Publications by authors named "João Pereira Leite"

68 Publications

Conceptual Framework for Insomnia: A Cognitive Model in Practice.

Front Neurosci 2021 22;15:628836. Epub 2021 Jul 22.

Neurocognitive Engineering Laboratory (NEL), Institute of Mathematics and Computer Science, University of São Paulo, São Carlos, Brazil.

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 ( = 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.
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http://dx.doi.org/10.3389/fnins.2021.628836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339273PMC
July 2021

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

Seizure 2021 Aug 11;90:145-154. Epub 2021 Feb 11.

Department of Neurosciences and Behavioral Sciences, Ribeirao Preto Medical School, University of Sao Paulo, Brazil. Electronic address:

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.
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http://dx.doi.org/10.1016/j.seizure.2021.02.006DOI Listing
August 2021

Network Asynchrony Underlying Increased Broadband Gamma Power.

J Neurosci 2021 03 16;41(13):2944-2963. Epub 2021 Feb 16.

Department of Neuroscience, Karolinska Institutet, Stockholm, 17177, Sweden

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. 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.
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http://dx.doi.org/10.1523/JNEUROSCI.2250-20.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018896PMC
March 2021

Histological correlates of hippocampal magnetization transfer images in drug-resistant temporal lobe epilepsy patients.

Neuroimage Clin 2020 8;28:102463. Epub 2020 Oct 8.

Department of Neurosciences and Behavioral Sciences, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil. Electronic address:

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 < 0.05.

Results: Compared to the respective controls, TLE patients had reduced hippocampal MTR, increased reactive astrocytes and activated microglia, increased extracellular chondroitin sulfate, and reduced neuron density, compares to controls. MTR correlated positively with neuron density in CA3 and with chondroitin sulfate in CA3 and CA1. Multiple linear regressions reinforced the correlations between chondroitin sulfate and MTR.

Significance: Our data indicate that extracellular matrix molecules are the most significant histological correlates of magnetization transfer ratio in the hippocampus of TLE patients.
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http://dx.doi.org/10.1016/j.nicl.2020.102463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586233PMC
June 2021

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

Dysphagia 2021 08 6;36(4):533-540. Epub 2020 Aug 6.

Speech-Language Pathology, University of Toronto, Toronto, ON, Canada.

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-PT 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-PT 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-PT 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-PT TOR-BSST proven to have high sensitivity and negative predictive values when compared to gold standard videofluoroscopy.
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http://dx.doi.org/10.1007/s00455-020-10167-2DOI Listing
August 2021

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

Epilepsia 2020 08 14;61(8):1581-1594. Epub 2020 Jul 14.

Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.

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.
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http://dx.doi.org/10.1111/epi.16595DOI Listing
August 2020

Impact of epilepsy surgery on quality of life and burden of caregivers in children and adolescents.

Epilepsy Behav 2020 05 19;106:106961. Epub 2020 Mar 19.

Department of Neurosciences and Behavioural Sciences, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil; Center for Epilepsy Surgery (CIREP), Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil. Electronic address:

Objective: The objective of this study was to analyze the impact of pediatric epilepsy surgery on the quality of life (QOL), determining whether patients improve, worsen, or maintain their preoperative patterns, as it relates to the burden of caregivers, as well as evaluating potential related factors, from both the children and caregivers perspectives.

Material And Methods: This is a retrospective study of children and adolescents who underwent epilepsy surgery and were evaluated through clinical data, videoelectroencephalogram (V-EEG), neuroimaging findings, neuropsychological testing, and aspects of QOL. These assessments were performed prior to surgery and after six months and two years of follow-up. Quality of life was assessed with epilepsy-specialized questionnaires, namely Questionnaire health-related quality of life for children with epilepsy (QVCE-50), Autoquestionnaire Qualité de Vie Enfant Image Scale (AUQUEI), Quality of life in epilepsy inventory for adolescents (QOLEI-AD-48); and burden of caregivers with Burden Interview - ZARIT scale. Postoperative changes in QVCE-50 were quantified using measures of the analysis of variance (ANOVA MR) for comparison of the difference between the three times of the scale and domains.

Results: Fifty patients were enrolled. Of these, 27 (54%) were male, with a mean age at surgery of 8.2 years (range: 1-18 years). Thirty-five patients (70%) were Engel I and one was Engel II (2%) at six months of follow-up, whereas 28 (56%) were Engel I and 32 (64%) were Engel I or II at two years of follow-up. Preoperatively, 21 (42%) presented with moderate or severe intellectual disability. Postoperative cognitive evaluations at the two-year follow-up showed 18 (36%) maintained similar deficits. The QVCE-50 showed postoperative improvement in the two-year follow-up period, but not at six months after surgery. Postoperative improvements were associated mainly with better seizure outcome. Autoperception evaluations were limited because of the clinical and cognitive severity of patients. The burden of caregivers was quoted as mild to moderate and remained unchanged postoperatively.

Conclusions: Children and adolescents with surgically treated epilepsy reach a good seizure outcome, stabilize in intellectual and adaptive functions, and have an increase in QOL, from the caregiver's perspective. Nevertheless, their burden remains unchanged. Seizure outcome is the main factor for improvement in the QOL. The upgrading of structured questionnaires and QOL instruments specific to pediatric epilepsy can be helpful to assess patient- and caregiver-reported surgical outcomes, allowing for better planning of therapeutic approaches.
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http://dx.doi.org/10.1016/j.yebeh.2020.106961DOI Listing
May 2020

Relationship of spontaneous microembolic signals to risk stratification, recurrence, severity, and mortality of ischemic stroke: a prospective study.

Ultrasound J 2020 Feb 11;12(1). Epub 2020 Feb 11.

Department of Neuroscience and Behavior, Ribeirão Preto School of Medicine, USP-Univ São Paulo, Ribeirão Preto, Brazil.

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 < 0.05.

Results: Of the 111 patients studied, 70 were men (63.1%) and 90 were white (81.1%), with a median age of 68 years. The MES frequency was 7%. There was a significant relationship between MES and symptomatic carotid disease (OR = 22.7; 95% CI 4.1-125.7; P < 0.001), a shorter time to monitoring (OR = 12.4; 95% CI  1.4-105.4; P = 0.02), and stroke recurrence (OR = 16.83; 95% CI 2.01-141; P = .009).

Discussion: It was observed that the stroke recurrence adjusted for prior stroke was higher and earlier among patients with MES detection. In conclusion, MES demonstrated a significant correlation with symptomatic carotid disease and a shorter DELAY until monitoring, and could be a predictor for the early recurrence of stroke in the long term.
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http://dx.doi.org/10.1186/s13089-020-0156-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7013020PMC
February 2020

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

Epilepsy Behav 2021 08 26;121(Pt B):106542. Epub 2019 Dec 26.

Neurosciences and Behavioral Sciences, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil; Department of Neurology and Neurosurgery, Paulista School of Medicine, UNIFESP, Sao Paulo, Brazil.

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".
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http://dx.doi.org/10.1016/j.yebeh.2019.106542DOI Listing
August 2021

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

Epilepsy Behav 2021 08 15;121(Pt B):106608. Epub 2019 Nov 15.

Núcleo de Neurociências, Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil. Electronic address:

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".
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http://dx.doi.org/10.1016/j.yebeh.2019.106608DOI Listing
August 2021

Diagnostic Accuracy of Positive Airway Pressure Device for Sleep Apnea Detection in Acute Stroke Patients.

Stroke 2020 01 24;51(1):324-326. Epub 2019 Oct 24.

From the Department of Neurosciences and Behavioral Sciences, Ribeirão Preto Medical School, University of São Paulo, Brazil.

Background and Purpose- Sleep apnea has been associated with a poor outcome in acute stroke patients. Polysomnography is the gold standard diagnostic method for sleep apnea, but it is not feasible as a routine in the acute stroke setting. The current generation of positive airway pressure (PAP) devices can detect the different types of respiratory events. This study aimed to compare the algorithms used in PAP device to manually scored events on polysomnography in patients with acute stroke. Methods- A sleep study was performed with standard polysomnography and PAP device, simultaneously, within the first 48 hours after acute stroke onset. Results- We prospectively evaluated 29 patients with acute stroke (59.5±12.1 years). The area under the receiver operating characteristic curve for each apnea-hypopnea index value was above 0.90 by PAP device. There was a good correlation of apnea-hypopnea index (=0.92; <0.001), hypopnea index (=0.89; <0.001), and apnea index (=0.70; <0.001) between device-detected events and manually scored polysomnography. Conclusions- Given the high frequency of sleep apnea during the acute phase of stroke and the complexity of a full polysomnography study in this setting, PAP device on diagnostic mode can be used as an alternative tool for sleep apnea detection in acute stroke patients.
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http://dx.doi.org/10.1161/STROKEAHA.119.027141DOI Listing
January 2020

Multimodal quantitative magnetic resonance imaging analysis with individualized postprocessing in patients with drug-resistant focal epilepsy and conventional visual inspection negative for epileptogenic lesions.

Clinics (Sao Paulo) 2019 22;74:e908. Epub 2019 Jul 22.

Divisao de Neurorradiologia, Faculdade de Medicina de Ribeirao Preto, Universidade de Sao Paulo, Ribeirao Preto, SP, BR.

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.
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http://dx.doi.org/10.6061/clinics/2019/e908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6636588PMC
April 2020

Manual Hippocampal Subfield Segmentation Using High-Field MRI: Impact of Different Subfields in Hippocampal Volume Loss of Temporal Lobe Epilepsy Patients.

Front Neurol 2018 20;9:927. Epub 2018 Nov 20.

Department of Neurosciences and Behavioral Sciences, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.

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 ( ≤ 0.038). Neuronal cell densities always decreased in CA4, CA3, CA2, and CA1 of TLE-HS1 but only in CA1 of TLE-HS2 ( ≤ 0.003). In addition, TLE-HS2 had a higher volume ( = 0.016) and higher neuronal density ( < 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.
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http://dx.doi.org/10.3389/fneur.2018.00927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6256705PMC
November 2018

Using Postmortem hippocampi tissue can interfere with differential gene expression analysis of the epileptogenic process.

PLoS One 2017 4;12(8):e0182765. Epub 2017 Aug 4.

Department of Cellular and Molecular Biology, Institute of Biological Sciences and Health, Federal University of Alagoas, Maceio, Alagoas, Brazil.

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<0.05). We then investigated if these PMI-related changes in gene expression have the potential to adulterate or mask RT-qPCR results obtained with PILO-injected rats euthanized at acute or chronic phases. In the acute group, Npy transcript was significantly higher when compared with 0h-PMI rats, whereas Ppia transcript was lower than 6h-PMI group. When we used epileptic rats (chronic group), the RT-qPCR results showed higher Tnf-α only when compared to 6h-PMI group. In conclusion, our study demonstrates that PMI influences gene transcription and can mask changes in gene transcription seen during epileptogenesis in the PILO-SE model. Thus, to avoid erroneous conclusions, we strongly recommend that researchers account for changes in postmortem gene expression in their experimental design.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0182765PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5544225PMC
October 2017

Genetic susceptibility in Juvenile Myoclonic Epilepsy: Systematic review of genetic association studies.

PLoS One 2017 21;12(6):e0179629. Epub 2017 Jun 21.

Department of Cellular and Molecular Biology, Institute of Biological Sciences and Health, Federal University of Alagoas, Maceio, Alagoas, Brazil.

Background: Several 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.

Methodology: A 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.

Results: Fifty 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.

Conclusions: Thus, 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 Number: CRD42016036063.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0179629PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5479548PMC
September 2017

Can somatosensory electrical stimulation relieve spasticity in post-stroke patients? A TMS pilot study.

Biomed Tech (Berl) 2018 Jul;63(4):501-506

Departamento de Biociências e Atividades Físicas, Escola de Educação Física e Desportos - Universidade Federal do Rio de Janeiro - Avenida Carlos Chagas Filho, 540 - Cidade Universitária - Ilha do Fundão, Rio de Janeiro, RJ 21941-599,Brazil, Phone:

Evidence suggests that somatosensory electrical stimulation (SES) may decrease the degree of spasticity from neural drives, although there is no agreement between corticospinal modulation and the level of spasticity. Thus, stroke patients and healthy subjects were submitted to SES (3 Hz) for 30' on the impaired and dominant forearms, respectively. Motor evoked potentials induced by single-pulse transcranial magnetic stimulation were collected from two forearm muscles before and after SES. The passive resistance of the wrist joint was measured with an isokinetic system. We found no evidence of an acute carry-over effect of SES on the degree of spasticity.
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http://dx.doi.org/10.1515/bmt-2016-0162DOI Listing
July 2018

Selective post-training time window for memory consolidation interference of cannabidiol into the prefrontal cortex: Reduced dopaminergic modulation and immediate gene expression in limbic circuits.

Neuroscience 2017 05 24;350:85-93. Epub 2017 Mar 24.

Brain Institute, Federal University of Rio Grande do Norte, Natal - RN, Brazil. Electronic address:

The prefrontal cortex (PFC), amygdala and hippocampus display a coordinated activity during acquisition of associative fear memories. Evidence indicates that PFC engagement in aversive memory formation does not progress linearly as previously thought. Instead, it seems to be recruited at specific time windows after memory acquisition, which has implications for the treatment of post-traumatic stress disorders. Cannabidiol (CBD), the major non-psychotomimetic phytocannabinoid of the Cannabis sativa plant, is known to modulate contextual fear memory acquisition in rodents. However, it is still not clear how CBD interferes with PFC-dependent processes during post-training memory consolidation. Here, we tested whether intra-PFC infusions of CBD immediately after or 5h following contextual fear conditioning was able to interfere with memory consolidation. Neurochemical and cellular correlates of the CBD treatment were evaluated by the quantification of extracellular levels of dopamine (DA), serotonin, and their metabolites in the PFC and by measuring the cellular expression of activity-dependent transcription factors in cortical and limbic regions. Our results indicate that bilateral intra-PFC CBD infusion impaired contextual fear memory consolidation when applied 5h after conditioning, but had no effect when applied immediately after it. This effect was associated with a reduction in DA turnover in the PFC following retrieval 5days after training. We also observed that post-conditioning infusion of CBD reduced c-fos and zif-268 protein expression in the hippocampus, PFC, and thalamus. Our findings support that CBD interferes with contextual fear memory consolidation by reducing PFC influence on cortico-limbic circuits.
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http://dx.doi.org/10.1016/j.neuroscience.2017.03.019DOI Listing
May 2017

Everyday memory impairment in patients with temporal lobe epilepsy caused by hippocampal sclerosis.

Epilepsy Behav 2017 04 20;69:31-36. Epub 2017 Feb 20.

Laboratory of Clinical Neurophysiology, Psychiatry Department, University of São Paulo (USP) School of Medicine, São Paulo, SP, Brazil; Laboratory of Neuroimaging in Neuroscience (LIM 21), University of São Paulo (USP) School of Medicine, São Paulo, SP, Brazil; Group for the Study of Cognitive and Psychiatric Disorders in Epilepsy, Clinics Hospital, University of Sao Paulo (USP), Brazil; Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of Sao Paulo (USP), Brazil.

Objective: Patients with temporal lobe epilepsy caused by hippocampal sclerosis (TLE-HS) have episodic memory impairment. Memory has rarely been evaluated using an ecologic measure, even though performance on these tests is more related to patients' memory complaints. We aimed to measure everyday memory of patients with TLE-HS to age- and gender-matched controls.

Methods: We evaluated 31 patients with TLE-HS and 34 healthy controls, without epilepsy and psychiatric disorders, using the Rivermead Behavioral Memory Test (RBMT), Visual Reproduction (WMS-III) and Logical Memory (WMS-III). We evaluated the impact of clinical variables such as the age of onset, epilepsy duration, AED use, history of status epilepticus, and seizure frequency on everyday memory. Statistical analyses were performed using MANCOVA with years of education as a confounding factor.

Results: Patients showed worse performance than controls on traditional memory tests and in the overall score of RBMT. Patients had more difficulties to recall names, a hidden belonging, to deliver a message, object recognition, to remember a story full of details, a previously presented short route, and in time and space orientation. Clinical epilepsy variables were not associated with RBMT performance. Memory span and working memory were correlated with worse performance on RBMT.

Significance: Patients with TLE-HS demonstrated deficits in everyday memory functions. A standard neuropsychological battery, designed to assess episodic memory, would not evaluate these impairments. Impairment in recalling names, routes, stories, messages, and space/time disorientation can adversely impact social adaptation, and we must consider these ecologic measures with greater attention in the neuropsychological evaluation of patients with memory complaints.
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http://dx.doi.org/10.1016/j.yebeh.2017.01.008DOI Listing
April 2017

Experience on Mechanical Thrombectomy for Acute Stroke Treatment in a Brazilian University Hospital.

J Stroke Cerebrovasc Dis 2017 Mar 5;26(3):532-537. Epub 2017 Jan 5.

Interventional Radiology Division, Department of Internal Medicine, Hospital das Clínicas-Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.

Background: Brazil is a developing country struggling to reduce its extreme social inequality, which is reflected on shortage of health-care infrastructure, mainly to the low-income class, which depends exclusively on the public health system. In Brazil, less than 1% of stroke patients have access to intravenous thrombolysis in a stroke unit, and constraints to the development of mechanical thrombectomy in the public health system increase the social burden of stroke.

Objective: Report the feasibility of mechanical thrombectomy as part of routine stroke care in a Brazilian public university hospital.

Methods: Prospective data were collected from all patients treated for acute ischemic stroke with mechanical thrombectomy from June 2011 to March 2016. Combined thrombectomy was performed in eligible patients for intravenous thrombolysis if they presented occlusion of large artery. For those patients ineligible for intravenous thrombolysis, primary thrombectomy was performed as long as there was no evidence of significant ischemia for anterior circulation stroke (Alberta Stroke Program Early CT score  >6) within a 6-hour time window, and also for those patients with wake-up stroke or posterior circulation stroke, regardless of the time of symptoms onset.

Results: A total of 161 patients were evaluated, resulting in an overall successful recanalization rate of 76% and symptomatic intracranial hemorrhage rate of 6.8%. At 3 months, 36% of the patients had modified Rankin Scale score less than or equal to 2. The overall mortality rate was 23%.

Conclusion: Our study, the first ever large series of mechanical thrombectomy in Brazil, demonstrates acceptable efficacy and safety results, even under restricted conditions outside the ideal scenario of trial studies.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2016.11.128DOI Listing
March 2017

Individual hippocampal subfield assessment indicates that matrix macromolecules and gliosis are key elements for the increased T2 relaxation time seen in temporal lobe epilepsy.

Epilepsia 2017 01 18;58(1):149-159. Epub 2016 Nov 18.

Department of Neurosciences and Behavioral Sciences, Ribeirao Preto School of Medicine, University of Sao Paulo, Ribeirao Preto, Brazil.

Objective: Increased T2 relaxation time is often seen in temporal lobe epilepsy (TLE) with hippocampal sclerosis. Water content directly affects the effective T2 in a voxel. Our aim was to evaluate the relation between T2 values and two molecules associated with brain water homeostasis aquaporin 4 (AQP4) and chondroitin sulfate proteoglycan (CSPG), as well as cellular populations in the hippocampal region of patients with TLE.

Methods: Hippocampal T2 imaging and diffusion tensor imaging (DTI) were obtained from 42 drug-resistant patients with TLE and 20 healthy volunteers (radiologic controls, RCs). A similar protocol (ex vivo) was applied to hippocampal sections from the same TLE cases and 14 autopsy control hippocampi (histologic and radiologic controls, HRCs), and each hippocampal subfield was evaluated. Hippocampal sections from TLE cases and HRC controls were submitted to immunohistochemistry for neurons (neuron nuclei [NeuN]), reactive astrocytes (glial fibrillary acidic protein [GFAP]), activated microglia (human leukocyte antigen-D-related [HLA-DR]), polarized AQP4, and CSPG.

Results: Patients with TLE had higher in vivo and ex vivo hippocampal T2 relaxation time. Hippocampi from epilepsy cases had lower neuron density, higher gliosis, decreased AQP4 polarization, and increased CSPG immunoreactive area. In vivo relaxation correlated with astrogliosis in the subiculum and extracellular CSPG in the hilus. Ex vivo T2 relaxation time correlated with astrogliosis in the hilus, CA4, and subiculum, and with microgliosis in CA1. The difference between in vivo and ex vivo relaxation ratio correlated with mean diffusivity and with the immunopositive area for CSPG in the hilus.

Significance: Our data indicate that astrogliosis, microgliosis, and CSPG expression correlate with the increased T2 relaxation time seen in the hippocampi of patients with TLE.
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http://dx.doi.org/10.1111/epi.13620DOI Listing
January 2017

Identification of microRNAs with Dysregulated Expression in Status Epilepticus Induced Epileptogenesis.

PLoS One 2016 3;11(10):e0163855. Epub 2016 Oct 3.

Department of Cellular and Molecular Biology, Institute of Biological Sciences and Health, Federal University of Alagoas, Maceio, Alagoas, Brazil.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0163855PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5047645PMC
June 2017

Decreased neuron loss and memory dysfunction in pilocarpine-treated rats pre-exposed to hypoxia.

Neuroscience 2016 09 29;332:88-100. Epub 2016 Jun 29.

Department of Neuroscience and Behavioral Sciences, Ribeirão Preto School of Medicine, University of São Paulo, Ribeiãro Preto 14049-900, Brazil. Electronic address:

Preconditioning can induce a cascade of cellular events leading to neuroprotection against subsequent brain insults. In this study, we investigated the chronic effects of hypoxic preconditioning on spontaneous recurrent seizures (SRS), neuronal death, and spatial memory performance in rats subjected to pilocarpine (Pilo)-induced status epilepticus (SE). Rats underwent a short hypoxic episode (7% O2+93% N2; 30min on two consecutive days) preceding a 4-h SE (HSE group). Control groups were rats submitted to SE only (SE), rats subjected to hypoxia only (H) or normoxia-saline (C). Animals were monitored for the occurrence of SRS, and spatial memory performance was evaluated in the radial-arm maze. Hippocampal sections were analyzed for cell death and mossy fiber sprouting at 1 or 60days after SE. Compared to SE group, HSE had increased SE latency, reduced number of rats with SRS, reduced mossy fiber sprouting at 60days, and reduced cell death in the hilus and the CA3 region 1 and 60days after SE. Additionally, HSE rats had better spatial memory performance than SE rats. Our findings indicated that short hypoxic preconditioning preceding SE promotes long-lasting protective effects on neuron survival and spatial memory.
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http://dx.doi.org/10.1016/j.neuroscience.2016.06.047DOI Listing
September 2016

Decision-making in patients with temporal lobe epilepsy: Delay gratification ability is not impaired in patients with hippocampal sclerosis.

Epilepsy Behav 2016 07 18;60:158-164. Epub 2016 May 18.

Laboratory of Clinical Neurophysiology,Psychiatry Department,University of São Paulo (USP) School of Medicine,São Paulo, SP, Brazil; Laboratory of Neuroimaging in Psychiatry (LIM 21),University of São Paulo (USP) School of Medicine,São Paulo, SP, Brazil; Group for the Study of Cognitive and Psychiatric Disorders in Epilepsy - Clinics Hospital,University of Sao Paulo (USP),Brazil; Center for Interdisciplinary Research on Applied Neurosciences (NAPNA),University of Sao Paulo (USP),Brazil.

Background: Decision-making abilities have rarely been examined in patients with temporal lobe epilepsy related to hippocampal sclerosis (TLE-HS). We aimed to investigate the ability to delay gratification, a decision-making subdomain, in patients with intractable TLE-HS and to verify the association of delay gratification performance and cool executive function tests.

Methods: We evaluated 27 patients with TLE-HS (mean age: 35.46 [±13.31] years; 7 males) and their cognitive performance was compared with that of 27 age- and gender-matched healthy controls (mean age: 35.33 [±12.05] years; 7 males), without epilepsy and psychiatric disorders. Patients were assessed using the delay discounting task (DDT) and tests of attention, shifting, inhibitory control, and concept formation. Results were correlated with clinical epilepsy variables such as age of onset, epilepsy duration, AED use, history of status epilepticus, febrile seizures, and the presence of generalized seizures. Statistical analysis was performed using one-way ANCOVA with years of education as a confounding factor.

Results: Patients and controls demonstrated similar performance on DDT, showing similar discount rate (p=0.935) and probability rate (p=0.585). Delay gratification was not related to cool executive function tests (Digit Span, Stroop Color Test, Trail Making Test, Wisconsin Card Sorting Test, and Connors' CPT). History of status epilepticus, presence of generalized seizures and higher seizure frequency, age at onset, and epilepsy duration had a significant impact on DDT.

Conclusion: Patients with intractable TLE-HS showed unimpaired delay gratification abilities, being able to accept a higher delay and a lower amount of chance for receiving a higher reward in the future. Clinical variables related to the epilepsy severity impacted the performance on delay gratification. Impairment on cool aspects of executive function was unrelated to this decision-making domain.
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http://dx.doi.org/10.1016/j.yebeh.2016.04.042DOI Listing
July 2016

Characterization of ICP Behavior in an Experimental Model of Hemorrhagic Stroke in Rats.

Acta Neurochir Suppl 2016 ;122:121-4

Physics Institute of Sao Carlos, University of Sao Paulo, Sao Carlos, Brazil.

Intracranial pressure (ICP) monitoring is sometimes required in clinical pictures of stroke, as extensive intraparenchymal hematomas and intracranial bleeding may severely increase ICP, which can lead to irreversible conditions, such as dementia and cognitive derangement. ICP monitoring has been accepted as a procedure for the safe diagnosis of increased ICP, and for the treatment of intracranial hypertension in some diseases. In this work, we evaluated ICP behavior during the induction of an experimental model of autologous blood injection in rats, simulating a hemorrhagic stroke. Rats were subjected to stereotactic surgery for the implantation of a unilateral cannula into the left striatal region of the brain. Autologous blood was infused into the left striatal region with an automatic microinfusion pump. ICP monitoring was performed throughout the procedure of hemorrhagic stroke induction. Analyses consisted of short-time Fourier transform for ICP before and after stroke induction and the histological processing of the animals' brains. Short-time Fourier transform analysis demonstrated oscillations in the ICP frequency components throughout time after the microinjections compared with data before them. Histological analysis revealed neuropathological changes in the striatum in all microinjected animals.
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http://dx.doi.org/10.1007/978-3-319-22533-3_24DOI Listing
July 2017

Pre-ictal increase in theta synchrony between the hippocampus and prefrontal cortex in a rat model of temporal lobe epilepsy.

Exp Neurol 2016 May 4;279:232-242. Epub 2016 Mar 4.

Brain Institute, Federal University of Rio Grande do Norte, Av. Nascimento de Castro 2155, 59056-450 Natal, RN, Brazil; Unit of Developmental Genetics, Department of Neuroscience, Uppsala University, Uppsala, Sweden.

The pathologically synchronized neuronal activity in temporal lobe epilepsy (TLE) can be triggered by network events that were once normal. Under normal conditions, hippocampus and medial prefrontal cortex (mPFC) work in synchrony during a variety of cognitive states. Abnormal changes in this circuit may aid to seizure onset and also help to explain the high association of TLE with mood disorders. We used a TLE rat model generated by perforant path (PP) stimulation to understand whether synchrony between dorsal hippocampal and mPFC networks is altered shortly before a seizure episode. We recorded hippocampal and mPFC local field potentials (LFPs) of animals with spontaneous recurrent seizures (SRSs) to verify the connectivity between these regions. We showed that SRSs decrease hippocampal theta oscillations whereas coherence in theta increases over time prior to seizure onset. This increase in synchrony is accompanied by a stronger coupling between hippocampal theta and mPFC gamma oscillation. Finally, using Granger causality we showed that hippocampus/mPFC synchrony increases in the pre-ictal phase and this increase is likely to be caused by hippocampal networks. The dorsal hippocampus is not directly connected to the mPFC; however, the functional coupling in theta between these two structures rises pre-ictally. Our data indicates that the increase in synchrony between dorsal hippocampus and mPFC may be predictive of seizures and may help to elucidate the network mechanisms that lead to seizure generation.
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http://dx.doi.org/10.1016/j.expneurol.2016.03.007DOI Listing
May 2016

Diurnal Variation Has Effect on Differential Gene Expression Analysis in the Hippocampus of the Pilocarpine-Induced Model of Mesial Temporal Lobe Epilepsy.

PLoS One 2015 16;10(10):e0141121. Epub 2015 Oct 16.

Department of Cellular and Molecular Biology, Institute of Biological Sciences and Health, Federal University of Alagoas, Maceio, Alagoas, Brazil.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0141121PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4608695PMC
June 2016

Systematic review of the efficacy in seizure control and safety of neuronavigation in epilepsy surgery: The need for well-designed prospective studies.

Seizure 2015 Sep 23;31:99-107. Epub 2015 Jul 23.

Nuclear Medicine & Molecular Imaging Section, Image Science and Medical Physics Center, Internal Medicine Department and Post-graduation Program, University of São Paulo, Ribeirão Preto, Brazil; Health Technology Assessment Center of the Clinical Hospital, University of São Paulo, Ribeirão Preto, Brazil; Bioengineering Interunits Program, São Carlos School of Engineering, University of São Paulo, São Carlos, Brazil; The Center for Interdisciplinary Research on Applied Neurosciences - NAPNA - University of São Paulo (USP), Brazil. Electronic address:

Purpose: To evaluate the efficacy of surgery with neuronavigation compared to conventional neurosurgical treatment of epilepsy in terms of safety and seizure outcomes and to assess the quality of the evidence base of neuronavigation in this clinical context.

Method: Systematic review using the electronic databases of Cochrane, CRD, PubMed, Embase, SciELO and LILACS in Portuguese, English and Spanish. The [MeSH] terms included "epilepsy" and "neuronavigation".

Eligibility Criteria: Studies assessing surgery with neuronavigation for the surgical treatment of epilepsy or brain injuries associated with epileptic seizures.

Results: We identified 28 original articles. All articles yielded scientific evidence of low quality. Outcome data presented in the articles identified was heterogeneous and did not amount to compelling evidence that epilepsy surgery with neuronavigation produces higher rates of seizure control, a reduced need for reoperations, or lower rates of complications or postoperative neurological deficits.

Conclusion: We were unable to find any publications providing convincing evidence that neuronavigation improves outcomes of epilepsy surgery. Whilst this does not mean that neuronavigation cannot improve neurosurgical outcomes in this clinical setting, well-designed research studies evaluating the role of neuronavigation are urgently needed.
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http://dx.doi.org/10.1016/j.seizure.2015.07.010DOI Listing
September 2015

Temporal lobe epilepsy patients with severe hippocampal neuron loss but normal hippocampal volume: Extracellular matrix molecules are important for the maintenance of hippocampal volume.

Epilepsia 2015 Oct 27;56(10):1562-70. Epub 2015 Jul 27.

Department of Neurosciences and Behavior, Ribeirão Preto School of Medicine, University of São Paulo, Ribeirao Preto, Sao Paulo, Brazil.

Objective: Hippocampal sclerosis is a common finding in patients with temporal lobe epilepsy (TLE), and magnetic resonance imaging (MRI) studies associate the reduction of hippocampal volume with the neuron loss seen on histologic evaluation. Astrogliosis and increased levels of chondroitin sulfate, a major component of brain extracellular matrix, are also seen in hippocampal sclerosis. Our aim was to evaluate the association between hippocampal volume and chondroitin sulfate, as well as neuronal and astroglial populations in the hippocampus of patients with TLE.

Methods: Patients with drug-resistant TLE were subdivided, according to hippocampal volume measured by MRI, into two groups: hippocampal atrophy (HA) or normal volume (NV) cases. Hippocampi from TLE patients and age-matched controls were submitted to immunohistochemistry to evaluate neuronal population, astroglial population, and chondroitin sulfate expression with antibodies against neuron nuclei protein (NeuN), glial fibrillary acidic protein (GFAP), and chondroitin sulfate (CS-56) antigens, respectively.

Results: Both TLE groups were clinically similar. NV cases had higher hippocampal volume, both ipsilateral and contralateral, when compared to HA. Compared to controls, NV and HA patients had reduced neuron density, and increased GFAP and CS-56 immunopositive area. There was no statistical difference between NV and HA groups in neuron density or immunopositive areas for GFAP and CS-56. Hippocampal volume correlated positively with neuron density in CA1 and prosubiculum, and with immunopositive areas for CS-56 in CA1, and negatively with immunopositive area for GFAP in CA1. Multiple linear regression analysis indicated that both neuron density and CS-56 immunopositive area in CA1 were statistically significant predictors of hippocampal volume.

Significance: Our findings indicate that neuron density and chondroitin sulfate immunopositive area in the CA1 subfield are crucial for the hippocampal volume, and that chondroitin sulfate is important for the maintenance of a normal hippocampal volume in some cases with severe neuron loss.
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http://dx.doi.org/10.1111/epi.13082DOI Listing
October 2015

Evaluation of the Temporal Acoustic Window for Transcranial Doppler in a Multi-Ethnic Population in Brazil.

Ultrasound Med Biol 2015 Aug 9;41(8):2131-4. Epub 2015 May 9.

Ribeirão Preto Medical School, Department of Neuroscience and Behavior, University of São Paulo, São Paulo, Brazil.

The aim of this study was to relate the presence of a temporal acoustic window (TAW) to the variables sex, age and race. This observational study was conducted in patients under etiologic investigation after stroke, sickle-cell anemia and hospitalization in an intensive therapy neurologic unit. TAW presence was confirmed by bilateral assessment by two neurologists via transcranial Doppler (TCD). Multiple logistic regression was performed to explain the presence of the window as a function of sex, age and race. In 20% of the 262 patients evaluated, a TAW was not present. The incidence of TAW presence was greater in men (odds ratio [OR] = 5.4, 95% confidence interval [CI] = 2.5-11.7, p < 0.01); lower with increased age (OR = 0.9, 95% CI = 0.92-0.97, p < 0.01); and lower among those of African and Asian descent (OR = 0.32, 95% CI = 0.14-0.70, p = 0.005). On the basis of the results, more men than women had TAWs, and the decrease in TAWs was associated with increased age and African or Asian descent.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2015.04.008DOI Listing
August 2015
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