Background In multiple sclerosis (MS), demyelination and degeneration of transcallosal pathways impair interhemispheric communication. While white matter damage is well documented, the impact of cortical lesions on transcallosal conduction remains unclear. Objective To determine whether cortical lesions in the sensorimotor hand area (SM1‑HAND) contribute to impaired transcallosal motor interaction using ultra‑high‑field MRI and transcranial magnetic stimulation (TMS). Methods Twenty healthy controls (HCs) and 38 MS patients underwent 7 T structural and diffusion‑weighted MRI. Structural scans were used to identify cortical lesions in SM1‑HAND, while diffusion tensor imaging (DTI) quantified microstructural properties in the transcallosal tract connecting left and right SM1‑HAND. Single‑pulse TMS was delivered to each SM1‑HAND during tonic first dorsal interosseous contraction to measure the ipsilateral silent period (iSP). Corticospinal conduction was measured with contralateral motor‑evoked potentials (MEPs), while the iSP was used to compute transcallosal conduction time (TCT). Results Among MS patients, 41 of 76 hemispheres contained an SM1‑HAND lesion. TCT was significantly prolonged in MS relative to HCs (P < 0.001). In patients, cortical lesions delayed transcallosal conduction from the non‑lesion‑bearing to the lesion‑bearing hemisphere (P = 0.026). This direction-specific delay was associated with an intracortical lesion type (P < 0.001), but not with DTI‑derived microstructural measures (P > 0.05). Conclusions The presence of cortical lesions in the sensorimotor cortex affects transcallosal inhibition between homologous sensorimotor regions in MS, slowing the build-up of inhibitory influence on the corticospinal output in the lesioned cortex. This delayed inhibitory build‑up appears to be associated with an intracortical lesion type.

Background: Oceans of Hope is an initiative enabling people with multiple sclerosis (MS) to participate in ocean sailing. Long-term ocean sailing has been hypothesized to promote physical performance and cognitive function in people with MS. However, the effects and feasibility of ocean sailing for rehabilitation purposes remain unexplored. The aim of this study was to evaluate the feasibility of ocean sailing to improve mechanical muscle function, physical capacity, and fine motor control in people with MS. Methods: In this exploratory study, 15 people with MS participated in 10 days of ocean sailing. Mechanical muscle function, gait speed, postural balance, and fine motor control were tested before and after the intervention. No control group was included. Feasibility was evaluated using adverse events, serious adverse events, drop-outs, and adherence. Results: No serious adverse events were reported, but 10 participants experienced mild or moderate seasickness. Adherence was excellent. Manual dexterity improved, and body weight was reduced after the intervention (P< .05). No other statistically significant pre- to postintervention changes were found. Conclusions: Ocean sailing for 10 days is feasible in people with MS, as none of the participants reported serious adverse events, and seasickness was the only adverse event. No deteriorations were observed in physical or cognitive function. Thus, initial evidence suggests ocean sailing may represent a feasible and safe form of physical activity for people with MS.

Background:Fatigue is a common and disabling symptom in multiple sclerosis (MS), quantifiable by patient reported outcome instruments such as the Fatigue Scale for Motor and Cognitive Functions (FSMC). The pathophysiology of fatigue remains poorly understood, and effective treatments are limited. Emerging evidence implicates disrupted excitation-inhibition balance in the premotor cortex as a potential culprit of fatigue in MS. Converging evidence now show that such network imbalance can be modulated with repetitive transcranial magnetic stimulation (TMS). The efficacy of premotor rTMS retuning excitation-inhibition balance, thus improving MS-related fatigue, has yet to be examined in a clinical trial. Methods:This randomized, double-blinded, sham-controlled, parallel-group trial investigates the efficacy of premotor TMS in treating fatigue in MS. Fifty-eight patients with MS will receive either active or sham TMS targeting the left dorsal premotor cortex (PMd). On five consecutive days, participants will undergo 30-min sessions using a novel low-frequency (0.72 Hz) paired-pulse repetitive TMS protocol with an interstimulus interval of 33 ms. The primary endpoint is the change in FSMC score 6 days post-intervention. Secondary outcomes include additional fatigue assessments and quantification of regional γ-aminobutyric acid (GABA) and glutamate concentrations of the targeted PMd, via ultra-high-field (7T) magnetic resonance spectroscopy. We hypothesize that active treatment will result in greater fatigue reduction than sham treatment and correlate positively with an increase in regional GABA in the stimulated premotor region. Exploratory endpoints include structural and functional connectivity changes assessed with 7T resonance imaging and motor cortical excitability changes measured with TMS. Discussion:This study will assess the feasibility and efficacy of a novel low-frequency paired-pulse TMS protocol for fatigue in MS. Repeated neurophysiological measurements of cortical excitation-inhibition balance will yield mechanistic insights and guide future repetitive TMS trials targeting MS-related fatigue. Clinical Trial Registration:http://www.clinicaltrials.gov, NCT06569550.

BACKGROUND:Neoehrlichia mikurensis is an emerging tick-borne pathogen posing a particular risk to individuals undergoing B-cell depleting therapy (BCDT). OBJECTIVE:To establish a rational testing strategy for N. mikurensis among individuals on BCDT. METHODS:We conducted a prospective cohort study between January 2023 and December 2024 on Adults receiving BCDT, in the Capital Region of Denmark. A digital questionnaire covered tick exposure and symptoms. Blood was tested for N. mikurensis DNA by real-time PCR. RESULTS:Of 1211 eligible individuals, 443 (37%) were enrolled. The median age was 54 years, and 62% were female. PCR testing was performed on 389 participants, detecting N. mikurensis DNA in 1.0% (4/389; 95% CI: 0.4-2.6). All infected individuals reported prolonged symptoms (e.g., fatigue, fever, unintended weight loss) and responded rapidly to doxycycline therapy. Notably, only one of the four cases exhibited elevated CRP. Symptom-based screening yielded a high likelihood ratio of 25 for identifying positive cases. CONCLUSIONS:Our results indicate that employing a symptom-based testing strategy for N. mikurensis is a rational approach for individuals undergoing BCDT.

BACKGROUND:Pediatric-onset multiple sclerosis (POMS) constitutes ~5% of multiple sclerosis (MS) cases and presents distinct clinical and diagnostic challenges. Puberty, characterized by significant hormonal changes, may influence disease presentation, relapse rates, and long-term outcomes. OBJECTIVES:To investigate the impact of pubertal stages on clinical characteristics, relapse activity and disability progression in POMS using data from the Danish MS Registry (DMSR). METHODS:A nationwide cohort of 185 POMS patients were included and categorized by pre- (<11 years), peri- (11-14 years), and post-pubertal (>14 years) onset. Demographics, presenting symptoms, magnetic resonance imaging (MRI) findings, relapse rates, and Expanded Disability Status Scale (EDSS) scores were compared. Patients transitioning across the three pubertal stages (n = 54) were analyzed longitudinally for relapse rate. RESULTS:Pre-pubertal onset was associated with severe symptoms (cerebellar involvement, p = 0.042), greater lesion burden, higher 10-year disability (EDSS median = 3.75, p = 0.039), and lower relapse rates (annualized relapse rate (ARR) = 0.200). Male sex reduced relapse rates (p = 0.013). Female-to-male ratio increased from 1:1 pre-puberty to ~2:1 after puberty. Patients with pre-pubertal onset transitioning to peri- or post-puberty showed increasing relapse rates, peaking during peri-puberty (ARR = 0.302). CONCLUSIONS:Puberty significantly modulates disease course in POMS, emphasizing the need for early, sex-specific interventions, proactive monitoring, and further exploration of hormonal influences on disease progression and treatment response.

BACKGROUND AND OBJECTIVES:Cortical lesions contribute to disability in multiple sclerosis (MS), but their impact on regional neurotransmitter levels remains to be clarified. We tested the hypothesis that cortical lesions are associated with regional glutamate and gamma-aminobutyric acid (GABA) concentrations within the affected cortical region. METHODS:In this cross-sectional study, we used structural 7T MRI to segment cortical lesions and 7T proton MR-spectroscopy of the bilateral sensorimotor hand areas to quantify regional GABA, glutamate, N-acetylaspartate, and myoinositol concentrations in patients with MS (inclusion criteria: diagnosis of relapsing-remitting [RR] or secondary progressive MS [SPMS]; age 18-80 years) and age and sex-matched healthy controls. Data were collected at a single center between August 2018 and September 2020. Linear mixed-effects models were used to test for associations between metabolite concentrations and cortical lesion volumes within the same MR-spectroscopy voxel. RESULTS:Forty-seven patients with MS (34 RRMS, 13 SPMS; 45.1 ± 12.5 years; 31 women) and 23 healthy controls (44.4 ± 13 years, 15 women) were studied. In patients, higher regional glutamate and lower regional GABA concentrations were associated with larger cortical lesion volume within the MR-spectroscopy voxel [glutamate: 0.61 (95% CI 0.19-1.03) log(mm3), p = 0.005, GABA: -0.71 (-1.24 to -0.18) log(mm3), p = 0.01]. In addition, lower N-acetylaspartate levels [-0.37 (-0.67 to -0.07) log(mm3), p = 0.016] and higher myoinositol levels [0.48 (0.03-0.93) log(mm3), p = 0.037] were associated with a larger regional cortical lesion volume. Furthermore, glutamate concentrations were reduced in patients with SPMS compared with healthy participants [-0.75 (-1.3 to -0.19) mM, p = 0.005] and patients with RRMS [-0.55 (-1.07 to -0.02) mM, p = 0.04]. N-acetylaspartate levels were lower in both patients with RRMS [-0.81 (-1.39 to -0.24) mM, p = 0.003] and SPMS [-1.31 (-2.07 to -0.54) mM, p < 0.001] when compared with healthy controls. Creatine-normalized N-acetylaspartate levels were associated with performance in the 9-hole peg test of the contralateral hand [-0.004 (-0.007 to -0.002) log(s), p = 0.002], and reduced mean creatine-normalized glutamate was associated with increased Expanded Disability Status Scale (R = -0.39, p = 0.02). DISCUSSION:Cortical lesions are associated with local increases in glutamate and a reduction in GABA concentration within the lesional or perilesional tissue. Further studies are needed to investigate the causal relationship between cortical lesions and changes in neurotransmitter concentrations.

To propose criteria to distinguish multiple sclerosis (MS) from acute disseminated encephalomyelitis (ADEM) at onset based on age at onset, sex, cerebrospinal fluid (CSF) oligoclonal bands and MRI.

OBJECTIVE:To describe a case of neoehrlichiosis, an emerging opportunistic tick-borne infection, in a patient with multiple sclerosis (MS) treated with ocrelizumab. METHODS:This is a case study. RESULTS:Our patient developed clinical infection over several months while on ocrelizumab and was ultimately diagnosed with neoehrlichiosis, caused by the bacteria Neoehrlichia mikurensis. Resolution of symptoms began within a few days after the initiation of antibiotic treatment. CONCLUSION:We describe the first probable case of ocrelizumab-associated neoehrlichiosis in a patient with MS. Clinicians should be aware of this potentially debilitating and life-threatening infection in patients receiving CD20-depleting therapy.

Background: Autologous hematopoietic stem cell treatment (AHSCT) is considered an effective treatment option for patients with aggressive relapsing-remitting multiple sclerosis (RRMS). Still there are few randomized and controlled studies of AHSCT to shed light on the safety and efficacy of the treatment, and therefore experiences from single centers are important. Aim: To describe the Danish experience with AHSCT regarding patient characteristics, safety, and efficacy. Method: Nationwide retrospective single center study of patients with multiple sclerosis (MS) treated with AHSCT. Results: A total of 32 patients were treated with AHSCT from May 2011 to May 2021. Seven were treated with carmustine, etoposide, cytarabine arabinoside, and melphalan (BEAM) as well as antithymocyte globulin (ATG). Twenty-five patients were treated with cyclophosphamide (CY) and ATG. In the whole cohort, relapse-free survival (RFS) was 77% (95% CI: 64-94%), worsening-free survival (WFS) was 79% (95% CI: 66-96%), MRI event-free survival (MFS) was 93% (95% CI: 85-100%), and no evidence of disease (NEDA-3) was 69% (95% CI: 54-89%) at the end of year two post-AHSCT. We had no treatment related mortality and only few severe adverse events (AEs). Conclusion: AHSCT of patients with aggressive RRMS was an effective and relatively safe treatment with few serious AEs and no mortality in Danish patients.

Abstract This figure presents a comparison of molecular imaging of the translocator protein (TSPO) and contrast-enhanced MRI in 2 patients with tumefactive multiple sclerosis and glioblastoma, respectively. In the case of the tumefactive multiple sclerosis patient, TSPO uptake is primarily located centrally, while in the glioblastoma patient, TSPO uptake is predominantly situated peripherally to the central necrotic area. These findings suggest that TSPO imaging could be a noninvasive imaging technique for distinguishing between these 2 diagnoses.

Importance Cortical lesions contribute to disability in multiple sclerosis (MS) but their impact on regional neurotransmitter levels remains to be clarified.Objective To test the hypothesis that cortical lesions in MS alter the regional concentrations of the main excitatory and inhibitory neurotransmitters, glutamate and gamma-aminobutyric acid (GABA), in the affected cortex.Design Prospective, cross-sectional, observational proton MR-spectroscopy (1H-MRS) and structural MRI study at 7T.Setting Data were collected at a single center between August 2018 and September 2020.Participants A volunteer sample of 57 MS patients and 38 healthy participants were screened for participation in the study. 50 MS patients and 28 healthy participants were included. In the final cohort, three patients and five healthy participants were excluded due to drop out (n=6) or insufficient data-quality (n=2).Exposures Two-voxel 7T 1H-MRS covering the right and left sensorimotor hand areas (SM1-HAND) and high-resolution structural brain 7T MRI.Main outcome Regional concentrations of glutamate and GABA in SM1-HAND and their relation to cortical lesion volume within the MRS voxel.Results Data from 34 relapsing remitting (RR) and 13 secondary progressive (SP)MS patients (mean +/− standard deviation, 45.1 +/− 12.5 years, 31 female) along with 23 age- and sex-matched healthy participants (44.4 +/− 13 years, 15 female) entered data-analyses. Patient data were pooled to assess the relationship between cortical lesion volume and neurotransmitter levels. Larger cortical lesion volume within SM1-HAND was associated with higher regional glutamate (0.61 +/− 0.21 log(mm3), P=0.005) and lower regional GABA (−0.71 +/− 0.27 log(mm3), P=0.01) concentration. Between-group comparison showed that glutamate concentration within the SM1-voxel was reduced in SPMS patients compared to healthy participants (−0.75 +/− 0.24 mM, P=0.004) and RRMS patients (−0.55 +/− 0.22 mM, P=0.04), while regional GABA levels did not differ among groups.Conclusion Our results link cortical lesion load in SM1-HAND with regional glutamate and GABA levels in patients with RRMS and SPMS, showing a shift in balance between regional excitatory and inhibitory neurotransmitters towards increased excitation with increasing cortical lesion volume. Between-group comparisons provide preliminary evidence that a progressive disease course may be associated with a decrease in cortical glutamate levels.Key points Question: How do cortical lesions change the regional metabolic profile in multiple sclerosis?Findings: This observational cross-sectional study employed voxel-based proton MR-spectroscopy (1H-MRS) of the primary sensorimotor hand areas (SM1-HAND) at ultra-high field (7T) to show that cortical lesions alter regional concentrations of glutamate and gamma-aminobutyric acid (GABA) in patients with multiple sclerosis. We found that higher regional glutamate concentrations were associated with larger regional cortical lesion volume, whereas higher GABA concentrations were associated with lower regional cortical lesion volume.Meaning: These findings suggest that cortical lesions shift the regional excitation-inhibition balance towards excitation.### Competing Interest StatementM.A.J.M., M.F.M.M., V.W., S.C. and O.P., have nothing to declare. H.R.S has received honoraria as speaker from Sanofi Genzyme, Denmark and Novartis, Denmark, as consultant for Sanofi Genzyme, Denmark, and Lundbeck AS, Denmark, and as editor-in-chief (Neuroimage Clinical) and senior editor (NeuroImage) from Elsevier Publishers, Amsterdam, The Netherlands. He has received royalties as book editor from Springer Publishers, Stuttgart, Germany and from Gyldendal Publishers, Copenhagen, Denmark. H.L. is inventor on two patent applications with royalty agreement with RWI AB, Lund, Sweden. F.S. has served on scientific advisory boards for, served as consultant for, received support for congress participation or received speaker honoraria from Alexion, Biogen, Bristol Myers Squibb, H. Lundbeck A/S, Merck, Novartis, Roche and Sanofi Genzyme. His laboratory has received research support from Biogen, Merck, Novartis, Roche and Sanofi Genzyme. J.R.C. has received speaker honoraria from Biogen. M.B., reports personal fees from the Danish Multiple Sclerosis Society, Biogen, Sanofi Genzyme, Biogen, Merck, Novartis, Bristol-Myers Squibb, Roche and non-financial support from Biogen, Roche and Sanofi Genzyme.### Funding StatementThis study was funded by the Danish Multiple Sclerosis Society [A31942; A33409; A35202; A38506], the independent research fund Denmark [9039-00330B], Gangstedfonden [A38060], and Copenhagen University Hospital Amager & Hvidovre. The 7T scanner was donated by the John and Birthe Meyer Foundation and The Danish Agency for Science, Technology and Innovation [0601-01370B]. H.R.S. holds a 5-year professorship in precision medicine at the Faculty of Health Sciences and Medicine, University of Copenhagen, sponsored by the Lundbeck Foundation [R186-2015-2138]. V.W. is supported by the Danish Multiple Sclerosis Society [A40219] and the Lundbeck Foundation [R347-2020-2413]. H.L is supported by the European Research Council (ERC) under the European Union Horizon 2020 research and innovation programme (grant agreement No 804746). S.C has received funding from the European Union Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No 765148.### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The Committees on Health Research Ethics of the Capital Region of Denmark gave ethical approval for this work (H-17033372)I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesPseudonymized data can only be shared with a formal Data Processing Agreement and a formal approval by the Danish Data Protection Agency in line with the requirements of the GDPR.

Background: Motor fatigue is common in multiple sclerosis (MS), but its pathophysiology is still poorly under-stood. Here we used functional magnetic resonance imaging (fMRI) to delineate how the acute induction of motor fatigue alters functional activity of the motor system and how these activity changes are related to motor fatigue.Method: Forty-four right-handed mildly disabled patients with relapsing-remitting MS and 25 healthy controls performed a maximal tonic precision grip with their right hand until they developed motor fatigue. Before and after the fatiguing task, participants performed a non-fatiguing tonic grip force task, producing 15-20% of their maximum grip force based on visual feedback. Task related brain activity was mapped with blood-oxygen level dependent fMRI at 3 T. Statistical parametric mapping was used to identify relative changes in task-related activation from the pre-fatigue to the recovery MRI session.Results: Following fatigue induction, task performance was perturbed in both groups, and task-related activation increased in the right (ipsilateral) primary motor hand area. In patients with MS, task-related activity increased bilaterally during the recovery phase in the ventrolateral portion of the middle putamen and lateral prefrontal cortex relative to controls. The more patients increased task-related activity in left dorsal premotor cortex after the fatiguing task, the less they experienced motor fatigue during daily life.Conclusion: Patients with MS show enhanced functional engagement of the associative cortico-basal ganglia loop following acute induction of motor fatigue in the contralateral hand. This may reflect increased mental effort to generate movements in the recovery phase after fatigue induction. The ability to recruit the contralateral dorsal premotor cortex after fatigue induction may constitute a protective mechanism against experiencing motor fa-tigue in everyday life.

Background: In relapsing-remitting multiple sclerosis (RRMS), early disease control reduces the risk of permanent disability. The blood-brain barrier (BBB) is compromised in MS, and its permeability is a potential biomarker. Objective: To investigate BBB permeability measured by MRI as a marker of alemtuzumab efficacy. Methods: Patients with RRMS initiating alemtuzumab treatment were recruited prospectively. BBB permeability was assessed as the Patlak-derived influx constant (K-j) by dynamic contrast-enhanced MRI before and 6, 12, and 18 months after the first course of alemtuzumab. No Evidence of Disease Activity-3 (NEDA-3) status was ascertained two years after treatment initiation. Results: Patients who maintained NEDA-3 status at two years (n = 7) had a larger decrease in Ki between baseline and six months (-0.029 ml/100 g/min [CI -0.005 - -0.053]) and between baseline and 12 months in normal appearing white matter (0.043 [CI 0.022 - -0.065]), than those who experienced disease activity (n = 8). ROC curve analysis of the Ki change between baseline and 12 months in NAWM predicted a loss of NEDA status at 2 years with 86% sensitivity and 86% specificity (AUC 0.98, p = 0.002). Conclusion: BBB permeability predicted alemtuzumab efficacy at two years, indicating that BBB permeability is a biomarker of treatment response in RRMS.

To validate MS-specific outcomes in hospital MRI reports in pediatric MS by comparing MS-specific outcomes in MRI reports with secondary MRI review of the MS-specific outcomes.

BACKGROUND:MRI of the nervous system is the critical in distinguishing pediatric MS from acute disseminated encephalomyelitis (ADEM). Our aim was to propose MRI criteria to distinguish MS from monophasic ADEM based on the first MRI and to validate previously proposed MRI criteria. METHODS:A neuroradiologist undertook retrospective evaluation of the MRI at the first demyelinating event in children (<18 years) with medical record-validated MS and ADEM in Denmark during 2008-15. We used forward stepwise logistic regression to identify MRI categories that differed significantly between MS and ADEM. We estimated accuracy statistics for all MRI criteria to distinguish MS from ADEM. RESULTS:The monophasic ADEM cohort (n=46) was nationwide and population-based during 2008-15; the median age at onset of 5.3 years (range 0.8‒17.2) and children had at least five years of follow-up to ensure a monophasic disease course. Children with MS (n=67) had a median age at onset of 16.3 years (range 3.3‒17.9). Having at least two categories best distinguished MS from monophasic ADEM by an area under the curve of 83% to 89%: (a) corpus callosum long axis perpendicular lesion; (b) only well-defined lesions; (c) absence of basal ganglia or thalamus lesion OR, (a) corpus callosum long axis perpendicular lesion; (b) only well-defined lesions; (c) absence of diffuse large lesions; (d) black holes. The Callen, KIDMUS, and IPMSSG criteria performed well. The McDonald 2017, Barkhof, MAGNIMS, and Verhey criteria had poorer performance. CONCLUSION:This study provides Class II evidence that MRI has good performance in differentiating MS from monophasic ADEM at onset.

Cortical lesions constitute a key manifestation of multiple sclerosis and contribute to clinical disability and cognitive impairment. Yet it is unknown whether local cortical lesions and cortical lesion subtypes contribute to domain-specific impairments attributable to the function of the lesioned cortex. In this cross-sectional study, we assessed how cortical lesions in the primary sensorimotor hand area relate to corticomotor physiology and sensorimotor function of the contralateral hand. Fifty relapse-free patients with relapsing-remitting or secondary-progressive multiple sclerosis and 28 healthy age- and sex-matched participants underwent whole-brain 7 T MRI to map cortical lesions. Brain scans were also used to estimate normalized brain volume, pericentral cortical thickness, white matter lesion fraction of the corticospinal tract, infratentorial lesion volume and the cross-sectional area of the upper cervical spinal cord. We tested sensorimotor hand function and calculated a motor and sensory composite score for each hand. In 37 patients and 20 healthy controls, we measured maximal motor-evoked potential amplitude, resting motor threshold and corticomotor conduction time with transcranial magnetic stimulation and the N20 latency from somatosensory-evoked potentials. Patients showed at least one cortical lesion in the primary sensorimotor hand area in 47 of 100 hemispheres. The presence of a lesion was associated with worse contralateral sensory (P = 0.014) and motor (P = 0.009) composite scores. Transcranial magnetic stimulation of a lesion-positive primary sensorimotor hand area revealed a decreased maximal motor-evoked potential amplitude (P < 0.001) and delayed corticomotor conduction (P = 0.002) relative to a lesion-negative primary sensorimotor hand area. Stepwise mixed linear regressions showed that the presence of a primary sensorimotor hand area lesion, higher white-matter lesion fraction of the corticospinal tract, reduced spinal cord cross-sectional area and higher infratentorial lesion volume were associated with reduced contralateral motor hand function. Cortical lesions in the primary sensorimotor hand area, spinal cord cross-sectional area and normalized brain volume were also associated with smaller maximal motor-evoked potential amplitude and longer corticomotor conduction times. The effect of cortical lesions on sensory function was no longer significant when controlling for MRI-based covariates. Lastly, we found that intracortical and subpial lesions had the largest effect on reduced motor hand function, intracortical lesions on reduced motor-evoked potential amplitude and leucocortical lesions on delayed corticomotor conduction. Together, this comprehensive multilevel assessment of sensorimotor brain damage shows that the presence of a cortical lesion in the primary sensorimotor hand area is associated with impaired corticomotor function of the hand, after accounting for damage at the subcortical level. The results also provide preliminary evidence that cortical lesion types may affect the various facets of corticomotor function differentially. Madsen et al. show that patients with multiple sclerosis with cortical lesions in the sensorimotor hand area (visible on 7 T MRI) have reduced sensorimotor hand function and reduced corticomotor output. These results indicate that cortical lesions lead to domain-specific functional impairment and local cortical dysfunction.