A pioneering FreeSurfer volumetric study of a series of patients with mesial temporal lobe epilepsy and hippocampal sclerosis with comorbid depression.

Depression is the most frequent psychiatric comorbidity in patients with mesial temporal lobe epilepsy (MTLE) and hippocampal sclerosis (HS). This study aimed to confirm whether patients with comorbid depression have different volumetric patterns on magnetic resonance imaging, analysing the influence of HS sides. Psychiatrists conducted semi-structured interviews with 75 patients, who were divided into non-depression group (NDG, n = 52) and depression group (DG, n = 23), and compared with 98 controls. The FreeSurfer software was used in the volumetric analysis of the estimated total intracranial volume (eTIV), bilateral cortical and subcortical regions of interest (ROIs), and for presence of left (L-, n = 41) or right (R-, n = 34) MTLE-HS. Twenty-three (30.7%) patients had depression, of whom 14 (34.1%) had l-MTLE-HS and 9 (26.5%) had R-MTLE-HS. No difference was observed between DG and NDG vs. controls in terms of eTIV and cortical ROIs, regardless of the severity of depression. In patients with l-MTLE-HS, the eTIV in the DG was reduced in comparison with that in the NDG and control group, with a small effect size. Hippocampal reduction occurred ipsilateral to HS in the l-MTLE-HS and R-MTLE-HS subgroups when DG and NDG were compared with controls, as expected according to Enhancing Neuro Imaging Genetics through Meta-Analysis (2018).

Neuropsychological findings related to the presence of pre-surgical comorbid depression in Latin-American patients with mesial temporal lobe epilepsy and hippocampal sclerosis.

PURPOSE: To evaluate the neuropsychological findings related to the presence of pre-surgical comorbid depression in Latin-American patients with mesial temporal lobe epilepsy (MTLE) and unilateral hippocampal sclerosis (HS). METHOD: Patients with drug-resistant MTLE and unilateral, left (L-) or right (R-) HS were studied. To diagnose depression, psychiatrists with expertise in epilepsy applied a semi-structured interview based on DSM. The depression group (DG) included patients with a psychiatric diagnosis in addition to a Beck Depression Inventory (BDI) score >16 points, and the non-depression group (NDG) included those without this diagnosis and with a BDI score ≤16. We analysed two clusters of neuropsychological tests, which evaluated memory (Complex Rey Figure III, Logical Memory II and RAVLT VII) and attention plus executive functions (Stroop I/II/III and Trail Making A/B). Moreover, we calculated the z-scores (Zs) using a local control group. The DG was compared to the NDG, independently and according to the HS side, using non-parametrical analyses. Due to the multivariate analysis, the p-value was corrected by applyingpost hoc Bonferroni adjustment. RESULTS: We analysed 65 patients. The NDG included 51 (78.4 %) patients, and the DG included 14 (21.5 %) patients. Pre-surgical comorbid depression occurred in eight patients with L- (n = 29) and in six patients with R-MTLE-HS (n = 36). All of these groups had similar gender, age, IQs, and years of schooling. Compared to the healthy subjects, the L-MTLE-HS patients had lower Zs in verbal episodic memory tests [Logical Memory II (p < 0.001), and RAVLT VII (p < 0.001)], and the R-MTLE-HS patients had lower scores in visual episodic memory [Complex Rey Figure III (p < 0.001)]. In the analysis of the DGvs. NDG, there were no differences in the clusters of tests of memory or in those of attention and executive functions. Moreover, when we analysed the patients according to HS side, no neuropsychological difference was observed in the DG and NDG in terms of L- and R-MTLE-HS. CONCLUSIONS: The patients with MTLE and unilateral HS in this study showed no differences in memory, attention and executive functions in relation to the presence of pre-surgical comorbid depression and independently of HS side. In this series from Latin-America, this psychiatric comorbidity did not affect cognition more than epilepsy alone.

Funções de Estímulos Pré-experimentais na Formação de Classes de Equivalência / Pre-experimental Stimuli Functions in Equivalence Class Formation

Resumo Relações condicionais pré-experimentais que eliciam respostas emocionais, como ciúme, podem afetar a formação de classes de equivalência? Haveria diferenças entre homens e mulheres? Para abordar essas questões, 19 participantes, de ambos os sexos, foram expostos a treinos e testes para a formação de quatro classes de equivalência, uma delas constituída pelo nome do(a) namorado(a), o nome de mulher/homem desconhecida(o) e duas figuras não-familiares. Após os testes, aplicou-se a Escala de Ciúme Romântico. Os participantes classificados com maior grau de ciúme não formaram as classes de equivalência, independentemente de serem homens ou mulheres. Sugere-se que relações pré-experimentais com funções afetivas interferiram na formação das classes de equivalência em que o nome do namorado(a) deveria ser relacionado ao nome de desconhecido(a).

Abstract Can pre-experimental conditional relations that elicit emotional responses, such as jealousy, affect the formation of equivalence classes? Would there be differences between men and women? To address these questions, 19 participants of both sexes were exposed to training and testing of the formation of four equivalence classes, one consisting of the boyfriend's/girlfriend's name, an unknown woman's/man's name, and two unfamiliar figures. After the tests, the Romantic Jealousy Scale was applied. Participants classified as having a higher degree of jealousy did not form equivalence classes regardless of whether they were men or women. It is suggested that pre-experimental relations with affective functions interfere in the formation of equivalence classes in which the boyfriend's/girlfriend's name should be related to the unknown woman's/man's name.

The impact of epilepsy duration in a series of patients with mesial temporal lobe epilepsy due to unilateral hippocampal sclerosis.

PURPOSE: To evaluate if the duration of epilepsy influences MRI volumes of the hippocampus, amygdala, parahippocampal gyrus, entorhinal cortex and temporal pole of both hemispheres and epileptogenic hippocampus neuronal cell density and dentate gyrus granular cells distribution in patients with refractory mesial temporal lobe epilepsy due to hippocampal sclerosis (MTLE/HS). METHODS: Seventy-seven patients with refractory MTLE/HS submitted to surgery were included. Histopathological analysis included: (1) quantitative: hippocampal subfields and total estimated hippocampal cell density (HCD), thickness of the dentate gyrus - normal, thinning or dispersion; (2) qualitative: type of HS and granule cells pathology in the dentate gyrus (normal, neuronal cell loss, dispersion and bilamination). Automated MRI-derived measurements from bilateral temporal structures (hippocampus, amygdala, parahippocampal gyrus, temporal pole, entorhinal cortex) were obtained for 58 subjects. Histopathological and imaging findings were compared with data from specimens obtained in autopsies of age-matched individuals and living controls, respectively, and the data were adjusted for the age at epilepsy onset and the frequency of focal impaired awareness seizures/month. RESULTS: Forty-two (54.5%) patients presented right HS. The greater the duration of epilepsy, the smaller the total estimated HCD (p = 0.025; r = -0.259). Patients with a normal distribution of the granular cells had a shorter epilepsy duration than those with dispersion (p = 0.018) or thinning (p = 0.031). A reduced ipsilateral hippocampal volume (r = -0.551, p = 0.017) and a smaller hippocampal asymmetry index (r = -0.414, p = 0.002) were correlated to a longer epilepsy duration. The estimated HCD was correlated to the volume of the ipsilateral hippocampus (r = 0.420, p = 0.001). CONCLUSION: Our study showed an increasing atrophy of the ipsilateral hippocampus in patients with a longer epilepsy duration. Our data suggest that this reduction in hippocampal volume is related to neuronal loss. Besides that, we also showed an increased probability of exhibiting an abnormal distribution of the granular cells in the dentate gyrus in patients with longer epilepsy duration.

Morphometric MRI features and surgical outcome in patients with epilepsy related to hippocampal sclerosis and low intellectual quotient.

OBJECTIVE: The objectives of this study were to verify in a series of patients with mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) if those with low intellectual quotient (IQ) levels have more extended areas of atrophy compared with those with higher IQ levels and to analyze whether IQ could be a variable implicated on a surgical outcome. MATERIAL AND METHODS: Patients (n=106) with refractory MTLE-HS submitted to corticoamygdalohippocampectomy (CAH) (57 left mesial temporal lobe epilepsy (MTLE); 45 males) were enrolled. To determine if the IQ was a predictor of seizure outcome, totally seizure-free (SF) versus nonseizure-free (NSF) patients were evaluated. FreeSurfer was used for cortical thickness and volume estimation, comparing groups with lower (<80) and higher IQ (90-109) levels. RESULTS: In the whole series, 42.45% of patients were SF (Engel Class 1a; n=45), and 57.54% were NSF (n=61). Total cortical volume was significantly reduced in the group with lower IQ (p=0.01). Significant reductions in the left hemisphere included the following: rostral middle frontal (p=0.001), insula (p=0.002), superior temporal gyrus (p=0.003), thalamus (p=0.004), and precentral gyrus (p=0.02); and those in the right hemisphere included the following: rostral middle frontal (p=0.003), pars orbitalis (p=0.01), and insula (p=0.02). Cortical thickness analysis also showed reductions in the right superior parietal gyrus in patients with lower IQ. No significant relationship between IQ and seizure outcome was found. CONCLUSIONS: This is the first study of a series of patients with pure MTLE-HS, including those with low IQ and their morphometric magnetic resonance imaging (MRI) features using FreeSurfer. Although patients with lower intellectual scores presented more areas of brain atrophy, IQ was not a predictor of surgical outcome. Therefore, when evaluating seizure follow-up, low IQ in patients with MTLE-HS might not contraindicate resective surgery.

Impact of hippocampal subfield histopathology in episodic memory impairment in mesial temporal lobe epilepsy and hippocampal sclerosis.

OBJECTIVE: The objective of the study was to analyze preoperative visual and verbal episodic memories in a homogeneous series of patients with mesial temporal lobe epilepsy (MTLE) and unilateral hippocampal sclerosis (HS) submitted to corticoamygdalohippocampectomy and its association with neuronal cell density of each hippocampal subfield. METHODS: The hippocampi of 72 right-handed patients were collected and prepared for histopathological examination. Hippocampal sclerosis patterns were determined, and neuronal cell density was calculated. Preoperatively, two verbal and two visual memory tests (immediate and delayed recalls) were applied, and patients were divided into two groups, left and right MTLE (36/36). RESULTS: There were no statistical differences between groups regarding demographic and clinical data. Cornu Ammonis 4 (CA4) neuronal density was significantly lower in the right hippocampus compared with the left (p=0.048). The groups with HS presented different memory performance - the right HS were worse in visual memory test [Complex Rey Figure, immediate (p=0.001) and delayed (p=0.009)], but better in one verbal task [RAVLT delayed (p=0.005)]. Multiple regression analysis suggested that the verbal memory performance of the group with left HS was explained by CA1 neuronal density since both tasks were significantly influenced by CA1 [Logical Memory immediate recall (p=0.050) and Logical Memory and RAVLT delayed recalls (p=0.004 and p=0.001, respectively)]. For patients with right HS, both CA1 subfield integrity (p=0.006) and epilepsy duration (p=0.012) explained Complex Rey Figure immediate recall performance. Ultimately, epilepsy duration also explained the performance in the Complex Rey Figure delayed recall (p<0.001). SIGNIFICANCE: Cornu Ammonis 1 (CA1) hippocampal subfield was related to immediate and delayed recalls of verbal memory tests in left HS, while CA1 and epilepsy duration were associated with visual memory performance in patients with right HS.

Morphometric MRI features are associated with surgical outcome in mesial temporal lobe epilepsy with hippocampal sclerosis.

PURPOSE: Corticoamygdalohippocampectomy (CAH) improves seizure control, quality of life, and decreases mortality for refractory mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS). One-third of patients continue having seizures, and it is pivotal to determine structural abnormalities that might influence the postoperative outcome. Studies indicate that nonhippocampal regions may play a role in the epileptogenic network in MTLE-HS and could generate seizures postoperatively. The aim of this study is to analyze areas of atrophy, not always detected on routine MRI, comparing patients who became seizure free (SF) with those non seizure free (NSF) after CAH, in an attempt to establish possible predictors of surgical outcome. METHODS: 105 patients with refractory MTLE-HS submitted to CAH (59 left MTLE; 46 males) and 47 controls were enrolled. FreeSurfer was performed for cortical thickness and volume estimation comparing patients to controls and SF versus NSF patients. The final sample after post processing procedures resulted in 99 patients. RESULTS: Cortical thickness analyses showed reductions in left insula in NSF patients compared to those SF. Significant volume reductions in SF patients were present in bilateral thalami, hippocampi and pars opercularis, left parahippocampal gyrus and right temporal pole. In NSF patients reductions were present bilaterally in thalami, hippocampi, entorhinal cortices, superior frontal and supramarginal gyri; on the left: superior and middle temporal gyri, temporal pole, parahippocampal gyrus, pars opercularis and middle frontal gyrus; and on the right: precentral, superior, middle and inferior temporal gyri. Comparison between SF and NSF patients showed ipsilateral gray matter reductions in the right entorhinal cortex (p=0.003) and contralateral parahippocampal gyrus (p=0.05) in right MTLE-HS. Patients NSF had a longer duration of epilepsy than those SF (p=0.028). CONCLUSION: NSF patients exhibited more extensive areas of atrophy than SF ones. As entorhinal cortex and parahippocampal gyrus are reduced in NSF patients compared to those SF these structures might be implicated in the network responsible for the maintenance of postoperative seizures. Duration of epilepsy is a predictor of seizure outcome.

Hippocampal atrophy on MRI is predictive of histopathological patterns and surgical prognosis in mesial temporal lobe epilepsy with hippocampal sclerosis.

PURPOSE: To correlate hippocampal volumes obtained from brain structural imaging with histopathological patterns of hippocampal sclerosis (HS), in order to predict surgical outcome. METHODS: Patients with mesial temporal lobe epilepsy (MTLE) with HS were selected. Clinical data were assessed pre-operatively and surgical outcome in the first year post surgery. One block of mid hippocampal body was selected for HS classification according to ILAE criteria. NeuN-immunoreactive cell bodies were counted within hippocampal subfields, in four randomly visual fields, and cell densities were transformed into z-score values. FreeSurfer processing of 1.5T brain structural images was used for subcortical and cortical volumetric estimation of the ipsilateral hippocampus. Univariate analysis of variance and Pearson's correlation test were applied for statistical analyses. RESULTS: Sixty-two cases (31 female, 32 right HS) were included. ILAE type 1 HS was identified in 48 patients, type 2 in eight, type 3 in two, and four had no-HS. Better results regarding seizure control, i.e. ILAE 1, were achieved by patients with type 1 HS (58.3%). Patients with types 1 and 2 had smaller hippocampal volumes compared to those with no-HS (p<0.001 and p=0.004, respectively). Positive correlation was encountered between hippocampal volumes and CA1, CA3, CA4, and total estimated neuronal densities. CA2 was the only sector which did not correlate its neuronal density with hippocampal volume (p=0.390). CONCLUSION: This is the first study correlating hippocampal volume on MRI submitted to FreeSurfer processing with ILAE patterns of HS and neuronal loss within each hippocampal subfield, a fundamental finding to anticipate surgical prognosis for patients with drug-resistant MTLE and HS.

Equivalência de estímulos e ciúme: efeito de história pré-experimental / Stimulus equivalence and jealousy: effect of pre-experimental history

A formação de classes de estímulos equivalentes tem sido usada como modelo experimental para investigar uma série de fenômenos comportamentais, tais como o desenvolvimento de comportamento simbólico e a transferência de funções que os eventos ambientais adquirem por meio de relações condicionais. O objetivo deste estudo consistiu em analisar o efeito de estímulos com alto grau afetivo pré-experimentalmente constituído, na formação de classes de equivalência estabelecidas em contexto experimental, quando as relações emergentes podem se caracterizar por um conflito na escolha dos estímulos. Participaram 17 estudantes universitários que foram submetidos ao procedimento de escolha de acordo com modelo e aos testes das relações emergentes, para formar quatro classes de equivalência com quatro estímulos cada. Verificou-se que 10 dos 17 participantes formaram as classes equivalentes e observou-se correlação positiva entre o desempenho no Teste de Equivalência e o escore na Escala de Ciúme Romântico, sugerindo que a história pré-experimental referente ao envolvimento afetivo interferiu no desempenho dos participantes. O efeito de interferência provavelmente é devido ao conflito entre contingências: uma que controla o responder diante de relações condicionais pré-experimentalmente estabelecidas, envolvendo estímulos com alto valor afetivo, e outra estabelecida no contexto experimental.

The formation of stimulus equivalence classes has been used as an experimental model to investigate a series of behavioral phenomena, such as the development of symbolic behavior and transfer of functions that environmental events acquire through conditional relations. The aim of this study was to analyze the effect of stimuli with high pre-experimentally constituted affective grade in the formation of equivalence classes established in an experimental context, when the emergent relations can be characterized by a conflict in choosing stimuli. Participants were 17 college students exposed to matching to sample procedure and the tests of emergent relations to form four equivalence classes with four stimuli each. The results showed that 10 out of 17 participants formed equivalence classes, and positive correlation was observed between the performance on the Equivalence Test and the score on the Romantic Jealousy Scale, suggesting that the pre-experimental history related to emotional involvement interfered with participants' performance. The interference effect is probably due to the conflict between contingencies: one that controls responses to pre-experimentally established conditional relations involving stimuli with high emotional value, and another one, established in the experimental setting.