Significance: Neuroinflammation is a hallmark of multiple sclerosis and is linked to neurodegeneration. This study provides pathophysiological insights into the cross-dependency between neuroinflammation and choroid plexus characteristics in both mice and humans. Our work relates an enlargement of choroid plexus volume to ongoing neuroinflammation and emerging clinical disability in two large cohorts of multiple sclerosis patients as well as in two mouse models, the cuprizone diet-related demyelination and the experimental autoimmune encephalomyelitis. Choroid plexus characterization as measured by high-resolution MRI thus represents a reliable and translatable interspecies marker for the quantification of neuroinflammation and disease trajectories that is strongly associated with functional outcomes.

Objective: Fatigue is a frequent and severe symptom in multiple sclerosis (MS), but its pathophysiological origin remains incompletely understood. We aimed to examine the predictive value of subcortical gray matter volumes for fatigue severity at disease onset and after 4 years by applying structural equation modeling (SEM).Methods: This multicenter cohort study included 601 treatment‐naive patients with MS after the first demyelinating event. All patients underwent a standardized 3T magnetic resonance imaging (MRI) protocol. A subgroup of 230 patients with available clinical follow‐up data after 4 years was also analyzed. Associations of subcortical volumes (included into SEM) with MS‐related fatigue were studied regarding their predictive value. In addition, subcortical regions that have a central role in the brain network (hubs) were determined through structural covariance network (SCN) analysis.Results: Predictive causal modeling identified volumes of the caudate (s [standardized path coefficient] = 0.763, p = 0.003 [left]; s = 0.755, p = 0.006 [right]), putamen (s = 0.614, p = 0.002 [left]; s = 0.606, p = 0.003 [right]) and pallidum (s = 0.606, p = 0.012 [left]; s = 0.606, p = 0.012 [right]) as prognostic factors for fatigue severity in the cross‐sectional cohort. Moreover, the volume of the pons was additionally predictive for fatigue severity in the longitudinal cohort (s = 0.605, p = 0.013). In the SCN analysis, network hubs in patients with fatigue worsening were detected in the putamen (p = 0.008 [left]; p = 0.007 [right]) and pons (p = 0.0001).Interpretation: We unveiled predictive associations of specific subcortical gray matter volumes with fatigue in an early and initially untreated MS cohort. The colocalization of these subcortical structures with network hubs suggests an early role of these brain regions in terms of fatigue evolution. ANN NEUROL 2022;91:192–202

Deep brain stimulation (DBS) has developed over the last twenty years into a highly effective evidenced-based treatment option for neuropsychiatric disorders. Moreover, it has become a fascinating tool to provide illustrative insights into the functioning of brain networks. New anatomical and pathophysiological models of DBS action have accelerated our understanding of neurological and psychiatric disorders and brain functioning. The description of the brain networks arose through the unique ability to illustrate long-range interactions between interconnected brain regions as derived from state-of-the-art neuroimaging (structural, diffusion, and functional MRI) and the opportunity to record local and large-scale brain activity at millisecond temporal resolution (microelectrode recordings, local field potential, electroencephalography, and magnetoencephalography). In the first part of this review, we describe how neuroimaging techniques have led to current understanding of DBS effects, by identifying and refining the DBS targets and illustrate the actual view on the relationships between electrode locations and clinical effects. One step further, we discuss how neuroimaging has shifted the view of localized DBS effects to a modulation of specific brain circuits, which has been possible from the combination of electrode location reconstructions with recently introduced network imaging methods. We highlight how these findings relate to clinical effects, thus postulating neuroimaging as a key factor to understand the mechanisms of DBS action on behavior and clinical effects. In the second part, we show how invasive electrophysiology techniques have been efficiently integrated into the DBS set-up to precisely localize the neuroanatomical targets of DBS based on distinct region-specific patterns of neural activity. Next, we show how multi-site electrophysiological recordings have granted a real-time window into the aberrant brain circuits within and beyond DBS targets to quantify and map the dynamic properties of rhythmic oscillations. We also discuss how DBS alters the transient synchrony states of oscillatory networks in temporal and spatial domains during resting, task-based and motion conditions, and how this modulation of brain states ultimately shapes the functional response. Finally, we show how a successful decoding and management of electrophysiological proxies (beta bursts, phase-amplitude coupling) of aberrant brain circuits was translated into adaptive DBS stimulation paradigms for a targeted and state-dependent invasive electrical neuromodulation.

Objective We applied longitudinal 3T MRI and advanced computational models in 2 independent cohorts of patients with early MS to investigate how white matter (WM) lesion distribution and cortical atrophy topographically interrelate and affect functional disability. Methods Clinical disability was measured using the Expanded Disability Status Scale Score at baseline and at 1-year follow-up in a cohort of 119 patients with early relapsing-remitting MS and in a replication cohort of 81 patients. Covarying patterns of cortical atrophy and baseline lesion distribution were extracted by parallel independent component analysis. Predictive power of covarying patterns for disability progression was tested by receiver operating characteristic analysis at the group level and support vector machine for individual patient outcome. Results In the study cohort, we identified 3 distinct distribution types of WM lesions (cerebellar, bihemispheric, and left lateralized) that were associated with characteristic cortical atrophy distributions. The cerebellar and left-lateralized patterns were reproducibly detected in the second cohort. Each of the patterns predicted to different extents, short-term disability progression, whereas the cerebellar pattern was associated with the highest risk of clinical worsening, predicting individual disability progression with an accuracy of 88% (study cohort) and 89% (replication cohort), respectively. Conclusion These findings highlight the role of distinct spatial distribution of cortical atrophy and WM lesions predicting disability. The cerebellar involvement is shown as a key determinant of rapid clinical deterioration.

Neurological complications of the newly appeared severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are increasingly recognized. Here, we report a case of a young male presenting with a clinical and neuroimaging scenario of an acute necrotizing encephalopathy related to the coronavirus disease 2019 (COVID-19). This case is notable by its distinct pattern of magnetic resonance imaging findings of an extensive involvement of the cerebellum, and emergence of cognitive and behavioral impairment.

Episodic migraine is a debilitating condition associated with vast impairments of health, daily living, and life quality. Several prophylactic treatments exist, having a moderate ratio of action related to side effects and therapy costs. Repetitive transcranial magnetic stimulation (rTMS) is an evidence based therapy in several neuropsychiatric conditions, showing robust efficacy in alleviating specific symptoms. However, its efficacy in migraine disorders is unequivocal and might be tightly linked to the applied rTMS protocol. We hypothesized that multifocal rTMS paradigm could improve clinical outcomes in patients with episodic migraine by reducing the number of migraine days, frequency and intensity of migraine attacks, and improve the quality of life. We conducted an experimental, double-blind, randomized controlled study by applying a multifocal rTMS paradigm. Patients with episodic migraine with or without aura were enrolled in two centers from August 2018, to December 2019, and randomized to receive either real (n = 37) or sham (sham coil stimulation, n = 28) multifocal rTMS for six sessions over two weeks. Patients, physicians, and raters were blinded to the applied protocol. The experimental multifocal rTMS protocol included two components; first, swipe stimulation of 13 trains of 140 pulses/train, 67 Hz, 60% of RMT, and 2s intertrain interval and second, spot burst stimulation of 33 trains of 15 pulses/train, 67 Hz, 85% of RMT, and 8s intertrain interval. Reduction >50% from the baseline in migraine days (as primary outcome) and frequency and intensity of migraine attacks (as key secondary outcomes) over a 12-week period were assessed. To balance the baseline variables between the treatment arms, we applied the propensity score matching through the logistic regression. Among 65 randomized patients, sixty (age 39.7 ± 11.6; 52 females; real rTMS n = 33 and sham rTMS n = 27) completed the trial and five patients dropped out. Over 12 weeks, the responder's rate in the number of migraine days was significantly higher in the real rTMS compared to the sham group (42% vs. 26%, p < 0.05). The mean migraine days per month decreased from 7.6 to 4.3 days in the real rTMS group and from 6.2 to 4.3 days in the sham rTMS group, resulting in a difference with real vs. sham rTMS of -3.2 days (p < 0.05). Similarly, over the 12-week period, the responder's rate in the reduction of migraine attacks frequency was higher in the real rTMS compared to the sham group (42% vs 33%, p < 0.05). No serious adverse events were observed. Our pilot study shows compelling evidence in a double placebo-controlled trial that multifocal rTMS is an effective and well-tolerated preventive treatment in patients with episodic migraine.