Brain communications最新文献

{"title":"Systemic increase of AMPA receptors associated with cognitive impairment of long COVID.","authors":"Yu Fujimoto, Hiroki Abe, Tsuyoshi Eiro, Sakiko Tsugawa, Meiro Tanaka, Mai Hatano, Waki Nakajima, Sadamitsu Ichijo, Tetsu Arisawa, Yuuki Takada, Kimito Kimura, Akane Sano, Koichi Hirahata, Nobuyuki Sasaki, Yuichi Kimura, Takuya Takahashi","doi":"10.1093/braincomms/fcaf337","DOIUrl":"10.1093/braincomms/fcaf337","url":null,"abstract":"<p><p>Long COVID primarily presents with persistent cognitive impairment (Cog-LC), imposing a substantial and lasting global burden. Even after the pandemic, there remains a critical global need for diagnostic and therapeutic strategies targeting Cog-LC. Nevertheless, the underlying neural mechanisms remain poorly understood. Given the central role of synapses in brain function, investigation of synaptic molecular changes may provide vital insights into Cog-LC pathophysiology. In this study, we used [¹¹C]K-2 PET to characterize the density of AMPA receptors (AMPARs) on the post-synaptic cell surface, which are crucial synaptic components in brain signalling. Statistical parametrical mapping was used to spatially normalize and apply independent <i>t</i>-test for a voxel-based comparison. We selected patients with Cog-LC (<i>n</i> = 30) based on Repeatable Battery for the Assessment of Neuropsychological Status assessed persistent cognitive impairment and healthy controls (<i>n</i> = 80) with no diagnosed neuropsychiatric disorders. The primary objective was to compare [¹¹C]K-2 standardized uptake value ratio with white matter (SUVR_WM) as a reference region between patients with Cog-LC and healthy controls, and to define the regional extent of differences. The secondary objective was to examine associations between [¹¹C]K-2 SUVR_WM and plasma concentrations of cytokines or chemokines. As an exploratory objective, we tested whether [¹¹C]K-2 PET data could distinguish Cog-LC from healthy controls using a partial least squares based classification algorithm. A voxel-based comparison (<i>P</i> < 0.05, <i>T</i> > 1.66, one-tailed, false discovery rate control) and a volume of interests analysis (<i>P</i> < 0.05, Bonferroni multiple comparison) demonstrated that increased index of AMPAR density in large parts of the brains of patients with Cog-LC compared with that in healthy controls. A voxel-based correlation analysis also showed the brain regions where [¹¹C]K-2 SUVR_WM correlated positively with plasma TNFSF12 and negatively with plasma CCL2 concentrations. A partial least squares model trained on the index of AMPAR density data demonstrated high diagnostic accuracy, achieving 100% sensitivity and 91.2% specificity. [¹¹C]K-2 PET signal represents the index of AMPAR density on the post-synaptic neural cell surface, not on the glial cell surface. A systemic increase in synaptic AMPARs across the brain may drive abnormal information processing in Cog-LC and, through excessive excitatory signalling, pose a risk of excitotoxic neuronal damage. We derived the hypothesis that [¹¹C]K-2 PET would be helpful in establishing a diagnostic framework for Cog-LC and that antagonists for cell surface AMPARs, such as perampanel, would be a potential therapeutic target. These hypotheses should be investigated in future large-scale clinical studies.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 5","pages":"fcaf337"},"PeriodicalIF":4.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12483584/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145208711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fingolimod treatment exacerbates tau phosphorylation and neurodegeneration in a mouse model of tauopathy with accumulated brain CD8⁺ T cells.","authors":"Ryohei Uenishi, Rinna Kawata, Tatsuya Manabe, Toru Takeo, Masanori Hijioka, Takashi Saito","doi":"10.1093/braincomms/fcaf330","DOIUrl":"10.1093/braincomms/fcaf330","url":null,"abstract":"<p><p>It is known that T cells play an important role in the progression of neurodegenerative disorders, including tauopathies. In this study, we used fingolimod (FTY720), an approved medication for the treatment of multiple sclerosis (MS), to manipulate T cell dynamics in P301S-Tau transgenic (Tau Tg) mice. FTY720 dramatically decreased the population of circulating T cells in blood. However, unexpectedly, we observed a marked increase in the number of CD8⁺ T cells in the hippocampus of FTY720-treated Tau Tg mice. This increase in CD8⁺ T cell number was significantly correlated with enhanced tau phosphorylation. Notably, FTY720-treated Tau Tg mice exhibited brain atrophy and neurodegeneration compared with controls. These findings indicate that CD8⁺ T cells in the brain contribute to the progression of tauopathies, and that brain CD8⁺ T cells may be a promising target for the treatment of tauopathies. This study provides new insights into the dynamics of brain T cells in neurodegenerative disorders. In addition, these results raise caution regarding FTY720 treatment in individuals predisposed to tauopathies, as it may promote neurodegeneration despite reducing peripheral T cells.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 5","pages":"fcaf330"},"PeriodicalIF":4.5,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12459988/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145152147","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical and molecular characterization of SLC31A1-related developmental and epileptic encephalopathy: insights from 13 new cases.","authors":"Natalia Juliá-Palacios, Gerard Muñoz-Pujol, Reza Maroofian, Aida M Bertoli-Avella, Marta Gómez-Chiari, Jordi Muchart-López, Abraham J Paredes-Fuentes, Mar O'Callaghan, Irene S Machado-Casas, Ingrid Cristian, Jennifer Morrison, Angels Garcia-Cazorla, Anna Codina, Mohammad Miryounesi, Emir Zonic, Peter Bauer, Huma Cheema, Muhammad Nadeem Anjum, Nouriya Al-Sannaa, Marwa Abd Elmaksoud, Faroug Ababneh, Sahar Alijanpour, Seyed Hassan Tonekaboni, Afshin Fayazi, Maria Urbaniak, Uxía Barba, Janet Hoenicka, Francesc Palau, Henry Houlden, Juan Darío Ortigoza-Escobar, Antonia Ribes, Carlos Santos-Ocaña, Millie Tyler, Patrick Gaffney, Christopher J Carroll, Frederic Tort, Klaas J Wierenga, Bryn D Webb, Rafael Artuch, Heidy Baide-Mairena, Roser Urreizti","doi":"10.1093/braincomms/fcaf348","DOIUrl":"10.1093/braincomms/fcaf348","url":null,"abstract":"<p><p>Copper is indispensable for various metabolic processes, notably mitochondrial respiration. In humans, copper homeostasis hinges on transporters such as copper transporter 1 (CTR1), encoded by the <i>SLC31A1</i> gene. Recently, bi-allelic mutations in <i>SLC31A1</i> have been associated with a new neurodevelopmental disorder. This study presents clinical, genetic, and biochemical findings from 13 new cases across 10 families worldwide. RNA sequencing evaluated gene expression, and Western blotting assessed copper transporter 1 protein levels. Additionally, mitochondrial respiratory capacity was measured via high-resolution respirometry. Affected individuals exhibited a distinct clinical phenotype characterized by early-onset epileptic encephalopathy, severe neurodevelopmental delay and hypotonia, with high mortality. Neuroimaging revealed significant brain atrophy and white matter abnormalities. Genetic analysis identified bi-allelic <i>SLC31A1</i> variants, predominantly p.His120Gln in six cases and p.(Arg102Cys/His) in three cases. Functional studies in patient fibroblasts demonstrated impaired mitochondrial respiration. This study significantly broadens the clinical spectrum of this recently described syndrome, presenting as a severe developmental encephalopathy with high mortality risk, and suggests mitochondrial dysfunction as a potential pathomechanism. These findings contribute to the mounting evidence linking copper transporter 1 dysfunction to neurodegeneration, underscoring the urgency for further therapeutic investigations.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 5","pages":"fcaf348"},"PeriodicalIF":4.5,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12484445/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The bi-phasic behaviour of grey matter networks after the first demyelinating attack.","authors":"Sara Collorone, Giuseppe Pontillo, Michael A Foster, Ferran Prados, Baris Kanber, Marios C Yiannakas, Ailbhe Burke, Lola Ogunbowale, Indran Davagnanam, Claudia A M Gandini Wheeler-Kingshott, Frederik Barkhof, Olga Ciccarelli, Ahmed T Toosy","doi":"10.1093/braincomms/fcaf367","DOIUrl":"10.1093/braincomms/fcaf367","url":null,"abstract":"<p><p>Multiple sclerosis can be considered a network disease. Accumulating evidence recognizes the following importance of grey matter networks: they only require high-resolution anatomical scans for their extraction, they capture changes beyond detectable atrophy and their alteration is associated with disability progression and cognitive impairment. Therefore, it is crucial to understand their behaviours over the initial years of the disease. This observational longitudinal study aimed to investigate changes in grey matter networks after the first demyelinating attack, and how they correlate with brain damage, disability, and conversion to multiple sclerosis over 3-5 years. So far, in multiple sclerosis, network construction has only been based on cortical grey matter, neglecting a possible role for deep grey matter. We applied a radiomics-based network methodology incorporating both deep and cortical grey matter. Patients recruited within 3 months of disease onset and healthy controls attended study visits at 6 months, 1 year, 3 years and 5 years. Study visits included physical and cognitive scales and brain MRI scans. Individual grey matter networks were constructed by computing the correlations between T1w-based radiomic features extracted from any pair of regions of the Brainnetome atlas and characterized with measures of network integration (global efficiency and characteristic path length), segregation (clustering coefficient and modularity), resilience (assortativity) and smallworldness. Additionally, eigenvector centrality was computed for all brain regions as a measure of nodal influence. We enrolled 89 patients (median follow-up 7 months, range 0-75) and 31 healthy controls. Patients showed higher global efficiency, lower shortest characteristic path length and higher smallworldness than controls suggesting a reorganization that prioritize more efficient global communication over local processing. Over time, patients' networks converged towards healthy controls' values by increasing the shortest characteristic path length and decreasing the smallworldness. Assortativity, and the eigenvector centrality in the right ventromedial putamen decreased compared with controls. All the observed changes were driven by non-converters to multiple sclerosis. This study shows that grey matter networks adopt a biphasic behaviour. They respond to the demyelinating event with an increase in nodal integration and then converge to healthy control values. In the process, however, their network resilience is compromised. This suggests that a single demyelinating event has longer-lasting effects on grey matter networks, even in non-converters, and that studying these networks may reveal relevant changes that are not captured by conventional MRI in the early years of the disease.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 5","pages":"fcaf367"},"PeriodicalIF":4.5,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12495409/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145234562","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diagnosis and etiologic classification of optic tract lesions.","authors":"Natalie S Chen, Heather M McDonald, Jonathan Micieli, Edward Margolin","doi":"10.1093/braincomms/fcaf354","DOIUrl":"10.1093/braincomms/fcaf354","url":null,"abstract":"<p><p>Existing literature regarding optic tract syndrome, which arises from lesions affecting the optic tract(s), is limited. The objective of this retrospective cohort study was to elucidate the diverse clinical and imaging manifestations of the optic tract syndrome relative to the causative lesion. The study population comprised of all patients with optic tract syndrome who were seen at two tertiary neuro-ophthalmology practices from 2014 to 2024. Inclusion criteria were (i) signs associated with optic tract syndrome (homonymous hemianopia and/or relative afferent pupillary defect and/or characteristic findings on peripapillary optical coherence tomography or ganglion cell analysis) and (ii) radiographically confirmed optic tract lesion. Patient records were ascertained through medical databases and reviewed. Statistical analysis was performed to identify relationships between clinical/imaging manifestations and lesion type. Fifty-six patients with optic tract syndrome were identified. The mean age was 49.4 ± 16.7 years, and 37 were female patients. Aetiologies included space-occupying lesions (<i>n</i> = 25), demyelination (<i>n</i> = 11), ischaemia/haemorrhage (<i>n</i> = 9), non-specific optic tract atrophy (<i>n</i> = 8), perinatal insult (<i>n</i> = 2) and trauma (<i>n</i> = 1). At presentation, visual field defects were observed in 98% of patients (<i>n</i> = 55). Of these patients, 20% (<i>n</i> = 11) demonstrated complete field loss while 80% (<i>n</i> = 44) demonstrated partial field loss, of which 95% (<i>n</i> = 42) were incongruent and 5% (<i>n</i> = 2) were congruent. Of the 40 patients with homonymous hemianopia, 78% (<i>n</i>  <i>=</i> 31) demonstrated incongruous defects. Of the 54 patients with peripapillary optical coherence tomography findings, 41% (<i>n</i> = 22) had contralateral band atrophy and ipsilateral hourglass atrophy. Of the 51 patients with available data, 29% (<i>n</i> = 15) had contralateral relative afferent pupillary defect. Patients with demyelinating lesions were most likely to present within 2 weeks of symptom onset (<i>P</i> = 0.0180) and least likely to exhibit band/hourglass atrophy (<i>P</i> = 0.0112). In contrast to previous studies that found a significant percentage of optic tract lesions to produce congruent homonymous hemianopia, most patients in this study demonstrated incongruent homonymous hemianopia. As such, optic tract lesions should be considered in patients with incomplete, incongruous and subtle homonymous defects. Peripapillary optical coherence tomography should be examined for the presence of band and hourglass atrophy in these patients but may be less commonly observed, especially in those with a demyelinating aetiology.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 5","pages":"fcaf354"},"PeriodicalIF":4.5,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12477588/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145201491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cycles in seizure duration and their underlying dynamics in the tetanus toxin rat model.","authors":"Parvin Zarei Eskikand, Sepehr Kazemi, Mark J Cook, Anthony N Burkitt, David B Grayden","doi":"10.1093/braincomms/fcaf364","DOIUrl":"10.1093/braincomms/fcaf364","url":null,"abstract":"<p><p>Seizure duration, a characteristic of epilepsy that is understudied in relation to its relationship with rhythmic cycles, provides critical insights into the severity and temporal dynamics of seizures. This study investigates the rhythmic patterns of seizure duration in the tetanus toxin rat model of epilepsy, which is a well-established platform enabling long-term, stable recordings and observation of seizure emergence and remission. Our analysis shows significant cyclical patterns in seizure durations, with periods ranging from 4 to 8 days across rats. The synchronization index and circular-linear correlations revealed phase-locked relationships between seizure durations and cycles, suggesting non-random, predictable temporal dynamics. Further analyses examined the relationship between seizure durations, inter-seizure intervals and dominant EEG power. The relationship between inter-seizure intervals and seizure duration was modest, suggesting little to no temporal dependency. In contrast, seizure duration showed stronger associations with EEG power in dominant frequency bands. The findings highlight that seizure durations exhibit predictable rhythms, which could transform seizure prediction and enable time-based intervention strategies, ultimately improving epilepsy management and patient outcomes. These insights lay the groundwork for personalized, rhythm-aware therapeutic approaches.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 5","pages":"fcaf364"},"PeriodicalIF":4.5,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12492870/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145234505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex differences in pain perception and modulation in the brain: effects of insular cortex stimulation on chronic pain relief.","authors":"Minjee Kwon, Kyeongmin Kim, Young-Ji Eum, Guanghai Nan, Leejeong Kim, Hyeji Park, Un Jeng Kim, Jin-Hun Sohn, Chaejoon Cheong, Jee-Hyun Cho, Myeounghoon Cha, Bae Hwan Lee","doi":"10.1093/braincomms/fcaf362","DOIUrl":"10.1093/braincomms/fcaf362","url":null,"abstract":"<p><p>Sex-specific differences in brain activation related to chronic pain remain poorly understood. In particular, how stimulation of the insular cortex-a key modulator of pain processing-differentially affects neural pathways in males and females is not well characterized. This study aimed to determine whether insular cortex stimulation activates distinct pain modulation circuits in a sex-dependent manner using a rat model of chronic pain. Understanding these differences may help inform more personalized and effective pain treatment. Neuropathic pain was induced in male and female rats to establish a chronic pain model, followed by insular cortex stimulation. Pain sensitivity was assessed using mechanical allodynia tests to evaluate the behavioural responses. Functional brain connectivity was examined using diffusion tensor imaging, and fractional anisotropy values were calculated across key brain regions. Correlation analyses were conducted between behavioural pain scores and fractional anisotropy values to investigate the relationship between the structural connectivity changes and pain modulation. Under sham conditions, males exhibited lower fractional anisotropy values than females. In the pain condition, both sexes showed reduced fractional anisotropy values; however, females displayed a significantly greater decrease in the ventral posterior thalamic nucleus-amygdala pathway than did males. Following insular cortex stimulation, males showed a more pronounced increase in fractional anisotropy values, with significant sex differences observed in the ventral posterior thalamic nucleus-anterior cingulate cortex, ventral posterior thalamic nucleus-insular cortex, ventral posterior thalamic nucleus-nucleus accumbens, ventral posterior thalamic nucleus-primary somatosensory cortex, primary somatosensory cortex-insular cortex and primary somatosensory cortex-prefrontal cortex pathways. These findings underscore the sex-related differences in brain activation and pain modulation pathways in chronic pain. A deeper understanding of these mechanisms may inform the development of more effective sex-tailored interventions for chronic pain and improve clinical outcomes.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 5","pages":"fcaf362"},"PeriodicalIF":4.5,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12492487/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145234417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Brain health operationalized as brain parenchymal fraction impacts stroke severity both in acute phase and 3 months post stroke.","authors":"Roza M Umarova, Laura Gallucci, Arsany Hakim, Marcel Arnold, Christoph Sperber","doi":"10.1093/braincomms/fcaf360","DOIUrl":"10.1093/braincomms/fcaf360","url":null,"abstract":"<p><p>Stroke lesion imaging alone is not sufficient to predict stroke severity and outcome at a clinically meaningful level, and non-lesional factors are to be defined to enable stroke prognosis and individually tailored therapy. While brain health concept is mainly discussed in the context of primary prevention of neurological diseases, quantitative parameters of brain health like brain parenchymal fraction (BPF) might be associated with better maintenance of function and compensation in (acute) brain pathology. We aimed to investigate whether BPF independently mediates neurological impairment and functional outcome after stroke. We retrospectively analysed patients with first-ever middle cerebral artery stroke. We used generalized linear models with gamma distribution and log link to model neurological impairment [NIH Stroke Scale (NIHSS) 24 h and 3 months] and ordinal logistic regression to model functional outcome at 3 months (modified Rankin scale, 0-6) with the independent variables age, sex, BPF and lesion size. We analysed data of 832 patients (mean age: 67.7 ± 15.3 years, female: 43.5%, median NIHSS 24 h: 3 (1-6)]. A higher BPF was associated with lower neurological impairment: 10% higher BPF was associated with a 16% reduction of NIHSS 24 h (mean ratio 0.840, 95% confidence interval [CI] 0.751-0.940) and a 15% reduction of NIHSS 3 months (mean ratio 0.845, 95% CI 0.745-0.957) independent of age, sex and lesion size. Similarly, BPF had an independent protective effect on functional disability 3 months post stroke (10% higher BPF decreased the odds of worse outcome for 1 modified Rankin scale point by odds ratio [OR] 0.593; 95% CI 0.407-0.864). Brain health, operationalized as BPF, is independently associated with lower neurological impairment both 24 h and 3 months post stroke and better functional stroke outcome. BPF might improve the prediction of stroke outcome and explain interindividual variability in lesion-outcome associations: the same lesion load leads to higher neurological impairment in the presence of brain atrophy, whereas the lesion burden might be clinically less apparent in healthier brains. The data might improve personalized treatment prospects and suggest that efforts on brain health improvement might represent both the primary and secondary reduction of burden of stroke.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 5","pages":"fcaf360"},"PeriodicalIF":4.5,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12495403/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145234462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional validation of human SK channels variants causing NEDMAB and Zimmermann-Laband syndrome-3 in <i>C. elegans</i>.","authors":"Sara Sechi, Charlotte Galaup, Maelle Jospin, Thomas Boulin","doi":"10.1093/braincomms/fcaf351","DOIUrl":"10.1093/braincomms/fcaf351","url":null,"abstract":"<p><p>Small conductance Ca²⁺-activated K⁺ channels (SK channels) are widely expressed in the central nervous system, where they play a crucial role in modulating neuronal excitability. Recent studies have identified missense variants in the genes encoding SK2 and SK3 channels as the cause of two rare neurodevelopmental disorders: NEDMAB and ZLS3, respectively. Here, we used <i>Caenorhabditis elegans</i> as an <i>in vivo</i> model to investigate the functional consequences of these patient variants. The <i>C. elegans</i> orthologue KCNL-1 regulates neuronal and muscle excitability in the egg-laying system, a well-characterized model circuit. To visualize KCNL-1 expression and localization, we generated a fluorescent translational reporter at the endogenous <i>kcnl-1</i> locus. We then introduced eight point mutations corresponding to pathogenic variants reported in NEDMAB or ZLS3 patients. Our study confirmed the molecular pathogenicity of the ZLS3-associated mutations, revealing a gain-of-function effect that led to increased <i>in utero</i> egg retention, likely due to electrical silencing of the egg-laying circuitry. NEDMAB mutations exhibited more complex phenotypic effects. Most caused a loss-of-function phenotype, indistinguishable from null mutants, while one displayed a clear gain-of-function effect. Additionally, a subset of NEDMAB variants altered KCNL-1 localization, suggesting an impairment in channel biosynthesis, trafficking or stability. These findings provide new insights into the molecular mechanisms underlying NEDMAB and ZLS3 physiopathology, enhancing our understanding of SK channel dysfunction in human disease. Moreover, they establish <i>C. elegans</i> as a robust and cost-effective <i>in vivo</i> model for rapid functional validation of new SK channel mutations, paving the way for future investigations.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 5","pages":"fcaf351"},"PeriodicalIF":4.5,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12484442/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alterations of the neural substrate in childhood apraxia of speech: new evidence from neuroimaging.","authors":"Paolo Bosco, Irina Podda, Emilio Cipriano, Clara Bombonato, Paola Cipriani, Mariaelisa Bartoli, Rosa Pasquariello, Simona Fiori, Laura Biagi, Anna Chilosi","doi":"10.1093/braincomms/fcaf302","DOIUrl":"10.1093/braincomms/fcaf302","url":null,"abstract":"<p><p>Childhood apraxia of speech is a motor speech disorder characterized by deficits in programming, planning, and movement control, necessary for speech production with severe impact on oral and written language. Currently there are few studies on how speech is functionally rooted in neuroanatomy in children with apraxia of speech. The present cross-sectional study aimed at further identifying the specific neuroanatomical substrate of childhood apraxia of speech and at analysing the relationship between Magnetic Resonance Imaging findings and speech measures in a relatively large group of Italian children with this disorder. The brain structures of 71 children with apraxia of speech were compared to those of 30 age-matched typically developing peers. For each subject, the morphological brain images were segmented according to a specific atlas, and cortical thickness and volume measures were extracted from cortical and subcortical structures, respectively. Moreover, using voxel-based morphometry with a diffeomorphic anatomical registration procedure, grey matter morphometry of the two groups was compared. We also used diffusion weighted imaging (in 67 out of 71 children with apraxia of speech and all typically developing peers) to investigate the white matter integrity in specific speech-language-related tracts, comparing the mean fractional anisotropy along the tracts. Children with apraxia showed significantly greater grey matter volumes and increased cortical thickness than their typically developing peers in several areas involved in speech and language processing. After correction for multiple comparisons, significant increments in cortical thickness and volume survived in the left postcentral gyrus and bilaterally in the thalami. The diffusion study revealed a significant reduction of fractional anisotropy in childhood apraxia of speech with respect to typically developing children in the left frontal aslant tract in both supplementary motor area and pre-supplementary motor components. Speech severity and diadochokinetic rate of children with apraxia of speech correlated significantly with cortical thickness and volume measures extracted from the rostral middle-frontal gyrus, the left precuneus, and the left thalamus. The same speech measures correlated also with the fractional anisotropy values along the frontal aslant tract. Our results revealed grey matter alterations in childhood apraxia of speech, in a widespread circuit of cortical and subcortical areas, and in particular in both thalami and the left postcentral gyrus, crucial regions for sensorimotor control. Moreover, diffusion study results also provided further support to the involvement, in childhood apraxia of speech, of the left frontal aslant tract, a fundamental pathway for speech movement planning and programming.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 5","pages":"fcaf302"},"PeriodicalIF":4.5,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12448706/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145115412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}