OBJECTIVE:The thalamus is a key hub in seizure propagation, and its nuclei are emerging targets for neuromodulation. However, the contributions of individual nuclei to epileptic networks remain unclear, particularly in children, who are less studied than adults. We investigated structural and functional thalamic alterations across different pediatric focal epilepsies and their associations with clinical features and postsurgical outcomes. METHODS:We retrospectively studied children with temporal lobe epilepsy (TLE), frontal lobe epilepsy (FLE), and posterior quadrant epilepsy (PQE) and healthy controls. The thalamus was segmented into four nuclei groups (anterior, lateral, medial, pulvinar) using the THOMAS pipeline on T1-weighted magnetic resonance imaging (MRI) to estimate volumes. Functional connectivity was assessed with functional MRI using node strength, capturing total thalamic connectivity across the brain. We compared patients with controls and evaluated associations with hippocampal sclerosis, history of focal to bilateral tonic-clonic seizures, and postsurgical seizure freedom. RESULTS:Among 136 children with focal epilepsy (81 TLE, 36 FLE, 19 PQE; mean age = 13.0 years) and 70 controls (mean age = 13.4 years), ipsilateral thalamic volume reductions were observed in the following: anterior and lateral nuclei and pulvinar in TLE, anterior and lateral nuclei in FLE, and pulvinar in PQE (Cohen d = .52-.70, all Bonferroni-corrected p < .05). In contrast, medial nuclei volume increase was associated with history of seizure generalization (partial η2 = .06). Functional connectivity was bilaterally reduced across epilepsy groups (partial η2 = .03), most consistently in the pulvinar (Cohen d = .25-.68). Within TLE, hippocampal sclerosis was associated with increased anterior nucleus connectivity (partial η2 = .17), distinguishing it from other pathologies. SIGNIFICANCE:We demonstrate both shared and syndrome-specific thalamic abnormalities in pediatric focal epilepsy. Common patterns included ipsilateral thalamic volume loss, indicating cumulative disease burden, and reduced bilateral functional connectivity, particularly in the pulvinar, likely reflecting thalamocortical decoupling. These findings advance understanding of seizure networks beyond the epileptogenic zone and provide a foundation for personalized thalamic-targeted neuromodulation strategies.

Enhanced heartbeat perception is believed to contribute to the development and maintenance of panic disorder. Studies have demonstrated better Heartbeat Counting Task (HCT) performance in individuals with panic disorder compared to controls. This has been proposed to reflect increased interoceptive accuracy, which is thought to increase the risk of individuals perceiving bodily sensations, which in turn may trigger panic attacks. Drawing on contemporary evidence that HCT performance may reflect heartbeat estimation, rather than perception, we argue that greater HCT performance in panic disorder likely reflects greater heart rate knowledge, and thus existing data do not provide evidence for enhanced perceptual acuity predisposing to panic attacks. We propose that a more parsimonious explanation of these data is that body monitoring drives elevated HCT performance through increased knowledge and predisposes to panic attacks, by narrowing the range of 'acceptable' cardiac sensations, which, when coupled with misinterpretation of these sensations as problematic, may trigger panic attacks. This novel reinterpretation clarifies mixed results in the literature and provides useful future directions for the identification of targeted interventions and future work in this area.

Right and bilateral language representation is common in focal epilepsy, possibly reflecting the influence of epileptogenic lesions and/or seizure activity in the left hemisphere. Atypical language lateralization is assumed to be more likely in cases of early seizure onset, due to greater language plasticity in childhood. However, evidence for this association is mixed, with most research based on small samples and heterogenous cohorts. In this preregistered meta-analysis we examined the association between age at seizure onset and fMRI-derived language lateralization in individuals with focal epilepsy. The pooled effect size demonstrated a correlation between an earlier onset and rightward language lateralization in the total sample (r = 0.1, p = .005, k = 58, n = 1240), with no difference in the correlation between age at seizure onset and language lateralization between left and right hemisphere epilepsy samples (Q=62.03, p = .302). In exploratory analyses of the individual participant data (n = 1157), we demonstrated strong evidence that a logarithmic model fits the data better than a linear (BF=350) or categorical model with 6 years of age as a cut-off (BF=36). These findings indicate that there is a small but significant relationship between age at seizure onset and language lateralization. The relationship was consistent with theories of language plasticity proposing an exponential decline in plasticity over early childhood. However, given that this effect was subtle and only found in larger sample sizes, an early age at seizure onset would not serve as a good indicator of atypical language lateralization on the individual patient level.

OBJECTIVE:To identify predictors of language lateralization derived from functional magnetic resonance imaging (fMRI) in children and adults with left- and right-sided focal epilepsy. METHODS:We conducted a mega-analysis of data from 914 individuals from 24 samples. We used multilevel models to identify predictors of language lateralization in left and right hemisphere epilepsy groups. We assigned each participant a clinical predictor score to explore whether there was a cumulative influence of predictors on increasing atypical language lateralization. RESULTS:Left hemisphere epilepsy was a predictor of greater atypical language lateralization in the combined sample. Additional predictors of atypical language lateralization included left/ambidextrous handedness in both the left and right hemisphere groups, and longer duration of epilepsy, frontal lobe involvement, and history of a stroke or other precipitating injury in the left hemisphere group only. There was a cumulative effect of predictors in the left hemisphere groups. Eighty percent of individuals with four or more predictors had atypical language lateralization, compared to 19% of individuals with no predictors, other than left hemisphere epilepsy. SIGNIFICANCE:Consistent with theories of language plasticity, we demonstrated a robust effect of early acquired left hemisphere injury on language lateralization. There was also a subtle effect of duration of epilepsy, perhaps reflecting increasing bilaterality with age in adulthood. The association between left/ambidextrous handedness and atypical language lateralization in the left and right hemisphere groups likely reflects both genetic and epilepsy-associated effects. The total number of predictors identified for an individual could serve as an indication for presurgical language fMRI, when surgical management is considered.

OBJECTIVE:The thalamus participates in seizure propagation and is a target for neuromodulation in epilepsy. Although thalamic connectivity changes have been reported in adults with temporal lobe epilepsy (TLE), pediatric TLE is distinct, characterized by greater etiological diversity and impact on brain maturation. This study applied a novel gradient mapping technique to investigate whole-brain thalamic connectivity patterns in children with TLE. METHODS:Sixty-two children with TLE (ages 5-18) and 61 controls (ages 6-20) underwent a covert verb generation task functional magnetic resonance imaging (fMRI). Thalamic connectivity gradients were computed to capture primary axes of variation and compared between groups. Associations between thalamic gradients and focal to bilateral tonic-clonic seizure (FBTCS) history, hippocampal sclerosis, and post-surgical seizure outcomes were examined. RESULTS:Two primary thalamic connectivity gradients were identified across both groups. The first (G1) followed an anterior-posterior axis, with anterior thalamic regions connected to prefrontal cortices and basal ganglia, and posterior regions to somatosensory and visual cortices. The second (G2) spanned a superior-inferior axis, with superior thalamus connected to dorsal frontal and parietal cortices, and inferior regions to ventral areas such as the inferior temporal lobe. No differences were found in neocortical connectivity; however, subcortical alterations were observed. Both gradients showed increased thalamic connectivity to the bilateral basal ganglia and mesial temporal regions in TLE compared to controls. Increased anterior thalamic-basal ganglia connectivity along G1 was more pronounced in children with a FBTCS history. Hippocampal sclerosis was associated with reduced bilateral thalamo-hippocampal connectivity along both gradients, and along G2, stronger ipsilateral thalamo-hippocampal connectivity predicted better post-surgical seizure control. SIGNIFICANCE:This study identified two key thalamic connectivity patterns in pediatric TLE, revealing heightened thalamic connectivity to mesial temporal regions and to the basal ganglia. Findings suggest an adaptive inhibitory basal ganglia output on thalamo-cortical seizure transmission and the potential predictive value of thalamo-hippocampal connectivity for surgical outcomes.

Neuropsychological impairments are common in children with drug-resistant epilepsy. It has been proposed that epilepsy surgery might alleviate these impairments by providing seizure freedom; however, findings from prior studies have been inconsistent. We mapped long-term neuropsychological trajectories in children before and after undergoing epilepsy surgery, to measure the impact of disease course and surgery on functioning. We performed a retrospective cohort study of 882 children who had undergone epilepsy surgery at Great Ormond Street Hospital (1990-2018). We extracted patient information and neuropsychological functioning [obtained from IQ tests (domains: full-scale IQ, verbal IQ, performance IQ, working memory and processing speed) and tests of academic attainment (reading, spelling and numeracy)] and investigated changes in functioning using regression analyses. We identified 500 children (248 females) who had undergone epilepsy surgery [median age at surgery = 11.9 years, interquartile range = (7.8, 15.0)] and neuropsychological assessment. These children showed declines in all domains of neuropsychological functioning in the time leading up to surgery (all P-values ≤0.001; e.g. βFSIQ = -1.9, SEFSIQ = 0.3, PFSIQ < 0.001). Children lost on average one to four points per year, depending on the domain considered; 27%-43% declined by ≥10 points from their first to their last preoperative assessment. At the time of presurgical evaluation, most children (46%-60%) scored one or more standard deviations below the mean (<85) on the different neuropsychological domains; 37% of these met the threshold for intellectual disability (full-scale IQ < 70). On a group level, there was no change in performance from pre- to postoperative assessment on any of the domains (all P-values ≥0.128). However, children who became seizure free through surgery showed higher postoperative neuropsychological performance (e.g. rrb-FSIQ = 0.37, P < 0.001). These children continued to demonstrate improvements in neuropsychological functioning over the course of their long-term follow-up (e.g. βFSIQ = 0.9, SEFSIQ = 0.3, PFSIQ = 0.004). Children who had discontinued antiseizure medication treatment at 1-year follow-up showed an 8- to 13-point advantage in postoperative working memory, processing speed and numeracy, and greater improvements in verbal IQ, working memory, reading and spelling (all P-values ≤0.034) over the postoperative period compared with children who were seizure free and still receiving antiseizure medication. In conclusion, by providing seizure freedom and the opportunity for antiseizure medication cessation, epilepsy surgery might not only halt but reverse the downward trajectory that children with drug-resistant epilepsy display in neuropsychological functioning. To halt this decline as soon as possible or, potentially, to prevent it from occurring in the first place, children with focal epilepsy should be considered for epilepsy surgery as early as possible after diagnosis.

Epilepsy is increasingly recognised as a brain network disorder and many studies have investigated functional connectivity (FC) in children with epilepsy using functional MRI (fMRI). This systematic review of fMRI studies, published up to November 2023, investigated profiles of FC changes and their clinical relevance in children with focal epilepsy compared to healthy controls. A literature search in PubMed and Web of Science yielded 62 articles. We categorised the results into three groups: 1) differences in correlation-based FC between patients and controls; 2) differences in other FC measures between patients and controls; and 3) associations between FC and disease variables (for example, age of onset), cognitive and seizure outcomes. Studies revealed either increased or decreased FC across multiple brain regions in children with focal epilepsy. However, findings lacked consistency: conflicting FC alterations (decreased and increased FC) co-existed within or between brain regions across all focal epilepsy groups. The studies demonstrated overall that 1) interhemispheric connections often displayed abnormal connectivity and 2) connectivity within and between canonical functional networks was decreased, particularly for the default mode network. Focal epilepsy disrupted FC in children both locally (e.g., seizure-onset zones, or within-brain subnetworks) and globally (e.g., whole-brain network architecture). The wide variety of FC study methodologies limits clinical application of the results. Future research should employ longitudinal designs to understand the evolution of brain networks during the disease course and explore the potential of FC biomarkers for predicting cognitive and postsurgical seizure outcomes.

Interoceptive accuracy, the ability to correctly perceive internal signals arising from the body, is thought to be disrupted in numerous mental and physical health conditions. Whilst evidence suggests poorer interoceptive accuracy in females compared to males, raising the possibility that interoceptive differences may relate to sex differences in mental and physical health, results concerning sex differences in interoceptive accuracy are mixed. Given such ambiguity, this meta-analysis aimed to establish the presence or absence of sex differences in interoceptive accuracy across cardiac, respiratory, and gastric domains. A review of 7956 abstracts resulted in 93 eligible studies. Results demonstrated superior accuracy in males across cardiac, but not gastric, tasks, while findings on respiratory tasks were mixed. Effect sizes were consistent across cardiac tasks, but instability and/or moderate heterogeneity was observed across other domains, likely due to the small number of eligible studies. Despite such limitations, results indicate the possibility of sex differences across interoception tasks and domains. Methodological limitations concerning the influence of physiological factors, and directions for future research are discussed.

Most theories of emotion describe a crucial role for interoceptive accuracy, the perception of the body's internal physiological signals, in emotional experience. Despite support for interoceptive accuracy's role in emotion, findings of gender differences in emotional and interoceptive processing are incompatible with theory; women typically show poorer interoceptive accuracy, but women often outperform men on measures of emotional processing and recognition. This suggests a need to re-evaluate the relationship between interoceptive accuracy and emotion considering sex and gender. Here we extend Pennebaker and Roberts' (1992) theory of gender differences in the use of interoceptive signals for emotional experience, proposing that language socialisation may result in gender differences in the propensity to label internal state changes as physiological or emotional, respectively. Despite outstanding questions concerning the fractionation of interoceptive and emotional domains, this theory provides a plausible explanation for seemingly incompatible findings of gender differences in interoceptive and emotional abilities.

Autistic traits are over-represented in transgender populations, and gender variance is high in autistic individuals. Furthermore, some evidence suggests that the autism/transgender overlap is limited to individuals sex assigned female. Few studies, however, have investigated the impact of this overlap on mental health. This study therefore sought to investigate whether the autism/transgender overlap confers an increased risk of depression or anxiety. An online study of 727 individuals revealed a substantial overlap between transgender identity and autism, with increased autistic traits found in trans men compared to trans women. Depression and anxiety were highest in autistic-trans individuals, but no superadditive effect was observed. The implications of these findings are discussed in relation to the wider healthcare system.