3 and 2 patients, respectively. The mean follow-up was 5.8 years. Seventeen patients were seizure free and favorable outcome (Engel's I and II) was found in 69.7%. FCD type I tend to have more favorable seizure outcome. Duration of epilepsy and hypometabolism on FDG-PET was significantly related to outcome, whereas involved lobe was not. CONCLUSIONS: Our results suggest it is worth pursuing resective surgery in adults as well as in children with drug-resistant epilepsy with normal MRI.