Dysfunctional hippocampal-prefrontal network underlies a multidimensional neuropsychiatric phenotype following early-life seizure.

Brain disturbances during development can have a lasting impact on neural function and behavior. Seizures during this critical period are linked to significant long-term consequences such as neurodevelopmental disorders, cognitive impairments, and psychiatric symptoms, resulting in a complex spectrum of multimorbidity. The hippocampus-prefrontal cortex (HPC-PFC) circuit emerges as a potential common link between such disorders. However, the mechanisms underlying these outcomes and how they relate to specific behavioral alterations are unclear. We hypothesized that specific dysfunctions of hippocampal-cortical communication due to early-life seizure would be associated with distinct behavioral alterations observed in adulthood. Here, we performed a multilevel study to investigate behavioral, electrophysiological, histopathological, and neurochemical long-term consequences of early-life Status epilepticus in male rats. We show that adult animals submitted to early-life seizure (ELS) present working memory impairments and sensorimotor disturbances, such as hyperlocomotion, poor sensorimotor gating, and sensitivity to psychostimulants despite not exhibiting neuronal loss. Surprisingly, cognitive deficits were linked to an aberrant increase in the HPC-PFC long-term potentiation (LTP) in a U-shaped manner, while sensorimotor alterations were associated with heightened neuroinflammation, as verified by glial fibrillary acidic protein (GFAP) expression, and altered dopamine neurotransmission. Furthermore, ELS rats displayed impaired HPC-PFC theta-gamma coordination and an abnormal brain state during active behavior resembling rapid eye movement (REM) sleep oscillatory dynamics. Our results point to impaired HPC-PFC functional connectivity as a possible pathophysiological mechanism by which ELS can cause cognitive deficits and psychiatric-like manifestations even without neuronal loss, bearing translational implications for understanding the spectrum of multidimensional developmental disorders linked to early-life seizures.

Multidimensional behavioral profiles associated with resilience and susceptibility after inescapable stress.

Clinical depression is characterized by multiple concurrent symptoms, manifesting as a complex heterogeneous condition. Although some well-established classical behavioral assessments are widespread in rodent models, it remains uncertain whether rats also display stress-induced depression-related phenotypes in a multidimensional manner, i.e., simultaneous alterations in multiple behavioral tests. Here, we investigated multivariate patterns and profiles of depression-related behavioral traits in male Wistar rats subjected to inescapable footshocks (IS) or no-shocks (NS), followed by a comprehensive battery of behavioral tests and ethological characterization. We observed generalized stronger intra-test but weaker inter-test correlations. However, feature clustering of behavioral measures successfully delineated variables linked to resilience and susceptibility to stress. Accordingly, a noteworthy covariation pattern emerged, characterized by increased open field locomotion, reduced time in the elevated plus maze open arms, lower sucrose preference, and increased shuttle box escape failures that consistently differentiated IS from NS. Surprisingly there is little contribution from forced swim. In addition, individual clustering revealed a diversity of behavioral profiles, naturally separating NS and IS, including subpopulations entirely characterized by resilience or susceptibility. In conclusion, our study elucidates intricate relationships among classical depression-related behavioral measures, highlighting multidimensional individual variability. Our work emphasizes the importance of a multivariate framework for behavioral assessment in animal models to understand stress-related neuropsychiatric disorders.

Conceptual framework for tinnitus: a cognitive model in practice.

Tinnitus is a conscious attended awareness perception of sourceless sound. Widespread theoretical and evidence-based neurofunctional and psychological models have tried to explain tinnitus-related distress considering the influence of psychological and cognitive factors. However, tinnitus models seem to be less focused on causality, thereby easily misleading interpretations. Also, they may be incapable of individualization. This study proposes a Conceptual Cognitive Framework (CCF) providing insight into cognitive mechanisms involved in the predisposition, precipitation, and perpetuation of tinnitus and consequent cognitive-emotional disturbances. The current CCF for tinnitus relies on evaluative conditional learning and appraisal, generating negative valence (emotional value) and arousal (cognitive value) to annoyance, distress, and distorted perception. The suggested methodology is well-defined, reproducible, and accessible, which can help foster future high-quality clinical databases. Perceived tinnitus through the perpetual-learning process can always lead to annoyance, but only in the clinical stage directly cause annoyance. In the clinical stage, tinnitus perception can lead indirectly to distress only with experiencing annoyance either with (" I n d - 1 C " = 1.87; 95% CI 1.18-2.72)["1st indirect path in the Clinical stage model": Tinnitus Loudness → Attention Bias → Cognitive-Emotional Value → Annoyance → Clinical Distress]or without (" I n d - 2 C "= 2.03; 95% CI 1.02-3.32)[ "2nd indirect path in the Clinical stage model": Tinnitus Loudness → Annoyance → Clinical Distress] the perpetual-learning process. Further real-life testing of the CCF is expected to express a meticulous, decision-supporting platform for cognitive rehabilitation and clinical interventions. Furthermore, the suggested methodology offers a reliable platform for CCF development in other cognitive impairments and supports the causal clinical data models. It may also enhance our knowledge of psychological disorders and complicated comorbidities by supporting the design of different rehabilitation interventions and comprehensive frameworks in line with the "preventive medicine" policy.

An open-source, ready-to-use and validated ripple detector plugin for the Open Ephys GUI.

Objective. Sharp wave-ripples (SWRs, 100-250 Hz) are oscillatory events extracellularly recorded in the CA1 subfield of the hippocampus during sleep and quiet wakefulness. Many studies employed closed-loop strategies to either detect and abolish SWRs within the hippocampus or manipulate other relevant areas upon ripple detection. However, the code and schematics necessary to replicate the detection system are not always available, which hinders the reproducibility of experiments among different research groups. Furthermore, information about performance is not usually reported. Here, we sought to provide an open-source, validated ripple detector for the scientific community.Approach. We developed and validated a ripple detection plugin integrated into the Open Ephys graphical user's interface. It contains a built-in movement detector based on accelerometer or electromyogram data that prevents false ripple events (due to chewing, grooming, or moving, for instance) from triggering the stimulation/manipulation device.Main results. To determine the accuracy of the detection algorithm, we first carried out simulations in MATLAB with real ripple recordings. Using a specific combination of detection parameters (amplitude threshold of 5 standard deviations above the mean, time threshold of 10 ms, and root mean square block size of 7 samples), we obtained a 97% true positive rate and 2.48 false positives per minute. Next, an Open Ephys plugin based on the same detection algorithm was developed, and a closed-loop system was set up to evaluate the round trip (ripple onset-to-stimulation) latency over synthetic data. The lowest latency obtained was 34.5 ± 0.5 ms. The embedded movement monitoring was effective in reducing false positives and the plugin's flexibility to detect pathological events was also verified.Significance. Besides contributing to increased reproducibility, we anticipate that the developed ripple detector plugin will be helpful for many closed-loop applications in the field of systems neuroscience.

Dose-Response Transcranial Electrical Stimulation Study Design: A Well-Controlled Adaptive Seamless Bayesian Method to Illuminate Negative Valence Role in Tinnitus Perception.

The use of transcranial Electrical Stimulation (tES) in the modulation of cognitive brain functions to improve neuropsychiatric conditions has extensively increased over the decades. tES techniques have also raised new challenges associated with study design, stimulation protocol, functional specificity, and dose-response relationship. In this paper, we addressed challenges through the emerging methodology to investigate the dose-response relationship of High Definition-transcranial Direct Current Stimulation (HD tDCS), identifying the role of negative valence in tinnitus perception. In light of the neurofunctional testable framework and tES application, hypotheses were formulated to measure clinical and surrogate endpoints. We posited that conscious pairing adequately pleasant stimuli with tinnitus perception results in correction of the loudness misperception and would be reinforced by concurrent active HD-tDCS on the left Dorsolateral Prefrontal Cortex (dlPFC). The dose-response relationship between HD-tDCS specificity and the loudness perception is also modeled. We conducted a double-blind, randomized crossover pilot study with six recruited tinnitus patients. Accrued data was utilized to design a well-controlled adaptive seamless Bayesian dose-response study. The sample size (n = 47, for 90% power and 95% confidence) and optimum interims were anticipated for adaptive decision-making about efficacy, safety, and single session dose parameters. Furthermore, preliminary pilot study results were sufficient to show a significant difference (90% power, 99% confidence) within the longitudinally detected self-report tinnitus loudness between before and under positive emotion induction. This study demonstrated a research methodology used to improve emotion regulation in tinnitus patients. In the projected method, positive emotion induction is essential for promoting functional targeting under HD-tDCS anatomical specificity to indicate the efficacy and facilitate the dose-finding process. The continuous updating of prior knowledge about efficacy and dose during the exploratory stage adapts the anticipated dose-response model. Consequently, the effective dose range to make superiority neuromodulation in correcting loudness misperception of tinnitus will be redefined. Highly effective dose adapts the study to a standard randomized trial and transforms it into the confirmatory stage in which active HD-tDCS protocol is compared with a sham trial (placebo-like). Establishing the HD-tDCS intervention protocols relying on this novel method provides reliable evidence for regulatory agencies to approve or reject the efficacy and safety. Furthermore, this paper supports a technical report for designing multimodality data-driven complementary investigations in emotion regulation, including EEG-driven neuro markers, Stroop-driven attention biases, and neuroimaging-driven brain network dynamics.

Long-Term Outcome of Temporal Lobe Epilepsy Surgery in 621 Patients With Hippocampal Sclerosis: Clinical and Surgical Prognostic Factors.

Temporal lobe epilepsy (TLE) is the most common type of focal epilepsy and is frequently drug-resistant (DR) to antiseizure medication (ASM), corresponding to approximately one-third of the cases. When left inadequately treated, it can worsen the quality of life, cognitive deficits, and risk of death. The standard treatment for drug-resistant TLE is the surgical removal of the structures involved, with good long-term outcome rates of 60-70 % and a low rate of adverse effects. The goal of successful treatment is sustained seizure freedom. In our study, we evaluated sustained long-term (up to 23 years) surgical outcomes in 621 patients with DR-TLE associated with hippocampal sclerosis, who underwent a temporal lobectomy. We analyzed the main predictive factors that influence the surgical outcome related to seizure control, through a longitudinal and retrospective study, using a multivariable regression model. We found that 73.6% of the patients were free from disabling seizures (Engel Class I), maintained over time in 65% of patients followed up to 23 years after surgery. We found that four independent variables predicted seizure outcomes. The presence of dysmnesic and olfactory aura predicted a less favorable outcome. The history of febrile seizure and the surgical technique predicted a good outcome. Regarding the type of surgical technique, the standard anteromesial temporal lobectomy (ATL) led to significantly better outcomes (78.6% Engel Class I) when compared to the selective amygdalohippocampectomy via subtemporal approach (67.2% Engel Class I; p = 0.002), suggesting that the neuronal networks involved in the epileptogenic zone may be beyond mesial temporal structures. The multivariable regression model with the above-mentioned predictor variables revealed an ExpB = 3.627 (N = 621, p < 0.001), indicating that the model was able to distinguish between patients with a seizure-free. We conclude that epilepsy surgery is a safe procedure, with low rates of postoperative complications and good long-term results.

Dysphagia is a strong predictor of death and functional dependence at three months post-stroke / Disfagia é um forte preditor de morte e dependência funcional três meses após acidente vascular cerebral

ABSTRACT Background: Few Brazilian studies investigated risk factors for dysphagia and associated complications in a large cohort. Objective: To investigate frequency, predictors, and associated outcomes of dysphagia in patients up to three months post-stroke. Methods: Prospective cohort study of consecutively admitted patients in a specialized center for acute stroke. Patients with a transient ischemic attack, subarachnoid hemorrhage, cerebral venous thrombosis, hemorrhagic stroke with secondary cause, non-acute stroke, or those who did not consent to participate were excluded. Swallowing was evaluated by speech language pathologists using Volume-Viscosity Swallow Test. General function at three months post-stroke was assessed using the following instruments: Modified Rankin scale, Barthel Index and Functional Independence Measure. Results: A total of 831 patients were admitted and 305 patients were included according to the inclusion and exclusion criteria. The mean age of patients was 63.6±13.3 years, mean time from stroke to swallowing assessment was 4.2±4.1 days, and 45.2% of the patients had dysphagia. Age (OR=1.02; 95%CI 1.00-1.04; p=0.017), known medical history of obstructive sleep apnea (OR=5.13; 95%CI 1.74-15.15; p=0.003), and stroke severity at hospital admission (OR=1.10; 95%CI 1.06-1.15; p<0.001) were independently associated with dysphagia. Dysphagia (OR=3.78; 95%CI 2.16-6.61; p<0.001) and stroke severity (OR=1.05; 95%CI 1.00-1.09; p=0.024) were independently associated with death or functional dependence at three months. Conclusions: Dysphagia was present in almost half of stroke patients. Age, obstructive sleep apnea, and stroke severity were predictors of dysphagia, which was independently associated with death or functional dependence at three months.

RESUMO Antecedentes: Poucos estudos brasileiros investigaram fatores de risco para disfagia e suas complicações associadas em uma grande coorte. Objetivo: Investigar frequência, preditores e desfechos associados da disfagia em pacientes até três meses após acidente vascular cerebral (AVC). Métodos: Selecionamos pacientes admitidos consecutivamente em um centro especializado em AVC agudo. Excluímos pacientes com ataque isquêmico transitório, hemorragia subaracnóidea, trombose venosa cerebral, AVC hemorrágico de causa secundária, AVC não agudo ou aqueles que não consentiram em participar. A deglutição foi avaliada por fonoaudiólogos, por meio do teste de deglutição de volume-viscosidade. A função geral foi avaliada usando-se escala de Rankin modificada, índice de Barthel e medida de independência funcional. Resultados: Foram admitidos 831 pacientes e incluídos 305. A idade média foi 63,6±13,3 anos, o tempo médio da avaliação foi 4,2±4,1 dias e 45,2% apresentavam disfagia. Idade (razão de chances [OR] 1,02; intervalo de confiança [IC95%] 1,00-1,04; p=0,017), história médica conhecida de apneia obstrutiva do sono (OR=5,13; IC95% 1,74-15,15; p=0,003) e gravidade do AVC na admissão hospitalar (OR=1,10; IC95% 1,06-1,15; p<0,001) foram independentemente associados à disfagia. Disfagia (OR=3,78; IC95% 2,16-6,61; p<0,001) e gravidade do AVC (OR=1,05; IC95% 1,00-1,09; p=0,024) foram independentemente associadas com morte ou dependência funcional em três meses. Conclusões: A disfagia esteve presente em quase metade dos pacientes com AVC. Idade, apneia obstrutiva do sono e gravidade do AVC foram preditores de disfagia, que esteve independentemente associada com morte ou dependência funcional em três meses.

Parvalbumin Role in Epilepsy and Psychiatric Comorbidities: From Mechanism to Intervention.

Parvalbumin is a calcium-binding protein present in inhibitory interneurons that play an essential role in regulating many physiological processes, such as intracellular signaling and synaptic transmission. Changes in parvalbumin expression are deeply related to epilepsy, which is considered one of the most disabling neuropathologies. Epilepsy is a complex multi-factor group of disorders characterized by periods of hypersynchronous activity and hyperexcitability within brain networks. In this scenario, inhibitory neurotransmission dysfunction in modulating excitatory transmission related to the loss of subsets of parvalbumin-expressing inhibitory interneuron may have a prominent role in disrupted excitability. Some studies also reported that parvalbumin-positive interneurons altered function might contribute to psychiatric comorbidities associated with epilepsy, such as depression, anxiety, and psychosis. Understanding the epileptogenic process and comorbidities associated with epilepsy have significantly advanced through preclinical and clinical investigation. In this review, evidence from parvalbumin altered function in epilepsy and associated psychiatric comorbidities were explored with a translational perspective. Some advances in potential therapeutic interventions are highlighted, from current antiepileptic and neuroprotective drugs to cutting edge modulation of parvalbumin subpopulations using optogenetics, designer receptors exclusively activated by designer drugs (DREADD) techniques, transcranial magnetic stimulation, genome engineering, and cell grafting. Creating new perspectives on mechanisms and therapeutic strategies is valuable for understanding the pathophysiology of epilepsy and its psychiatric comorbidities and improving efficiency in clinical intervention.

Dysphagia is a strong predictor of death and functional dependence at three months post-stroke.

BACKGROUND: Few Brazilian studies investigated risk factors for dysphagia and associated complications in a large cohort. OBJECTIVE: To investigate frequency, predictors, and associated outcomes of dysphagia in patients up to three months post-stroke. METHODS: Prospective cohort study of consecutively admitted patients in a specialized center for acute stroke. Patients with a transient ischemic attack, subarachnoid hemorrhage, cerebral venous thrombosis, hemorrhagic stroke with secondary cause, non-acute stroke, or those who did not consent to participate were excluded. Swallowing was evaluated by speech language pathologists using Volume-Viscosity Swallow Test. General function at three months post-stroke was assessed using the following instruments: Modified Rankin scale, Barthel Index and Functional Independence Measure. RESULTS: A total of 831 patients were admitted and 305 patients were included according to the inclusion and exclusion criteria. The mean age of patients was 63.6±13.3 years, mean time from stroke to swallowing assessment was 4.2±4.1 days, and 45.2% of the patients had dysphagia. Age (OR=1.02; 95%CI 1.00-1.04; p=0.017), known medical history of obstructive sleep apnea (OR=5.13; 95%CI 1.74-15.15; p=0.003), and stroke severity at hospital admission (OR=1.10; 95%CI 1.06-1.15; p<0.001) were independently associated with dysphagia. Dysphagia (OR=3.78; 95%CI 2.16-6.61; p<0.001) and stroke severity (OR=1.05; 95%CI 1.00-1.09; p=0.024) were independently associated with death or functional dependence at three months. CONCLUSIONS: Dysphagia was present in almost half of stroke patients. Age, obstructive sleep apnea, and stroke severity were predictors of dysphagia, which was independently associated with death or functional dependence at three months.

Prediction of Learned Resistance or Helplessness by Hippocampal-Prefrontal Cortical Network Activity during Stress.

The perception of control over a stressful experience may determine its impacts and generate resistance against future stressors. Although the medial prefrontal cortex (PFC) and the hippocampus (HPC) are implicated in the encoding of stressor controllability, the neural dynamics underlying this process are unknown. Here, we recorded HPC and PFC neural activities in male rats during the exposure to controllable, uncontrollable, or no shocks and investigated electrophysiological predictors of escape performance upon exposure to subsequent uncontrollable shocks. We were able to accurately discriminate stressed from nonstressed animals and predict resistant (R) or helpless (H) individuals based on hippocampal-cortical oscillatory dynamics. Remarkably, R animals exhibited an increase in theta power during CS, while H exhibited a decrease. Furthermore, R exhibited higher HPC to PFC θ synchronization during stress. Notably, HPC-PFC θ connectivity in the initial stress exposure showed strong correlations with escape performance evaluated days later. R rats also showed stronger θ coupling to both γ oscillations and neuronal firing in the PFC. Finally, we found that these distinct features of network dynamics collectively formed a pattern that accurately predicted learned resistance and was lacking in H individuals. Our findings suggest that hippocampal-prefrontal network θ activity supports cognitive mechanisms of stress coping, whose impairment may underlie vulnerability to stress-related disorders.SIGNIFICANCE STATEMENT The appraisal of adversities as controllable or uncontrollable is key in determining resilience or risk for stress-related disorders. Here, we performed the first electrophysiological investigation during controllable or uncontrollable stress. Pharmacological studies showed that the prefrontal cortex (PFC) and the hippocampus (HPC) encode stressor controllability, and here we identified the neural activity underlying this process. This "neural signature of stressor controllability" accurately predicted resistance to future stressors and was characterized by increased HPC-PFC oscillatory activity in the θ frequency (4-10 Hz). Our findings suggest a new role of frontal θ oscillations in adaptive stress coping, integrating its emotional and cognitive functions. We also endorse the potential of this biomarker to guide neurophysiologically-informed and rhythm-based stimulation therapies for depression.

Neuromodulation of Hippocampal-Prefrontal Cortical Synaptic Plasticity and Functional Connectivity: Implications for Neuropsychiatric Disorders.

The hippocampus-prefrontal cortex (HPC-PFC) pathway plays a fundamental role in executive and emotional functions. Neurophysiological studies have begun to unveil the dynamics of HPC-PFC interaction in both immediate demands and long-term adaptations. Disruptions in HPC-PFC functional connectivity can contribute to neuropsychiatric symptoms observed in mental illnesses and neurological conditions, such as schizophrenia, depression, anxiety disorders, and Alzheimer's disease. Given the role in functional and dysfunctional physiology, it is crucial to understand the mechanisms that modulate the dynamics of HPC-PFC communication. Two of the main mechanisms that regulate HPC-PFC interactions are synaptic plasticity and modulatory neurotransmission. Synaptic plasticity can be investigated inducing long-term potentiation or long-term depression, while spontaneous functional connectivity can be inferred by statistical dependencies between the local field potentials of both regions. In turn, several neurotransmitters, such as acetylcholine, dopamine, serotonin, noradrenaline, and endocannabinoids, can regulate the fine-tuning of HPC-PFC connectivity. Despite experimental evidence, the effects of neuromodulation on HPC-PFC neuronal dynamics from cellular to behavioral levels are not fully understood. The current literature lacks a review that focuses on the main neurotransmitter interactions with HPC-PFC activity. Here we reviewed studies showing the effects of the main neurotransmitter systems in long- and short-term HPC-PFC synaptic plasticity. We also looked for the neuromodulatory effects on HPC-PFC oscillatory coordination. Finally, we review the implications of HPC-PFC disruption in synaptic plasticity and functional connectivity on cognition and neuropsychiatric disorders. The comprehensive overview of these impairments could help better understand the role of neuromodulation in HPC-PFC communication and generate insights into the etiology and physiopathology of clinical conditions.

Conceptual Framework for Insomnia: A Cognitive Model in Practice.

Insomnia is a widespread neuropsychological sleep-related disorder known to result in various predicaments including cognitive impairments, emotional distress, negative thoughts, and perceived sleep insufficiency besides affecting the incidence and aggravation of other medical disorders. Despite the available insomnia-related theoretical cognitive models, clinical studies, and related guidelines, an evidence-based conceptual framework for a personalized approach to insomnia seems to be lacking. This study proposes a conceptual cognitive framework (CCF) providing insight into cognitive mechanisms involved in the predisposition, precipitation, and perpetuation of insomnia and consequent cognitive deficits. The current CCF for insomnia relies on evaluative conditional learning and appraisal which generates negative valence (emotional value) and arousal (cognitive value). Even with the limitations of this study, the suggested methodology is well-defined, reproducible, and accessible can help foster future high-quality clinical databases. During clinical insomnia but not the neutral one, negative mood (trait-anxiety) causes cognitive impairments only if mediating with a distorted perception of insomnia ( Ind-1 = 0.161, 95% CI 0.040-0.311). Further real-life testing of the CCF is intended to formulate a meticulous, decision-supporting platform for clinical interventions. Furthermore, the suggested methodology is expected to offer a reliable platform for CCF-development in other cognitive impairments and support the causal clinical data models. It may also improve our knowledge of psychological disturbances and complex comorbidities to help design rehabilitation interventions and comprehensive frameworks in line with the "preventive medicine" policies.

Network Asynchrony Underlying Increased Broadband Gamma Power.

Synchronous activity of cortical inhibitory interneurons expressing parvalbumin (PV) underlies expression of cortical γ rhythms. Paradoxically, deficient PV inhibition is associated with increased broadband γ power in the local field potential. Increased baseline broadband γ is also a prominent characteristic in schizophrenia and a hallmark of network alterations induced by NMDAR antagonists, such as ketamine. Whether enhanced broadband γ is a true rhythm, and if so, whether rhythmic PV inhibition is involved or not, is debated. Asynchronous and increased firing activities are thought to contribute to broadband power increases spanning the γ band. Using male and female mice lacking NMDAR activity specifically in PV neurons to model deficient PV inhibition, we here show that neuronal activity with decreased synchronicity is associated with increased prefrontal broadband γ power. Specifically, reduced spike time precision and spectral leakage of spiking activity because of higher firing rates (spike "contamination") affect the broadband γ band. Desynchronization was evident at multiple time scales, with reduced spike entrainment to the local field potential, reduced cross-frequency coupling, and fragmentation of brain states. Local application of S(+)-ketamine in (control) mice with intact NMDAR activity in PV neurons triggered network desynchronization and enhanced broadband γ power. However, our investigations suggest that disparate mechanisms underlie increased broadband γ power caused by genetic alteration of PV interneurons and ketamine-induced power increases in broadband γ. Our study confirms that enhanced broadband γ power can arise from asynchronous activities and demonstrates that long-term deficiency of PV inhibition can be a contributor.SIGNIFICANCE STATEMENT Brain oscillations are fundamental to the coordination of neuronal activity across neurons and structures. γ oscillations (30-80 Hz) have received particular attention through their association with perceptual and cognitive processes. Synchronous activity of inhibitory parvalbumin (PV) interneurons generates cortical γ oscillation, but, paradoxically, PV neuron deficiency is associated with increases in γ oscillations. We here reconcile this conundrum and show how deficient PV inhibition can lead to increased and asynchronous excitatory firing, contaminating the local field potential and manifesting as increased γ power. Thus, increased γ power does not always reflect a genuine rhythm. Further, we show that ketamine-induced γ increases are caused by separate network mechanisms.

Improving surgical outcome with electric source imaging and high field magnetic resonance imaging.

While most patients with focal epilepsy present with clear structural abnormalities on standard, 1.5 or 3 T MRI, some patients are MRI-negative. For those, quantitative MRI techniques, such as volumetry, voxel-based morphometry, and relaxation time measurements can aid in finding the epileptogenic focus. High-field MRI, just recently approved for clinical use by the FDA, increases the resolution and, in several publications, was shown to improve the detection of focal cortical dysplasias and mild cortical malformations. For those cases without any tissue abnormality in neuroimaging, even at 7 T, scalp EEG alone is insufficient to delimitate the epileptogenic zone. They may benefit from the use of high-density EEG, in which the increased number of electrodes helps improve spatial sampling. The spatial resolution of even low-density EEG can benefit from electric source imaging techniques, which map the source of the recorded abnormal activity, such as interictal epileptiform discharges, focal slowing, and ictal rhythm. These EEG techniques help localize the irritative, functional deficit, and seizure-onset zone, to better estimate the epileptogenic zone. Combining those technologies allows several drug-resistant cases to be submitted to surgery, increasing the odds of seizure freedom and providing a must needed hope for patients with epilepsy.

Hijacking of hippocampal-cortical oscillatory coupling during sleep in temporal lobe epilepsy.

Memory impairment is the most common cognitive deficit in patients with temporal lobe epilepsy (TLE). This type of epilepsy is currently regarded as a network disease because of its brain-wide alterations in functional connectivity between temporal and extra-temporal regions. In patients with TLE, network dysfunctions can be observed during ictal states, but are also described interictally during rest or sleep. Here, we examined the available literature supporting the hypothesis that hippocampal-cortical coupling during sleep is hijacked in TLE. First, we look at studies showing that the coordination between hippocampal sharp-wave ripples (100-200 Hz), corticothalamic spindles (9-16 Hz), and cortical delta waves (1-4 Hz) during nonrapid eye movement (NREM) sleep is critical for spatial memory consolidation. Then, we reviewed studies showing that animal models of TLE display precise coordination between hippocampal interictal epileptiform discharges (IEDs) and spindle oscillations in the prefrontal cortex. This aberrant oscillatory coupling seems to surpass the physiological ripple-delta-spindle coordination, which could underlie memory consolidation impairments. We also discuss the role of rapid eye movement (REM) sleep for local synaptic plasticity and memory. Sleep episodes of REM provide windows of opportunity for reactivation of expression of immediate early genes (i.e., zif-268 and Arc). Besides, hippocampal theta oscillations during REM sleep seem to be critical for memory consolidation of novel object place recognition task. However, it is still unclear which extend this particular phase of sleep is affected in TLE. In this context, we show some preliminary results from our group, suggesting that hippocampal theta-gamma phase-amplitude coupling is exacerbated during REM in a model of basolateral amygdala fast kindling. In conclusion, there is an increasing body of evidence suggesting that circuits responsible for memory consolidation during sleep seem to be gradually coopted and degraded in TLE. This article is part of the Special Issue "NEWroscience 2018".

Glia and extracellular matrix molecules: What are their importance for the electrographic and MRI changes in the epileptogenic zone?

Glial cells and extracellular matrix (ECM) molecules are crucial for the maintenance of brain homeostasis. Especially because of their actions regarding neurotransmitter and ionic control, and synaptic function, these cells can potentially contribute to the hyperexcitability seen in the epileptogenic, while ECM changes are linked to synaptic reorganization. The present review will explore glial and ECM homeostatic roles and their potential contribution to tissue plasticity. Finally, we will address how glial, and ECM changes in the epileptogenic zone can be seen in magnetic resonance imaging (MRI), pointing out their importance as markers for the extension of the epileptogenic area. This article is part of the Special Issue "NEWroscience 2018".

Translation and Validation of the TOR-BSST© into Brazilian Portuguese for Adults with Stroke.

Brazil has a higher rate of dysphagia in stroke patients compared to developed countries, but does not have a fully validated method for early identification of dysphagia in this population. The aim of this study is to translate the TOR-BSST© into Brazilian Portuguese and assess the newly translated version for reliability and validity with Brazilian adult patients with stroke. The translation of the TOR-BSST© followed a multi-step process, according to the International Quality of Life Assessment project. For validation, we included patients with age ≥ 18 years and stroke diagnosis confirmed by neuroimaging and tolerance for videofluoroscopic swallowing assessment. The BR-PTfinal TOR-BSST© was administered by two trained screeners within two hours of videofluoroscopy. All assessors were independent and blinded. Estimates for reliability used the intraclass correlation coefficient (ICC) and for accuracy both sensitivity (SN) and negative predictive (NP) values were used, along with 95% confidence intervals (CI). Sixty patients were enrolled and tested for a mean (SD) of 14.4 (6.9) days from last seen normal. Of all the patients, 41 (68.3%) failed the BR-PTfinal TOR-BSST© and 21 (35%) were scored to have dysphagia on videofluoroscopy, of which 11 (52.4%) had mild dysphagia. The overall reliability between screeners was satisfactory (ICC = 0.59; 95% CI 0.32 to 0.76). The SN and NP values for the BR-PTfinal TOR-BSST© were 85.7% (95% CI 0.62-0.96) and 84.2% (95% CI 0.72-0.95), respectively. The TOR-BSST© was successfully translated to Brazilian Portuguese with the BR-PTfinal TOR-BSST© proven to have high sensitivity and negative predictive values when compared to gold standard videofluoroscopy.

Drebrin expression patterns in patients with refractory temporal lobe epilepsy and hippocampal sclerosis.

OBJECTIVE: Drebrins are crucial for synaptic function and dendritic spine development, remodeling, and maintenance. In temporal lobe epilepsy (TLE) patients, a significant hippocampal synaptic reorganization occurs, and synaptic reorganization has been associated with hippocampal hyperexcitability. This study aimed to evaluate, in TLE patients, the hippocampal expression of drebrin using immunohistochemistry with DAS2 or M2F6 antibodies that recognize adult (drebrin A) or adult and embryonic (pan-drebrin) isoforms, respectively. METHODS: Hippocampal sections from drug-resistant TLE patients with hippocampal sclerosis (HS; TLE, n = 33), of whom 31 presented with type 1 HS and two with type 2 HS, and autopsy control cases (n = 20) were assayed by immunohistochemistry and evaluated for neuron density, and drebrin A and pan-drebrin expression. Double-labeling immunofluorescences were performed to localize drebrin A-positive spines in dendrites (MAP2), and to evaluate whether drebrin colocalizes with inhibitory (GAD65) and excitatory (VGlut1) presynaptic markers. RESULTS: Compared to controls, TLE patients had increased pan-drebrin in all hippocampal subfields and increased drebrin A-immunopositive area in all hippocampal subfields but CA1. Drebrin-positive spine density followed the same pattern as total drebrin quantification. Confocal microscopy indicated juxtaposition of drebrin-positive spines with VGlut1-positive puncta, but not with GAD65-positive puncta. Drebrin expression in the dentate gyrus of TLE cases was associated negatively with seizure frequency and positively with verbal memory. TLE patients with lower drebrin-immunopositive area in inner molecular layer (IML) than in outer molecular layer (OML) had a lower seizure frequency than those with higher or comparable drebrin-immunopositive area in IML compared with OML. SIGNIFICANCE: Our results suggest that changes in drebrin-positive spines and drebrin expression in the dentate gyrus of TLE patients are associated with lower seizure frequency, more preserved verbal memory, and a better postsurgical outcome.