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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)., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Lathouwers et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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., (© 2023. Springer Nature Limited.)

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., Competing Interests: The authors have no conflicts of interest to disclose., (© 2023 The Authors.)

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., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

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., (© 2022. The Author(s).)

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.

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Albajara Sáenz, Villemonteix, Van Schuerbeek, Baijot, Septier, Defresne, Delvenne, Passeri, Raeymaekers, Victoor, Willaye, Peigneux, Deconinck and Massat.)

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., (Copyright © 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

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., Competing Interests: Isabelle Massat received an investigator-initiated research grant from Shire Pharmaceutical Development Limited, a member of the Takeda group of companies (Study ID: IST-BEL- 00520). This does not alter our adherence to PLOS ONE policies on sharing data and materials. Ariadna Albajara Sáenz is supported by a grant from the Belgian Kids’ Fund (www.belgiankidsfund.be), the David et Alice Van Buuren Fund and by the Fondation Jaumotte-Demoulin. Isabelle Massat and Ariadna Albajara Sáenz are supported by the Fonds National de la Recherche Scientifique (FNRS)-Belgium and the Fonds Erasme. The funders had no role in the study design, the data collection and analysis, the decision to publish, or the preparation of the manuscript.

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., (© 2020 World Institute of Pain.)

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., Competing Interests: Declaration of Competing Interest Bengt Linderoth serves as a consultant to Medtronic, St Jude/Abbott, Boston Sci and Elekta AB. Philippe Rigoard serves as a consultant for Medtronic Inc. He received honoraria for medical training from St. Jude Medical and research grants from St. Jude Medical, Medtronic Inc. and Boston Scientific. Maarten Moens has received speaker fees from Medtronic and Nevro Corp. There is no other conflict of interests to declare., (Copyright © 2020 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

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., (Copyright © 2020 Hostenbach, Raeymaekers, Van Schuerbeek, Vanbinst, Cools, De Keyser and D'Haeseleer.)

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 18 FDG 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.

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., Competing Interests: Conflict of interest: The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article., (© The British Pain Society 2019.)

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.

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.

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 ( 1 H-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., (Copyright © 2019 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

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.

Background and Purpose: Failed back surgery syndrome (FBSS) is a common and devastating chronic neuropathic pain disorder. Conventional spinal cord stimulation (SCS) applies electrical suprathreshold pulses to the spinal cord at a frequency of 40-60 Hz and relieves pain in FBSS patients. During the last decade, two major changes have emerged in the techniques of stimulating the spinal cord: paresthesia-free or subthreshold stimulation and administration of higher frequency or higher amounts of energy to the spinal cord. Despite the positive clinical results, the mechanism of action remains unclear. A functional MRI (fMRI) study was conducted to investigate the brain alterations during subthreshold and suprathreshold stimulation at different frequencies., Methods: Ten subjects with FBSS, treated with externalized SCS, received randomly four different stimulation frequencies (4 Hz, 60 Hz, 500 Hz, and 1 kHz) during four consecutive days. At every frequency, the patient underwent sub- and suprathreshold stimulation. Cerebral activity was monitored and assessed using fMRI., Results: Suprathreshold stimulation is generally accompanied with more activity than sub-threshold SCS. Suprathreshold SCS resulted in increased bilateral activation of the frontal cortex, thalamus, pre- and postcentral gyri, basal ganglia, cingulate gyrus, insula, thalamus, and claustrum. We observed deactivation of the bilateral parahippocampus, amygdala, precuneus, posterior cingulate gyrus, postcentral gyrus, and unilateral superior temporal gyrus., Conclusion: Suprathreshold stimulation resulted in greater activity (both activation and deactivation) of the frontal brain regions; the sensory, limbic, and motor cortices; and the diencephalon in comparison with subthreshold stimulation. Each type of frequency at suprathreshold stimulation was characterized by an individual activation pattern., Competing Interests: Disclosure MM received research grants from Medtronic and Nevro. The authors report no conflicts of interest in this work.

The application of repetitive transcranial magnetic stimulation (rTMS) to prevent relapse in alcohol addiction is currently being evaluated. However, how rTMS may influence the related brain processes is far from clear. Here we wanted to investigate whether baseline grey matter volume (GMV) can predict relapse and whether 15 accelerated high-frequency (HF)- rTMS sessions may influence GMV in areas related to relapse. Voxel-based morphometric (VBM) measurements were used to compare baseline GMV of 22 detoxified, hospitalized, alcohol-dependent patients with 22 age and gender matched healthy control subjects. Only patients received 15 accelerated HF-rTMS sessions at the right dorsolateral prefrontal cortex (DLPFC) followed by VBM measurements. Relapse rates were assessed four weeks after the end of the stimulation protocol. At baseline, alcohol-dependent patients overall showed less GMV in diffuse brain areas compared to healthy controls. Relapsers compared to abstainers displayed larger GMV decreases, especially in brain midline structures, insular, hippocampal, and amygdalar areas. Accelerated HF-rTMS treatment had no significant effect on GMV in alcohol-dependent patients, regardless of the relapse state. Although an accelerated HF-rTMS treatment protocol did not influence GMV in alcohol-dependent patients, baseline GMV predicted future relapse., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Smoking is a common phenomenon and kills over 6 million people every year. Many smokers try to quit smoking by using nicotine replacement therapy (NRT). Most of the time, relapse occurs in less than six months after finishing the program of NRT. We performed a single blinded study in which our aim was to figure out what the effect of the nicotine patch is on craving in the brain of smokers deprived from smoking., Methods: Five heavy smokers (Fagerström Test for Nicotine Dependence ≥4) underwent a functional magnetic resonance imaging (fMRI) in 4 random conditions: smoking (S); smoking deprivation (SD); SD combined with a NP (SD + NP); SD combined with a placebo patch (SD + PP). Visual stimulation provoked craving in block design by randomly displaying images of smoking related scenes. After image preprocessing, a fixed-effect analysis was performed to compare average group activations. The Questionnaire for Smoking Urges (QSU) was obtained before and after each scan., Results: The fMRI results showed higher activation in areas involved in craving in S compared with SD + NP, SD + PP, and SD. In the SD + NP, limbic circuit and attention area were higher activated compared with SD and SD + PP. The SD + PP and SD showed higher activation in the frontal cortex and limbic system compared with S and SD + NP. Nonsmokers showed higher limbic activation compared with SD.The QSU increased significantly after the fMRI experiment in S (P = .036).The SD had higher QSU scores compared with the S before (P = .002), and also after (P = .022) the fMRI experiment. The NP showed lower scores than the SD before the experiment (P = .046)., Conclusion: The fMRI experiment revealed lower activity in areas associated with attention when subjects were nicotine deprived (SD + PP and SD). Areas involved with craving showed less activity when nicotine is present (S and SD + NP). The QSU showed a significant difference between SD and when nicotine is present (S and SD + NP).

Introduction: With the development of new neuroimaging tools it has become possible to assess neurochemical alterations in patients experiencing chronic pain and to determine how these factors change during pharmacological treatment. The goal of this study was to examine the exact neurochemical mechanism underlying pregabalin treatment, utilizing magnetic resonance spectroscopy ( 1 H-MRS), in a population of patients with painful diabetic polyneuropathy (PDN), with the overall aim to ultimately objectify the clinical effect of pregabalin., Methods: A double blind, randomized, placebo-controlled study was conducted. A total of 27 patients with PDN were enrolled in the study, of whom 13 received placebo treatment (control group) and 14 received pregabalin (intervention group). Pregabalin treatment consisted of stepwise dose escalation over the study period from 75 mg daily ultimately to 600 mg daily. 1 H-MRS was performed at 3T on four regions of interest in the brain: the rostral anterior cingulate cortex (rACC), left and right thalamus and prefrontal cortex. The absolute concentrations of N-acetyl aspartate, glutamate, glutamine, gamma-amino-butyric-acid (GABA), glucose (Glc) and myo-inositol (mINS) were determined using LCModel., Results: The concentration of most neurometabolites in the placebo and pregabalin group did not significantly differ over time, with only a small significant difference in Glc level in the left thalamus (p = 0.049). Comparison of the effects of the different doses revealed significant differences for mINS in the rACC (baseline 2.42 ± 1.21 vs. 450 mg 1.58 ± 0.94; p = 0.022) and dorsolateral prefrontal cortex (75 mg 2.38 ± 0.89 vs. 450 mg 1.59 ± 0.85; p = 0.042) and also for GABA in the rACC (75 mg 0.53 ± 0.51 vs. 225 mg 0.28 ± 0.19; p = 0.014)., Conclusion: No differences were found in metabolite concentrations between the placebo (control) and intervention groups, but some differences, although small, were found between the different doses., Trial Registration: This study is registered at ClinicalTrials.gov (NCT01180608)., Funding: Lyrica Independent Investigator Research Award (LIIRA) 2010 (Pfizer) funded the study.

Purpose: Besides chiasmal hemidecussation, interhemispheric connections are likely important in human binocularity. The corpus callosum (CC) is the major fiber bundle in the mammalian brain which mostly connects homologous cortical areas in the two hemispheres. Visual interhemispheric connections were found abnormal in strabismic cats. No studies have investigated these pathways in humans with infantile strabismus., Methods: Diffusion tensor imaging was used in four subjects with infantile esotropia (IE) and nine control subjects with normal binocularity, in order to study interhemispheric fibers in the CC connecting the right and left primary visual cortical areas., Results: The number of callosal fibers linking both visual cortical areas between the hemispheres was found to be higher in subjects with IE. Also in IE, the amount of visual callosal fibers found after analysis from the primary visual cortical areas on one side appeared significantly different from the amount starting from the contralateral primary visual areas. The distribution area on one side is wider., Conclusion: We show callosal visual fibers to be abnormal in human IE. Subjects with IE showed abnormal numbers of transcallosal fibers connecting the visual cortical areas on both sides which likely results from an abnormal elimination process during development. Pruning of these fibers in IE favors the side of the visual cortex ipsilateral to the dominant eye. This study underlines the likely role of the CC in the development of human binocularity.

Objective: Although accelerated repetitive transcranial magnetic stimulation (rTMS) designs seem to be able to alleviate mood over a relatively short period of time, no studies yet examined the cellular effects on neurochemicals with regard to working mechanisms, safety and neural integrity., Methods: Eighteen right-handed antidepressant-free unipolar treatment resistant depressed (TRD) patients participated in this sham-controlled accelerated high frequency (aHF)-rTMS 1 H MR spectroscopy study applied to the left dorsolateral prefrontal cortex (DLPFC). Baseline measurements were compared to eighteen age- and gender-matched healthy controls. We explicitly focused on neurochemical concentrations in the bilateral DLPFC and rostral anterior cingulate cortex (rACC)., Results: Compared to healthy individuals, TRD patients displayed significantly lower baseline glutamatergic (sum absolute concentrations glutamate and glutamine) concentrations in the left DLPFC. aHF-rTMS does not significantly alter neurochemical concentrations in the three predefined brain regions. Clinical improvement was related to significant GABA concentration increases in the left DLPFC., Conclusions: Accelerated HF-rTMS treatment did not affect neural integrity in the examined regions. The observed GABA concentration increases suggest that the immediate therapeutic effects of aHF-rTMS could be mediated through a locally increased GABAergic inhibitory neurotransmission., Significance: Although more statistical power is needed for reaching firm conclusions, aHF-rTMS does not appear to negatively influence neural integrity., (Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Aim: In humans, images in the median plane of the head either fall on both nasal hemi-retinas or on both temporal hemi-retinas. Interhemispheric connections allow cortical cells to have receptive fields on opposite sides. The major interhemispheric connection, the corpus callosum, is implicated in central stereopsis and disparity detection in front of the fixation plane. Yet individuals with agenesis of the corpus callosum may show normal stereopsis and disparity vergence. We set out to study a possible interhemispheric connection between primary visual cortical areas via the anterior commissure to explain this inconsistency because of the major role of these cortical areas in elaborating 3D visual perception. Methods: MRI, DTI and tractography of the brain of a 53-year old man with complete callosal agenesis and normal binocular single vision was undertaken. Tractography seed points were placed in both the right and the left V1 and V2. Nine individuals with both an intact corpus callosum and normal binocularity served as controls. Results: Interhemispheric tracts through the anterior commissure linking both V1 and V2 visual cortical areas bilaterally were indeed shown in the subject with callosal agenesis. All other individuals showed interhemispheric visual connections through the corpus callosum only. Conclusion: Callosal agenesis may result in anomalous interhemispheric connections of the primary visual areas via the anterior commissure. It is proposed here that these connections form as alternative to the normal callosal pathway and may participate in binocularity.

Concerns are raising about the large variability in reported correlations between gray matter morphology and affective personality traits as 'Harm Avoidance' (HA). A recent review study (Mincic 2015) stipulated that this variability could come from methodological differences between studies. In order to achieve more robust results by standardizing the data processing procedure, as a first step, we repeatedly analyzed data from healthy females while changing the processing settings (voxel-based morphology (VBM) or region-of-interest (ROI) labeling, smoothing filter width, nuisance parameters included in the regression model, brain atlas and multiple comparisons correction method). The heterogeneity in the obtained results clearly illustrate the dependency of the study outcome to the opted analysis settings. Based on our results and the existing literature, we recommended the use of VBM over ROI labeling for whole brain analyses with a small or intermediate smoothing filter (5-8mm) and a model variable selection step included in the processing procedure. Additionally, it is recommended that ROI labeling should only be used in combination with a clear hypothesis and that authors are encouraged to report their results uncorrected for multiple comparisons as supplementary material to aid review studies.

Background: The application of accelerated high-frequency (HF) repetitive transcranial magnetic stimulation (rTMS) could be a potential treatment option for alcohol-dependent patients and may result in a faster clinical response. In this open-label HF-rTMS feasibility study, we wanted to replicate previous findings of baseline brain activation as a predictor of relapse, and to evaluate how this intervention influences the relapse neurocircuit of "treatment-seeking" alcohol-dependent patients, by means of functional magnetic resonance imaging (fMRI) cue-exposure paradigms. Because relapsing patients have a diminished resilience of the emotion regulation/cognitive control system, before HF-rTMS treatment, we expected lower neuronal activation of especially the ventromedial prefrontal cortex and anterior cingulate cortex (ACC) during the presentation of alcohol-related cues in these patients. The relapse neurocircuit should be modified after accelerated HF-rTMS treatment, only in those patients who did not relapse., Methods: After being administered a single sham-controlled HF-rTMS session (20 Hz to 110% motor threshold), 19 alcohol-dependent patients received an accelerated HF-rTMS protocol, consisting of 14 right dorsolateral prefrontal cortical sessions spread over 3 days. Before and after stimulation, during fMRI patients were confronted with a block and an event-related alcoholic cue-exposure paradigm. Relapse was defined as the consumption of any amount of alcohol within 4 weeks after the stimulation. A region of interest analysis was performed to evaluate how HF-rTMS exerts its effect., Results: After 4 weeks, 13 of 19 patients had already consumed alcohol. When abstainers were compared to patients who had relapsed, we found higher dorsal ACC (dACC) activation at baseline, but only during the blocked cue-exposure paradigm. The effects of HF-rTMS on dACC blood oxygen level-dependent response were negatively correlated with the baseline dACC activation. Due to susceptibility artifacts located at the ventral cortical aspects in 6 of our participants, reliable data were only obtained for the ACC., Conclusions: Our data indicate that higher baseline dACC activation may serve as a protective mechanism regarding relapse. For the first time, it is demonstrated that accelerated HF-rTMS treatment influences dACC activation in a rate-dependent manner: the lower the baseline dACC activation, the more dACC activity was increased after HF-rTMS treatment., (Copyright © 2016 by the Research Society on Alcoholism.)

In alcohol-dependent patients craving is a difficult-to-treat phenomenon. It has been suggested that high-frequency (HF) repetitive transcranial magnetic stimulation (rTMS) may have beneficial effects. However, exactly how this application exerts its effect on the underlying craving neurocircuit is currently unclear. In an effort to induce alcohol craving and to maximize detection of HF-rTMS effects to cue-induced alcohol craving, patients were exposed to a block and event-related alcohol cue-reactivity paradigm while being scanned with fMRI. Hence, we assessed the effect of right dorsolateral prefrontal cortex (DLPFC) stimulation on cue-induced and general alcohol craving, and the related craving neurocircuit. Twenty-six recently detoxified alcohol-dependent patients were included. First, we evaluated the impact of one sham-controlled stimulation session. Second, we examined the effect of accelerated right DLPFC HF-rTMS treatment: here patients received 15 sessions in an open label accelerated design, spread over 4 consecutive days. General craving significantly decreased after 15 active HF-rTMS sessions. However, cue-induced alcohol craving was not altered. Our brain imaging results did not show that the cue-exposure affected the underlying craving neurocircuit after both one and fifteen active HF-rTMS sessions. Yet, brain activation changes after one and 15 HF-rTMS sessions, respectively, were observed in regions associated with the extended reward system and the default mode network, but only during the presentation of the event-related paradigm. Our findings indicate that accelerated HF-rTMS applied to the right DLPFC does not manifestly affect the craving neurocircuit during an alcohol-related cue-exposure, but instead it may influence the attentional network.

Although numerous people grow up speaking more than one language, the impact of bilingualism on brain developing neuroanatomy is still poorly understood. This study aimed to determine whether the changes in the mean fractional-anisotropy (MFA) of language pathways are different between bilingual and monolingual children. Simultaneous-bilinguals, sequential-bilinguals and monolingual, male and female 10-13 years old children participated in this longitudinal study over a period of two years. We used diffusion tensor tractography to obtain mean fractional-anisotropy values of four language related pathways and one control bundle: 1-left-inferior-occipitofrontal fasciculus/lIFOF, 2-left-arcuate fasciculus/lAF/lSLF, 3-bundle arising from the anterior part of corpus-callosum and projecting to orbital lobe/AC-OL, 4-fibres emerging from anterior-midbody of corpus-callosum (CC) to motor cortices/AMB-PMC, 5- right-inferior-occipitofrontal fasciculus rIFOF as the control pathway unrelated to language. These values and their rate of change were compared between 3 groups. FA-values did not change significantly over two years for lAF/lSLF and AC-OL. Sequential-bilinguals had the highest degree of change in the MFA value of lIFOF, and AMB-PMC did not present significant group differences. The comparison of MFA of lIFOF yielded a significantly higher FA-value in simultaneous bilinguals compared to monolinguals. These findings acknowledge the existing difference of the development of the semantic processing specific pathway between children with different semantic processing procedure. These also support the hypothesis that age of second language acquisition affects the maturation and myelination of some language specific white-matter pathways.

Background: In their daily communication, bilinguals switch between two languages, a process that involves the selection of a target language and minimization of interference from a nontarget language. Previous studies have uncovered the neural structure in bilinguals and the activation patterns associated with performing verbal conflict tasks. One question that remains, however is whether this extra verbal switching affects brain function during nonverbal conflict tasks., Methods: In this study, we have used fMRI to investigate the impact of bilingualism in children performing two nonverbal tasks involving stimulus-stimulus and stimulus-response conflicts. Three groups of 8-11-year-old children--bilinguals from birth (2L1), second language learners (L2L), and a control group of monolinguals (1L1)--were scanned while performing a color Simon and a numerical Stroop task. Reaction times and accuracy were logged., Results: Compared to monolingual controls, bilingual children showed higher behavioral congruency effect of these tasks, which is matched by the recruitment of brain regions that are generally used in general cognitive control, language processing or to solve language conflict situations in bilinguals (caudate nucleus, posterior cingulate gyrus, STG, precuneus). Further, the activation of these areas was found to be higher in 2L1 compared to L2L., Conclusion: The coupling of longer reaction times to the recruitment of extra language-related brain areas supports the hypothesis that when dealing with language conflicts the specialization of bilinguals hampers the way they can process with nonverbal conflicts, at least at early stages in life.

Brain imaging studies have consistently shown subgenual Anterior Cingulate Cortical (sgACC) involvement in emotion processing. catechol-O-methyltransferase (COMT) Val(158) and Met(158) polymorphisms may influence such emotional brain processes in specific ways. Given that resting-state fMRI (rsfMRI) may increase our understanding on brain functioning, we integrated genetic and rsfMRI data and focused on sgACC functional connections. No studies have yet investigated the influence of the COMT Val(158)Met polymorphism (rs4680) on sgACC resting-state functional connectivity (rsFC) in healthy individuals. A homogeneous group of 61 Caucasian right-handed healthy female university students, all within the same age range, underwent rsfMRI. Compared to Met(158) homozygotes, Val(158) allele carriers displayed significantly stronger rsFC between the sgACC and the left parahippocampal gyrus, ventromedial parts of the inferior frontal gyrus (IFG), and the nucleus accumbens (NAc). On the other hand, compared to Val(158) homozygotes, we found in Met(158) allele carriers stronger sgACC rsFC with the medial frontal gyrus (MFG), more in particular the anterior parts of the medial orbitofrontal cortex. Although we did not use emotional or cognitive tasks, our sgACC rsFC results point to possible distinct differences in emotional and cognitive processes between Val(158) and Met(158) allele carriers. However, the exact nature of these directions remains to be determined.

Background: The affective personality trait 'harm avoidance' (HA) from Cloninger's psychobiological personality model determines how an individual deals with emotional stimuli. Emotional stimuli are processed by a neural network that include the left and right amygdalae as important key nodes. Explicit, implicit and passive processing of affective stimuli are known to activate the amygdalae differently reflecting differences in attention, level of detailed analysis of the stimuli and the cognitive control needed to perform the required task. Previous studies revealed that implicit processing or passive viewing of affective stimuli, induce a left amygdala response that correlates with HA. In this new study we have tried to extend these findings to the situation in which the subjects were required to explicitly process emotional stimuli., Methods: A group of healthy female participants was asked to rate the valence of positive and negative stimuli while undergoing fMRI. Afterwards the neural responses of the participants to the positive and to the negative stimuli were separately correlated to their HA scores and compared between the low and high HA participants., Results: Both analyses revealed increased neural activity in the left laterobasal (LB) amygdala of the high HA participants while they were rating the positive and the negative stimuli., Conclusions: Our results indicate that the left amygdala response to explicit processing of affective stimuli does correlate with HA.

Objectives: Intensified repetitive transcranial magnetic stimulation (rTMS) applied to the left dorsolateral prefrontal cortex (DLPFC) may result in fast clinical responses in treatment resistant depression (TRD). In these kinds of patients, subgenual anterior cingulate cortex (sgACC) functional connectivity (FC) seems to be consistently disturbed. So far, no de novo data on the relationship between sgACC FC changes and clinical efficacy of accelerated rTMS were available., Methods: Twenty unipolar TRD patients, all at least stage III treatment resistant, were recruited in a randomized sham-controlled crossover high-frequency (HF)-rTMS treatment study. Resting-state (rs) functional MRI scans were collected at baseline and at the end of treatment., Results: HF-rTMS responders showed significantly stronger resting-state functional connectivity (rsFC) anti-correlation between the sgACC and parts of the left superior medial prefrontal cortex. After successful treatment an inverted relative strength of the anti-correlations was observed in the perigenual prefrontal cortex (pgPFC). No effects on sgACC rsFC were observed in non-responders., Conclusions: Strong rsFC anti-correlation between the sgACC and parts of the left prefrontal cortex could be indicative of a beneficial outcome. Accelerated HF-rTMS treatment designs have the potential to acutely adjust deregulated sgACC neuronal networks in TRD patients.

Background: The left and right amygdalae are key regions distinctly involved in emotion-regulation processes. Individual differences, such as personality features, may affect the implicated neurocircuits. The lateralized amygdala affective processing linked with the temperament dimension Harm Avoidance (HA) remains poorly understood. Resting state functional connectivity imaging (rsFC) may provide more insight into these neuronal processes., Methods: In 56 drug-naive healthy female subjects, we have examined the relationship between the personality dimension HA on lateralized amygdala rsFC., Results: Across all subjects, left and right amygdalae were connected with distinct regions mainly within the ipsilateral hemisphere. Females scoring higher on HA displayed stronger left amygdala rsFC with ventromedial prefrontal cortical (vmPFC) regions involved in affective disturbances. In high HA scorers, we also observed stronger right amygdala rsFC with the dorsomedial prefrontal cortex (dmPFC), which is implicated in negative affect regulation., Conclusions: In healthy females, left and right amygdalae seem implicated in distinct mPFC brain networks related to HA and may represent a vulnerability marker for sensitivity to stress and anxiety (disorders).

Introduction: Although spinal cord stimulation (SCS) is a widely used treatment for chronic neuropathic pain secondary to spinal surgery, little is known about the underlying physiological mechanisms., Methods: The primary aim of this study is to investigate the neural substrate underlying short-term SCS by means of (1)H MR spectroscopy with short echo time, in 20 patients with failed back surgery syndrome., Results: Marked increase of γ-aminobutyric acid (GABA) and decrease in glucose in the ipsilateral thalamus were found between baseline situation without SCS and after 9' of SCS, indicating the key role of the ipsilateral thalamus as a mediator of chronic neuropathic pain. In addition, this study also showed a progressive decrease in glucose in the ipsilateral thalamus over time, which is in line with the findings of previous studies reporting deactivation in the ipsilateral thalamic region., Conclusions: The observation of GABA increase and glucose decrease over time in the ipsilateral thalamus may be the causal mechanism of the pain relief due to SCS or an epiphenomenon.

Depressive brooding - a passive ruminative focus on one's problems, negative mood and their consequences - is a thinking style that places individuals at a greater risk to develop future psychopathology. In this study, we investigated whether inter-individual differences in depressive brooding are related to neural differences underlying the inhibition of a dominant response towards negative information in favor of the concurrent (positive) response. To exclude the possibility that information processes would be confounded by sustained negative mood or enhanced stress responses, a sample of thirty never-depressed healthy individuals was selected. The Cued Emotional Control Task (CECT) was used to index the ability to enhance cognitive control when encountering a negative stimulus associated with an incompatible stimulus-response mapping. Individual brooding scores were not related to behavioral performances on the CECT. On the other hand, whole brain analyses demonstrated that trait depressive brooding scores were positively associated with activation in the posterior parts of the dorsal anterior cingulate cortex (pdACC) while successfully inhibiting a response to negative relative to positive information. These findings demonstrate that brooding minds need to recruit more pdACC activation when inhibiting a dominant response towards negative information (in favor of a response towards positive), although they are performing similarly as low brooders at the behavioral level. Future research should investigate whether and how these brooding related neural adjustments in healthy volunteers are related to future psychopathology., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Two different emotion regulation strategies, cognitive reappraisal and expressive suppression, are strongly associated with increased neural activity in the prefrontal cognitive control network. In this event-related fMRI study, we investigated whether individual differences in habitual reappraisal and suppression tendencies are related to differences in prefrontal cognitive control processes for emotional information. In order to measure cognitive control over inhibiting a dominant response to happy or sad stimuli (in favor of the opposite valence), thirty-one healthy female participants performed the Cued Emotional Conflict Task (CECT). The Emotion Regulation Questionnaire was used to measure individual differences in everyday use of emotion regulation. Results demonstrate that high reappraisers are behaviorally faster and exert more fronto-cingulate activity when inhibiting a response to sad faces (compared to happy faces, FDR corrected). On the other hand, suppression scores are not correlated with performance to CECT trials. Interestingly, suppression scores are associated with higher amygdala activation during the inhibition of a response to sad faces (compared to happy faces). These data suggest that habitual reappraisal is associated with underlying functional cognitive control processes to inhibit a dominant response to negative material. In contrast, the effort to control negative material has negative consequences in individuals who have a tendency to suppress emotions., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Diffusion weighted imaging sequences are now widely available on Magnetic Resonance Imaging (MRI) scanners. Diffusion Tensor Imaging (DTI) of the brain is able to show white matter tracts and is now commonly used in human medicine to study brain anatomy, tumors, structural pathways,… The purpose of this study was to show the interest of DTI to reveal the white matter fibers in the dogs' brain. DTI MR Images for this study were obtained with a 3 T system of 4 dogs euthanized for other reasons than neurological disorders. Combined fractional anisotropic (FA) and directional maps were obtained in the first 2 hours after death. The heads were amputated immediately after scanning and stored in 10% formalin until preparation for dissection. An experienced anatomist tracked white matter tracts with clinical relevance using the scanner software. The selected tracts were REFVIDume rendered and correlated with gross dissection. Using DTI we were able to track relevant neurological connections, such as the corticospinal tract, the optic and the cerebellar tract. The three dimensional anatomy is better presented using modern visualization techniques. DTI seems to be a valuable tool in order to present clinically relevant white matter tracts to neurological clinicians and researchers., (Copyright © 2012 Wiley Periodicals, Inc.)

The amygdalae are key players in the processing of a variety of emotional stimuli. Especially aversive visual stimuli have been reported to attract attention and activate the amygdalae. However, as it has been argued that passively viewing withdrawal-related images could attenuate instead of activate amygdalae neuronal responses, its role under passive viewing conditions remains unclear. Furthermore, because individual sensitivity to stress reactions has been shown to modulate amygdalae processing, the aim of the current event-related fMRI study was to investigate whether individual differences in stress proneness could influence amygdala responses while passively viewing withdrawal and approach-related visual images. We presented 14 healthy female subjects with a random sequence of images of happy 'healthy' baby faces (approach-related) and baby faces disfigured by severe dermatological conditions (withdrawal-related). No instructions were given other than to watch the images attentively. We integrated individual perceived stress (PSS) scores in our analysis. The processing of withdrawal-related pictures resulted in less left amygdala activity in females scoring higher on perceived stress. Our findings suggest that stress-sensitive healthy females are less able to fully attend to withdrawal-related visual material and in essence avoid exposure to such images in an effort to reduce strong psychophysiological responses. Although the relatively small number of participants limits drawing firm conclusions, we suggest that in passive viewing emotional brain imaging paradigms, individual information on stress proneness should be included in the interpretation of amygdala neuronal processes., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Events coupled with an emotional context seem to be better retained than non-emotional events. The aim of our study was to investigate whether an emotional context could influence the neural substrates of memory associations with novel portrait art stimuli. In the current prospective fMRI study, we have investigated for one specific visual art form (modern artistic portraits with a high degree of abstraction) whether memory is influenced by priming with emotional facial pictures. In total forty healthy female volunteers in the same age range were recruited for the study. Twenty of these women participated in a prospective brain imaging memory paradigm and were asked to memorize a series of similar looking, but different portraits. After randomization, for twelve participants (Group 1), a third of the portraits was emotionally primed with approach-related pictures (smiling baby faces), a third with withdrawal-related pictures (baby faces with severe dermatological conditions), and another third with neutral images. Group 2 consisted of eight participants and they were not primed. Then, during an fMRI session 2h later, these portraits were viewed in random order intermixed with a set of new (previously unseen) ones, and the participants had to decide for each portrait whether or not they had already been seen. In a separate experiment, a different sample of twenty healthy females (Group 3) rated their mood after being exposed to the same art stimuli, without priming. The portraits did not evoke significant mood changes by themselves, supporting their initial neutral emotional character (Group 3). The correct decision on whether the portraits were Familiar of Unfamiliar led to similar neuronal activations in brain areas implicated in visual and attention processing for both groups (Groups 1 and 2). In contrast, whereas primed participants showed significant higher neuronal activities in the left midline superior frontal cortex (Brodmann area (BA) 6), unprimed volunteers displayed higher right medial frontal cortical (BA 10) activities. Furthermore, specifically in Group 1, correct retrieval of negatively primed portraits evoked increased neuronal activity in the left medial orbitofrontal cortex (BA 11) and in the right (posterior) insula, suggesting enhanced stress-related responses to the memory of withdrawal-related primed modern artistic portraits in this group. Our prospective memory data in healthy females indicate that, to reach a correct retrieval decision, different midline anterior neuronal networks are recruited for portraits that were emotionally primed than for the unprimed ones. Importantly, our results also suggest that the negative emotional context leads to the formation of associations that are reactivated during memory retrieval processes of the initially neutral art portraits. When correctly recognized, the portraits evoke neuronal activities consistent with the withdrawal-related character of the emotional visual stimuli with which they have been associated. Although our results show that abstract portrait art can be associated with emotional primes this doesn't mean that this effect is specific for art images., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Object: Spinal cord stimulation (SCS) is a well-known treatment option for intractable neuropathic pain after spinal surgery, but its pathophysiological mechanisms are poorly stated. The goal of this study is to analyse the feasibility of using brain MRI, functional MRI (fMRI) and Magnetic Resonance Spectroscopy (MRS) as tools to analyse these mechanisms in patients with externalised neurostimulators during trial period., Methods: The authors conducted in an in vitro and in vivo study analysing safety issues when performing brain MRI, fMRI and MRS investigations in human subjects with externalised SCS. Temperature measurements in vitro were performed simulating SCS during MRI sequences using head transmit-receive coils in 1.5 and 3 T MRI systems. 40 Patients with externalised SCS were included in the in vivo study. 20 patients underwent brain MRI, fMRI and another 20 patients underwent brain MRI and MRS., Results: A maximal temperature increase of 0.2°C was measured and neither electrode displacements nor hardware failures were observed. None of the patients undergoing the MRS sequences at the 1.5 or 3 T MRI scanners described any discomfort or unusual sensations., Conclusion: We can conclude that brain MRI, fMRI and MRS studies performed in patients with externalised SCS can be safely executed., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The impact of bilingualism on the microstructure of the white matter pathways related to language processing is assessed in elementary school children by magnetic resonance diffusion tensor imaging (MR-DTI). Forty children, 8-11 years old, subdivided into 3 different groups (15 simultaneous bilinguals, 15 sequential bilinguals and 10 monolinguals), were scanned. The hypothesis was that the starting age and the manner of second language acquisition would affect the characteristics of language circuitry. In each subject the mean fractional anisotropy (FA) was obtained for four major white matter pathways: 1 - the left arcuate fasciculus/superior longitudinal fasciculus (lAF/lSLF) that connects Broca's area in the opercular and triangular regions of the left inferior frontal gyrus to the posterior language zone, 2 - the left inferior occipitofrontal fasciculus (lIFOF), connecting anterior regions in the frontal lobe with posterior regions in the temporal occipital lobes, 3 - the bundle arising from the anterior part of the corpus callosum projecting to the orbital lobe (AC-OL) and 4 - the fibers emerging from the anterior midbody (AMB) of the corpus callosum that associate with the premotor and supplementary motor cortices (AMB-PMC). The three groups did not show significant differences in mean FA over the lAF/lSLF or AMB-PMC tracts. In simultaneous bilingual subjects the lIFOF tracts had higher mean FA value compared to monolinguals and also sequential bilinguals, whereas the comparison for the AC-OL fibers yielded a significantly lower mean FA value in simultaneous bilingual subjects compared to monolinguals. In both cases the FA value for sequential bilinguals was intermediate to that of the other two groups. To our knowledge, this study provides the first evidence of bilingualism related adaptation of white matter microstructure in the human brain., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The psychobiological personality model of Cloninger distinguishes four heritable temperament traits (harm avoidance (HA), novelty seeking (NS), reward dependence (RD) and persistence (P)) and three character traits (self-directedness (SD), cooperativeness (CO) and self-transcendence (ST)) which develop during lifetime. Prior research already showed that individual differences in temperament are reflected in structural variances in specific brain areas. In this study, we used voxel-based morphometry (VBM) to correlate the different temperament and character traits with local gray and white matter volumes (GMV and WMV) in young healthy female volunteers. We found correlations between the temperament traits and GMV and WMV in the frontal, temporal and limbic regions involved in controlling and generating the corresponding behavior as proposed in Cloninger's theory: anxious for HA, impulsive for NS, reward-directed for RD and goal-directed for P. The character traits correlated with GMV and WMV in the frontal, temporal and limbic regions involved in the corresponding cognitive tasks: self-reflection for SD, mentalizing and empathizing with others for CO and religious belief for ST. This study shows that individual variations in brain morphology can be related to the temperament and character dimensions, and lends support to the hypothesis of a neurobiological basis of personality traits., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Current evidence concerning the neurocircuitry underlying the interplay between attention and emotion is mainly correlational. We used high-frequency repetitive Transcranial Magnetic Stimulation (HF-rTMS) to experimentally manipulate activity within the right or left dorsolateral prefrontal cortex (DLPFC) of healthy women and examined changes in attentional processing of emotional information using an emotional modification of the exogenous cueing task during event-related fMRI. Right prefrontal HF-rTMS resulted in impaired disengagement from angry faces, associated with decreased activation within the right DLPFC, dorsal anterior cingulate cortex (dACC) and left superior parietal gyrus, combined with increased activity within the right amygdala. Left prefrontal HF-rTMS resulted in diminished attentional engagement by angry faces and was associated with increased activity within the right DLPFC, dACC, right superior parietal gyrus and left orbitofrontal cortex. The present observations are in line with reports of a functionally interactive network of cortical-limbic pathways that play a central role in emotion regulation., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Although repetitive Transcranial Magnetic Stimulation (rTMS) is frequently used to examine emotional changes in healthy volunteers, it remains largely unknown how rTMS is able to influence emotion.We carried out a sham-controlled single-blind crossover study using fMRI, we examined in 20 right-handed healthy female volunteers whether a single high frequency (HF)-rTMS session applied to the left dorsolateral prefrontal cortex (DLPFC) could influence emotional processing while focussing on blocks of positively and negatively valenced baby faces. A single HF-rTMS session selectively influenced the processing of positively and negatively valenced baby faces. In essence, our results indicate that the effects of one left-sided HF-rTMS sessions results in improved processing of positive emotions and reduced negative emotional processing in never depressed female subjects.

The amygdalae play an important role in the evaluation and processing of emotionally salient visual stimuli. However, individual differences in personality traits, such as Harm Avoidance (HA), have been reported to influence emotional amygdalae responses. To trigger strong approach and withdrawal-related emotions in 'never depressed' young female subjects under fMRI, we presented them with blocks of happy 'healthy' baby faces and baby faces disfigured by severe dermatological conditions and we integrated the temperament dimension HA into our analysis. No other instructions were given than to watch the images attentively. Only in withdrawal-related emotional experience, we observed a negative correlation between HA and left amygdala activity, suggesting that during passive viewing females scoring higher on HA 'avoid' images with highly aversive content. When investigating the amygdala's emotional role in passive viewing paradigms, personality features such as HA should be taken into account., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

Transcranial magnetic stimulation (TMS) is currently used as a non-invasive treatment for depression. In most clinical trials, the left dorsolateral prefrontal cortex (DLPFC) has been selected as the target site for TMS treatment and this region is commonly determined by a "standard procedure", using a fixed position with respect to the motor cortex. In this study, to evaluate the relevance of using individual anatomical data during coil positioning, we used a more individualized localization method, based on three-dimensional magnetic resonance imaging of the head (3D-MRI). We wanted to examine the intra-individual variability of the localization of the stimulation area using a method taking into account individual brain anatomy by 3D-MRI, by comparing this method to the "standard procedure". As expected, even in a gender-controlled sample, our results demonstrate that the difference between the anatomical localization and the standard procedure of a well-defined part of the prefrontal cortex varies within subjects. Therefore, our results confirm the need for a TMS-coil positioning method which incorporates individual anatomical information.

Research regarding the lateralization of processing emotional visual stimuli suggests various roles for affective information-processing by the amygdalae. However, individual differences seem to influence outcome results. In this study we re-investigate this question, paying special attention to the salient nature of the mood inducing stimuli. We presented blocks of happy looking baby faces and sad looking baby faces (disfigured by severe dermatological conditions), as well as blurred isoluminescent neutral pictures to a 'homogeneous' group of 40 healthy female subjects during fMRI. We used the temperament dimension harm avoidance (HA), extracted from the Temperament and Character Inventory (TCI), to evaluate the impact of this personality feature on 'emotional' amygdala responses. HA is related to behavioral inhibition and it implies a genetically determined bias towards being cautious, apprehensive and overly pessimistic. Because emotional valence and arousal may be controlled by different neural systems, the positively and negatively valenced baby faces were selected to be equal in arousal levels. Viewing blocks of negatively valenced baby faces evoked bilateral amygdala activity, whereas viewing positively valenced ones resulted in left amygdala activity only. Globally, we found no evidence of lateralized amygdala specialization. When taking into account individual differences in HA, only in female subjects who score high on this dimension did we find predominantly left amygdala activation when viewing blocks of negatively valenced baby faces. HA did not influence amygdala activity when processing positively valenced images. Our results might indicate that personality features, such as HA, could be of importance in 'emotional' fMRI paradigms examining amygdala lateralization patterns.