Estelle Raffin,Michele Bevilacqua,Fabienne Windel,Pauline Menoud,Roberto F Salamanca-Giron,Sarah Feroldi,Sarah B Zandvliet,Nicola Ramdass,Laurijn Draaisma,Patrik Vuilleumier,Adrian G Guggisberg,Christophe Bonvin,Lisa Fleury,Krystel R Huxlin,Elena Beanato,Friedhelm C Hummel
Visual field loss is a common consequence of stroke and manifests in approximatively one-third of patients in the chronic stage. Such loss can significantly impact daily life activities, compromising tasks such as reading, navigating or driving. Although slow and labour intensive, evidence suggests that early interventions with tailored rehabilitation programmes might stimulate visual recovery and improve quality of life in stroke survivors. To enhance the effects of such rehabilitation programmes, we designed a novel, non-invasive, pathway-specific, physiology-inspired cross-frequency brain stimulation protocol, where complex oscillatory signal integration was inferred from phase-amplitude coupling of oscillatory signals between the primary visual cortex and the motion-sensitive medio-temporal area. Sixteen stroke patients were enrolled in a double-blind, randomized, cross-over trial, during which they performed two blocks of 10 daily training sessions of a direction discrimination task, combined with one of the two cross-frequency transcranial alternative brain stimulation (cf-tACS versus control cf-tACS) conditions. We found that the cf-tACS condition promoting feedforward visual inputs to the medio-temporal area significantly enhanced motion discrimination performance and shifted visual field borders (i.e. through localized enlargement of isopters). Behavioural improvements associated with a change in oscillatory activity within motion processing pathways were proportional to the amount of residual structural fibres along these pathways and perilesional primary visual cortex activity. In sum, we report, for the first time, that cf-tACS, a novel, pathway-specific, physiology-inspired brain stimulation approach, is able to boost the efficacy of perceptual training, restoring visual motion processing and reducing the severity of visual impairments in adult stroke patients.
{"title":"Boosting hemianopia recovery: the power of interareal cross-frequency brain stimulation.","authors":"Estelle Raffin,Michele Bevilacqua,Fabienne Windel,Pauline Menoud,Roberto F Salamanca-Giron,Sarah Feroldi,Sarah B Zandvliet,Nicola Ramdass,Laurijn Draaisma,Patrik Vuilleumier,Adrian G Guggisberg,Christophe Bonvin,Lisa Fleury,Krystel R Huxlin,Elena Beanato,Friedhelm C Hummel","doi":"10.1093/brain/awaf252","DOIUrl":"https://doi.org/10.1093/brain/awaf252","url":null,"abstract":"Visual field loss is a common consequence of stroke and manifests in approximatively one-third of patients in the chronic stage. Such loss can significantly impact daily life activities, compromising tasks such as reading, navigating or driving. Although slow and labour intensive, evidence suggests that early interventions with tailored rehabilitation programmes might stimulate visual recovery and improve quality of life in stroke survivors. To enhance the effects of such rehabilitation programmes, we designed a novel, non-invasive, pathway-specific, physiology-inspired cross-frequency brain stimulation protocol, where complex oscillatory signal integration was inferred from phase-amplitude coupling of oscillatory signals between the primary visual cortex and the motion-sensitive medio-temporal area. Sixteen stroke patients were enrolled in a double-blind, randomized, cross-over trial, during which they performed two blocks of 10 daily training sessions of a direction discrimination task, combined with one of the two cross-frequency transcranial alternative brain stimulation (cf-tACS versus control cf-tACS) conditions. We found that the cf-tACS condition promoting feedforward visual inputs to the medio-temporal area significantly enhanced motion discrimination performance and shifted visual field borders (i.e. through localized enlargement of isopters). Behavioural improvements associated with a change in oscillatory activity within motion processing pathways were proportional to the amount of residual structural fibres along these pathways and perilesional primary visual cortex activity. In sum, we report, for the first time, that cf-tACS, a novel, pathway-specific, physiology-inspired brain stimulation approach, is able to boost the efficacy of perceptual training, restoring visual motion processing and reducing the severity of visual impairments in adult stroke patients.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"146 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145531271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Matthew D Zammit,Hailey Bruzzone,Karly A Cody,Jacob Morse,Rachael Wilson,Brecca T Bettcher,Max J McLachlan,Andrew K McVea,Alexandra H DiFilippo,Finnuella J Carey,Shorena Janelidze,Oskar Hansson,Julie C Price,Charles M Laymon,Davneet S Minhas,Weiquan Luo,H Diana Rosas,Florence Lai,Joseph H Lee,Patrick J Lao,Beau M Ances,Sharon J Krinsky-McHale,Christy L Hom,Sigan L Hartley,Shahid H Zaman,Sterling C Johnson,Ann D Cohen,Elizabeth Head,Mark E Mapstone,Benjamin L Handen,Bradley T Christian,Dana L Tudorascu,Rebecca E Langhough,Tobey J Betthauser,
Characterizing the timing and progression of Alzheimer's disease biomarker onset in Down syndrome (DS) and contrasting potential timing differences with neurotypical adults is needed to identify optimal Alzheimer's disease therapeutic treatment windows in DS. In this study, 198 adults with DS from the Alzheimer Biomarker Consortium - Down Syndrome and 172 neurotypical adults from the Wisconsin Registry for Alzheimer's Prevention with available longitudinal beta-amyloid PET, tau PET and plasma p-tau217 analyzed on Lilly MSD were included. Individuals with DS had a significantly higher lifetime risk of beta-amyloid plaque onset. Temporal modeling of longitudinal biomarker measures revealed earlier age at positivity of beta-amyloid plaques, p-tau217 and neurofibrillary tau tangles in DS relative to the neurotypical cohort. The onset of p-tau217 and tau PET positivity in DS occurred nearly simultaneously, roughly 4-6 years following beta-amyloid onset, whereas the neurotypical group displayed greater temporal latency between positivity of the two biomarkers. The early and simultaneous onset of these biomarkers in DS highlights the necessity for early therapeutic interventions in this population. This work, combined with the upcoming anti-amyloid safety and efficacy clinical trials for DS will help identify optimal treatment windows for these individuals.
{"title":"The tau biomarker cascade is condensed in Down syndrome compared to sporadic Alzheimer's disease.","authors":"Matthew D Zammit,Hailey Bruzzone,Karly A Cody,Jacob Morse,Rachael Wilson,Brecca T Bettcher,Max J McLachlan,Andrew K McVea,Alexandra H DiFilippo,Finnuella J Carey,Shorena Janelidze,Oskar Hansson,Julie C Price,Charles M Laymon,Davneet S Minhas,Weiquan Luo,H Diana Rosas,Florence Lai,Joseph H Lee,Patrick J Lao,Beau M Ances,Sharon J Krinsky-McHale,Christy L Hom,Sigan L Hartley,Shahid H Zaman,Sterling C Johnson,Ann D Cohen,Elizabeth Head,Mark E Mapstone,Benjamin L Handen,Bradley T Christian,Dana L Tudorascu,Rebecca E Langhough,Tobey J Betthauser, ","doi":"10.1093/brain/awaf428","DOIUrl":"https://doi.org/10.1093/brain/awaf428","url":null,"abstract":"Characterizing the timing and progression of Alzheimer's disease biomarker onset in Down syndrome (DS) and contrasting potential timing differences with neurotypical adults is needed to identify optimal Alzheimer's disease therapeutic treatment windows in DS. In this study, 198 adults with DS from the Alzheimer Biomarker Consortium - Down Syndrome and 172 neurotypical adults from the Wisconsin Registry for Alzheimer's Prevention with available longitudinal beta-amyloid PET, tau PET and plasma p-tau217 analyzed on Lilly MSD were included. Individuals with DS had a significantly higher lifetime risk of beta-amyloid plaque onset. Temporal modeling of longitudinal biomarker measures revealed earlier age at positivity of beta-amyloid plaques, p-tau217 and neurofibrillary tau tangles in DS relative to the neurotypical cohort. The onset of p-tau217 and tau PET positivity in DS occurred nearly simultaneously, roughly 4-6 years following beta-amyloid onset, whereas the neurotypical group displayed greater temporal latency between positivity of the two biomarkers. The early and simultaneous onset of these biomarkers in DS highlights the necessity for early therapeutic interventions in this population. This work, combined with the upcoming anti-amyloid safety and efficacy clinical trials for DS will help identify optimal treatment windows for these individuals.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"108 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145525183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
This scientific commentary refers to ‘Collapse of interictal suppressive networks permits seizure spread’ by Makhoul et al. (https://doi.org/10.1093/brain/awaf215).
Mitchell B Moyer, Svetlana Ivanova, Kaspar Keledijan, Matthew Kreinbrink, Jenna Langbein, Penghua Yang, Darrian McAfee, Ujwal Boddeti, Ziam Khan, Jemima Owotade, Timothy Zhang, David R Benavides, Joshua Diamond, Kareem Zaghloul, Muznabanu Bachani, Volodymyr Gerzanich, J Marc Simard, Alexander Ksendzovsky
One third of epilepsy patients do not achieve sufficient seizure freedom with current standard anti-seizure medications. Better understanding of the pathological mechanisms contributing to epileptogenesis is thus necessary to improve current therapies. SUR1-TRPM4 is a depolarizing ion channel minimally expressed in healthy brain that is upregulated de novo in neurons and glia after epileptogenic CNS injuries such as traumatic brain injury and stroke. However, its role in epilepsy is not well understood. Here, we demonstrate using immunofluorescent microscopy that SUR1-TRPM4 expression is elevated in neurons within electrographically sorted human epileptic brain compared to non-epileptic brain obtained after resection from six drug-resistant temporal lobe epilepsy patients. Additionally, we utilized immunofluorescence and co-immunoprecipitation to observe that SUR1-TRPM4 is upregulated within the hippocampus and temporal cortex in mice after PTZ kindling, a chronic model of rodent epilepsy. Pharmacologic inhibition of SUR1-TRPM4 using either the FDA-approved drug glyburide or 9-phenanthrol, as well as either constitutive or neuron-specific knock-out of this channel, attenuated chronic seizure development in this model. Exogenous overexpression of SUR1-TRPM4 by plasmid transfection in neurons in vitro increased neuronal hyperexcitability in response to low Mg2+ stimulation, while pharmacologic inhibition of endogenous TRPM4 attenuated neuronal population hyperexcitation. Collectively, our results reveal that elevated SUR1-TRPM4 expression found in human and rodent epileptic neurons promotes chronic seizures by increasing neuronal excitation. These findings directly support clinical investigation of SUR1-TRPM4 inhibitors as potential anti-seizure therapies in epilepsy patients and suggest further investigations into the contribution of SUR1-TRPM4 to seizures induced by specific epileptogenic insults, such as TBI, are warranted.
{"title":"SUR1-TRPM4 is expressed in human epilepsy and promotes neuron hyperactivity and seizures in rodents","authors":"Mitchell B Moyer, Svetlana Ivanova, Kaspar Keledijan, Matthew Kreinbrink, Jenna Langbein, Penghua Yang, Darrian McAfee, Ujwal Boddeti, Ziam Khan, Jemima Owotade, Timothy Zhang, David R Benavides, Joshua Diamond, Kareem Zaghloul, Muznabanu Bachani, Volodymyr Gerzanich, J Marc Simard, Alexander Ksendzovsky","doi":"10.1093/brain/awaf435","DOIUrl":"https://doi.org/10.1093/brain/awaf435","url":null,"abstract":"One third of epilepsy patients do not achieve sufficient seizure freedom with current standard anti-seizure medications. Better understanding of the pathological mechanisms contributing to epileptogenesis is thus necessary to improve current therapies. SUR1-TRPM4 is a depolarizing ion channel minimally expressed in healthy brain that is upregulated de novo in neurons and glia after epileptogenic CNS injuries such as traumatic brain injury and stroke. However, its role in epilepsy is not well understood. Here, we demonstrate using immunofluorescent microscopy that SUR1-TRPM4 expression is elevated in neurons within electrographically sorted human epileptic brain compared to non-epileptic brain obtained after resection from six drug-resistant temporal lobe epilepsy patients. Additionally, we utilized immunofluorescence and co-immunoprecipitation to observe that SUR1-TRPM4 is upregulated within the hippocampus and temporal cortex in mice after PTZ kindling, a chronic model of rodent epilepsy. Pharmacologic inhibition of SUR1-TRPM4 using either the FDA-approved drug glyburide or 9-phenanthrol, as well as either constitutive or neuron-specific knock-out of this channel, attenuated chronic seizure development in this model. Exogenous overexpression of SUR1-TRPM4 by plasmid transfection in neurons in vitro increased neuronal hyperexcitability in response to low Mg2+ stimulation, while pharmacologic inhibition of endogenous TRPM4 attenuated neuronal population hyperexcitation. Collectively, our results reveal that elevated SUR1-TRPM4 expression found in human and rodent epileptic neurons promotes chronic seizures by increasing neuronal excitation. These findings directly support clinical investigation of SUR1-TRPM4 inhibitors as potential anti-seizure therapies in epilepsy patients and suggest further investigations into the contribution of SUR1-TRPM4 to seizures induced by specific epileptogenic insults, such as TBI, are warranted.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"11 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145515551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
In multiple sclerosis (MS) patients under therapy, the increase of serum glial fibrillary acidic protein (sGFAP) concentrations is associated with the course of 'progression in absence of relapse' (PIRA). While serum neurofilament light chain (sNfL) reflects both response as well as insufficient or lack of efficiency of disease modifying therapies (DMT), the longitudinal course of sGFAP levels as drug response marker for future PIRA in relation to specific types of DMT is less clear. We aimed to compare the predictive capacity of sGFAP and sNfL for PIRA and relapse activity and the longitudinal course in persons with MS (PwMS) treated with fingolimod, based on Z scores derived from normative values. 420 PwMS under fingolimod treatment with follow-up of 9.1 years (IQR: 7.0-11.0) from the Swiss MS Cohort, contributing 2935 longitudinal serum samples, were included. A reference data set for sGFAP established from 4297 healthy controls across three European and North American cohorts was used to calculate Z scores. The longitudinal course and the predictive capacity of biomarkers for time to PIRA and relapse were assessed by Cox proportional hazards and linear mixed-effects models. In controls, sGFAP concentrations were 13.6% higher in females than males and increased exponentially with age. 31.0% of PwMS experienced ≥1 PIRA event. Elevated sGFAP Z scores (>0.75) were associated with increased risk of PIRA (HR: 1.64; 95% CI: [1.16-2.32]; p=0.006), while this was not the case for sNfL. Conversely, elevated sNfL predicted relapses (HR: 1.58 [1.13-2.23]; p=0.008), while sGFAP did not. Both biomarkers decreased under treatment: sGFAP by 0.19 Z score units (ZSU)/10 years (95% CI: -0.27 - -0.11; p<0.001) and sNfL by 0.16 ZSU/10 years (95% CI: -0.27 - -0.06; p=0.002). sGFAP remained elevated in PwMS with future PIRA events (estimate: 0.29; [0.07-0.50]; p=0.009); no such association was found for sNfL. sGFAP and sNfL Z scores provide complementary predictive capacity for PIRA and relapse risk. The decrease of sGFAP under fingolimod is a feature not observed with other types of DMT and may hint to a specific anti-neurodegenerative effect of Sphingosine-1-phosphate-receptor modulators on astrocytes.
{"title":"GFAP and NfL as predictors of disease progression and relapse activity in fingolimod-treated multiple sclerosis.","authors":"Aleksandra Maleska Maceski,Pascal Benkert,Maximilian Einsiedler,Sabine Schaedelin,Johanna Oechtering,Lester Melie-Garcia,Alessandro Cagol,Riccardo Galbusera,Edoardo Galli,Jannis Mueller,Sebastian Finkener,Patrice H Lalive,Marjolaine Uginet,Stefanie Müller,Caroline Pot,Amandine Mathias,Renaud Du Pasquier,Robert Hoepner,Andrew Chan,Giulio Disanto,Chiara Zecca,Marcus D'Souza,Lars G Hemkens,Özgür Yaldizli,Tobias Derfuss,Patrick Roth,Claudio Gobbi,David Brassat,Björn Tackenberg,Rosetta Pedotti,Catarina Raposo,Jorge Oksenberg,Ari J Green,Heinz Wiendl,Klaus Berger,Marco Hermesdorf,Fredrik Piehl,David Conen,Ludwig Kappos,Michael Khalil,Cristina Granziera,Ahmed Abdelhak,David Leppert,Eline A J Willemse,Jens Kuhle, ","doi":"10.1093/brain/awaf433","DOIUrl":"https://doi.org/10.1093/brain/awaf433","url":null,"abstract":"In multiple sclerosis (MS) patients under therapy, the increase of serum glial fibrillary acidic protein (sGFAP) concentrations is associated with the course of 'progression in absence of relapse' (PIRA). While serum neurofilament light chain (sNfL) reflects both response as well as insufficient or lack of efficiency of disease modifying therapies (DMT), the longitudinal course of sGFAP levels as drug response marker for future PIRA in relation to specific types of DMT is less clear. We aimed to compare the predictive capacity of sGFAP and sNfL for PIRA and relapse activity and the longitudinal course in persons with MS (PwMS) treated with fingolimod, based on Z scores derived from normative values. 420 PwMS under fingolimod treatment with follow-up of 9.1 years (IQR: 7.0-11.0) from the Swiss MS Cohort, contributing 2935 longitudinal serum samples, were included. A reference data set for sGFAP established from 4297 healthy controls across three European and North American cohorts was used to calculate Z scores. The longitudinal course and the predictive capacity of biomarkers for time to PIRA and relapse were assessed by Cox proportional hazards and linear mixed-effects models. In controls, sGFAP concentrations were 13.6% higher in females than males and increased exponentially with age. 31.0% of PwMS experienced ≥1 PIRA event. Elevated sGFAP Z scores (>0.75) were associated with increased risk of PIRA (HR: 1.64; 95% CI: [1.16-2.32]; p=0.006), while this was not the case for sNfL. Conversely, elevated sNfL predicted relapses (HR: 1.58 [1.13-2.23]; p=0.008), while sGFAP did not. Both biomarkers decreased under treatment: sGFAP by 0.19 Z score units (ZSU)/10 years (95% CI: -0.27 - -0.11; p<0.001) and sNfL by 0.16 ZSU/10 years (95% CI: -0.27 - -0.06; p=0.002). sGFAP remained elevated in PwMS with future PIRA events (estimate: 0.29; [0.07-0.50]; p=0.009); no such association was found for sNfL. sGFAP and sNfL Z scores provide complementary predictive capacity for PIRA and relapse risk. The decrease of sGFAP under fingolimod is a feature not observed with other types of DMT and may hint to a specific anti-neurodegenerative effect of Sphingosine-1-phosphate-receptor modulators on astrocytes.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"101 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145516225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zachary T Watson, Silvana Valdebenito-Silva, Michael Spurgat, Wenjuan Ru, Junying Zheng, Mark K Maurelli, Yuejin Liang, Subo Yuan, Eliseo Eugenin, Shao-Jun Tang
Synapse loss is a common neuropathology in the central nervous system (CNS) of HIV patients, likely contributing to neurological complications such as neurocognitive disorders and pain. However, the underlying mechanism remains poorly understood. Here, we show microglia- and astrocyte-mediated synaptic pruning of excitatory and inhibitory synapses in the frontal cortex (FC) and the spinal dorsal horn (SDH) of HIV-1 gp120 transgenic (gp120Tg) mice. Confocal imaging and 3D reconstruction revealed significant increase of internalized synaptic elements in microglia and astroglia in gp120Tg mice, in a region- and synapse-type-specific manner. Microglia in the FC of gp120Tg mice showed increased pruning activity on the pre-synaptic but not post-synaptic compartment of both excitatory and inhibitory synapses. In contrast, microglia in the SDH of gp120Tg mice had increased pruning activity of both pre-and post-synaptic compartments excitatory and inhibitory compartments in the SDH. However, astrocytes in the gp120 transgenic model increased their pruning activity of both the pre-and post-synaptic compartments of excitatory but not inhibitory synapses in the FC and the SDH. We confirmed synaptic engulfment in viral reservoirs in the brain tissues of human HIV patients. These findings provide important insights into the pathogenic mechanism of synapse loss induced by HIV.
{"title":"Differential selectivity of microglia and astrocytes in HIV-1 gp120-induced synaptic pruning","authors":"Zachary T Watson, Silvana Valdebenito-Silva, Michael Spurgat, Wenjuan Ru, Junying Zheng, Mark K Maurelli, Yuejin Liang, Subo Yuan, Eliseo Eugenin, Shao-Jun Tang","doi":"10.1093/brain/awaf429","DOIUrl":"https://doi.org/10.1093/brain/awaf429","url":null,"abstract":"Synapse loss is a common neuropathology in the central nervous system (CNS) of HIV patients, likely contributing to neurological complications such as neurocognitive disorders and pain. However, the underlying mechanism remains poorly understood. Here, we show microglia- and astrocyte-mediated synaptic pruning of excitatory and inhibitory synapses in the frontal cortex (FC) and the spinal dorsal horn (SDH) of HIV-1 gp120 transgenic (gp120Tg) mice. Confocal imaging and 3D reconstruction revealed significant increase of internalized synaptic elements in microglia and astroglia in gp120Tg mice, in a region- and synapse-type-specific manner. Microglia in the FC of gp120Tg mice showed increased pruning activity on the pre-synaptic but not post-synaptic compartment of both excitatory and inhibitory synapses. In contrast, microglia in the SDH of gp120Tg mice had increased pruning activity of both pre-and post-synaptic compartments excitatory and inhibitory compartments in the SDH. However, astrocytes in the gp120 transgenic model increased their pruning activity of both the pre-and post-synaptic compartments of excitatory but not inhibitory synapses in the FC and the SDH. We confirmed synaptic engulfment in viral reservoirs in the brain tissues of human HIV patients. These findings provide important insights into the pathogenic mechanism of synapse loss induced by HIV.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"39 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145509429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Valerie M Wiemer, Theresa Paul, Lukas Hensel, Matthew Cieslak, Caroline Tscherpel, Christian Grefkes, Scott T Grafton, Gereon R Fink, Lukas J Volz
Structural cortico-cortical connectivity is essential for motor recovery after stroke, with undamaged fibre tracts potentially serving as structural reserve for functional reorganization. Yet, the mechanisms by which the structural reserve contributes to changes in functional network configurations to improve post-stroke motor control remains unknown. Here, we assessed structural (diffusion spectrum imaging) and effective (fMRI-based Dynamic Causal Modelling) connectivity to examine how the structural reserve may guide motor network reorganization of upper limb motor control. Specific features of cortico-cortical structural reserve were associated with distinct patterns of functional network configurations: limited intrahemispheric structural reserve between ipsilesional primary motor cortex and premotor areas was linked to interhemispheric rerouting of motor commands via the contralesional primary motor cortex, particularly when ipsilesional corticospinal tract integrity was low. In contrast, limited interhemispheric structural reserve between ipsilesional primary motor cortex and contralesional premotor areas was related to intrahemispheric rerouting via the ipsilesional premotor cortex, especially in patients with high residual corticospinal tract integrity. Even though both alternative pathways may allow bypassing damaged corticospinal tract fibres originating from the ipsilesional primary motor cortex, we observed a clear behavioural dissociation: in patients who substantially recovered, enhanced intrahemispheric rerouting was indicative of better hand function, reflecting beneficial reorganization. Conversely, interhemispheric rerouting was associated with pronounced motor impairment of the paretic arm and primarily observed in non-substantially recovered patients, in line with task-specific maladaptive reorganization. Our findings emphasize that the motor network’s available structural reserve critically shapes functional network reorganization by predetermining whether motor commands are primarily rerouted intra- or interhemispherically with distinct implications for motor recovery. Besides helping to reconcile previous conflicting interpretations on the role of contralesional primary motor cortex, our results underscore that the individual level of structural motor network reserve should be considered for future therapeutic approaches aiming at amplifying motor recovery after stroke.
{"title":"Structural reserve-dependent cortical rerouting of motor control after stroke","authors":"Valerie M Wiemer, Theresa Paul, Lukas Hensel, Matthew Cieslak, Caroline Tscherpel, Christian Grefkes, Scott T Grafton, Gereon R Fink, Lukas J Volz","doi":"10.1093/brain/awaf434","DOIUrl":"https://doi.org/10.1093/brain/awaf434","url":null,"abstract":"Structural cortico-cortical connectivity is essential for motor recovery after stroke, with undamaged fibre tracts potentially serving as structural reserve for functional reorganization. Yet, the mechanisms by which the structural reserve contributes to changes in functional network configurations to improve post-stroke motor control remains unknown. Here, we assessed structural (diffusion spectrum imaging) and effective (fMRI-based Dynamic Causal Modelling) connectivity to examine how the structural reserve may guide motor network reorganization of upper limb motor control. Specific features of cortico-cortical structural reserve were associated with distinct patterns of functional network configurations: limited intrahemispheric structural reserve between ipsilesional primary motor cortex and premotor areas was linked to interhemispheric rerouting of motor commands via the contralesional primary motor cortex, particularly when ipsilesional corticospinal tract integrity was low. In contrast, limited interhemispheric structural reserve between ipsilesional primary motor cortex and contralesional premotor areas was related to intrahemispheric rerouting via the ipsilesional premotor cortex, especially in patients with high residual corticospinal tract integrity. Even though both alternative pathways may allow bypassing damaged corticospinal tract fibres originating from the ipsilesional primary motor cortex, we observed a clear behavioural dissociation: in patients who substantially recovered, enhanced intrahemispheric rerouting was indicative of better hand function, reflecting beneficial reorganization. Conversely, interhemispheric rerouting was associated with pronounced motor impairment of the paretic arm and primarily observed in non-substantially recovered patients, in line with task-specific maladaptive reorganization. Our findings emphasize that the motor network’s available structural reserve critically shapes functional network reorganization by predetermining whether motor commands are primarily rerouted intra- or interhemispherically with distinct implications for motor recovery. Besides helping to reconcile previous conflicting interpretations on the role of contralesional primary motor cortex, our results underscore that the individual level of structural motor network reserve should be considered for future therapeutic approaches aiming at amplifying motor recovery after stroke.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"54 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145509483","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Identifying novel neuromodulatory targets for deep brain stimulation (DBS) in psychiatric disorders is an urgent clinical need. Equally critical is the discovery of simple oscillatory biomarkers that bridge behaviour and clinical symptoms, enabling personalized treatment strategies. The bed nucleus of the stria terminalis (BNST), a pivotal output structure of the amygdala, is a potential candidate for DBS due to its key role in regulating fear, emotional valence, and prosocial behaviour. However, owing to the small size, its neural dynamics and functional contributions are poorly understood, precluding behavioural-clinical relevance. In a cross-sectional design, we acquired BNST neural recordings from 23 patients with depression undergoing DBS during two tasks: pain perception with painful/non-painful scenarios and an affect task with emotionally valenced images. We first localized the electrode contacts in the BNST and using their neural recordings for further analysis. We subjected the preprocessed data to time frequency decompositions to find condition differences. The significant clusters were then used to link to the behavioural ratings and clinical symptom severity. Furthermore, cross-frequency interactions were also undertaken. Pain perception elicited late theta and alpha activity (∼1s), with theta activity linked to subjective pain ratings and alpha correlating with anxiety/depression scores and anxiety symptoms post-DBS. Negative imagery induced early theta (∼250 ms), resembling previously reported amygdalar responses, and which link to valence ratings, depression and anxiety symptom severity. These results reveal distinct BNST dynamics in depression: early theta for rapid threat processing and late theta/alpha for complex socio-cognitive responses. Task-dependent theta and alpha activity linked behavioural profiles and symptom severity, highlighting BNST's role in behaviourally and clinically relevant oscillatory patterns, contributing novel insights for advancing precision neuromodulation strategies.
{"title":"Behavioural and clinical biomarkers of the human bed nucleus of stria terminalis from direct neural recordings","authors":"Saurabh Sonkusare, Yingying Zhang, Qiong Ding, Yashu Feng, Yijie Zhao, Linbin Wang, Violeta Casero, Kuanghao Ye, Yijie Lai, Xin Lv, Peng Huang, Xian Qiu, Luling Dai, Xiaoxiao Zhang, Yuhan Wang, Kejia Hu, Yixin Pan, Dianyou Li, Wei Liu, Shikun Zhan, Bomin Sun, Valerie Voon","doi":"10.1093/brain/awaf431","DOIUrl":"https://doi.org/10.1093/brain/awaf431","url":null,"abstract":"Identifying novel neuromodulatory targets for deep brain stimulation (DBS) in psychiatric disorders is an urgent clinical need. Equally critical is the discovery of simple oscillatory biomarkers that bridge behaviour and clinical symptoms, enabling personalized treatment strategies. The bed nucleus of the stria terminalis (BNST), a pivotal output structure of the amygdala, is a potential candidate for DBS due to its key role in regulating fear, emotional valence, and prosocial behaviour. However, owing to the small size, its neural dynamics and functional contributions are poorly understood, precluding behavioural-clinical relevance. In a cross-sectional design, we acquired BNST neural recordings from 23 patients with depression undergoing DBS during two tasks: pain perception with painful/non-painful scenarios and an affect task with emotionally valenced images. We first localized the electrode contacts in the BNST and using their neural recordings for further analysis. We subjected the preprocessed data to time frequency decompositions to find condition differences. The significant clusters were then used to link to the behavioural ratings and clinical symptom severity. Furthermore, cross-frequency interactions were also undertaken. Pain perception elicited late theta and alpha activity (∼1s), with theta activity linked to subjective pain ratings and alpha correlating with anxiety/depression scores and anxiety symptoms post-DBS. Negative imagery induced early theta (∼250 ms), resembling previously reported amygdalar responses, and which link to valence ratings, depression and anxiety symptom severity. These results reveal distinct BNST dynamics in depression: early theta for rapid threat processing and late theta/alpha for complex socio-cognitive responses. Task-dependent theta and alpha activity linked behavioural profiles and symptom severity, highlighting BNST's role in behaviourally and clinically relevant oscillatory patterns, contributing novel insights for advancing precision neuromodulation strategies.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"233 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145509484","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kajus Merkevicius, Dmitrii Smirnov, Lea D Schlieben, Rebecca Ganetzky, René G Feichtinger, Huafang Jiang, Fang Fang, Tomohiro Ebihara, Kei Murayama, Giulia Ferrera, Anna Ardissone, Dariusz Rokicki, Dorota Wesol-Kucharska, Sabine Schröder, Peter Bauer, Aida Bertoli-Avella, Elsebeth Østergaard, Peter Freisinger, Mirian C H Janssen, Matias Wagner, Omar Abouyousef, Bader Alhaddad, Lama AlAbdi, Fowzan Alkuraya, Charlotte L Alston, Anna Baghdasaryan, Diana Barca, Ivo Barić, Marcello Bellusci, Andrea Bevot, Eugen Boltshauser, Ingo Borggraefe, Juliette Bouchereau, Claudio Bruno, Birute Burnyte, Amy Calhoun, Kari Casas, Mahmut Coker, Ellen Crushell, Pascal De Lonlay, Carlo Dionisi-Vici, Felix Distelmaier, Marni J Falk, Ana Cristina Ferreira, Carlos R Ferreira, Can Ficicioglu, Gulden Fatma Gokçay, Johannes Häberle, Oliver Heath, Albrecht Hellenschmidt, Julia Hoefele, Georg F Hoffmann, Tomas Honzik, Martina Huemer, Patrícia Janeiro, Amel Karaa, Çiğdem Seher Kasapkara, Ilse Kern, Joerg Klepper, Thomas Klopstock, Ina Knerr, Johannes Koch, Zita Krumina, Costanza Lamperti, Elise Lebigot, Zhimei Liu, Esther M Maier, Diego Martinelli, Robert McFarland, Bryce Mendelsohn, Maria Judits Molnar, Helen Mundy, Marie-Cecile Nassogne, Anabela Oliveira, Katrin Õunap, Chiara Panicucci, Sumit Parikh, Heidi Peters, Samia Pichard, Barbara Plecko, Danijela P Ramadža, Gabriela M Repetto, Isabel Rivera, Richard J Rodenburg, Alessandro Rossi, Manuel Schiff, Kathrin Seidemann, Wendy E Smith, Sérgia Soares, Barbara Siri, Katja Steinbrucker, Pasquale Striano, Jolanta Sykut-Cegielska, Galit Tal, Robert W Taylor, Kostas Tsiakas, Sema Kalkan Ucar, Eva Hoytema van Konijnenburg, Mathias Woidy, Joy Yaplito-Lee, Yilmaz Yildiz, Martin Zenker, Petra Zsidegh, Dominik Westphal, Wolfgang Sperl, Thomas Meitinger, Garry K Brown, Holger Prokisch, Johannes A Mayr, Saskia B Wortmann
This retrospective study on X-linked PDHA1-related pyruvate dehydrogenase complex (PDHc) deficiency combined a systematic literature review with a multicenter survey exploring genotypes, phenotypes, and survival. Data from 891 individuals (45% unpublished) were included. Of note, 53% of cases were females. Median age at last assessment was six years (range 0-80 years, n = 622). We detected 331 different (118 unpublished) PDHA1 variants of which 75% (305/405) had occurred de novo. Variants in this study were uploaded to ClinVar (SCV006297015 – SCV006297345). The 10 most frequent variants accounted for 36% of the diagnoses. Sixty-nine percent of the variants were private; missense (50%) and frameshift (20%) variants were most common. Frameshift/nonsense (FS/N) variants in males (44/401, 11%) were confined to regions escaping nonsense-mediated decay (NMD) and were significantly less frequent than in females (151/461, 33%). Neonatal or infantile (405/529, 77%) presentations were most frequent, with pre/perinatal abnormalities reported in 47% (159/342). FS/N variants in NMD-predicted region 3.9 (95% Confidence Interval (CI) 1.54-11.04) times increased the odds of fetal findings. Females presented significantly earlier (2 months, interquartile range (IQR) 7.0, n = 224) than males (8 months, IQR 16.6, n = 233), with increased risk of neonatal presentation (odds ratio (OR) 3.01 (95% CI 1.279-7.616) when harboring FS/N variants in NMD-predicted region. The overall (n = 242) mean survival time was 10.9 (95% CI 9.9-11.9) years. On average, females survived 4.5 (95% CI 2.62-6.40) years longer than males despite presenting more severe phenotypes. Poor survival was associated with male sex (hazard ratio (HR) 3.3 (95% CI 1.95-5.62)), neonatal presentation (HR 5.5 (95% CI 2.17-14.09)), FS/N variants in NMD-predicted region (HR 4.0 (95% CI 1.78, 9.16)), and splice variants (HR 2.3 (95% CI 1.15, 4.59)). More severe clinical phenotypes were predicted by neonatal or infantile presentations and by female sex. Developmental delay (DD), intellectual disability (ID), muscle hypotonia, abnormal movements, seizures, feeding difficulties, and microcephaly were the most frequent phenotypes, all occurring in more than half. Corpus callosum or basal ganglia alterations and cerebral atrophy were common. Four percent (36/891) were reported to have mild phenotypes with no DD nor ID (25/36 males). This is the largest dataset on a nuclear-encoded defect of mitochondrial energy metabolism. The genotypic and phenotypic details further defines disease landscape and can be used for variant interpretation. The correlations between genotypes, sex, phenotypes and survival, adds a substantial improvement to counselling.
这项关于x连锁pdha1相关的丙酮酸脱氢酶复合物（PDHc）缺乏症的回顾性研究结合了系统文献综述和多中心调查，探讨了基因型、表型和生存率。数据来自891人（45%未发表）。值得注意的是，53%的病例是女性。最后一次评估的中位年龄为6岁（范围0-80岁，n = 622）。我们检测到331种不同的（118种未发表的）PDHA1变异，其中75%（305/405）是从头发生的。本研究中的变异被上传到ClinVar （SCV006297015 - SCV006297345）。10种最常见的变异占诊断的36%。69%的变异是私人的；错义变异（50%）和移码变异（20%）最为常见。移码/无义（FS/N）变异在男性中（44/401,11%）局限于逃避无义介导的衰变（NMD）的区域，显著低于女性（151/461,33%）。新生儿或婴儿（405/ 529,77%）的表现最为常见，47%（159/342）报告了产前/围产期异常。nmd预测区的FS/N变异增加了3.9倍（95%可信区间（CI） 1.54-11.04）的胎儿发现几率。女性（2个月，四分位数间距（IQR） 7.0, n = 224）明显早于男性（8个月，IQR 16.6, n = 233），当在nmd预测区域携带FS/ n变异时，新生儿出现的风险增加(优势比（OR） 3.01 （95% CI 1.279-7.616）。总体（n = 242）平均生存时间为10.9年（95% CI 9.9-11.9）。尽管表现出更严重的表型，但女性平均存活时间比男性长4.5年（95% CI 2.62-6.40）。生存率差与男性（风险比3.3 (95% CI 1.95-5.62)）、新生儿表现（风险比5.5 (95% CI 2.17-14.09)）、nmd预测区域FS/N变异（风险比4.0 (95% CI 1.78, 9.16)）和剪接变异（风险比2.3 (95% CI 1.15, 4.59)）相关。更严重的临床表型由新生儿或婴儿表现和女性预测。发育迟缓（DD）、智力残疾（ID）、肌肉张力减退、异常运动、癫痫、进食困难和小头畸形是最常见的表型，所有这些都发生在一半以上。胼胝体或基底神经节改变和脑萎缩是常见的。4%（36/891）有轻度表型，无DD或ID（25/36男性）。这是关于线粒体能量代谢核编码缺陷的最大数据集。基因型和表型细节进一步定义了疾病景观，并可用于变异解释。基因型、性别、表现型和存活率之间的相关性大大改善了咨询服务。
{"title":"The genotypic and phenotypic landscape of PDHA1 -related pyruvate dehydrogenase complex deficiency","authors":"Kajus Merkevicius, Dmitrii Smirnov, Lea D Schlieben, Rebecca Ganetzky, René G Feichtinger, Huafang Jiang, Fang Fang, Tomohiro Ebihara, Kei Murayama, Giulia Ferrera, Anna Ardissone, Dariusz Rokicki, Dorota Wesol-Kucharska, Sabine Schröder, Peter Bauer, Aida Bertoli-Avella, Elsebeth Østergaard, Peter Freisinger, Mirian C H Janssen, Matias Wagner, Omar Abouyousef, Bader Alhaddad, Lama AlAbdi, Fowzan Alkuraya, Charlotte L Alston, Anna Baghdasaryan, Diana Barca, Ivo Barić, Marcello Bellusci, Andrea Bevot, Eugen Boltshauser, Ingo Borggraefe, Juliette Bouchereau, Claudio Bruno, Birute Burnyte, Amy Calhoun, Kari Casas, Mahmut Coker, Ellen Crushell, Pascal De Lonlay, Carlo Dionisi-Vici, Felix Distelmaier, Marni J Falk, Ana Cristina Ferreira, Carlos R Ferreira, Can Ficicioglu, Gulden Fatma Gokçay, Johannes Häberle, Oliver Heath, Albrecht Hellenschmidt, Julia Hoefele, Georg F Hoffmann, Tomas Honzik, Martina Huemer, Patrícia Janeiro, Amel Karaa, Çiğdem Seher Kasapkara, Ilse Kern, Joerg Klepper, Thomas Klopstock, Ina Knerr, Johannes Koch, Zita Krumina, Costanza Lamperti, Elise Lebigot, Zhimei Liu, Esther M Maier, Diego Martinelli, Robert McFarland, Bryce Mendelsohn, Maria Judits Molnar, Helen Mundy, Marie-Cecile Nassogne, Anabela Oliveira, Katrin Õunap, Chiara Panicucci, Sumit Parikh, Heidi Peters, Samia Pichard, Barbara Plecko, Danijela P Ramadža, Gabriela M Repetto, Isabel Rivera, Richard J Rodenburg, Alessandro Rossi, Manuel Schiff, Kathrin Seidemann, Wendy E Smith, Sérgia Soares, Barbara Siri, Katja Steinbrucker, Pasquale Striano, Jolanta Sykut-Cegielska, Galit Tal, Robert W Taylor, Kostas Tsiakas, Sema Kalkan Ucar, Eva Hoytema van Konijnenburg, Mathias Woidy, Joy Yaplito-Lee, Yilmaz Yildiz, Martin Zenker, Petra Zsidegh, Dominik Westphal, Wolfgang Sperl, Thomas Meitinger, Garry K Brown, Holger Prokisch, Johannes A Mayr, Saskia B Wortmann","doi":"10.1093/brain/awaf430","DOIUrl":"https://doi.org/10.1093/brain/awaf430","url":null,"abstract":"This retrospective study on X-linked PDHA1-related pyruvate dehydrogenase complex (PDHc) deficiency combined a systematic literature review with a multicenter survey exploring genotypes, phenotypes, and survival. Data from 891 individuals (45% unpublished) were included. Of note, 53% of cases were females. Median age at last assessment was six years (range 0-80 years, n = 622). We detected 331 different (118 unpublished) PDHA1 variants of which 75% (305/405) had occurred de novo. Variants in this study were uploaded to ClinVar (SCV006297015 – SCV006297345). The 10 most frequent variants accounted for 36% of the diagnoses. Sixty-nine percent of the variants were private; missense (50%) and frameshift (20%) variants were most common. Frameshift/nonsense (FS/N) variants in males (44/401, 11%) were confined to regions escaping nonsense-mediated decay (NMD) and were significantly less frequent than in females (151/461, 33%). Neonatal or infantile (405/529, 77%) presentations were most frequent, with pre/perinatal abnormalities reported in 47% (159/342). FS/N variants in NMD-predicted region 3.9 (95% Confidence Interval (CI) 1.54-11.04) times increased the odds of fetal findings. Females presented significantly earlier (2 months, interquartile range (IQR) 7.0, n = 224) than males (8 months, IQR 16.6, n = 233), with increased risk of neonatal presentation (odds ratio (OR) 3.01 (95% CI 1.279-7.616) when harboring FS/N variants in NMD-predicted region. The overall (n = 242) mean survival time was 10.9 (95% CI 9.9-11.9) years. On average, females survived 4.5 (95% CI 2.62-6.40) years longer than males despite presenting more severe phenotypes. Poor survival was associated with male sex (hazard ratio (HR) 3.3 (95% CI 1.95-5.62)), neonatal presentation (HR 5.5 (95% CI 2.17-14.09)), FS/N variants in NMD-predicted region (HR 4.0 (95% CI 1.78, 9.16)), and splice variants (HR 2.3 (95% CI 1.15, 4.59)). More severe clinical phenotypes were predicted by neonatal or infantile presentations and by female sex. Developmental delay (DD), intellectual disability (ID), muscle hypotonia, abnormal movements, seizures, feeding difficulties, and microcephaly were the most frequent phenotypes, all occurring in more than half. Corpus callosum or basal ganglia alterations and cerebral atrophy were common. Four percent (36/891) were reported to have mild phenotypes with no DD nor ID (25/36 males). This is the largest dataset on a nuclear-encoded defect of mitochondrial energy metabolism. The genotypic and phenotypic details further defines disease landscape and can be used for variant interpretation. The correlations between genotypes, sex, phenotypes and survival, adds a substantial improvement to counselling.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"91 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145515546","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Andrew Vo, Christina Tremblay, Shady Rahayel, Sarah Al-Bachari, Henk W Berendse, Joanna K Bright, Fernando Cendes, Emile d'Angremont, John C Dalrymple-Alford, Ines Debove, Michiel F Dirkx, Jason Druzgal, Gaëtan Garraux, Rick C Helmich, Michele T Hu, Neda Jahanshad, Martin E Johansson, Johannes C Klein, Max A Laansma, Corey T McMillan, Tracy R Melzer, Bratislav Misic, Philip Mosley, Conor Owens-Walton, Laura M Parkes, Clelia Pellicano, Fabrizio Piras, Kathleen L Poston, Mario Rango, Christian Rummel, Petra Schwingenschuh, Melanie Suette, Paul M Thompson, Duygu Tosun, Chih-Chien Tsai, Tim D van Balkom, Odile A van den Heuvel, Ysbrand D van der Werf, Eva M van Heese, Chris Vriend, Jiun-Jie Wang, Roland Wiest, Clarissa L Yasuda, Alain Dagher
Parkinson’s disease (PD) is associated with extensive structural brain changes. Recent work has proposed that the spatial pattern of disease pathology is shaped by both network spread and local vulnerability. However, only few studies assessed these biological frameworks in large patient samples across disease stages. Analyzing the largest imaging cohort in PD to date (n = 3,096 patients), we investigated the roles of network architecture and local brain features by relating regional abnormality maps to normative profiles of connectivity, intrinsic networks, cytoarchitectonics, neurotransmitter receptor densities, and gene expression. We found widespread cortical and subcortical atrophy in PD to be associated with advancing disease stage, longer time since diagnosis, and poorer global cognition. Structural brain connectivity best explained cortical atrophy patterns in PD and across disease stages. These patterns were robust among individual patients. The precuneus, lateral temporal cortex, and amygdala were identified as likely network-based epicentres, with high convergence across disease stages. Individual epicentres varied significantly among patients, yet they consistently localized to the default mode and limbic networks. Furthermore, we showed that regional overexpression of genes implicated in synaptic structure and signalling conferred increased susceptibility to brain atrophy in PD. In summary, this study demonstrates in a well-powered sample that structural brain abnormalities in PD across disease stages and within individual patients are influenced by both network spread and local vulnerability.
{"title":"Global network and local vulnerabilities underlie brain atrophy across Parkinson’s disease stages","authors":"Andrew Vo, Christina Tremblay, Shady Rahayel, Sarah Al-Bachari, Henk W Berendse, Joanna K Bright, Fernando Cendes, Emile d'Angremont, John C Dalrymple-Alford, Ines Debove, Michiel F Dirkx, Jason Druzgal, Gaëtan Garraux, Rick C Helmich, Michele T Hu, Neda Jahanshad, Martin E Johansson, Johannes C Klein, Max A Laansma, Corey T McMillan, Tracy R Melzer, Bratislav Misic, Philip Mosley, Conor Owens-Walton, Laura M Parkes, Clelia Pellicano, Fabrizio Piras, Kathleen L Poston, Mario Rango, Christian Rummel, Petra Schwingenschuh, Melanie Suette, Paul M Thompson, Duygu Tosun, Chih-Chien Tsai, Tim D van Balkom, Odile A van den Heuvel, Ysbrand D van der Werf, Eva M van Heese, Chris Vriend, Jiun-Jie Wang, Roland Wiest, Clarissa L Yasuda, Alain Dagher","doi":"10.1093/brain/awaf432","DOIUrl":"https://doi.org/10.1093/brain/awaf432","url":null,"abstract":"Parkinson’s disease (PD) is associated with extensive structural brain changes. Recent work has proposed that the spatial pattern of disease pathology is shaped by both network spread and local vulnerability. However, only few studies assessed these biological frameworks in large patient samples across disease stages. Analyzing the largest imaging cohort in PD to date (n = 3,096 patients), we investigated the roles of network architecture and local brain features by relating regional abnormality maps to normative profiles of connectivity, intrinsic networks, cytoarchitectonics, neurotransmitter receptor densities, and gene expression. We found widespread cortical and subcortical atrophy in PD to be associated with advancing disease stage, longer time since diagnosis, and poorer global cognition. Structural brain connectivity best explained cortical atrophy patterns in PD and across disease stages. These patterns were robust among individual patients. The precuneus, lateral temporal cortex, and amygdala were identified as likely network-based epicentres, with high convergence across disease stages. Individual epicentres varied significantly among patients, yet they consistently localized to the default mode and limbic networks. Furthermore, we showed that regional overexpression of genes implicated in synaptic structure and signalling conferred increased susceptibility to brain atrophy in PD. In summary, this study demonstrates in a well-powered sample that structural brain abnormalities in PD across disease stages and within individual patients are influenced by both network spread and local vulnerability.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"28 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145515547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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