Focal Temporal Lobe Research Articles

Comparison of executive function in idiopathic generalized epilepsy versus temporal lobe epilepsy

ABSTRACT Executive function (EF) deficits are common in epilepsy and impact quality of life. This study compares EF in idiopathic generalized epilepsy (IGE) and temporal lobe epilepsy (TLE) patients to healthy controls. Fifty-six IGE patients, 56 TLE patients, and 60 controls (matched by age) completed cognitive tests assessing attention, memory, learning, and verbal fluency. Both epilepsy groups performed worse than controls, with TLE patients showing significantly poorer verbal learning and memory compared to IGE patients. These findings suggest that TLE patients have more severe EF impairments, likely due to focal temporal lobe dysfunction and disruptions in EF networks.

Hippocampal microscopic fractional anisotropy is reduced in temporal lobe epilepsy

Abstract Surgical resection is the method of choice for treating drug-resistant focal temporal lobe epilepsy (TLE). Postsurgical outcomes are better when magnetic resonance imaging (MRI) findings can localize the seizure focus for resection. However, many patients are MR-negative, meaning the focus cannot be differentiated from normal tissue in relaxation-weighted MRI. Diffusion MRI shows promise as a preoperative marker of neuronal abnormalities due to its sensitivity to cellular changes such as axon damage, indexed by fractional anisotropy. Microscopic fractional anisotropy is a recently introduced diffusion MRI metric that is sensitive to axon integrity regardless of axon orientation in both grey and white matter. In contrast, regular fractional anisotropy is only sensitive to axon integrity in coherently oriented bundles of fibers. This work investigated whether microscopic fractional anisotropy is sensitive to hippocampal abnormalities in drug-resistant TLE. Diffusion MRI was performed on a 3T scanner in 19 patients (age = 31±10 years) with drug-resistant TLE (of which 10 were MR-negative) and 18 healthy volunteers (age = 38±15). A deep-learning method was employed to segment the hippocampus into smaller subregions corresponding to the subiculum, cornu ammonis (CA) 1, CA2/3, and CA4 plus dentate gyrus (DG). Mean measurements of subregion volume, diffusivity, fractional anisotropy, and microscopic fractional anisotropy were compared between cohorts. In a subset of the TLE cohort suspected to have unilateral pathology (n=15, age = 32±10 years), the percentage differences between measurements ipsilateral and contralateral to the epileptogenic zone were evaluated to assess asymmetry. Microscopic fractional anisotropy was reduced in the hippocampus of drug-resistant TLE patients relative to healthy volunteers. In subregion-specific analysis, microscopic fractional anisotropy was significantly reduced in only the CA4/DG region in patients compared to healthy volunteers, after corrections for multiple comparisons. In the 15 patients with suspected unilateral pathology, microscopic fractional anisotropy was reliably and statistically lower in the ipsilateral CA4/DG region compared to the contralateral side. Significant differences were not observed between TLE patients and healthy volunteers, or between hemispheres for patients with suspected unilateral pathology, for the fractional anisotropy or volume metrics. Diffusion MRI may complement standard imaging procedures by detecting abnormalities in MRI-negative patients. Due to its ability to detect abnormality regardless of axon orientation, microscopic fractional anisotropy may improve seizure focus localization in surgical candidates.

Genetic and clinical correlates of two neuroanatomical AI dimensions in the Alzheimer’s disease continuum

Alzheimer’s disease (AD) is associated with heterogeneous atrophy patterns. We employed a semi-supervised representation learning technique known as Surreal-GAN, through which we identified two latent dimensional representations of brain atrophy in symptomatic mild cognitive impairment (MCI) and AD patients: the “diffuse-AD” (R1) dimension shows widespread brain atrophy, and the “MTL-AD” (R2) dimension displays focal medial temporal lobe (MTL) atrophy. Critically, only R2 was associated with widely known sporadic AD genetic risk factors (e.g., APOE ε4) in MCI and AD patients at baseline. We then independently detected the presence of the two dimensions in the early stages by deploying the trained model in the general population and two cognitively unimpaired cohorts of asymptomatic participants. In the general population, genome-wide association studies found 77 genes unrelated to APOE differentially associated with R1 and R2. Functional analyses revealed that these genes were overrepresented in differentially expressed gene sets in organs beyond the brain (R1 and R2), including the heart (R1) and the pituitary gland, muscle, and kidney (R2). These genes were enriched in biological pathways implicated in dendritic cells (R2), macrophage functions (R1), and cancer (R1 and R2). Several of them were “druggable genes” for cancer (R1), inflammation (R1), cardiovascular diseases (R1), and diseases of the nervous system (R2). The longitudinal progression showed that APOEε4, amyloid, and tau were associated with R2 at early asymptomatic stages, but this longitudinal association occurs only at late symptomatic stages in R1. Our findings deepen our understanding of the multifaceted pathogenesis of AD beyond the brain. In early asymptomatic stages, the two dimensions are associated with diverse pathological mechanisms, including cardiovascular diseases, inflammation, and hormonal dysfunction—driven by genes different from APOE—which may collectively contribute to the early pathogenesis of AD. All results are publicly available at https://labs-laboratory.com/medicine/.

Nine Neuroimaging-AI Endophenotypes Unravel Disease Heterogeneity and Partial Overlap across Four Brain Disorders: A Dimensional Neuroanatomical Representation.

Disease heterogeneity poses a significant challenge for precision diagnostics. Recent work leveraging artificial intelligence has offered promise to dissect this heterogeneity by identifying complex intermediate brain phenotypes, herein called dimensional neuroimaging endophenotypes (DNEs). We advance the argument that these DNEs capture the degree of expression of respective neuroanatomical patterns measured, offering a dimensional neuroanatomical representation for studying disease heterogeneity and similarities of neurologic and neuropsychiatric diseases. We investigate the presence of nine such DNEs derived from independent yet harmonized studies on Alzheimer's disease (AD1-2)1, autism spectrum disorder (ASD1-3)2, late-life depression (LLD1-2)3, and schizophrenia (SCZ1-2)4, in the general population of 39,178 participants in the UK Biobank study. Phenome-wide associations revealed prominent associations between the nine DNEs and phenotypes related to the brain and other human organ systems. This phenotypic landscape aligns with the SNP-phenotype genome-wide associations, revealing 31 genomic loci associated with the nine DNEs (Bonferroni corrected P-value < 5×10-8/9). The DNEs exhibited significant genetic correlations, colocalization, and causal relationships with multiple human organ systems and chronic diseases. A causal effect (odds ratio=1.25 [1.11, 1.40], P-value=8.72×10-4) was established from AD2, characterized by focal medial temporal lobe atrophy, to AD. The nine DNEs, along with their polygenic risk scores, significantly enhanced the predictive accuracy for 14 systemic disease categories, particularly for conditions related to mental health and the central nervous system, as well as mortality outcomes. These findings underscore the potential of the nine DNEs to capture the expression of disease-related brain phenotypes in individuals of the general population and to relate such measures with genetics, lifestyle factors, and chronic diseases. All results are publicly available at https://labs-laboratory.com/medicine/.

Seizure onset and offset pattern determine the entrainment of the cortex and substantia nigra in the nonhuman primate model of focal temporal lobe seizures.

Temporal lobe epilepsy (TLE) is the most common form of drug-resistant epilepsy. A major focus of human and animal studies on TLE network has been the limbic circuit. However, there is also evidence suggesting an active role of the basal ganglia in the propagation and control of temporal lobe seizures. Here, we characterize the involvement of the substantia nigra (SN) and somatosensory cortex (SI) during temporal lobe (TL) seizures induced by penicillin injection in the hippocampus (HPC) of two nonhuman primates. The seizure onset and offset patterns were manually classified and spectral power and coherence were calculated. We then compared the 3-second segments recorded in pre-ictal, onset, offset and post-ictal periods based on the seizure onset and offset patterns. Our results demonstrated an involvement of the SN and SI dependent on the seizure onset and offset pattern. We found that low amplitude fast activity (LAF) and high amplitude slow activity (HAS) onset patterns were associated with an increase in activity of the SN while the change in activity was limited to LAF seizures in the SI. However, the increase in HPC/SN coherence was specific to the farther-spreading LAF onset pattern. As for the role of the SN in seizure cessation, we observed that the coherence between the HPC/SN was reduced during burst suppression (BS) compared to other termination phases. Additionally, we found that this coherence returned to normal levels after the seizure ended, with no significant difference in post-ictal periods among the three types of seizure offsets. This study constitutes the first demonstration of TL seizures entraining the SN in the primate brain. Moreover, these findings provide evidence that this entrainment is dependent on the onset and offset pattern and support the hypothesis that the SN might play a role in the maintenance and termination of some specific temporal lobe seizure.

Anterior thalamic nucleus local field potentials during focal temporal lobe epileptic seizures.

To analyze the local field potentials (LFPs) in patients with focal drug-resistant epilepsy (DRE) from the anterior nucleus of the thalamus (ANT) during inter-ictal state and seizure state. ANT stereotactic EEG (SEEG) recordings were studied in four patients with focal temporal lobe epilepsy. SEEG data was classified as inter-ictal and ictal state and sub-categorized into electrographic (ESz), focal aware seizure (FAS), focal with impaired awareness (FIA), or focal to bilateral tonic-clonic seizure (FBTC). LFP was analyzed at 4 Hz, 8 Hz, 16 Hz, 32 Hz, high gamma (100 Hz), and ripples (200 Hz) using spectrogram analysis and a statistical comparison of normalized power spectral density (PSD) averaged during seizures versus pre-ictal baseline segments. The LFP recordings were analyzed for 162 seizures (127 ESz, 23 FAS, 6 FIA, and 6 FBTC). Based on time-frequency data (spectrogram), a broad band of activity, occurring between 2 and 6 Hz and centered at 4 Hz, and thin-band activity occurring specifically at 8 Hz on the frequency spectrogram were observed during the inter-ictal state. Statistically significant changes in LFP-PSD were seen for FAS, FIA, and FBTC. We observed a significant gain in LFP at the lower frequency band during FAS at 4 Hz, FIA, and FBTC at 4, 8, and 16 Hz while also observing increases at higher frequencies during FBTC at 100 and 200 Hz and a decrease during FAS seizures at 32 Hz. In contrast, no significant change in LFP power was seen for electrographic seizures. Our observations from a limited dataset indicate that all clinical seizure types, but not electrographic seizures, caused a change in ANT-LFP based on the magnitude of the associated power spectral density (PSD). Future work will be needed to validate the use of ANT-LFP at these frequencies as accurate measurements of seizure occurrence and severity. This work represents a first step toward understanding ANT thalamic LFP patterns during focal seizures and developing adaptive DBS strategies.

Edge-wise analysis reveals white matter connectivity associated with focal to bilateral tonic-clonic seizures.

Focal to bilateral tonic-clonic seizures (FBTCS) represent a challenging subtype of focal temporal lobe epilepsy (TLE) in terms of both severity and treatment response. Most studies have focused on regional brain analysis that is agnostic to the distribution of white matter (WM) pathways associated with a node. We implemented a more selective, edge-wise approach that allowed for identification of the individual connections unique to FBTCS. T1-weighted and diffusion-weighted images were obtained from 22 patients with solely focal seizures (FS), 43 FBTCS patients, and 65 age/sex-matched healthy participants (HPs), yielding streamline (STR) connectome matrices. We used diffusion tensor-derived STRs in an edge-wise approach to determine specific structural connectivity changes associated with seizure generalization in FBTCS compared to matched FS and HPs. Graph theory metrics were computed on both node- and edge-based connectivity matrices. Edge-wise analyses demonstrated that all significantly abnormal cross-hemispheric connections belonged to the FBTCS group. Abnormal connections associated with FBTCS were mostly housed in the contralateral hemisphere, with graph metric values generally decreased compared to HPs. In FBTCS, the contralateral amygdala showed selective decreases in the structural connection pathways to the contralateral frontal lobe. Abnormal connections in TLE involved the amygdala, with the ipsilateral side showing increases and the contralateral decreases. All the FS findings indicated higher graph metrics for connections involving the ipsilateral amygdala. Data also showed that some FBTCS connectivity effects are moderated by aging, recent seizure frequency, and longer illness duration. Data showed that not all STR pathways are equally affected by the seizure propagation of FBTCS. We demonstrated two key biases, one indicating a large role for the amygdala in the propagation of seizures, the other pointing to the prominent role of cross-hemispheric and contralateral hemisphere connections in FBTCS. We demonstrated topographic reorganization in FBTCS, pointing to the specific WM tracts involved.

When the Stomach Pain Is Literally “In Your Head”

Abdominal epilepsy (AE) is an extremely rare condition, classified as temporal lobe epilepsy, and is usually a diagnosis of exclusion. Temporal lobe epilepsy often has no clear cause, although it may be associated with diseases such as temporal lobe sclerosis, dysembryoplastic neuroepithelial tumours, and other benign tumours, as well as arterio-venous malformations, gliomas, defects in neuronal migration, or lesions of the cortex caused by encephalitis. AE is more common in children but has been reported in adults. AEs are characterised by recurrent and unexplained gastrointestinal symptoms such as seizure pain, nausea, bloating and diarrhoea, which improve with antiepileptic treatment. Given the vague nature of these symptoms, patients are at high risk of misdiagnosis. An electroencephalogram and neuroimaging of the brain are needed to confirm the diagnosis.&#x0D; We present the clinical case of a 67-year-old female patient who was investigated at the Gastroenterology Department for a sharp pain in the left side of the abdomen, frequent abdominal distension and gurgles, diarrhoeal episodes, weight loss, paroxysmal hallucinations, and headaches. After a thorough gastroenterological examination, consultations with a psychiatrist and a neurologist, an MRI and an EEG were performed and the patient was diagnosed with focal temporal lobe epilepsy.

The relationship between immunological and psychopathological characteristics in patients with focal epilepsy depending on the profile of interhemispheric asymmetry

To identify the possible influence of cellular immunity parameters and neurobiological variables (frequency of seizures of various semiotics and their severity) on comorbid psychopathological symptoms depending on the profile of interhemispheric asymmetry in patients with focal forms of epilepsy. The study included 92 patients with epilepsy (38 men, 54 women, mean age 38.7+8.45 years). Focal temporal lobe epilepsy was diagnosed in 36 patients, focal frontal lobe epilepsy in 16 patients, and temporal-frontal lobe epilepsy in 40 patients. For each type of seizure, severity was assessed according to the National Seizure Severity Scale (NHS3). The mental status of patients was assessed using the SCL-90 self-report questionnaire. The Annette scale was used to assess the profile of interhemispheric asymmetry. The number of different clusters of lymphocytes was studied, including the number of T-lymphocytes (CD3+), T-helpers (CD3+CD4+), T-cytotoxic (CD3+CD8+), T-NK (natural killers CD3+CD16+CD56+), B-lymphocytes (CD3-CD19+), as well as immunoregulatory index (CD4/CD8 ratio). In order to identify any possible relationships between neurobiological and immune variables, on the one hand, and the SCL-90 constructs, on the other hand, a separate correlation analysis of Spearman ranks within the left-handed group and the right-handed group was carried out. We revealed the differences between groups of patients with epilepsy with right and left profiles of hemispheric asymmetry regarding the relationship between the frequency of seizures, their severity and accompanying psychopathological variables, on the one hand, and between immunity indices and psychopathological constructs, on the other hand. It has been established that neurobiological and immune variables in left-handers can determine the psychopathological structure of the comorbid mental disorder. Prediction of concomitant psychopathological syndromes in patients with epilepsy on the basis of clinical data and data on immunity is quite possible, but only in left-handed patients.

Cognitive flexibility impairment in temporal lobe epilepsy: The impact of epileptic foci lateralization on executive functions

IntroductionTemporal Lobe Epilepsy (TLE) has been associated with memory impairments, which are typically linked to hippocampal and mesial temporal cortex lesions. Considering the presence of extensive bidirectional frontotemporal connections, it can be hypothesized that executive dysfunction in TLE is modulated by the lateralization of the epileptic foci. Material and MethodsA comprehensive neuropsychological executive functions protocol was administered to 63 participants, including 42 individuals with temporal lobe epilepsy (20 with right-TLE and 22 with left-TLE) and 21 healthy controls aged 20–49. ResultsThe results indicate that TLE patients exhibit poorer executive performance compared to healthy controls in working memory (F(2,60) = 4.18, p <.01), planning (F(2,60) = 4.71, p <.05), set shifting (F(2,60) = 10.1, p <.001), phonetic verbal fluency (F(2,60) = 11.71, p <.01) and semantic verbal fluency (F(2,60) = 9.61, p <.001. No significant differences were found in cognitive inhibition. Furthermore, right-TLE patients showed lower performance than left-TLE in set shifting (F(1,61) = 6.45, p <.05), while no significant differences were observed in working memory, planning, inhibition, and verbal fluency. ConclusionsThis research emphasize the importance of considering the lateralization of the temporal lobe focus to achieve a more accurate neuropsychological characterization. The cognitive differences between left and right TLE patients highlight the need for individualized approaches in their treatment and care.

Sleep disturbance associated with temporal lobe degeneration in frontotemporal dementia

AbstractBackgroundSleep abnormalities are increasingly recognized as markers and potential drivers of neurodegenerative proteinopathies. However, the sleep phenotype of less common dementias remains poorly characterised. In particular, clinical experience suggests that patients with focal temporal lobe degeneration in the frontotemporal dementia spectrum can experience sometimes striking sleep disruption. We recently had the opportunity to corroborate this clinical impression in a small series of representative patients participating in a larger cohort study.MethodsTo date, we have studied seven patients and three healthy age‐matched controls. The patients’ diagnoses comprise behavioural variant frontotemporal dementia associated with focal right temporal lobe atrophy (n = 3), semantic dementia associated with focal left temporal lobe atrophy (n = 2), young onset Alzheimer’s disease and logopenic aphasia (each n = 1). No participant had a past history of a clinical sleep disorder. Detailed data on sleep patterns, adapted standard sleep questionnaires (Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale), overnight oximetry and neuropsychological test scores (covering domains of executive function, emotion processing, memory, and auditory perceptual learning) pre‐/post‐overnight sleep were collected with the assistance of patients’ caregivers.ResultsTwo patients with right temporal lobe atrophy and one with left temporal lobe atrophy had marked sleep fragmentation, in one right temporal case accompanied by frequent sleep attacks, with increased overall time in bed and/or attempting to sleep. Epworth and Pittsburgh indices in these patients indicated significant daytime sleepiness and reduced sleep quality; none had evidence of significant sleep apnoea on overnight oximetry. Comparatively mild clinical sleep disturbances were reported in patients with other dementia diagnoses. However, there was evidence for reduced auditory perceptual learning benefit from overnight sleep relative to healthy older controls, particularly in the patients with underlying Alzheimer pathology.ConclusionsThese preliminary findings suggest that focal temporal lobe degeneration may be associated with clinically relevant sleep disruption, as part of the more pervasive derangement of homeostasis in these syndromes. Further work is indicated to define the hypnic phenotype in detail, with sleep electrophysiology and correlative behavioural, neuroimaging and laboratory data in larger patient cohorts.

Novel genomic loci shape two neuroanatomical dimensions of AD in non‐demented populations

AbstractBackgroundArtificial intelligence has been in burgeoning demand to be applied to magnetic imaging resonance (MRI) data to parse the neuroanatomical heterogeneity of Alzheimer’s disease (AD) and/or mild cognitive impairment (MCI) (Wen et al., 2021a, 2021b; Yang et al., 2021). However, the genetic heterogeneity leading to this neuroanatomical heterogeneity, especially at the early asymptomatic stages, is not fully elucidated.MethodA deep semi‐supervised representation learning method, called Surreal‐GAN (Yang et al., 2022), was applied to T1‐weighted MRI from AD/MCI patients from ADNI to define the two neuroanatomical dimensions of AD at the symptomatic stages. The R1 dimension was characterized by widespread brain atrophy without an exclusive focus on the medial temporal lobe, whereas the R2 dimension showed focal medial temporal lobe atrophy (Wen et al., 2022). We then applied the trained model to 33,540 non‐demented individuals from UK Biobank. Imputed genotyping data were analyzed in genome‐wide association studies (GWAS). We performed multiple linear regressions controlling for confounding factors (e.g., age) via Plink (Purcell et al., 2007). We defined a genomic locus (represented by the top lead SNP) considering linkage disequilibrium. Finally, we manually queried all leading SNPs on GWAS Catalog (Buniello et al., 2019) to determine if the genomic loci were novel, provided they were not previously associated with any clinical traits.ResultGWAS discovered 24 genomic loci, of which 7 were novel for R1 and R2, respectively (Fig. 1). For R1, 8 mapped genes, based on physical positions, eQTL, and chromatin interactions, were associated with AD‐related traits in the literature. For example, the KDM2B gene from the genomic locus (rs9795600, P‐value = 1.13e‐08) was previously associated with AD (Gouveia et al., 2022). For R2, 13 mapped genes were associated with AD‐related traits. For example, the TESC gene from the genomic locus (rs77956314, P‐value = 9.99e‐29) was associated with neurofibrillary tangles measurement, which is formed by hyperphosphorylation of a microtubule‐associated protein known as tau in AD (Wang et al., 2020).ConclusionOur results confirmed genetic variants previously associated with AD and identified novel genomic loci contributing to this neuroanatomical heterogeneity. Further research is needed to understand these novel loci’s biological pathways and functional consequences.

Novel genomic loci shape two neuroanatomical dimensions of AD in non‐demented populations

AbstractBackgroundArtificial intelligence has been in burgeoning demand to be applied to magnetic imaging resonance (MRI) data to parse the neuroanatomical heterogeneity of Alzheimer’s disease (AD) and/or mild cognitive impairment (MCI) (Wen et al., 2021a, 2021b; Yang et al., 2021). However, the genetic heterogeneity leading to this neuroanatomical heterogeneity, especially at the early asymptomatic stages, is not fully elucidated.MethodA deep semi‐supervised representation learning method, called Surreal‐GAN (Yang et al., 2022), was applied to T1‐weighted MRI from AD/MCI patients from ADNI to define the two neuroanatomical dimensions of AD at the symptomatic stages. The R1 dimension was characterized by widespread brain atrophy without an exclusive focus on the medial temporal lobe, whereas the R2 dimension showed focal medial temporal lobe atrophy (Wen et al., 2022). We then applied the trained model to 33,540 non‐demented individuals from UK Biobank. Imputed genotyping data were analyzed in genome‐wide association studies (GWAS). We performed multiple linear regressions controlling for confounding factors (e.g., age) via Plink (Purcell et al., 2007). We defined a genomic locus (represented by the top lead SNP) considering linkage disequilibrium. Finally, we manually queried all leading SNPs on GWAS Catalog (Buniello et al., 2019) to determine if the genomic loci were novel, provided they were not previously associated with any clinical traits.ResultGWAS discovered 24 genomic loci, of which 7 were novel for R1 and R2, respectively (Fig. 1). For R1, 8 mapped genes, based on physical positions, eQTL, and chromatin interactions, were associated with AD‐related traits in the literature. For example, the KDM2B gene from the genomic locus (rs9795600, P‐value = 1.13e‐08) was previously associated with AD (Gouveia et al., 2022). For R2, 13 mapped genes were associated with AD‐related traits. For example, the TESC gene from the genomic locus (rs77956314, P‐value = 9.99e‐29) was associated with neurofibrillary tangles measurement, which is formed by hyperphosphorylation of a microtubule‐associated protein known as tau in AD (Wang et al., 2020).ConclusionOur results confirmed genetic variants previously associated with AD and identified novel genomic loci contributing to this neuroanatomical heterogeneity. Further research is needed to understand these novel loci’s biological pathways and functional consequences.

Discovering Alzheimer’s disease subtypes with imaging and genetic signatures via multi‐view weakly‐supervised deep clustering

AbstractBackgroundThe heterogeneity of neurodegenerative diseases, including Alzheimer’s disease (AD), has hampered precision diagnosis and treatment. Machine learning methods enable the identification of genetically‐explained disease subtypes with distinct brain phenotypes.MethodGene‐SGAN is a novel, multi‐view, weakly‐supervised deep clustering method that jointly considers phenotypic and genetic data, thereby deriving subtypes of disease‐related brain changes with genetic associations. We apply the method to derive subtypes related to AD. Analyses used structural MRIs and whole‐genome sequencing data from the Alzheimer’s Disease Neuroimaging Initiative (1,533 participants, including controls and patients with Mild Cognitive Impairment (MCI) and AD).ResultGene‐SGAN identified four distinct subtypes within MCI/AD: A1, normal anatomy; A2, focal medial temporal lobe (MTL) atrophy; A3, severe atrophy in neocortex and MTL; A4, severe cortical but relatively modest MTL atrophy (Figure 1). The four subtypes reveal significant differences in seven known AD‐related genetic variants (Figure 2). The identified subtype‐associated SNPs not only resemble previous findings, but also suggest genetic protective effects contributing to the observed resilience (A1), potential inflammatory mechanisms underlying subtypes (A2&amp;A3), and the effect of SNPs on atypical atrophy patterns of AD (A4). Clinically, A1 and A3 participants showed the best and the worst cognitive performances (Figure 3). A3 participants had the most abnormal CSF Aβ (p&lt;0.001 vs. A1&amp;A4 and p = 0.039 vs. A2), and exhibited the highest white matter hyperintensity (WMH) volumes (p&lt;0.001 vs. A1&amp;A4 and p = 0.017 vs. A2). However, A2 participants showed significantly higher CSF phospho‐tau than A3 participants (p = 0.019). A4 participants were the youngest group (p&lt;0.001 vs. all other groups), suggesting the inclusion of early onset AD participants, who have a higher prevalence of hippocampal‐sparing variants such as posterior cortical atrophy. The four genetically‐associated subtypes also possess significant differences in a large set of plasma/CSF biomarkers, which are related to distinct biological mechanisms contributing to the heterogeneity of AD.ConclusionDeep learning revealed four morphologic/genetic MCI/AD subtypes. The derived subtypes display distinct neuroanatomical patterns and genetic determinants and also differ in many clinically interpretable biomarkers. These subtypes provide potential for drug discovery and repurposing, optimization of clinical trial recruitment, and personalized medicine based on an individual’s genetic profile.

Efficacy and tolerability of lacosamide and controlled-release carbamazepine monotherapy in patients with newly diagnosed temporal lobe epilepsy: Post hoc analysis of a randomized, double-blind trial

PurposeTemporal lobe epilepsy (TLE) is often associated with drug-resistant seizures. We evaluated the efficacy and tolerability of lacosamide (LCM) versus controlled-release carbamazepine (CBZ-CR) monotherapy in adults with newly diagnosed TLE. MethodsExploratory post hoc analysis of patients with temporal focus of localization (indicated as the only localization focus) in a double-blind, noninferiority, phase 3 trial (SP0993; NCT01243177) in patients aged ≥ 16 years with newly diagnosed epilepsy randomized 1:1 to LCM or CBZ-CR monotherapy. ResultsOf 886 treated patients in this trial, temporal lobe focus of localization (TLE) was reported as the single focus for 287 (32.4%) patients (LCM 134, CBZ-CR 153). A similar proportion of patients with TLE on LCM (82 [61.2%]) and CBZ-CR (99 [64.7%]) completed the trial. Kaplan-Meier estimates for 6- and 12-month seizure freedom at the last evaluated dose level (stratified by number of seizures in the 3 months before screening [≤2 or >2 seizures]) were similar with LCM and CBZ-CR (6 months overall: 88.7% and 89.7%; 12 months overall: 78.3% and 81.7%). Treatment-emergent adverse events (TEAEs) were reported by fewer patients on LCM (73.9%) than CBZ-CR (81.0%). Drug-related TEAEs (assessed by the investigator) were reported in 41.8% of patients on LCM and 52.3% of patients on CBZ-CR; 11.2% of patients on LCM and 15.0% on CBZ-CR discontinued due to TEAEs. ConclusionLacosamide was efficacious and generally well tolerated as monotherapy in patients with TLE with efficacy outcomes comparable with CBZ-CR, and fewer patients on LCM reported any TEAEs, drug-related TEAEs, or discontinued due to TEAEs.

Novel Approaches for Treatment of Epilepsy

Epilepsy is a serious neurological disorder on the juncture of psychiatry and neurology. It is characterized by recurrent and episodic seizures which are due to excessive discharge by the brain neurons. The therapeutic response failure of more than one or two antiepileptic drugs (AEDs) is the benchmark of refractory or intractable epilepsy. The aim of the study was to determine new approaches which lead towards the treatment of epilepsy. In order to treat focal mesial temporal lobe epilepsy or neocortical epilepsy in adults and any malformation of cortical development such as focal dysplasia surgical resection remains the gold standard treatment. Disconnection procedures such as corpus callosotomy and multiple subpial transections are the best alternative treatment for that patient whose seizure origin is in eloquent cortex or having generalized epilepsy syndromes. Palliative neuromodulation procedures such as Vagus nerve stimulation (VNS), Responsive neurostimulation (RNS) and Deep brain stimulation (DBS) are best approach to treat intractable epileptic patients who are not suitable candidates of surgery. As the search of better management of epilepsy continues gene therapy and optogenetics gain a momentum in neuroscience.

Expressive Prosody in Patients With Focal Anterior Temporal Neurodegeneration.

Progressive focal anterior temporal lobe (ATL) neurodegeneration has been historically called semantic dementia. More recently, semantic variant primary progressive aphasia (svPPA) and semantic behavioral variant frontotemporal dementia (sbvFTD) have been linked with predominant left and right ATL neurodegeneration, respectively. Nonetheless, clinical tools for an accurate diagnosis of sbvFTD are still lacking. Expressive prosody refers to the modulation of pitch, loudness, tempo, and quality of voice used to convey emotional and linguistic information and has been linked to bilateral but right-predominant frontotemporal functioning. Changes in expressive prosody can be detected with semiautomated methods and could represent a useful diagnostic marker of socioemotional functioning in sbvFTD. Participants underwent a comprehensive neuropsychological and language evaluation and a 3T MRI at the University of California San Francisco. Each participant provided a verbal description of the picnic scene from the Western Aphasia Battery. The fundamental frequency (f0) range, an acoustic measure of pitch variability, was extracted for each participant. We compared the f0 range between groups and investigated associations with an informant-rated measure of empathy, a facial emotion labeling task, and gray matter (GM) volumes using voxel-based morphometry. Twenty-eight patients with svPPA, 18 with sbvFTD, and 18 healthy controls (HCs) were included. f0 range was significantly different across groups: patients with sbvFTD showed reduced f0 range in comparison with both patients with svPPA (mean difference of -1.4 ± 2.4 semitones; 95% CI -2.4 to -0.4]; p < 0.005) and HCs (mean difference of -1.9 ± 3.0 semitones; 95% CI -3.0 to -0.7]; p < 0.001). A higher f0 range was correlated with a greater informant-rated empathy (r = 0.355; p ≤ 0.05), but not facial emotion labeling. Finally, the lower f0 range was correlated with lower GM volume in the right superior temporal gyrus, encompassing anterior and posterior portions (p < 0.05 FWE cluster corrected). Expressive prosody may be a useful clinical marker of sbvFTD. Reduced empathy is a core symptom in sbvFTD; the present results extend this to prosody, a core component of social interaction, at the intersection of speech and emotion. They also inform the long-standing debate on the lateralization of expressive prosody in the brain, highlighting the critical role of the right superior temporal lobe.

Focal drug-resistant temporal lobe epilepsy associated with an ipsilateral anterior choroidal artery aneurysm: illustrative case.

The occurrence of both an intracranial aneurysm and epilepsy, especially drug-resistant epilepsy (DRE), is rare. Although the overall incidence of aneurysms associated with DRE is unclear, it is thought to be particularly infrequent in the pediatric population. Surgical ligation of the offending aneurysm has been reported in conjunction with resolving seizure activity, although few cases have cited a combined approach of aneurysm ligation and resection of an epileptogenic focus. We present the case of a 14-year-old female patient with drug-resistant temporal lobe epilepsy and an ipsilateral supraclinoid internal carotid artery aneurysm. Seizure semiology, electroencephalography monitoring, and magnetic resonance imaging all indicated a left temporal epileptogenic focus, in addition to an incidental aneurysm. The authors recommended a combined surgery involving resection of the temporal lesion and surgical clip ligation of the aneurysm. Near-total resection and successful ligation were achieved, and the patient has remained seizure free since surgery at 1 year postoperatively. In patients with focal DRE and an adjacent intracranial aneurysm, a combined surgical approach involving both resection and surgical ligation can be used. Several surgical timing and neuroanesthetic considerations should be made to ensure the overall safety and efficacy of this procedure.

Facial Emotion Recognition in Patients with Juvenile Myoclonic Epilepsy.

Previous studies have found facial emotion recognition (FER) impairments in individuals with epilepsy. While such deficits have been extensively explored in individuals with focal temporal lobe epilepsy, studies on individuals with generalized epilepsies are rare. However, studying FER specifically in individuals with juvenile myoclonic epilepsy (JME) is particularly interesting since they frequently suffer from social and neuropsychological difficulties in addition to epilepsy-specific symptoms. Furthermore, recent brain imaging studies have shown subtle microstructural alterations in individuals with JME. FER is considered a fundamental social skill that relies on a distributed neural network, which could be disturbed by network dysfunction in individuals with JME. This cross-sectional study aimed to examine FER and social adjustment in individuals with JME. It included 27 patients with JME and 27 healthy controls. All subjects underwent an Ekman-60 Faces Task to examine FER and neuropsychological tests to assess social adjustment as well as executive functions, intelligence, depression, and personality traits. Individuals with JME performed worse in global FER and fear and surprise recognition than healthy controls. However, probably due to the small sample size, no significant difference was found between the two groups. A potential FER impairment needs to be confirmed in further studies with larger sample size. If so, patients with JME could benefit from addressing possible deficits in FER and social difficulties when treated. By developing therapeutic strategies to improve FER, patients could be specifically supported with the aim of improving social outcomes and quality of life.

Neural representations of self-perception of voice: An intracortical evoked potential analysis based on an adolescent with right temporal lobe epilepsy

IntroductionThe neural bases for language perception have been studied elsewhere using Transcranial Magnetic Stimulation, functional Magnetic Resonance Imaging and Direct Cortical Stimulation. However, to our knowledge, there is no previous report about a patient identifying the change in his voice tone, speed, and prosody because of right temporal cortical stimulation. Nor has there been a cortico-cortical evoked potential (CCEP) assessment of the network underlying this process. Case reportWe present CCEP from a patient with right focal refractory temporal lobe epilepsy of tumoral etiology who reported changes in the perception of his own speech prosody during stimulation. This report will serve as a complement to the understanding of the neural networks of language and prosody. ConclusionThe present report shows that right superior temporal gyrus, transverse temporal gyrus, right amygdala, hippocampus, and fusiform gyrus (FG) are part of the neural network subjacent to own human voice perception.