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Abstract 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 (“ $${\underset{{\mathcal {C}}}{{{\varvec{Ind-1}}}}}$$ I n d - 1 C ” = 1.87; 95% CI 1.18–2.72)[“1st indirect path in the Clinical stage model”: Tinnitus Loudness $$\rightarrow$$ → Attention Bias $$\rightarrow$$ → Cognitive-Emotional Value $$\rightarrow$$ → Annoyance $$\rightarrow$$ → Clinical Distress]or without (“ $${\underset{{\mathcal {C}}}{{{\varvec{Ind-2}}}}}$$ I n d - 2 C ”= 2.03; 95% CI 1.02–3.32)[ “2nd indirect path in the Clinical stage model”: Tinnitus Loudness $$\rightarrow$$ → Annoyance $$\rightarrow$$ → 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.

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.

Objective: Temporal lobe epilepsy patients (TLE) often present with hippocampal atrophy, increased T2 relaxation, and reduced magnetization transfer ratio (MTR) in magnetic resonance images (MRI). The histological correlates of the reduced hippocampal MTR are so far unknown. Since MTR is dependent on the tissue’s macromolecules, our aim was to evaluate the correlations between cellular populations, extracellular matrix molecules and the MTR in TLE patients. Methods: Patients with TLE (n = 26) and voluntaries (=20) were scanned in a 3 Tesla MRI scanner, and MTR images were calculated from 3DT1 sequences with magnetization pulse on resonance. Immunohistochemistry for neurons, reactive astrocytes, activated microglia, and extracellular matrix chondroitin sulfate were performed in formalin fixed, paraffin embedded tissues of TLE and autopsy controls (n = 10). Results were considered significant with adjusted p

In patients with temporal lobe epilepsy (TLE), presurgical magnetic resonance imaging (MRI) often reveals hippocampal atrophy, while neuropathological assessment indicates the different types of hippocampal sclerosis (HS). Different HS types are not discriminated in MRI so far. We aimed to define the volume of each hippocampal subfield on MRI manually and to compare automatic and manual segmentations for the discrimination of HS types. The T2-weighted images from 14 formalin-fixed age-matched control hippocampi were obtained with 4.7T MRI to evaluate the volume of each subfield at the anatomical level of the hippocampal head, body, and tail. Formalin-fixed coronal sections at the level of the body of 14 control cases, as well as tissue samples from 24 TLE patients, were imaged with a similar high-resolution sequence at 3T. Presurgical three-dimensional (3D) T1-weighted images from TLE went through a FreeSurfer 6.0 hippocampal subfield automatic assessment. The manual delineation with the 4.7T MRI was identified using Luxol Fast Blue stained 10-μm-thin microscopy slides, collected at every millimeter. An additional section at the level of the body from controls and TLE cases was submitted to NeuN immunohistochemistry for neuronal density estimation. All TLE cases were classified according to the International League Against Epilepsy's (ILAE's) HS classification. Manual volumetry in controls revealed that the dentate gyrus (DG)+CA4 region, CA1, and subiculum accounted for almost 90% of the hippocampal volume. The manual 3T volumetry showed that all TLE patients with type 1 HS (TLE-HS1) had lower volumes for DG+CA4, CA2, and CA1, whereas those TLE patients with HS type 2 (TLE-HS2) had lower volumes only in CA1 (p ≤ 0.038). Neuronal cell densities always decreased in CA4, CA3, CA2, and CA1 of TLE-HS1 but only in CA1 of TLE-HS2 (p ≤ 0.003). In addition, TLE-HS2 had a higher volume (p = 0.016) and higher neuronal density (p < 0.001) than the TLE-HS1 in DG + CA4. Automatic segmentation failed to match the manual or histological findings and was unable to differentiate TLE-HS1 from TLE-HS2. Total hippocampal volume correlated with DG+CA4 and CA1 volumes and neuronal density. For the first time, we also identified subfield-specific pathology patterns in the manual evaluation of volumetric MRI scans, showing the importance of manual segmentation to assess subfield-specific pathology patterns.

Abstract 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.

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.

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.

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

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.

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.

Abstract Introduction The presence of microembolic signals (MES) during the acute phase of stroke is poorly understood, and its role and clinical application in relation to risk stratification and prognosis in patients remain uncertain. We assessed the prevalence of spontaneous MES in acute stroke and their relationship with risk stratification, stroke recurrence, morbidity, and mortality. Patients and methods This was a prospective cohort study conducted in the Stroke Unit. The MES presence was evaluated by transcranial Doppler (TCD) in patients with ischemic stroke within 48 h. The outcomes (risk stratification, morbidity, mortality, and recurrence of a stroke) were followed up for 6 months. The relationship between risk stratification and MES was obtained by odds ratios and that between MES and stroke recurrence, morbidity, and mortality using multiple logistic regression; considering statistical significance at P

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.

BackgroundSeveral genetic association investigations have been performed over the last three decades to identify variants underlying Juvenile Myoclonic Epilepsy (JME). Here, we evaluate the accumulating findings and provide an updated perspective of these studies.MethodologyA systematic literature search was conducted using the PubMed, Embase, Scopus, Lilacs, epiGAD, Google Scholar and Sigle up to February 12, 2016. The quality of the included studies was assessed by a score and classified as low and high quality. Beyond outcome measures, information was extracted on the setting for each study, characteristics of population samples and polymorphisms.ResultsFifty studies met eligibility criteria and were used for data extraction. With a single exception, all studies used a candidate gene approach, providing data on 229 polymorphisms in or near 55 different genes. Of variants investigating in independent data sets, only rs2029461 SNP in GRM4, rs3743123 in CX36 and rs3918149 in BRD2 showed a significant association with JME in at least two different background populations. The lack of consistent associations might be due to variations in experimental design and/or limitations of the approach.ConclusionsThus, despite intense research evidence established, specific genetic variants in JME susceptibility remain inconclusive. We discussed several issues that may compromise the quality of the results, including methodological bias, endophenotype and potential involvement of epigenetic factors.Prospero registration numberCRD42016036063.

Neuropathological studies often use autopsy brain tissue as controls to evaluate changes in protein or RNA levels in several diseases. In mesial temporal lobe epilepsy (MTLE), several genes are up or down regulated throughout the epileptogenic and chronic stages of the disease. Given that postmortem changes in several gene transcripts could impact the detection of changes in case-control studies, we evaluated the effect of using autopsy specimens with different postmortem intervals (PMI) on differential gene expression of the Pilocarpine (PILO)induced Status Epilepticus (SE) of MTLE. For this, we selected six genes (Gfap, Ppia, Gad65, Gad67, Npy, and Tnf-α) whose expression patterns in the hippocampus of PILO-injected rats are well known. Initially, we compared hippocampal expression of naïve rats whose hippocampi were harvested immediately after death (0h-PMI) with those harvested at 6h postmortem interval (6h-PMI): Npy and Ppia transcripts increased and Tnf-α transcripts decreased in the 6h-PMI group (p

OBJECTIVE: Mounting evidence suggests that the limbic system is pathologically involved in cases of psychiatric comorbidities in temporal lobe epilepsy (TLE) patients. Our objective was to develop a conceptual framework describing how neuropathological and connectivity changes might contribute to the development of psychosis and to the potential neurobiological mechanisms that cause schizophrenia-like psychosis in TLE patients. METHODS: In this review, clinical and neuropathological findings, especially brain circuitry of the limbic system, were examined together to enhance our understanding of the association between TLE and psychosis. Finally, the importance of animal models in epilepsy and psychiatric disorders was discussed. CONCLUSIONS: TLE and psychiatric symptoms coexist more frequently than chance would predict. Damage and deregulation among critical anatomical regions, such as the hippocampus, amygdala, thalamus, and the temporal, frontal and cingulate cortices, might predispose TLE brains to psychosis. Studies of the effects of kindling and injection of neuroactive substances on behavior and electrophysiological patterns may offer a model of how limbic seizures in humans increase the vulnerability of TLE patients to psychiatric symptoms.OBJETIVO: Existem cada vez mais evidências de que o sistema límbico está envolvido na patologia das comorbidades psiquiátricas em pacientes com epilepsia do lobo temporal (ELT). Nosso objetivo foi elaborar um desenho conceitual descrevendo como aspectos neuropatológicos e de conectividade podem contribuir para o desenvolvimento de psicose em pacientes com ELT. MÉTODOS: Nesta revisão, achados clínicos e neuropatológicos, e especialmente os aspectos da circuitaria límbica, foram examinados em conjunto para auxiliar nossa compreensão sobre a associação entre ELT e psicose. Achados em modelos animais de epilepsia e esquizofrenia também foram levados em consideração. CONCLUSÕES: ELT e comorbidades psiquiátricas coexistem com maior frequência que o predito pela associação ao acaso. Dano e desregulação entre estruturas anatômicas críticas, como hipocampo, amígdala, tálamo, e córtices temporal, frontal e cingulado podem predispor o cérebro com ELT à psicose. Estudos sobre efeitos comportamentais e eletrofisiológicos do abrasamento elétrico e injeções de substâncias neuroativas em modelos animais podem oferecer pistas sobre como crises límbicas em humanos aumentam a vulnerabilidade de pacientes com ELT a sintomas psiquiátricos.

OBJECTIVE: Scarce data are available on the occurrence of symptomatic intracranial hemorrhage related to intravenous thrombolysis for acute stroke in South America. We aimed to address the frequency and clinical predictors of symptomatic intracranial hemorrhage after stroke thrombolysis at our tertiary emergency unit in Brazil. METHOD: We reviewed the clinical and radiological data of 117 consecutive acute ischemic stroke patients treated with intravenous thrombolysis in our hospital between May 2001 and April 2010. We compared our results with those of the Safe Implementation of Thrombolysis in Stroke registry. Univariate and multiple regression analyses were performed to identify factors associated with symptomatic intracranial transformation. RESULTS: In total, 113 cases from the initial sample were analyzed. The median National Institutes of Health Stroke Scale score was 16 (interquartile range: 10-20). The median onset-to-treatment time was 188 minutes (interquartile range: 155-227). There were seven symptomatic intracranial hemorrhages (6.2%; Safe Implementation of Thrombolysis in Stroke registry: 4.9%; p = 0.505). In the univariate analysis, current statin treatment and elevated National Institute of Health Stroke Scale scores were related to symptomatic intracranial hemorrhage. After the multivariate analysis, current statin treatment was the only factor independently associated with symptomatic intracranial hemorrhage. CONCLUSIONS: In this series of Brazilian patients with severe strokes treated with intravenous thrombolysis in a public university hospital at a late treatment window, we found no increase in the rate of symptomatic intracranial hemorrhage. Additional studies are necessary to clarify the possible association between statins and the risk of symptomatic intracranial hemorrhage after stroke thrombolysis.

Pusher behavior (PB) is a disorder of postural control affecting patients with encephalic lesions. This study has aimed to identify the brain substrates that are critical for the occurrence of PB, to analyze the influence of the midline shift (MS) and hemorrhagic stroke volume (HSV) on the severity and prognosis of the PB. We identified 31 pusher patients of a neurological unit, mean age 67.4±11.89, 61.3% male. Additional neurological and functional examinations were assessed. Neuroimaging workup included measurement of the MS, the HSV in patients with hemorrhagic stroke, the analysis of the vascular territory, etiology and side of the lesion. Lesions in the parietal region (p=0.041) and thalamus (p=0.001) were significantly more frequent in PB patients. Neither the MS nor the HSV were correlated with the PB severity or recovery time.

Heat shock proteins (HSPs) are molecular chaperones that bind to other proteins to shepherd them across membranes and direct them to specific locations within a cell. Several injurious stimuli can induce Hsp70 expression, including ischemia. This study aimed to investigate the pattern of expression of protein (immunohistochemistry) and gene (real-time PCR) Hsp70 in experimental focal cerebral ischemia in rats by occlusion of the middle cerebral artery for 1 hour and the role of neuroprotection with hypothermia (H) and ketoprofen (K). The infarct volume was measured using morphometric analysis defined by triphenyl tetrazolium chloride. It was observed increases in the protein (p=0.0001) and gene (p=0.0001) Hsp70 receptor in the ischemic areas that were reduced by H (protein and gene: pProteínas de choque térmico (HSPs) são chaperones moleculares que se ligam a outras proteínas para atravessar as membranas e encaminhá-las para locais específicos dentro de uma célula. Vários estímulos nocivos podem induzir a expressão de Hsp70, incluindo isquemia. Este estudo teve como objetivo investigar o padrão de expressão protéica (imunohistoquímica) e gênica (PCR em tempo real) de Hsp70 na isquemia cerebral focal experimental em ratos pela oclusão da artéria cerebral média durante 1 hora e o papel da neuroproteção com hipotermia (H) e cetoprofeno (C). O volume de infarto foi calculado através da análise morfométrica definido por cloreto de trifenil tetrazólio. Foi observado aumento na expressão proteína (p=0,0001) e gênica (p=0,0001) de Hsp70 nas áreas isquêmicas que foram reduzidas pela H (proteína e gene: p

The involvement of miRNA in mesial temporal lobe epilepsy (MTLE) pathogenesis has increasingly become a focus of epigenetic studies. Despite advances, the number of known miRNAs with a consistent expression response during epileptogenesis is still small. Addressing this situation requires additional miRNA profiling studies coupled to detailed individual expression analyses. Here, we perform a miRNA microarray analysis of the hippocampus of Wistar rats 24 hours after intra-hippocampal pilocarpine-induced Status Epilepticus (H-PILO SE). We identified 73 miRNAs that undergo significant changes, of which 36 were up-regulated and 37 were down-regulated. To validate, we selected 5 of these (10a-5p, 128a-3p, 196b-5p, 352 and 324-3p) for RT-qPCR analysis. Our results confirmed that miR-352 and 196b-5p levels were significantly higher and miR-128a-3p levels were significantly lower in the hippocampus of H-PILO SE rats. We also evaluated whether the 3 miRNAs show a dysregulated hippocampal expression at three time periods (0h, 24h and chronic phase) after systemic pilocarpine-induced status epilepticus (S-PILO SE). We demonstrate that miR-128a-3p transcripts are significantly reduced at all time points compared to the naïve group. Moreover, miR-196b-5p was significantly higher only at 24h post-SE, while miR-352 transcripts were significantly up-regulated after 24h and in chronic phase (epileptic) rats. Finally, when we compared hippocampi of epileptic and non-epileptic humans, we observed that transcript levels of miRNAs show similar trends to the animal models. In summary, we successfully identified two novel dysregulated miRNAs (196b-5p and 352) and confirmed miR-128a-3p downregulation in SE-induced epileptogenesis. Further functional assays are required to understand the role of these miRNAs in MTLE pathogenesis.

[This corrects the article DOI: 10.1371/journal.pone.0044709.].

Rubato has always been related to musical performance expressivity. In the last 150 years, however, Western art music teaching has emphasized strict metric regularity in the performance of pieces composed before the Romantic era. Such practice however is not consensual. The present study is an interdisciplinary, descriptive analysis, based on musicological, psychological, and neuroscientific data that aims to explain the reasons of the polemic related to the function of maintaining strict metric regularity in musical performance. We have found in cognitive psychological data, information that supports the relationship between rubato and musical expressiveness. There is also evidence that the maintenance of strict metric regularity could inhibit expressiveness. This inhibition seems to be related to the level of difficulty that one experiences when asked to keep a strict tempo. Despite the inhibiting component, observations in musical teaching indicate that the practice of strict metric regularity is an indispensable instrument to a more elaborated expressive musical interpretation. Therefore this present study analyzes the importance of this practice in the development of musical expressiveness.

The molecular mechanisms underlying epileptogenesis have been widely investigated by differential gene expression approach, especially RT-qPCR methodology. However, controversial findings highlight the occurrence of unpredictable sources of variance in the experimental designs. Here, we investigated if diurnal rhythms of transcript's levels may impact on differential gene expression analysis in hippocampus of rats with experimental epilepsy. For this, we have selected six core clock genes (Per1, Per3, Bmal1, Clock, Cry1 and Cry2), whose rhythmic expression pattern in hippocampus had been previously reported. Initially, we identified Tubb2a/Rplp1 and Tubb2a/Ppia as suitable normalizers for circadian studies in hippocampus of rats maintained to 12:12 hour light:dark (LD) cycle. Next, we confirmed the temporal profiling of Per1, Per3, Bmal1, Cry1 and Cry2 mRNA levels in the hippocampus of naive rats by both Acrophase and CircWave statistical tests for circadian analysis. Finally, we showed that temporal differences of sampling can change experimental results for Per1, Per3, Bmal1, Cry1 and Cry2, but not for Clock, which was consistently decreased in rats with epilepsy in all comparison to the naive group. In conclusion, our study demonstrates it is mandatory to consider diurnal oscillations, in order to avoid erroneous conclusions in gene expression analysis in hippocampus of rats with epilepsy. Investigators, therefore, should be aware that genes with circadian expression could be out of phase in different animals of experimental and control groups. Moreover, our results indicate that a sub-expression of Clock may be involved in epileptogenicity, although the functional significance of this remains to be investigated.

Functional MRI produces a more accurate localization of the language areas for epilepsy surgery purpose, but requires the patient cooperation. We report a 34 years-old woman with mental retardation who underwent two different verbal fluency tasks, category and word naming. We found a strong activation of the Broca’s area in the most difficult task. We suggest that a multi-task fMRI study could be successful in patients with cognitive delay.A ressonância magnética funcional permite uma localização acurada da área da linguagem para fins de cirurgia de epilepsia, mas requer a colaboração do paciente na execução da tarefa proposta, o que pode limitar a sua utilização em pacientes com retardo mental. Nós apresentamos o caso de uma mulher com 34 anos de idade, com retardo mental, que foi submetida a duas tarefas distintas de geração silenciosa de palavras, por categoria e letras. Encontramos forte ativação da área de Broca na tarefa mais complexa. Sugerimos que um estudo com múltiplas tarefas pode ser útil em pacientes com retardo mental.

OBJECTIVE: There is accumulating evidence that the limbic system is pathologically involved in cases of psychiatric comorbidities in temporal lobe epilepsy (TLE) patients. Our objective was to develop a conceptual framework describing how neuropathological, neurochemical and electrophysiological aspects might contribute to the development of psychiatric symptoms in TLE and the putative neurobiological mechanisms that cause mood disorders in this patient subgroup. METHODS: In this review, clinical, experimental and neuropathological findings, as well as neurochemical features of the limbic system were examined together to enhance our understanding of the association between TLE and psychiatric comorbidities. Finally, the value of animal models in epilepsy and mood disorders was discussed. CONCLUSIONS:TLE and psychiatric symptoms coexist more frequently than chance would predict. Alterations and neurotransmission disturbance among critical anatomical networks, and impaired or aberrant plastic changes might predispose patients with TLE to mood disorders. Clinical and experimental studies of the effects of seizures on behavior and electrophysiological patterns may offer a model of how limbic seizures increase the vulnerability of TLE patients to precipitants of psychiatric symptoms.OBJETIVO: Há evidências crescentes do envolvimento do sistema límbico nas comorbidades psiquiátricas associadas à epilepsia do lobo temporal (ELT). Nosso objetivo foi descrever o panorama atual das alterações neuropatológicas, neuroquímicas e eletrofisiológicas que podem contribuir para o desenvolvimento de sintomas psiquiátricos na ELT e explorar possíveis mecanismos neurobiológicos que podem levar ao aparecimento das desordens de humor nesse subgrupo de pacientes. MÉTODOS: Achados clínicos, de modelos experimentais e neuropatológicos foram revistos, assim como características neuroquímicas do sistema límbico foram examinadas em conjunto para auxiliar nossa compreensão sobre a associação entre ELT e transtornos de humor. CONCLUSÕES: A ELT e os sintomas psiquiátricos coexistem numa frequência muito maior do que o acaso poderia sugerir. Alterações e desregulação de redes anatômicas essenciais, além de mudanças plásticas aberrantes ou deficientes, podem predispor o cérebro de pacientes com ELT a transtornos de humor. Estudos experimentais e clínicos sobre o efeito das crises no comportamento e nos padrões eletrofisiológicos podem oferecer um modelo de como as crises límbicas aumentam a vulnerabilidade a sintomas psiquiátricos em pacientes com ELT.

In the central nervous system, zinc is released along with glutamate during neurotransmission and, in excess, can promote neuronal death. Experimental studies have shown that metallothioneins I/II (MT-I/II), which chelate free zinc, can affect seizures and reduce neuronal death after status epilepticus. Our aim was to evaluate the expression of MT-I/II in the hippocampus of patients with temporal lobe epilepsy (TLE). Hippocampi from patients with pharmacoresistant mesial temporal lobe epilepsy (MTLE) and patients with TLE associated with tumor or dysplasia (TLE-TD) were evaluated for expression of MT-I/II, for the vesicular zinc levels, and for neuronal, astroglial, and microglial populations. Compared to control cases, MTLE group displayed widespread increase in MT-I/II expression, astrogliosis, microgliosis and reduced neuronal population. In TLE-TD, the same changes were observed, except that were mainly confined to fascia dentata. Increased vesicular zinc was observed only in the inner molecular layer of MTLE patients, when compared to control cases. Correlation and linear regression analyses indicated an association between increased MT-I/II and increased astrogliosis in TLE. MT-I/II levels did not correlate with any clinical variables, but MTLE patients with secondary generalized seizures (SGS) had less MT-I/II than MTLE patients without SGS. In conclusion, MT-I/II expression was increased in hippocampi from TLE patients and our data suggest that it is associated with astrogliosis and may be associated with different seizure spread patterns.

The mediodorsal nucleus of the thalamus (MD) is a rich source of afferents to the medial prefrontal cortex (mPFC). Dysfunctions in the thalamo-prefrontal connections can impair networks implicated in working memory, some of which are affected in Alzheimer disease and schizophrenia. Considering the importance of the cholinergic system to cortical functioning, our study aimed to investigate the effects of global cholinergic activation of the brain on MD-mPFC synaptic plasticity by measuring the dynamics of long-term potentiation (LTP) and depression (LTD) in vivo. Therefore, rats received intraventricular injections either of the muscarinic agonist pilocarpine (PILO; 40 nmol/µL), the nicotinic agonist nicotine (NIC; 320 nmol/µL), or vehicle. The injections were administered prior to either thalamic high-frequency (HFS) or low-frequency stimulation (LFS). Test pulses were applied to MD for 30 min during baseline and 240 min after HFS or LFS, while field postsynaptic potentials were recorded in the mPFC. The transient oscillatory effects of PILO and NIC were monitored through recording of thalamic and cortical local field potentials. Our results show that HFS did not affect mPFC responses in vehicle-injected rats, but induced a delayed-onset LTP with distinct effects when applied following PILO or NIC. Conversely, LFS induced a stable LTD in control subjects, but was unable to induce LTD when applied after PILO or NIC. Taken together, our findings show distinct modulatory effects of each cholinergic brain activation on MD-mPFC plasticity following HFS and LFS. The LTP-inducing action and long-lasting suppression of cortical LTD induced by PILO and NIC might implicate differential modulation of thalamo-prefrontal functions under low and high input drive.

BACKGROUND: High level piano performance requires complex integration of perceptual, motor, cognitive and emotive skills. Observations in psychology and neuroscience studies have suggested reciprocal inhibitory modulation of the cognition by emotion and emotion by cognition. However, it is still unclear how cognitive states may influence the pianistic performance. The aim of the present study is to verify the influence of cognitive and affective attention in the piano performances. METHODS AND FINDINGS: Nine pianists were instructed to play the same piece of music, firstly focusing only on cognitive aspects of musical structure (cognitive performances), and secondly, paying attention solely on affective aspects (affective performances). Audio files from pianistic performances were examined using a computational model that retrieves nine specific musical features (descriptors)--loudness, articulation, brightness, harmonic complexity, event detection, key clarity, mode detection, pulse clarity and repetition. In addition, the number of volunteers' errors in the recording sessions was counted. Comments from pianists about their thoughts during performances were also evaluated. The analyses of audio files throughout musical descriptors indicated that the affective performances have more: agogics, legatos, pianos phrasing, and less perception of event density when compared to the cognitive ones. Error analysis demonstrated that volunteers misplayed more left hand notes in the cognitive performances than in the affective ones. Volunteers also played more wrong notes in affective than in cognitive performances. These results correspond to the volunteers' comments that in the affective performances, the cognitive aspects of piano execution are inhibited, whereas in the cognitive performances, the expressiveness is inhibited. CONCLUSIONS: Therefore, the present results indicate that attention to the emotional aspects of performance enhances expressiveness, but constrains cognitive and motor skills in the piano execution. In contrast, attention to the cognitive aspects may constrain the expressivity and automatism of piano performances.

OBJECTIVES: Approximately one-third of candidates for epilepsy surgery have no visible abnormalities on conventional magnetic resonance imaging. This is extremely discouraging, as these patients have a less favorable prognosis. We aimed to evaluate the utility of quantitative magnetic resonance imaging in patients with drug-resistant neocortical focal epilepsy and negative imaging. METHODS: A prospective study including 46 patients evaluated through individualized postprocessing of five quantitative measures: cortical thickness, white and gray matter junction signal, relaxation rate, magnetization transfer ratio, and mean diffusivity. Scalp video-electroencephalography was used to suggest the epileptogenic zone. A volumetric fluid-attenuated inversion recovery sequence was performed to aid visual inspection. A critical assessment of follow-up was also conducted throughout the study. RESULTS: In the subgroup classified as having an epileptogenic zone, individualized postprocessing detected abnormalities within the region of electroclinical origin in 9.7% to 31.0% of patients. Abnormalities outside the epileptogenic zone were more frequent, up to 51.7%. In five patients initially included with negative imaging, an epileptogenic structural abnormality was identified when a new visual magnetic resonance imaging inspection was guided by information gleaned from postprocessing. In three patients, epileptogenic lesions were detected after visual evaluation with volumetric fluid-attenuated sequence guided by video electroencephalography. CONCLUSION: Although quantitative magnetic resonance imaging analyses may suggest hidden structural lesions, caution is warranted because of the apparent low specificity of these findings for the epileptogenic zone. Conversely, these methods can be used to prevent visible lesions from being ignored, even in referral centers. In parallel, we need to highlight the positive contribution of the volumetric fluid-attenuated sequence.