Human-Prosthetic Interaction (HumanIT): A study protocol for a clinical trial evaluating brain neuroplasticity and functional performance after lower limb loss.

BACKGROUND: Lower limb amputation contributes to structural and functional brain alterations, adversely affecting gait, balance, and overall quality of life. Therefore, selecting an appropriate prosthetic ankle is critical in enhancing the well-being of these individuals. Despite the availability of various prostheses, their impact on brain neuroplasticity remains poorly understood. OBJECTIVES: The primary objective is to examine differences in the degree of brain neuroplasticity using magnetic resonance imaging (MRI) between individuals wearing a new passive ankle prosthesis with an articulated ankle joint and a standard passive prosthesis, and to examine changes in brain neuroplasticity within these two prosthetic groups. The second objective is to investigate the influence of prosthetic type on walking performance and quality of life. The final objective is to determine whether the type of prosthesis induces differences in the walking movement pattern. METHODS: Participants with a unilateral transtibial amputation will follow a 24-week protocol. Prior to rehabilitation, baseline MRI scans will be performed, followed by allocation to the intervention arms and commencement of rehabilitation. After 12 weeks, baseline functional performance tests and a quality of life questionnaire will be administered. At the end of the 24-week period, participants will undergo the same MRI scans, functional performance tests and questionnaire to evaluate any changes. A control group of able-bodied individuals will be included for comparative analysis. CONCLUSION: This study aims to unravel the differences in brain neuroplasticity and prosthesis type in patients with a unilateral transtibial amputation and provide insights into the therapeutic benefits of prosthetic devices. The findings could validate the therapeutic benefits of more advanced lower limb prostheses, potentially leading to a societal impact ultimately improving the quality of life for individuals with lower limb amputation. TRIAL REGISTRATION: NCT05818410 (Clinicaltrials.gov).

A cross-sectional case-control study on the structural connectome in recovered hospitalized COVID-19 patients.

COVID-19 can induce neurological sequelae, negatively affecting the quality of life. Unravelling this illness's impact on structural brain connectivity, white-matter microstructure (WMM), and cognitive performance may help elucidate its implications. This cross-sectional study aimed to investigate differences in these factors between former hospitalised COVID-19 patients (COV) and healthy controls. Group differences in structural brain connectivity were explored using Welch-two sample t-tests and two-sample Mann-Whitney U tests. Multivariate linear models were constructed (one per region) to examine fixel-based group differences. Differences in cognitive performance between groups were investigated using Wilcoxon Rank Sum tests. Possible effects of bundle-specific FD measures on cognitive performance were explored using a two-group path model. No differences in whole-brain structural organisation were found. Bundle-specific metrics showed reduced fiber density (p = 0.012, Hedges' g = 0.884) and fiber density cross-section (p = 0.007, Hedges' g = 0.945) in the motor segment of the corpus callosum in COV compared to healthy controls. Cognitive performance on the motor praxis and digit symbol substitution tests was worse in COV than healthy controls (p < 0.001, r = 0.688; p = 0.013, r = 422, respectively). Associations between the cognitive performance and bundle-specific FD measures differed significantly between groups. WMM and cognitive performance differences were observed between COV and healthy controls.

The effects of stimulating the cerebellum on social sequences: A tDCS-fMRI pilot study: Los efectos de estimular el cerebelo en secuencias sociales: Un estudio piloto con tDCS y fMRI.

Research on the involvement of the cerebellum in social behavior and its relationship with social mentalizing has just begun. Social mentalizing is the ability to attribute mental states such as desires, intentions, and beliefs to others. This ability involves the use of social action sequences which are believed to be stored in the cerebellum. In order to better understand the neurobiology of social mentalizing, we applied cerebellar transcranial direct current stimulation (tDCS) on 23 healthy participants in the MRI scanner, immediately followed by measuring their brain activity during a task that required to generate the correct sequence of social actions involving false (i.e., outdated) and true beliefs, social routines and non-social (control) events. The results revealed that stimulation decreased task performance along with decreased brain activation in mentalizing areas, including the temporoparietal junction and the precuneus. This decrease was strongest for true belief sequences compared to the other sequences. These findings support the functional impact of the cerebellum on the mentalizing network and belief mentalizing, contributing to the understanding of the role of the cerebellum in social sequences.

Cognitive-motor telerehabilitation in multiple sclerosis (CoMoTeMS): study protocol for a randomised controlled trial.

BACKGROUND: The management of cognitive impairment is an important goal in the treatment of multiple sclerosis (MS). While cognitive rehabilitation has been proven to be effective in improving cognitive performance in MS, research in the elderly indicates a higher effectiveness of combined cognitive-motor rehabilitation. Here, we present the protocol of a randomised controlled clinical trial to assess whether a combined cognitive-motor telerehabilitation programme is more effective in improving working memory than only cognitive or motor training. METHODS/DESIGN: The CoMoTeMS-trial is a two-centre, randomised, controlled and blinded clinical trial. A total of 90 patients with MS will receive 12 weeks of either a combined cognitive-motor telerehabilitation programme or only cognitive or motor training. The primary outcome is a change in the digit span backwards. Secondary outcomes are other cognitive changes (Brief International Cognitive Assessment for Multiple Sclerosis and Backward Corsi), Expanded Disability Status Scale (EDSS), 6-Min Walk Test, 25-Foot Walk Test, 9-Hole Peg Test, anxiety and depression, fatigue, quality of life, cognitive and physical activity level, electroencephalography and magnetic resonance imaging of the brain. DISCUSSION: We hypothesise that the improvement in digit span backwards after 12 weeks of treatment will be significantly higher in the group treated with the combined cognitive-motor telerehabilitation programme, compared to the groups receiving only cognitive and only motor training. TRIAL REGISTRATION: ClinicalTrials.gov NCT05355389. Registered on 2 May 2022.

Approaching or Decentering? Differential Neural Networks Underlying Experiential Emotion Regulation and Cognitive Defusion.

The current study investigated the bottom-up experiential emotion regulation in comparison to the cognitiveve top down-approach of cognitive defusion. Rooted in an experiential- and client-centered psychotherapeutic approach, experiential emotion regulation involves an active, non-intervening, accepting, open and welcoming approach towards the bodily felt affective experience in a welcoming, compassionate way, expressed in 'experiential awareness' in a first phase, and its verbalization or 'experiential expression' in a second phase. Defusion refers to the ability to observe one's thoughts and feelings in a detached manner. Nineteen healthy participants completed an emotion regulation task during fMRI scanning by processing highly arousing negative events by images. Both experiential emotion regulation and cognitive defusion resulted in higher negative emotion compared to a 'watch' control condition. On the neurophysiological level, experiential emotion regulation recruited brain areas that regulate attention towards affective- and somatosensorial experience such as the anterior cingulate cortex, the paracingulate gyrus, the inferior frontal gyrus, and the prefrontal pole, areas underlying multisensory information integration (e.g., angular gyrus), and linking body states to emotion recognition and awareness (e.g., postcentral gyrus). Experiential emotion regulation, relative to the control condition, also resulted in a higher interaction between the anterior insular cortex and left amygdala while participants experienced less negative emotion. Cognitive defusion decreased activation in the subcortical areas such as the brainstem, the thalamus, the amygdala, and the hippocampus. In contrast to cognitive defusion, experiential emotion regulation relative to demonstrated greater activation in the left angular gyrus, indicating more multisensory information integration. These findings provide insight into different and specific neural networks underlying psychotherapy-based experiential emotion regulation and cognitive defusion.

A drop in cognitive performance, whodunit? Subjective mental fatigue, brain deactivation or increased parasympathetic activity? It's complicated!

INTRODUCTION: The discussion on the mechanism(s) underlying mental fatigue is still ongoing. We want to reconfirm a performance-impairing effect of executing a lengthy cognitive task on the subsequent task, and determine how this effect is subtended by neurophysiological variations and subjective experience. METHODS: Twenty participants (12 females; age: 23 ± 1 y) performed an experimental (EXP) and a control trial (CON) in a randomized counter-balanced order. In both trials a 90-min cognitive task had to be performed (EXP, Stroop task; CON, documentary), that was preceded and followed up by a 10-min flanker task that was completed in the MRI scanner. Throughout the protocol, subjective self-evaluation, peripheral autonomic activation and metabolic measures, cognitive performance and functional brain imagery were recorded. Due to equipment issues, only 11 participants could be included in the analysis of the peripheral autonomic activation. RESULTS: Flanker performance dropped both in EXP and CON (p = .010). Heart rate variability increased in time, both in EXP and CON (p ≤ .047). A time-on-task related drop in Stroop performance (p = .007) and higher subjective mental fatigue was observed in EXP compared to CON (p < .001). Moreover, the BOLD signal of response inhibition-associated brain activity in corpus callosum, somatosensory association cortex and anterior cingulate cortex was reduced during the post-flanker task in EXP compared to CON (p < .001). Discussion Our results indicate two different processes: 1) A time-on-task effect as a peripheral physiological deactivation that coincided with the observed post-flanker performance drop both in EXP and CON; and 2) An increase in the level of subjective mental fatigue with prolonged performance on a 90-min Stroop task that is associated with a decrease in response inhibition-associated brain activity in both grey and white matter, specifically in the EXP-condition. CONCLUSION: Our results highlight the multifactoriality of carryover effects, in the present study increased parasympathetic activity was linked with the drop in performance.

Motor Abnormalities in Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder Are Associated With Regional Grey Matter Volumes.

Attention-Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) are associated with motor impairments, with some children holding a comorbid diagnosis of Developmental Coordination Disorder (DCD). However, DCD is underdiagnosed in these populations and the volume abnormalities that contribute to explaining these motor impairments are poorly understood. In this study, motor abilities as measured by the Developmental Coordination Disorder Questionnaire (DCDQ) were compared between children with ADHD, children with ASD and typically developing (TD) children, aged 8-12 years old. Additionally, the association between the DCDQ scores (general coordination, fine motor/handwriting, control during movement, total) and regional volume abnormalities were explored in 6 regions of interest (pre-central gyrus, post-central gyrus, inferior parietal cortex, superior frontal gyrus, middle frontal gyrus, medial frontal gyrus), within each group and across all participants. Children with ASD and children with ADHD showed impaired motor abilities in all the DCDQ-derived scores compared to TD children. Additionally, most children with ASD or ADHD had an indication or suspicion of DCD. Within the ASD group, coordination abilities were associated with the volume of the right medial frontal gyrus, and within the ADHD group, the total DCDQ score was associated with the volume of the right superior frontal gyrus. This study underlines the importance of routinely checking motor abilities in populations with ASD or ADHD in clinical practise and contributes to the understanding of structural abnormalities subtending motor impairments in these disorders.

Opposite effects of one session of 1 Hz rTMS on functional connectivity between pre-supplementary motor area and putamen depending on the dyskinesia state in Parkinson's disease.

OBJECTIVE: To explore the effects of low-frequency repetitive transcranial magnetic stimulation (LF rTMS) on cortico-striatal-cerebellar resting state functional connectivity in Parkinson's disease (PD), with and without dyskinesias. METHODS: Because there is increasing evidence of an involvement of the pre-supplementary motor area (pre-SMA) in the pathophysiology of levodopa induced dyskinesias, we targeted the right pre-SMA with LF rTMS in 17 PD patients. We explored the effects of one sham-controlled LF rTMS session on resting state functional connectivity of interconnected brain regions by using functional MRI, and how it is modified by levodopa. The clinical effect on motor function and dyskinesias was documented. RESULTS: As expected, one LF rTMS session did not alleviate dyskinesias. However, real, and not sham LF rTMS significantly increased the functional connectivity with the right putamen in patients with dyskinesias. In patients without dyskinesias, the real LF rTMS session significantly decreased functional connectivity in the right putamen and the cerebellum. We found no effects on functional connectivity after levodopa ingestion. CONCLUSION: One session of 1 Hz rTMS has opposing effects on pre-SMA functional connectivity depending on the PD patients' dyskinesia state. SIGNIFICANCE: Patients dyskinesias state determines the way LF rTMS affects functional connectivity in late stage PD.

Disorder-specific brain volumetric abnormalities in Attention-Deficit/Hyperactivity Disorder relative to Autism Spectrum Disorder.

The overlap/distinctiveness between Attention-Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) has been increasingly investigated in recent years, particularly since the DSM-5 allows the dual diagnosis of ASD and ADHD, but the underlying brain mechanisms remain unclear. Although both disorders are associated with brain volumetric abnormalities, it is necessary to unfold the shared and specific volume abnormalities that could contribute to explain the similarities and differences in the clinical and neurocognitive profiles between ADHD and ASD. In this voxel-based morphometry (VBM) study, regional grey matter volumes (GMV) were compared between 22 children with ADHD, 18 children with ASD and 17 typically developing (TD) children aged 8 to 12 years old, controlling for age and total intracranial volume. When compared to TD children or children with ASD, children with ADHD had a larger left precuneus, and a smaller right thalamus, suggesting that these brain abnormalities are specific to ADHD relative to ASD. Overall, this study contributes to the delineation of disorder-specific structural abnormalities in ADHD and ASD.

Effects of spinal cord stimulation on voxel-based brain morphometry in patients with failed back surgery syndrome.

OBJECTIVE: Despite the clinical effectiveness of Spinal Cord Stimulation (SCS), potential structural brain modifications have not been explored. Our aim was to identify structural volumetric changes during subsensory SCS, in patients with Failed Back Surgery Syndrome (FBSS). METHODS: In this cohort study, twenty-two FBSS patients underwent a magnetic resonance imaging protocol before SCS and 3 months after SCS. Clinical parameters were correlated with volumetric changes, calculated with voxel-based morphometry. RESULTS: After 3 months, a significant volume decrease was found in the inferior frontal gyrus, precuneus, cerebellar posterior lobe and middle temporal gyrus. Significant increases were found in the inferior temporal gyrus, precentral gyrus and the middle frontal gyrus after SCS. Additionally, significant increases in volume of superior frontal and parietal white matter and a significant decrease in volume of white matter underlying the premotor/middle frontal gyrus were revealed after SCS. A significant correlation was highlighted between white matter volume underlying premotor/middle frontal gyrus and leg pain relief. CONCLUSIONS: This study revealed for the first time that SCS is able to induce volumetric changes in gray and white matter, suggesting the reversibility of brain alterations after chronic pain treatment. SIGNIFICANCE: Volumetric brain alterations are observable after 3 months of subsensory SCS in FBSS patients.

The Role of Cerebral Hypoperfusion in Multiple Sclerosis (ROCHIMS) Trial in Multiple Sclerosis: Insights From Negative Results.

Background: Accumulating evidence indicates that mitochondrial energy failure is involved in the progressive axonal degeneration in multiple sclerosis (MS). In patients with MS, it has been shown that both levels of N-acetylaspartate (NAA), which is a marker of axonal mitochondrial energy, and cerebral blood flow (CBF) are reduced in cerebral normal appearing white matter (NAWM). The latter is likely due to the vasoconstrictive action of endothelin-1 (ET-1) produced by reactive astrocytes, which is triggered by local proinflammatory cytokines. A preliminary study in patients with MS showed that CBF could be restored to normal values after a single dose of 62.5 mg of the ET-1 antagonist bosentan. Objective: To investigate whether restoring CBF in patients with relapsing remitting MS (RRMS) increases levels of NAA in cerebral NAWM and improves clinical symptoms. Methods: 27 RRMS patients were included in a 4 weeks proof-of-concept, randomized, double-blind placebo-controlled trial (ROCHIMS) to investigate whether bosentan 62.5 mg twice daily could increase the NAA/creatine (NAA/Cr) ratio in NAWM of the centrum semiovale. Magnetic resonance imaging (MRI) assessing CBF and NAA/Cr, and clinical evaluations were performed at baseline and at end of study. Separately from the clinical trial, 10 healthy controls underwent the same baseline multimodal brain MRI protocol as the MS patients. Results: Eleven patients in the bosentan arm and thirteen patients in the placebo arm completed the study. Bosentan did not increase CBF. However, we found that CBF in the patients was not different from that of the healthy controls. There were no effects on NAA levels and clinical symptoms. Conclusions: Our study showed that CBF in RRMS patients is not always decreased and that bosentan has no effect when CBF values are within the normal range. We hypothesize that in our patients there was no significant astrocytic production of ET-1 because they had a mild disease course, with minimal local inflammatory activity. Future studies with bosentan in MS should focus on patients with elevated ET-1 levels in cerebrospinal fluid or blood.

A Regions of Interest Voxel-Based Morphometry Study of the Human Brain During High-Frequency Spinal Cord Stimulation in Patients With Failed Back Surgery Syndrome.

INTRODUCTION: The effectiveness of spinal cord stimulation (SCS) as pain-relieving treatment for failed back surgery syndrome (FBSS) has already been demonstrated. However, potential structural and functional brain alterations resulting from subsensory SCS are less clear. The aim of this study was to test structural volumetric changes in a priori chosen regions of interest related to chronic pain after 1 month and 3 months of high-frequency SCS in patients with FBSS. METHODS: Eleven patients with FBSS who were scheduled for SCS device implantation were included in this study. All patients underwent a magnetic resonance imaging protocol before SCS device implantation 1 and 3 months after high-frequency SCS. Pain intensity, pain catastrophizing, and sleep quality were also measured. Regions-of-interest voxel-based morphometry was used to explore grey matter volumetric changes over time. Additionally, volumetric changes were correlated with changes in pain intensity, catastrophizing, and sleep quality. RESULTS: Significant decreases were found in volume in the left and right hippocampus over time. More specifically, a significant difference was revealed between volumes before SCS implantation and after 3 months of SCS. Repeated-measures correlations revealed a significant positive correlation between volumetric changes in the left hippocampus and changes in back pain score over time and between volumetric changes in the right hippocampus and changes in back pain score over time. CONCLUSION: In patients with FBSS, high-frequency SCS influences structural brain regions over time. The volume of the hippocampus was decreased bilaterally after 3 months of high-frequency SCS with a positive correlation with back pain intensity.

Identification of the cerebral effects of paracetamol in healthy subjects: an fMRI study.

INTRODUCTION: Paracetamol is commonly used for its antipyretic properties and analgesic effects, but the central mechanism remains elusive. We designed a study in healthy volunteers to detect the central functional working mechanism of paracetamol. SUBJECTS MATERIAL AND METHODS: A total of 20 subjects had a baseline functional magnetic resonance imaging (fMRI) before the intake of 1000 mg paracetamol orally; 60 minutes later, a second fMRI was made aiming detection of regional blood flow differences. RESULTS: A decreased connectivity was observed in the ventral volume of interest (VOI), with the posterior cingulate (with both the left anterior cingulate cortex (ACC) and right ACC: respectively, Ke = 576; t = -6.8894 and Ke = 185; t = -4.8178) and the inferior temporal left (Ke = 103; t = -5.0993); in the combined ventral and dorsal VOIs, the posterior cingulate (with the left ACC; Ke = 149; t = -4.5658) and, both with the right ACC, the inferior temporal left (Ke = 88; t = -3.8456) and the inferior frontal gyrus (Ke = 86; t = -4.3937) had a decrease in connectivity. An increase was seen in other regions, including, among others, the middle frontal and temporal gyri (respectively, Ke = 85; t = 4.4256 and Ke = 85; t = 5.6851), the inferior frontal (with the left ACC: Ke = 165; t = 4.4998) and the superior frontal gyrus (with the right ACC; Ke = 281; t = 4.5992), and the post/precentral gyrus (with the right ACC, respectively, Ke = 102; t = 6.0582 and Ke = 105; t = 4.0776). CONCLUSIONS: On fMRIs in healthy volunteers, the ingestion of paracetamol affects connections with the ACC. This suggests a central effect of paracetamol in cerebral areas known to be associated with pain. Further studies are needed to demonstrate the same effects in acute and chronic pain states.

ADHD and ASD: distinct brain patterns of inhibition-related activation?

Attention-deficit/hyperactivity (ADHD) and autism spectrum (ASD) disorders often co-occur. In both cases, response inhibition deficits and inhibition-related atypical brain activation have been reported, although less consistently in ASD. Research exploring the overlap/distinctiveness between ADHD and ASD has significantly increased in recent years, but direct comparison of the inhibition-related neuronal correlates between these disorders are scarce in the literature. This study aimed at disentangling the shared and specific inhibitory brain dysfunctions in ASD and ADHD. Using functional magnetic resonance imaging (fMRI), brain activity was compared between children with ADHD, ASD and typically developing (TD) children aged 8-12 years during an inhibition stop-signal task, using stringent inclusion criteria. At the behavioural level, only children with ADHD exhibited inhibition deficits when compared with the TD group. Distinct patterns of brain activity were observed during successful inhibition. In children with ADHD, motor inhibition was associated with right inferior parietal activation, whereas right frontal regions were activated in children with ASD. Between-group comparisons disclosed higher middle frontal activation in the ASD group compared with the ADHD and the TD groups. Our results evidence different patterns of activation during inhibition in these two disorders, recruiting different regions of the fronto-parietal network associated to inhibition. Besides brain activity differences, behavioural inhibition deficits found only in children with ADHD further suggest that reactive inhibition is one of the core deficits in ADHD, but not in ASD. Our findings provide further evidence contributing to disentangle the shared and specific inhibitory dysfunctions in ASD and ADHD.

Opposite subgenual cingulate cortical functional connectivity and metabolic activity patterns in refractory melancholic major depression.

Although in treatment-resistant depression (TRD) subgenual anterior cingulate cortex (sgACC) functional connectivity (FC) is frequently used to examine deregulated brain networks, neurobiological data from other sources may be required to interpret these FC findings. In 16 melancholic TRD patients with a high level of treatment resistance and 16 closely matched healthy never-depressed individuals we verified whether sgACC FC patterns were related to regional metabolic activity (CMRglc) with 18FDG PET imaging. Notwithstanding that TRD patients displayed stronger sgACC FC with the right lateral frontotemporal cortex, metabolically they exhibited the opposite pattern. Our results indicate that the sgACC seed and its functionally connected regions not automatically follow a similar metabolic pattern in TRD, possibly reflecting the refractory state of the sample. Multimodal brain imaging may help to increase our insight into the pathophysiology of TRD.

The effect of acute cocoa flavanol intake on the BOLD response and cognitive function in type 1 diabetes: a randomized, placebo-controlled, double-blinded cross-over pilot study.

RATIONALE: Type 1 diabetes (T1D), a chronic autoimmune disease, can result in cognitive dysfunction and is associated with vascular dysfunction. Cocoa flavanols (CFs) can stimulate nitric oxide-dependent vasodilation, resulting in enhanced hemodynamic responses and better cognitive function. OBJECTIVES: To investigate whether acute CF supplementation can improve cognitive function and hemodynamic responses in T1D. METHODS: In this randomized, double-blinded, cross-over pilot study, 11 patients with T1D and their healthy matched controls consumed CF (900 mg CF) and placebo (15 mg CF) 2 h before a flanker test. fMRI was used to measure blood oxygen level-dependent (BOLD) response during the cognitive test. Repeated measure ANOVAs were used to test the effects of CF and T1D on BOLD response and cognitive performance. RESULTS: CF improved reaction time on the flanker test and increased the BOLD response in the supramarginal gyrus parietal lobe and inferior frontal gyrus, compared to placebo, in both groups. In patients with T1D, cognitive performance was not deteriorated while the BOLD response was smaller in T1D compared to healthy controls in the subgyral temporal lobe and the cerebellum. CONCLUSIONS: Acute CF intake improved reaction time on the flanker test and increased the BOLD response in the activated brain areas in patients with T1D and their matched controls.

The influence of one session of low frequency rTMS on pre-supplementary motor area metabolites in late stage Parkinson's disease.

OBJECTIVE: To study the effect of Low Frequency repetitive Transcranial Magnetic Stimulation (LF rTMS) on brain metabolites in late stage Parkinson's disease (PD) patients (disease duration at least 4 years and Hoehn and Yahr (1969) score at least 2 in OFF). Several neuroimaging data support a role for pre-Supplementary Motor Area (pre-SMA) involvement in the pathogenesis of Parkinson's disease. Proton magnetic resonance spectroscopy (1H-MRS) measures in vivo metabolites, but results in PD brain remain conflicting and little is known of the effect of LF rTMS thereupon. METHODS: We investigate the neurochemical profile of the right pre-SMA in 17 late stage PD patients (11 male and 6 female, mean age of 71 years) before and after one session of sham controlled 1 Hz rTMS (1000 pulses, 16 minutes), focusing on the tNAA/tCr and tCho/tCr ratios. RESULTS: The tNAA/tCr ratio was unaffected by one session of LF rTMS. We did observe a significant effect of real LF rTMS on the tCho/tCr ratio, inversely correlated with disease duration, and not related to the presence of dyskinesias. As expected, one session of LF rTMS did not affect clinical outcome. CONCLUSIONS: LF rTMS at the right pre-SMA in late stage Parkinson's disease patients does not alter tNAA/tCr, but influences tCho/tCr ratio, in particular in patients with shorter disease duration. SIGNIFICANCE: Pre-SMA LF rTMS seems to influence membrane turnover, more importantly in patients with shorter disease duration. Larger LF rTMS treatment studies applying multiple sessions are needed.

Role of cerebral hypoperfusion in multiple sclerosis (ROCHIMS): study protocol for a proof-of-concept randomized controlled trial with bosentan.

BACKGROUND: Axonal degeneration is related to long-term disability in patients with multiple sclerosis (MS). The underlying mechanism remains ill understood but appears to involve axonal energetic dysfunction. A globally impaired cerebral blood flow (CBF) has been observed in the normal-appearing white matter (NAWM) of patients with MS, which is probably related to astrocytic overexpression of endothelin-1 (ET-1). Cerebral hypoperfusion has been associated with reduced mitochondrial activity and disabling symptoms (e.g. fatigue and cognitive decline) of MS. Countering this process could therefore be beneficial in the disease course. Short-term CBF restoration with a single 62.5-mg dose of the ET-1 receptor antagonist bosentan has already been demonstrated in patients with MS. METHODS: The ROCHIMS study is a proof-of-concept double-blind randomized clinical trial in which patients with relapsing-remitting MS will receive either 62.5 mg bosentan or matching placebo twice daily during 28 ± 2 days. Clinical evaluation and brain magnetic resonance imaging (MRI) will be performed at baseline and treatment termination. Based on previous work, we expect a global increase of CBF in the individuals treated with bosentan. The primary outcome measure is the change of N-acetyl aspartate in centrum semiovale NAWM, which is a marker of regional axonal mitochondrial activity. Other parameters of interest include changes in fatigue, cognition, motor function, depression, and brain volume. DISCUSSION: We hypothesize that restoring cerebral hypoperfusion in MS patients improves axonal metabolism. Early positive effects on fatigue and cognitive dysfunction related to MS might additionally be detected. There is a medical need for drugs that can slow down the progressive axonal degeneration in MS, making this an important topic of interest. TRIAL REGISTRATION: Clinical Trials Register, EudraCT 2017-001253-13 . Registered on 15 February 2018.