Sensitivity to moral and conventional rules in temporal lobe epilepsy.

OBJECTIVES: Sensitivity to moral and conventional rules (SMCR) is supported by bilateral brain networks and psychosocial input both of which may be altered in temporal lobe epilepsy (TLE). This study evaluated the components of SMCR in patients with TLE, aiming to clarify their preservation and link to psychopathological and cognitive aspects. METHODS: Adult patients with unilateral TLE and healthy controls were evaluated using neuropsychological tests for SMCR, memory, language, and executive functions, the Empathy Questionnaire (EQ), and the Symptom Checklist-90-R (SCL-90-R). RESULTS: The SMCR test items showed good reliability and validity, yielding the Severity and Rules factors distinct from the Executive, Lexical and Memory factors. Patients with right TLE scored worse in moral rules recognition than controls, but this difference was nullified by a significant influence for age and sex. The Severity and Rules factors related to semantic fluency and age and, respectively, TLE side and psychoticism. However, these factors did predict TLE membership. CONCLUSIONS: In adult patients with TLE, the SMCR test reflects a distinct cognitive domain. Conventional rules are well-retained, while moral reasoning may be only affected in right TLE if unfavorable demographics coexist. Although age, TLE side, semantic abilities, and psychoticism cooperate to determine SMCR, impairment of such domain is not a distinctive feature of TLE.

Fifty Years of Handedness Research: A Neurological and Methodological Update.

Handedness, a complex human aspect that reflects the functional lateralization of the hemispheres, also interacts with the immune system. This study aimed to expand the knowledge of the lateralization of hand, foot, and eye activities in patients with immune-mediated (IM) or other (noIM) neurological diseases and to clarify the properties of the Edinburgh Handedness Inventory (EHI) in an Italian population. Three hundred thirty-four patients with IM or noIM diseases affecting the brain or spine and peripheral nervous system were interviewed about stressful events preceding the disease, subjective handedness, and familiarity for left-handedness or ambidexterity. The patients and 40 healthy subjects underwent EHI examination. In the whole group of participants, 24 items of the EHI were classified into five factors (Hand Transitive, Hand Refined, Hand Median, Foot, Eye), demonstrating good reliability and validity. Chronological age had a significant influence on hand and foot EHI factors and the laterality quotient (LQ), particularly on writing and painting. In the patient groups, EHI factors and the LQ were also predicted by age of disease onset, duration of disease, and family history of left-handedness or ambidexterity. No differences were found between patients and healthy subjects, but pencil use scored significantly lower in patients with IM diseases than in those with noIM brain diseases. These results demonstrate that the lateralization of hand and foot activities is not a fixed human aspect, but that it can change throughout life, especially for abstract and symbolic activities. Chronic neurological diseases can cause changes in handedness. This may explain why, unlike systemic immunological diseases, IM neurological diseases are not closely associated with left-handedness. In these patients, the long version of the EHI is appropriate for determining the lateralization of body activities to contextualize the neurological picture; therefore, these findings extend the Italian normative data sets.

Processing speed in temporal lobe epilepsy. A scoping review.

BACKGROUND: Impaired processing speed (PS) can affect patients with temporal lobe epilepsy (TLE). However, it is usually considered a nonspecific clinical feature and is not measured, but this raises lexical and methodological problems. This review aims to evaluate the existing terminology and assessment methods of PS in patients with TLE. METHODS: A scoping review was conducted based on the extended guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis. The electronic literature search was conducted on Medline-PubMed, American Psychological Association-PsycINFO, Elton Bryson Stephens Company, and Google Scholar, using the keywords "temporal lobe epilepsy" and "speed" or "slowing" plus "processing," "cognitive," "psychomotor," or "mental." Peer-reviewed articles published before December 2022 were analyzed if they were in English, including patients older than 14 years and at least one neuropsychological measure, reported original research focused on PS and had the selected keywords in the title, keywords, and abstract. RESULTS: Seven articles published between December 2004 and September 2021 were selected. The terms "processing speed," "psychomotor speed," and "information processing speed," based on similar theoretical constructs, were the most frequently used. Assessment methods included non-computerized or paper-and-pencil tests (WAIS-III Digit Symbol and Symbol Search subtests, Purdue Pegboard and Grooved Pegboard Tests, Trail Making Test and Stroop Color-Word Test) and computerized tests (Sternberg Memory Scanning Test, Pattern Comparison Processing Speed, Computerized Visual Searching). In some studies, impairment was associated with white and gray matter damage in the brain, independent of clinical and treatment variables. CONCLUSION: Clinical research on TLE has focused inconsistently on PS. Different evaluation terms and methods have been used while referring to similar theoretical constructs. These findings highlight a gap between the clinical importance of PS and its assessment. Studies are needed to share terms and tools among clinical centers and clarify the position of PS in the TLE phenotype.

Corrigendum: PMCA-based detection of prions in the olfactory mucosa of patients with sporadic Creutzfeldt-Jakob disease.

[This corrects the article DOI: 10.3389/fnagi.2022.848991.].

Understanding frontal lobe function in epilepsy: Juvenile myoclonic epilepsy vs. frontal lobe epilepsy.

AIM: To compare neuropsychological function in juvenile myoclonic epilepsy (JME) and frontal lobe epilepsy (FLE) since frontal circuitry is involved in both conditions. By drawing on previously theory-guided hypotheses and findings, a particular emphasis is placed on the way different cognitive-pathophysiological mechanisms act upon to produce frontal dysfunction in JME (frontal-executive and attention-related problems: vigilance, reaction times, processing speed, and response inhibition) and in FLE (reflecting the coproduct of the functional deficit zone), respectively. METHODS: A total of 16 patients with JME, 34 patients with FLE, and 48 normal controls, all matched for age and education, were administered a comprehensive battery of tests to assess frontal-executive functions, as well as attention, memory, and learning domains. Participants did not take medications other than antiepileptics or have a psychiatric history. RESULTS: Patients with FLE overall showed worse neuropsychological performance compared to both JME and HCs. With respect to JME, patients with FLE did significantly worse in measures of verbal and nonverbal executive function, short-term-, and long-term- auditory-verbal memory and learning, immediate and delayed episodic recall, visual attention and motor function, visuo-motor coordination and psychomotor speed, speed of visual information processing, and vocabulary. Patients with JME performed significantly worse compared to FLE only in associative semantic processing, while the former outperformed all groups in vocabulary, visuomotor coordination, and psychomotor speed. CONCLUSION: We suggest that selective impairments of visual- and mostly auditory-speed of information processing, vigilance, and response inhibition may represent a salient neuropsychological feature in JME. These findings suggest the existence of an aberrantly working executive-attention system, secondary to pathological reticulo-thalamo-cortical dynamics. Contrariwise, cortically (frontal and extra-frontal) and subcortically induced malfunction in FLE is determined by the functional deficit zone i.e., the ensemble of cortical and subcortical areas that are functionally abnormal between seizures.

PMCA-Based Detection of Prions in the Olfactory Mucosa of Patients With Sporadic Creutzfeldt-Jakob Disease.

Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare neurodegenerative disorder caused by the conformational conversion of the prion protein (PrPC) into an abnormally folded form, named prion (or PrPSc). The combination of the polymorphism at codon 129 of the PrP gene (coding either methionine or valine) with the biochemical feature of the proteinase-K resistant PrP (generating either PrPSc type 1 or 2) gives rise to different PrPSc strains, which cause variable phenotypes of sCJD. The definitive diagnosis of sCJD and its classification can be achieved only post-mortem after PrPSc identification and characterization in the brain. By exploiting the Real-Time Quaking-Induced Conversion (RT-QuIC) assay, traces of PrPSc were found in the olfactory mucosa (OM) of sCJD patients, thus demonstrating that PrPSc is not confined to the brain. Here, we have optimized another technique, named protein misfolding cyclic amplification (PMCA) for detecting PrPSc in OM samples of sCJD patients. OM samples were collected from 27 sCJD and 2 genetic CJD patients (E200K). Samples from 34 patients with other neurodegenerative disorders were included as controls. Brains were collected from 26 sCJD patients and 16 of them underwent OM collection. Brain and OM samples were subjected to PMCA using the brains of transgenic mice expressing human PrPC with methionine at codon 129 as reaction substrates. The amplified products were analyzed by Western blot after proteinase K digestion. Quantitative PMCA was performed to estimate PrPSc concentration in OM. PMCA enabled the detection of prions in OM samples with 79.3% sensitivity and 100% specificity. Except for a few cases, a predominant type 1 PrPSc was generated, regardless of the tissues analyzed. Notably, all amplified PrPSc were less resistant to PK compared to the original strain. In conclusion, although the optimized PMCA did not consent to recognize sCJD subtypes from the analysis of OM collected from living patients, it enabled us to estimate for the first time the amount of prions accumulating in this biological tissue. Further assay optimizations are needed to faithfully amplify peripheral prions whose recognition could lead to a better diagnosis and selection of patients for future clinical trials.

Profile of personality in frontal and temporal lobe epilepsy: A study using the Millon Clinical Multiaxial Inventory-III.

Personality disorders can influence and, along with cognitive deficits, compromise the quality of life of patients with epilepsy. This study evaluated personality traits and disorders in patients with frontal (FLE) or temporal lobe epilepsy (TLE) using the Millon Clinical Multiaxial Inventory-III with the aim to determine prevalent personality profiles. The results demonstrate the presence of particularly pronounced personality traits and disorders with prevalence of histrionic and obsessive-compulsive personality profiles, respectively, in FLE and TLE. These profiles may be related to different effects of pathophysiological and clinical aspects.

The cognitive phenotypes of Creutzfeldt-Jakob disease: comparison with secondary metabolic encephalopathy.

BACKGROUND: Rapidly progressive cognitive impairment is a diagnostic criterion in Creutzfeldt-Jakob disease (CJD), but the diagnosis is usually reached when an analysis of cognitive aspects is no longer possible. OBJECTIVE: This study aims to delineate the cognitive phenotypes preceding severe dementia in CJD compared to secondary metabolic encephalopathies (SME) with rapid cognitive impairment. METHODS: Patients with rapidly progressive neurological symptoms underwent neuropsychological evaluation, analysis of cerebrospinal fluid (CSF) and codon 129 polymorphism of the prion protein gene (PRNP), magnetic resonance imaging (MRI), and single positron emission computed tomography (99mTcSPECT). CSF real-time quaking-induced conversion analysis was applied in CJD patients. Based on literature and clinical expertise, cognitive profiles were correlated with brain areas. RESULTS: Thirty-one patients were diagnosed with CJD (n = 17) or SME; 77 cases of CJD were extracted from the literature. In patients with CJD, verbal initiative, lexical search, long-term memory, attention, and abstract reasoning were the most frequently impaired abilities. Cognitive profiles were mainly related to dysfunction in fronto-temporal areas. Furthermore, they were consistent with areas of hypoperfusion detected by 99mTc SPECT in six patients and cortical and subcortical MRI hyperintensities in eight and 14 patients, respectively, and were similar to those described in the literature. In contrast, cognitive profiles were different from those in SME characterized by visuospatial and constructive deficits relating to posterior brain areas. CONCLUSION: In CJD, clinical and neuropsychological analyses outline a salient cognitive phenotype suggestive of fronto-temporal dysfunction preceding severe dementia. This phenotype is different from that observed in other rapidly progressive encephalopathies.

Cognitive awareness after treatment for high-grade glioma.

OBJECTIVE: In patients with brain lesion, awareness of cognitive deficits is an important aspect of disease awareness. Glioblastoma (GBM) and anaplastic astrocytoma (AA) can cause cognitive deficits, but, to date, awareness of these deficits has not been documented. This study aimed to test cognitive awareness in these patients after the end of treatment. METHODS: Fifty patients with GBM or AA were assessed using the Multiple Ability Self-Report Questionnaire (MASQ), State-Trait Anxiety Inventory (STAI), Self Rating Depression Scale (SRDS), and memory, attention, mental speed, abstract reasoning, and flexibility neuropsychological tests. Cognitive awareness was calculated as the concordance between the composite score of neuropsychological performance (PEC) and the total MASQ score. The controls were 48 healthy subjects. Analysis of variance and regression analysis compared subject groups and explored variables predicting perceived abilities. RESULTS: Patients with GBM or AA showed similar attention, memory, and executive deficits compared with controls. Cognitive awareness was fair/full in 64% of patients. In the entire patients group, the worst MASQ scores were associated with neuropsychological deficits, anxiety, depression, and glioma location in the right hemisphere . In patients with fair/full awareness, MASQ scores were related to affective status and neuropsychological performance, whereas, in those with scarce/no awareness, they were related only to affective status. CONCLUSIONS: After treatment, many patients with GBM or AA are aware of their cognitive deficits. Anxiety, depression, and right hemisphere tumour exacerbate the perceived difficulties. This neurocognitive approach expands the behavioural phenotypes of high-grade gliomas and may have therapeutic implications over the course of the disease.

Diversified social cognition in temporal lobe epilepsy.

OBJECTIVES: In an integrated model of social cognition (SC), the theory of mind (ToM), the recognition of behavior in social situations (RBSS), empathy, and sensitivity to moral and conventional rules (SMCR) cooperate in generating mental representations of the interpersonal relationships. The aim of this study was to extend our knowledge of the SC of temporal lobe epilepsy (TLE) patients by characterizing its various aspects and predictors. MATERIALS AND METHODS: Fifty adult patients with TLE and 50 healthy controls were assessed using ToM, RBSS and SMCR neuropsychological tests, the Empathy Questionnaire, and the psychopathology Symptoms Check List 90R (SCL90-R). RESULTS: Patients and controls were similar in terms of occupation, income level, age, sex, marital status and the number of family members. Multivariate analysis of variance with demographic variables as the covariates showed that they were similar in SMCR and empathy. The patients, conversely, had lower ToM and RBSS scores, and higher scores on the SCL90-R psychoticism, depression, paranoid ideation, obsessive-compulsive, somatization and anxiety scales. Impaired RBSS was predicted by psychopathological symptoms, income level, schooling and the duration of epilepsy; ToM related to TLE laterality, seizure frequency and epilepsy duration. CONCLUSIONS: In adult patients with TLE, SC is simultaneously partially impaired and partially preserved, and the fact this is associated with clinical, demographic and psychological variables suggests that SC depends on the integrity of the temporal lobe and the interconnected brain regions, as well as psychosocial stimuli. This approach may contribute to clarify the neurobehavioural phenotype of TLE.

The contribution of the frontal lobe to creativity. Insights from epilepsy.

PURPOSE: This study was aimed to evaluate the impact of frontal (FLE) and temporal lobe epilepsy (TLE) on graphic creativity. METHODS: A hundred and six patients with FLE (n = 32) or TLE (n = 74) and 38 healthy subjects underwent a design fluency (DF) test constituted by a free and a fixed condition. For each condition, the number of correct designs, as an index of creativity, and unacceptable nonperseveration or perseveration designs were calculated. The participants also underwent a comprehensive neuropsychological battery. RESULTS: The number of novel correct designs significantly differed between the groups: patients with FLE produced fewer designs than patients with TLE and controls, while epilepsy laterality had no effect. Patients with FLE also produced more unacceptable nonperseveration designs than controls, with no between-group differences in the perseverations. The number of novel designs was predicted by the type of epilepsy, whereas word fluency, comprehension, attention, set shifting, visual matching, and constructive praxis had no influence. This score was a sensitive marker of FLE discriminating FLE cognitive pattern from the pattern of TLE and healthy condition. CONCLUSIONS: Left or right FLE, but not TLE, can impair graphic creativity. This finding and that DF was unrelated to other cognitive abilities suggest that creativity is a specific domain, sensitive to epilepsy-related frontal lobe dysfunctions. This behavioral approach including test accuracy may have implications in defining FLE cognitive phenotype.

The understanding of mental states and the cognitive phenotype of frontal lobe epilepsy.

OBJECTIVE: Previous studies of frontal lobe epilepsy (FLE) have documented different impairments of theory of mind (ToM), while the study of frontal lobe (FL) lesion without seizures has produced inconsistent results. Given the role played by the FLs in ToM, we evaluated this and other functions in patients with FLE with and without FL lesions. The main objective was to clarify the salience of ToM impairment in the cognitive pattern of FLE and its capacity to discriminate these patients from healthy subjects. The effects of FL lesions on ToM were also explored. METHODS: Seventy-five adult patients with FLE (40 cases with FL lesions) were compared with 42 healthy controls. The Faux Pas Task (FPT) and other neuropsychological tests were utilized to assess ToM, reasoning, language, memory, praxis, attention, and executive abilities. RESULTS: The patients obtained lower z scores for the FPT than for other tests. The ToM, Executive, and Verbal factors discriminated patients from healthy subjects. The patients with or without FL lesion showed significant impairments in recognizing and understanding others' epistemic and affective mental states, but adequate capacity to exclude inexistent mental states was retained. In comparison with controls, the patients with FL lesions obtained lower scores for lexical, memory, praxis, attention, and executive functions, whereas those without lesion only showed attention and initiative deficits. Schooling was the major predictor of ToM, whereas the capacity to exclude inexistent mental states was related to seizure onset age and epilepsy duration. Other cognitive functions were related to schooling, age, or FLE laterality. SIGNIFICANCE: Impaired understanding of real mental states is a specific, salient, and discriminating cognitive aspect of FLE. Poor education is a risk factor for ToM deficit, whereas the clinical variables and FL lesions have no impact. These results suggest that impaired ToM may be a marker of FLE neurobehavioral phenotype.

The visuospatial pattern of temporal lobe epilepsy.

PURPOSE: Unlike temporal lobe lesions, temporal lobe epilepsy (TLE) has no definite effects on visuospatial functions. This retrospective study evaluated these functions in patients with TLE, aiming to clarify their relationships to TLE laterality and magnetic resonance imaging (MRI)-detected brain lesions. METHODS: The Raven Colored Progressive Matrices (RCPM), Attentive Matrices (AM), Trail Making Test A (TMTA), Street Completion Test (SCT), Rey Complex Figure Copying (RCFC) and Delayed Reproduction (RCFDR), and Corsi Blocks Span (CBS) and Supraspan Learning (CBSSL) were used to assess different visuospatial functions in 198 patients with TLE and 90 healthy subjects. RESULTS: In 169 patients (83 left), MRI revealed focal temporal lobe lesions [unilateral mesial temporal lobe sclerosis (MTLS) in 88 cases]. The patients with left or right TLE obtained normal scores on the RCPM, AM, TMTA, SCT, and RCFC, but their scores were significantly low on the CBS, CBSSL, and RCFDR. The patients with MTLS obtained lower scores in comparison with the controls and the patients without lesions, whereas those with other lesions obtained low scores only on the CBSSL and those without lesions performed normally. CONCLUSIONS: Temporal lobe epilepsy does not affect nonmemory visuospatial functions but significantly impairs visuosopatial memory and learning. This pattern is independent of TLE laterality, in keeping with a modality-specific memory model. On the contrary, the type of temporal lobe lesion is relevant to the severity of impairment.

Investigating the social cognition phenotypes in children, adolescents, and adults with epilepsy.

In recent years, clinical and neuropsychological assessment of patients with epilepsy has dedicated increasing attention to social cognition (SC), which is relevant to interpersonal relations, psychological well-being, and autonomy. The components of SC are supported by distinct but interlinked brain regions that may be affected by focal and generalized epilepsy. This special issue sought to describe some of the societal, clinical, and pathophysiological correlates of SC in patients with epilepsy and healthy subjects, highlighting some of the questions key to clinical care and research. This article is part of the Special Issue "Epilepsy and social cognition across the lifespan".

Theory of mind across lifespan from ages 16 to 81 years.

PURPOSE: Impaired theory of mind (ToM) is a neurobehavioral phenotype of epilepsy. Given that the age transitions affect cognitive development and decline, it is important to refine ToM across the lifespan. This study evaluated ToM in healthy subjects, taking into account education, gender, and other functions, aiming to clarify its specificity and relationships to major demographic and cognitive domains. METHODS: A hundred and seventy subjects from ages 16 to 81 years (68 men) who received five to 17 years of schooling were evaluated using a Faux Pas Task (FPT) that is solved at the end of childhood and is highly sensitive to brain damage and tests for language, memory, praxis, visual perception, initiative, attention, shifting, and planning. Factor analysis, analysis of variance, and correlation and regression analyses were used to assess the data. RESULTS: The analysis yielded six factors: Beliefs, Delusions, and Facts, which express the understanding of mental states and contextual details; Matching-Learning, Executive, and Working Memory. On this basis, six composite scores (CSs) were computed. Age and schooling showed significant effects on the Matching-Learning, Executive, and Working Memory CSs. The FPT raw scores and CSs were unrelated to age or schooling, while females showed better performance than males. The Beliefs CS and FPT scores were predicted by the Executive, Working Memory, Delusions, and Facts CSs and gender. CONCLUSIONS: Theory of mind is a specific cognitive domain independent of age and formal education, but related to gender. Working memory, executive functions, and reality examination support some ToM processes. These findings may provide reference points against which impairment can be assessed. This article is part of the Special Issue "Epilepsy and social cognition across the lifespan".

Gamma electroencephalographic coherence and theory of mind in healthy subjects.

PURPOSE: Structural brain imaging has revealed that damage to different brain regions may impair theory of mind (ToM) while functional imaging has shown that distributed neural circuits are activated by ToM and empathy. However, the coherence of the electroencephalogram (EEG) frequencies in a definite time span may change during these processes, indicating different neurophysiological correlates. This study evaluated the changes of EEG coherence during ToM tasks in comparison with Empathy, Physical causality, and baseline conditions, aiming to determine the neurophysiological correlates of ToM. METHODS: Sixteen healthy adults underwent a visual activation paradigm using 30 comic strips concerning ToM, Empathy, or Physical causality during EEG recording. The interhemispheric coherence was estimated using a bivariate autoregressive (AR) parametric model. The coherence spectra were analyzed in the alpha, beta, and gamma frequency EEG bands. RESULTS: Coherence analysis taking all of the responses showed that in the gamma band, in comparison with the Empathy, Physical causality, and baseline conditions, ToM was associated with significantly higher peaks between the frontal and parietal areas in the right hemisphere and, in comparison with the Physical causality and baseline conditions, in the left hemisphere. Analysis taking the correct responses confirmed these results. CONCLUSIONS: In healthy adults, ToM processes are associated with immediate specific changes of brain connectivity, as expressed by high cortical coherence within the right frontal and parietal areas. These previously unexplored aspects indicate an online involvement of the right hemisphere networks in normal ToM. In patients with epilepsy, the study of EEG coherence during specific tasks may help determine the neural dysfunctions associated with impaired ToM. This article is part of the Special Issue "Epilepsy and social cognition across the lifespan".