Brain communications最新文献

{"title":"Modulating limbic circuits in temporal lobe epilepsy: impacts on seizures, memory, mood and sleep.","authors":"Vaclav Kremen, Vladimir Sladky, Filip Mivalt, Nicholas M Gregg, Benjamin H Brinkmann, Irena Balzekas, Victoria Marks, Michal Kucewicz, Brian Nils Lundstrom, Jie Cui, Erik K St Louis, Paul Croarkin, Eva C Alden, Boney Joseph, Julie Fields, Karla Crockett, Jindrich Adolf, Jordan Bilderbeek, Dora Hermes, Steven Messina, Kai Joshua Miller, Jamie Van Gompel, Timothy Denison, Gregory A Worrell","doi":"10.1093/braincomms/fcaf106","DOIUrl":"10.1093/braincomms/fcaf106","url":null,"abstract":"<p><p>Temporal lobe epilepsy is a common neurological disease characterized by recurrent seizures that often originate within limbic networks involving amygdala and hippocampus. The limbic network is involved in crucial physiologic functions involving memory, emotion and sleep. Temporal lobe epilepsy is frequently drug-resistant, and people often experience comorbidities related to memory, mood and sleep. Deep brain stimulation targeting the anterior nucleus of the thalamus (ANT-DBS) is an established therapy for temporal lobe epilepsy. However, the optimal stimulation parameters and their impact on memory, mood and sleep comorbidities remain unclear. We used an investigational brain sensing-stimulation implanted device to accurately track seizures, interictal epileptiform spikes (IES), and memory, mood and sleep comorbidities in five ambulatory subjects. Wireless streaming of limbic network local field potentials (LFPs) and subject behaviour were captured on a mobile device integrated with a cloud environment. Automated algorithms applied to the continuous LFPs were used to accurately cataloged seizures, IES and sleep-wake brain state. Memory and mood assessments were remotely administered to densely sample cognitive and behavioural response during ANT-DBS in ambulatory subjects living in their natural home environment. We evaluated the effect of continuous low-frequency and duty cycle high-frequency ANT-DBS on epileptiform activity and memory, mood and sleep comorbidities. Both low-frequency and high-frequency ANT-DBS paradigms reduced seizures. However, continuous low-frequency ANT-DBS showed greater reductions in IES, electrographic seizures and better sleep and memory outcomes. These results highlight the potential of synchronized brain sensing and dense behavioural tracking during ANT-DBS for optimizing neuromodulation therapy. While studies with larger patient numbers are needed to validate the benefits of low-frequency ANT-DBS, these findings are potentially translatable to individuals currently implanted with ANT-DBS systems.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 2","pages":"fcaf106"},"PeriodicalIF":4.1,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11972686/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143804795","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":"Beyond the cerebellum: perivascular space burden in spinocerebellar ataxia type 3 extends to multiple brain regions.","authors":"Yonghua Huang, Zhiming Zhen, Lihua Deng, Peiling Ou, Linfeng Shi, Feng Shi, Rui Hua, Jiaojiao Wu, Wei Chen, Ru Wen, Jian Wang, Chen Liu","doi":"10.1093/braincomms/fcaf118","DOIUrl":"10.1093/braincomms/fcaf118","url":null,"abstract":"<p><p>Spinocerebellar ataxia type 3 (SCA3) is an uncommon inherited (autosomal dominant) neurodegenerative disorder caused by abnormal accumulation of ataxin-3 protein. The perivascular space (PVS) burden reflects protein clearance and may worsen in SCA3 disease. This study aimed to quantify the PVS burden and investigate the relationship between the PVS burden and clinical characteristics in individuals with SCA3. This study enrolled 43 SCA3 patients and 43 age- and sex-matched healthy controls (HCs). The cross-sectional study assessed the severity of ataxia in SCA3 patients using the Scale for the Assessment and Rating of Ataxia (SARA) and the International Cooperative Ataxia Rating Scale (ICARS). Various cognitive functions were evaluated in all subjects using the Montreal Cognitive Assessment (MoCA), Rapid Verbal Retrieval (RAR) and Digital Span Test (DST) scales. MRI was used to automatically segment the PVS in all subjects and quantify the PVS burden in 15 brain regions. Compared with the HCs, the SCA3 patients showed a significantly higher PVS burden in the basal ganglia, temporal lobe, right parietal lobe and right cerebellum. There was a positive correlation in motor dysfunction between the PVS volume in the left parietal lobe, right cerebellum and PVS number in the right cerebellum with the SARA and ICARS scores. This study showed that SCA3 patients have an increased PVS burden in many brain regions, leading to motor impairment. The PVS burden could be a new imaging biomarker for disease monitoring and a therapeutic target for SCA3.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 2","pages":"fcaf118"},"PeriodicalIF":4.1,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11969673/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143797189","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":"Association of blood-based glial fibrillary acidic protein level with depression and suicidal ideation following traumatic brain injury with Glasgow Coma Scale score 13 to 15: a TRACK-TBI study.","authors":"Shawn R Eagle, Raquel C Gardner, Sonia Jain, Xiaoying Sun, Ava Puccio, David Brent, Lindsay D Nelson, Michael A McCrea, Joseph T Giacino, David O Okonkwo, John K Yue, Geoffrey T Manley, Murray B Stein","doi":"10.1093/braincomms/fcaf123","DOIUrl":"10.1093/braincomms/fcaf123","url":null,"abstract":"<p><p>Blood-based glial fibrillary acidic protein (GFAP) level within 24 h of traumatic brain injury (TBI) has been inversely associated with post-traumatic stress disorder at 6 months in the Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study. We sought to assess the relationship between day-of-injury GFAP and cumulative prevalence (CI) of depression or suicidal ideation in the first year after injury among patients presenting with Glasgow Coma Scale 13-15 who participated in Transforming Research and Clinical Knowledge in Traumatic Brain Injury (<i>n</i> = 1511). Multivariable logistic regression models were used to assess the association of day-of-injury GFAP levels with year 1 CI of depression or suicidal ideation adjusting for age, sex, prior TBI, psychiatric history and acute intracranial trauma on head computed tomography (CT) scan. Subgroup analyses categorized into 'high' and 'low' risk for mental health problems based upon a history of psychiatric disorder or TBI. Overall, 20.4% reported depression and 11.3% reported suicidal ideation in the first year. Participants with depression had significantly lower GFAP compared with participants without depression overall (median = 149.9 pg/mL versus 306.9 pg/mL, <i>P</i> < 0.001) and CT-negative high risk and CT-negative low risk subgroups. Participants with suicidal ideation had lower GFAP in the overall sample (155.8 pg/mL versus 299.1 pg/mL, <i>P</i> = 0.001). We found an interaction between GFAP and CT status, reflecting an inverse association of GFAP with cumulative depression among CT- subjects (adjusted odds ratio = 0.84, 95% CI: 0.77-0.92), but not among CT+ subjects. Blood biomarkers may warrant future investigation as potential predictors of depression following TBI in patients without evidence of acute intracranial trauma on CT scan.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 2","pages":"fcaf123"},"PeriodicalIF":4.1,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11968334/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143797271","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":"Distinct neural correlates of morphosyntactic and thematic comprehension processes in aphasia.","authors":"Sabrina Beber, Rita Capasso, Chiara Maffei, Marco Tettamanti, Gabriele Miceli","doi":"10.1093/braincomms/fcaf093","DOIUrl":"10.1093/braincomms/fcaf093","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Functional neuroimaging studies in neurotypical subjects correlate sentence comprehension to a left fronto-temporo-parietal network. Recent voxel-based lesion-symptom mapping (VLSM) studies of aphasia confirm the link between sentence comprehension and a left posterior region including the angular gyrus, the supra-marginal gyrus and the postero-superior division of the temporal lobe but support left pre-frontal involvement inconsistently. However, these studies focus on thematic role assignment without considering morphosyntactic processes. Hence, available VLSM evidence could provide a partial view of the neurofunctional substrate of sentence comprehension. In the present VLSM study, both morphosyntactic and thematic processes were evaluated systematically and in the same sentence types in each participant, to provide a more detailed picture of the sentence comprehension network. Participants (33 patients with post-stroke aphasia and 90 healthy controls) completed a sentence-picture matching task in which active and passive, declarative reversible sentences were paired with morphosyntactic, thematic and lexical-semantic alternatives. Phonological short-term memory tasks were also administered. Aphasic participants were selected from an initial pool of 70 because they scored below norm on thematic foils (&lt;i&gt;n&lt;/i&gt; = 18) or on thematic and morphological foils (&lt;i&gt;n&lt;/i&gt; = 15), but within the norm on lexical-semantic foils. The neurofunctional correlates of morphosyntactic and thematic processes were starkly distinguishable. Pre-frontal areas including the inferior and middle frontal gyrus were involved directly in processing local morphosyntactic features and only indirectly in thematic processes. When these areas were damaged, morphosyntactic errors always co-occurred with thematic errors, probably because morphosyntactic damage disrupts the assignment of grammatical roles and ultimately that of thematic roles. Morphosyntactic errors were not influenced by word order canonicity. In contrast, selective thematic role reversals were linked to temporal and parietal damage and were significantly influenced by word order, occurring on passive more than on active sentences. An area including the angular and supra-marginal gyrus was critical for processing non-canonical word order. In sentence comprehension, pre-frontal regions are critical for processing local morphosyntactic features (at least in simple declarative sentences). Temporal and parietal regions are critical for thematic processes. Postero-superior temporal areas are involved in retrieving verb argument structure. Parietal areas are critical for assigning morphosyntactically analysed constituents to the appropriate thematic role, thus serving a crucial function in thematic re-analysis. Each area plays a prevailing but not exclusive role in these processes, interacting with other areas in the network and possibly providing both the language-specific and the domain-general resources needed","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 2","pages":"fcaf093"},"PeriodicalIF":4.1,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11930358/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143701411","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":"Enduring differential patterns of neuronal loss and myelination along 6-month pulsatile gonadotropin-releasing hormone therapy in individuals with Down syndrome.","authors":"Michela Adamo, Mihaly Gayer, An Jacobs, Quentin Raynaud, Raphael Sebbah, Giulia di Domenicantonio, Adeliya Latypova, Nathalie Vionnet, Ferath Kherif, Antoine Lutti, Nelly Pitteloud, Bogdan Draganski","doi":"10.1093/braincomms/fcaf117","DOIUrl":"10.1093/braincomms/fcaf117","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Despite major progress in understanding the impact of the triplicated chromosome 21 on the brain and behaviour in Down syndrome, our knowledge of the underlying neurobiology in humans is still limited. We sought to address some of the pertinent questions about the drivers of brain structure differences and their associations with cognitive function in Down syndrome. To this aim, in a pilot magnetic resonance imaging (MRI) study, we monitored brain anatomy in individuals with Down syndrome receiving pulsatile gonadotropin-releasing hormone (GnRH) therapy over 6 months in comparison with typically developed age- and sex-matched healthy controls. We analysed cross-sectional (Down syndrome/healthy controls &lt;i&gt;n&lt;/i&gt;  &lt;i&gt;=&lt;/i&gt; 11/27; Down syndrome-2 females/9 males, age 26.7 ± 5.0 years old; healthy controls-8 females/19 males, age 24.1 ± 2.5 years old) and longitudinal (Down syndrome/healthy controls &lt;i&gt;n&lt;/i&gt;  &lt;i&gt;=&lt;/i&gt; 8&lt;i&gt;/&lt;/i&gt;13; Down syndrome-1 female/7 males, age 26.4 ± 5.3 years old; healthy controls-4 females/9 males, 24.7 ± 2.2 years old) relaxometry and diffusion-weighted MRI data alongside standard cognitive assessment. The statistical tests looked for cross-sectional baseline differences and for differential changes over time between Down syndrome and healthy controls. The &lt;i&gt;post hoc&lt;/i&gt; analysis confined to the Down syndrome group, tested for potential time-dependent interactions between individuals' overall cognitive performance and associated brain anatomy changes. The brain MRI statistical analyses covered both grey and white matter regions across the whole brain allowing for investigation of regional volume, macromolecular/myelin and iron content, additionally to diffusion tensor and neurite orientation and dispersion density characterization across major white matter tracts. The cross-sectional analysis showed reduced frontal, temporal and cerebellar volumes in Down syndrome with only the cerebellar differences remaining significant after adjustment for the presence of microcephaly (&lt;i&gt;P&lt;/i&gt; &lt;sub&gt;family-wise-corrected&lt;/sub&gt; &lt; 0.05). The volume reductions were paralleled by decreased cortical and subcortical macromolecular/myelin content confined to the cortical motor system, thalamus and basal ganglia (&lt;i&gt;P&lt;/i&gt; &lt;sub&gt;family-wise-corrected&lt;/sub&gt; &lt; 0.05). All major white matter tracts showed a ubiquitous mean diffusivity and intracellular volume fraction reduction contrasted with no differences in magnetization transfer saturation metrics (&lt;i&gt;P&lt;/i&gt; &lt;sub&gt;family-wise-corrected&lt;/sub&gt; &lt; 0.05). Compared with healthy controls over the same period, Down syndrome individuals under GnRH therapy showed cognitive improvement (Montreal Cognitive Assessment from 11.4 ± 5.5 to 15.1 ± 5.6; &lt;i&gt;P&lt;/i&gt; &lt; 0.01) on the background of stability of the observed differential neuroanatomical patterns. Despite the lack of adequate Down syndrome control group, we interpret the obtained cross-sectional and longitudinal findings in young adults as evidence for ","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 2","pages":"fcaf117"},"PeriodicalIF":4.1,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11969670/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143797191","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":"Transcranial ultrasound stimulation ameliorates dextran sulphate sodium-induced colitis and behavioural disorders by suppressing the inflammatory response in the brain.","authors":"Yu-Chen Lin, Yi-Ju Pan, Shu-Ming Chang, Feng-Yi Yang","doi":"10.1093/braincomms/fcaf119","DOIUrl":"10.1093/braincomms/fcaf119","url":null,"abstract":"<p><p>Inflammatory bowel disease (IBD) is associated with neuroinflammation, which may contribute to an increased risk of neurodegenerative disorders. This research investigated the potential of transcranial low-intensity pulsed ultrasound (LIPUS) to mitigate colonic inflammation induced by dextran sulphate sodium (DSS), focusing on its effects via the brain-gut axis. Colitis and neuroinflammation were induced in mice by administering 3% (wt/vol) DSS for 7 days. Subsequently, the brain was subjected to LIPUS stimulation at intensities of 0.5 or 1.0 W/cm² for 3 days. Biological samples were analyzed using real-time polymerase chain reaction, western blot, enzyme-linked immunosorbent assay, and histological observation. Behavioural dysfunctions were assessed using the open field test, novel object recognition task, and Y-maze test. The alteration in gut microbiota composition was assessed through 16S rRNA sequencing. LIPUS therapy notably alleviated colitis symptoms and suppressed inflammation in both the colon and hippocampus of DSS-exposed mice. Compared with the group treated only with DSS, the LIPUS treatment showed decreased crypt destruction and partial epithelial barrier preservation. Moreover, LIPUS preserved intestinal barrier function by upregulating the levels of occludin and zonula occludens, decreasing the levels of lipopolysaccharide (LPS) and LPS-binding protein in serum, and ameliorating behavioural disorders. Further analysis indicated that LIPUS did not significantly transform the composition of the intestinal microbiota, but the microbial community showed some differences from the community in the DSS-only treatment group. This study demonstrates that transcranial LIPUS stimulation could be a novel therapeutic strategy for IBD and neuroinflammation via regulation of inflammatory interactions across brain-gut axis.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 2","pages":"fcaf119"},"PeriodicalIF":4.1,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957916/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143766110","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":"K_v1.1 channels in cardiorespiratory regulation and sudden unexpected death in epilepsy: insights from mouse models.","authors":"Amanda Hu, Khaing Phyu Aung, Christopher A Reid, Ming S Soh","doi":"10.1093/braincomms/fcaf116","DOIUrl":"10.1093/braincomms/fcaf116","url":null,"abstract":"<p><p>This scientific commentary refers to 'Seizures and premature death in mice with targeted Kv1.1 deficiency in corticolimbic circuits', by Paulhus and Glasscock (https://doi.org/10.1093/braincomms/fcae444).</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 2","pages":"fcaf116"},"PeriodicalIF":4.1,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11969661/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143797194","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":"Intracranial pressure and pulsatility in different head and body positions.","authors":"Matthew J Bancroft, Eleanor M Moncur, Amy L Peters, Linda D'Antona, Lewis Thorne, Laurence D Watkins, Brian L Day, Ahmed K Toma","doi":"10.1093/braincomms/fcaf115","DOIUrl":"10.1093/braincomms/fcaf115","url":null,"abstract":"<p><p>Intracranial pressure (ICP) is typically measured with the head in a neutral position whilst the body is in an upright or supine posture. The effect of body position on ICP is well studied, with ICP greater when supine than when upright. In daily life the head is frequently moved away from the neutral position but how this impacts ICP dynamics is unclear. Knowledge of ICP dynamics in different head-on-body positions may improve future treatments that restore normal ICP dynamics such as CSF drainage shunts. We recruited 57 relatively well, ambulatory patients undergoing clinical ICP monitoring for investigation of possible CSF dynamics disturbances to a single-centre, cross-sectional study. Forty-one patients were non-shunted, seven had a working shunt and nine had a malfunctioning shunt. We measured ICP and ICP pulsatility (pulse amplitude) over 10 or 20 s in different combinations of head and body positions. Positions included right and left head turn and forward tilt in upright (seated, standing) and supine body positions, and right and left lateral tilt and backward tilt in upright body positions. ICP increased by 3-9 mmHg, on average, when the head moved away from neutral to each head position in upright and supine body positions, except for head forward tilt when supine, where ICP did not change. The increase in ICP with head turn and forward tilt in upright body positions was larger in patients with a malfunctioning shunt than with no shunt or a functioning shunt. Pulsatility also increased by 0.5-2 mmHg on average when the head moved away from neutral to each head position in upright and supine body positions, except for head forward tilt in upright body positions where pulsatility slightly decreased by 0.7 mmHg on average. ICP and pulsatility generally increase when the head is moved away from the neutral position, but this depends on a combination of head and body position and shunt status. We propose our results can be explained by a combination of changes to neck vasculature and head orientation relative to gravity. Our findings provide potential reason for patient reports that ICP-related symptoms can be induced and/or exacerbated by head movement and could explain behaviours that avoid excess head movement, such as turning the body rather than the head when looking to the side. Our data describe the predicted change in ICP in different head and body positions and could underpin future smart shunt design.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 2","pages":"fcaf115"},"PeriodicalIF":4.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11954551/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143756427","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":"Unveiling amyotrophic lateral sclerosis complexity: insights from proteomics, metabolomics and microbiomics.","authors":"Simone Scarcella, Lorenzo Brambilla, Lorenzo Quetti, Mafalda Rizzuti, Valentina Melzi, Noemi Galli, Luca Sali, Gianluca Costamagna, Giacomo Pietro Comi, Stefania Corti, Delia Gagliardi","doi":"10.1093/braincomms/fcaf114","DOIUrl":"10.1093/braincomms/fcaf114","url":null,"abstract":"<p><p>Amyotrophic lateral sclerosis is the most common motor neuron disease and manifests as a clinically and genetically heterogeneous neurodegenerative disorder mainly affecting the motor systems. To date, despite promising results and accumulating knowledge on the pathomechanisms of amyotrophic lateral sclerosis, a specific disease-modifying treatment is still not available. <i>In vitro</i> and <i>in vivo</i> disease models coupled with multiomics techniques have helped elucidate the pathomechanisms underlying this disease. In particular, omics approaches are powerful tools for identifying new potential disease biomarkers that may be particularly useful for diagnosis, prognosis and assessment of treatment response. In turn, these findings could support physicians in stratifying patients into clinically relevant subgroups for the identification of the best therapeutic targets. Here, we provide a comprehensive review of the most relevant literature highlighting the importance of proteomics approaches in determining the role of pathogenic misfolded/aggregated proteins and the molecular mechanisms involved in the pathogenesis and progression of amyotrophic lateral sclerosis. In addition, we explored new findings arising from metabolomic and lipidomic studies, which can aid to elucidate the intricate metabolic alterations underlying amyotrophic lateral sclerosis pathology. Moreover, we integrated these insights with microbiomics data, providing a thorough understanding of the interplay between metabolic dysregulation and microbial dynamics in disease progression. Indeed, a greater integration of these multiomics data could lead to a deeper understanding of disease mechanisms, supporting the development of specific therapies for amyotrophic lateral sclerosis.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 2","pages":"fcaf114"},"PeriodicalIF":4.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11952287/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143756460","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":"Analysis of DNA from brain tissue on stereo-EEG electrodes reveals mosaic epilepsy-related variants.","authors":"Alissa M D'Gama, Harold Westley Phillips, Yilan Wang, Michelle Y Chiu, Yasmine Chahine, Amanda C Swanson, Richard S Smith, Phillip L Pearl, Melissa Tsuboyama, Joseph R Madsen, Hart Lidov, Eunjung Alice Lee, Sanjay P Prabhu, August Yue Huang, Scellig S D Stone, Christopher A Walsh, Annapurna Poduri","doi":"10.1093/braincomms/fcaf113","DOIUrl":"10.1093/braincomms/fcaf113","url":null,"abstract":"<p><p>Somatic mosaic variants contribute to focal epilepsy, with variants often present only in brain tissue and not in blood or other samples typically assayed for genetic testing. Thus, genetic analysis for mosaic variants in focal epilepsy has been limited to patients with drug-resistant epilepsy who undergo surgical resection and have resected brain tissue samples available. Stereo-EEG (sEEG) has become part of the evaluation for many patients with focal drug-resistant epilepsy, and sEEG electrodes provide a potential source of small amounts of brain-derived DNA. We aimed to identify, validate, and assess the distribution of deleterious mosaic variants in epilepsy-associated genes in DNA extracted from trace brain tissue on individual sEEG electrodes. We enrolled a prospective cohort of 10 paediatric patients with drug-resistant epilepsy who had sEEG electrodes implanted for invasive monitoring. We extracted unamplified DNA and in parallel performed whole-genome amplification from trace brain tissue on each sEEG electrode. We also extracted DNA from resected brain tissue and blood/saliva samples where available. We performed deep sequencing (panel and exome) and analysis for candidate germline and mosaic variants. We validated candidate mosaic variants and assessed the variant allele fraction in amplified and unamplified electrode-derived DNA and across electrodes. We extracted unamplified DNA and performed whole-genome amplification from >150 individual electrodes from 10 individuals. Immunohistochemistry confirmed the presence of neurons in the brain tissue on electrodes. Deep sequencing and analysis demonstrated similar depth of coverage between amplified and unamplified DNA samples but significantly more potential mosaic variants in amplified samples. We validated four deleterious mosaic variants in epilepsy-associated genes in electrode-derived DNA in three patients who underwent laser ablation and did not have resected brain tissue samples available. Three of the four variants were detected in both amplified and unamplified electrode-derived DNA, with higher variant allele fraction observed in DNA from electrodes in closest proximity to the electrical seizure focus in one case. We demonstrate that mosaic variants can be identified and validated from DNA extracted from trace brain tissue on individual sEEG electrodes in patients with drug-resistant focal epilepsy, from both unamplified and amplified electrode-derived DNA. Our findings support a relationship between the extent of regional genetic abnormality and electrophysiology and suggest that with further optimization, this minimally invasive diagnostic approach holds promise for advancing precision medicine for patients with drug-resistant epilepsy as part of the surgical evaluation.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 2","pages":"fcaf113"},"PeriodicalIF":4.1,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11961356/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143775179","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}