Prior-guided individualized thalamic parcellation based on local diffusion characteristics.

Comprising numerous subnuclei, the thalamus intricately interconnects the cortex and subcortex, orchestrating various facets of brain functions. Extracting personalized parcellation patterns for these subnuclei is crucial, as different thalamic nuclei play varying roles in cognition and serve as therapeutic targets for neuromodulation. However, accurately delineating the thalamic nuclei boundary at the individual level is challenging due to intersubject variability. In this study, we proposed a prior-guided parcellation (PG-par) method to achieve robust individualized thalamic parcellation based on a central-boundary prior. We first constructed probabilistic atlas of thalamic nuclei using high-quality diffusion MRI datasets based on the local diffusion characteristics. Subsequently, high-probability voxels in the probabilistic atlas were utilized as prior guidance to train unique multiple classification models for each subject based on a multilayer perceptron. Finally, we employed the trained model to predict the parcellation labels for thalamic voxels and construct individualized thalamic parcellation. Through a test-retest assessment, the proposed prior-guided individualized thalamic parcellation exhibited excellent reproducibility and the capacity to detect individual variability. Compared with group atlas registration and individual clustering parcellation, the proposed PG-par demonstrated superior parcellation performance under different scanning protocols and clinic settings. Furthermore, the prior-guided individualized parcellation exhibited better correspondence with the histological staining atlas. The proposed prior-guided individualized thalamic parcellation method contributes to the personalized modeling of brain parcellation.

Spatio-molecular profiles shape the human cerebellar hierarchy along the sensorimotor-association axis.

Cerebellar involvement in both motor and non-motor functions manifests in specific regions of the human cerebellum, revealing the functional heterogeneity within it. One compelling theory places the heterogeneity within the cerebellar functional hierarchy along the sensorimotor-association (SA) axis. Despite extensive neuroimaging studies, evidence for the cerebellar SA axis from different modalities and scales was lacking. Thus, we establish a significant link between the cerebellar SA axis and spatio-molecular profiles. Utilizing the gene set variation analysis, we find the intermediate biological principles the significant genes leveraged to scaffold the cerebellar SA axis. Interestingly, we find these spatio-molecular profiles notably associated with neuropsychiatric dysfunction and recent evolution. Furthermore, cerebello-cerebral interactions at genetic and functional connectivity levels mirror the cerebral cortex and cerebellum's SA axis. These findings can provide a deeper understanding of how the human cerebellar SA axis is shaped and its role in transitioning from sensorimotor to association functions.

Brain stimulation with 40 Hz heterochromatic flicker extended beyond red, green, and blue.

Alzheimer's disease (AD) is associated with electrophysiological changes in the brain. Pre-clinical and early clinical trials have shown promising results for the possible therapy of AD with 40 Hz neurostimulation. The most notable findings used stroboscopic flicker, but this technique poses an inherent barrier for human applications due to its visible flickering and resulting high level of perceived discomfort. Therefore, alternative options should be investigated for entraining 40 Hz brain activity with light sources that appear less flickering. Previously, chromatic flicker based on red, green, and blue (RGB) have been studied in the context of brain-computer interfaces, but this is an incomplete representation of the colours in the visual spectrum. This study introduces a new kind of heterochromatic flicker based on spectral combinations of blue, cyan, green, lime, amber, and red (BCGLAR). These combinations are investigated by the steady-state visually evoked potential (SSVEP) response from the flicker with an aim of optimising the choice of 40 Hz light stimulation with spectrally similar colour combinations in BCGLAR space. Thirty healthy young volunteers were stimulated with heterochromatic flicker in an electroencephalography experiment with randomised complete block design. Responses were quantified as the 40 Hz signal-to-noise ratio and analysed using mixed linear models. The size of the SSVEP response to heterochromatic flicker is dependent on colour combinations and influenced by both visual and non-visual effects. The amber-red flicker combination evoked the highest SSVEP, and combinations that included blue and/or red consistently evoked higher SSVEP than combinations only with mid-spectrum colours. Including a colour from either extreme of the visual spectrum (blue and/or red) in at least one of the dyadic phases appears to be more important than choosing pairs of colours that are far from each other on the visual spectrum. Spectrally adjacent colour pairs appear less flickering to the perceiver, and thus the results motivate investigations into the limits for how alike the two phases can be and still evoke a 40 Hz response. Specifically, combining a colour on either extreme of the visual spectrum with another proximal colour might provide the best trade-off between flickering sensation and SSVEP magnitude.

End-to-end volumetric segmentation of white matter hyperintensities using deep learning.

BACKGROUND AND OBJECTIVES: Reliable detection of white matter hyperintensities (WMH) is crucial for studying the impact of diffuse white-matter pathology on brain health and monitoring changes in WMH load over time. However, manual annotation of 3D high-dimensional neuroimages is laborious and can be prone to biases and errors in the annotation procedure. In this study, we evaluate the performance of deep learning (DL) segmentation tools and propose a novel volumetric segmentation model incorporating self-attention via a transformer-based architecture. Ultimately, we aim to evaluate diverse factors that influence WMH segmentation, aiming for a comprehensive analysis of the state-of-the-art algorithms in a broader context. METHODS: We trained state-of-the-art DL algorithms, and incorporated advanced attention mechanisms, using structural fluid-attenuated inversion recovery (FLAIR) image acquisitions. The anatomical MRI data utilized for model training was obtained from healthy individuals aged 62-70 years in the Live active Successful Aging (LISA) project. Given the potential sparsity of lesion volume among healthy aging individuals, we explored the impact of incorporating a weighted loss function and ensemble models. To assess the generalizability of the studied DL models, we applied the trained algorithm to an independent subset of data sourced from the MICCAI WMH challenge (MWSC). Notably, this subset had vastly different acquisition parameters compared to the LISA dataset used for training. RESULTS: Consistently, DL approaches exhibited commendable segmentation performance, achieving the level of inter-rater agreement comparable to expert performance, ensuring superior quality segmentation outcomes. On the out of sample dataset, the ensemble models exhibited the most outstanding performance. CONCLUSIONS: DL methods generally surpassed conventional approaches in our study. While all DL methods performed comparably, incorporating attention mechanisms could prove advantageous in future applications with a wider availability of training data. As expected, our experiments indicate that the use of ensemble-based models enables the superior generalization in out-of-distribution settings. We believe that introducing DL methods in the WHM annotation workflow in heathy aging cohorts is promising, not only for reducing the annotation time required, but also for eventually improving accuracy and robustness via incorporating the automatic segmentations in the evaluation procedure.

Individualized brain mapping for navigated neuromodulation.

ABSTRACT: The brain is a complex organ that requires precise mapping to understand its structure and function. Brain atlases provide a powerful tool for studying brain circuits, discovering biological markers for early diagnosis, and developing personalized treatments for neuropsychiatric disorders. Neuromodulation techniques, such as transcranial magnetic stimulation and deep brain stimulation, have revolutionized clinical therapies for neuropsychiatric disorders. However, the lack of fine-scale brain atlases limits the precision and effectiveness of these techniques. Advances in neuroimaging and machine learning techniques have led to the emergence of stereotactic-assisted neurosurgery and navigation systems. Still, the individual variability among patients and the diversity of brain diseases make it necessary to develop personalized solutions. The article provides an overview of recent advances in individualized brain mapping and navigated neuromodulation and discusses the methodological profiles, advantages, disadvantages, and future trends of these techniques. The article concludes by posing open questions about the future development of individualized brain mapping and navigated neuromodulation.

Study on the effect of 40 Hz non-invasive light therapy system. A protocol for a randomized, double-blinded, placebo-controlled clinical trial.

Introduction: With no cure or effective treatment, the prevalence of patients with Alzheimer's disease (AD) is expected to intensify, thereby increasing the social and financial burden on society. Light-based 40 Hz brain stimulation is considered a novel treatment strategy for patients with AD that may alleviate some of this burden. The clinical trial ALZLIGHT will utilize a novel Light Therapy System (LTS). The LTS uses Invisible Spectral Flicker for non-invasive induction of 40 Hz neural activity. This protocol describes a trial evaluating the efficacy and safety of a light-based 40 Hz brain stimulation in patients with mild-to-moderate AD. Methods: 62 patients with mild-to-moderate AD will participate in a randomized, double-blinded, placebo-controlled, parallel-group, and single-center trial. The participants will partake in an enrollment period of 1 month, an intervention period of 6 months, and a 1.5-month post-interventional follow-up period. Prior to the baseline measurement (week 0), the patients will be randomized to either active or placebo intervention from baseline (week 0) to post-intervention follow-up (week 26). Discussion: This protocol describes a randomized, double-blinded, placebo-controlled clinical trial that may increase the understanding of the effect of gamma oscillations in the human brain and how it could be utilized as a novel and important tool for the treatment of AD. The effect is measured through a large, multidisciplinary assessment battery.Clinical trial registration:www.ClinicalTrials.gov, (NCT05260177). Registered on March 2, 2022.

Executive Control and Associated Brain Activity in Children With Familial High-Risk of Schizophrenia or Bipolar Disorder: A Danish Register-based Study.

BACKGROUND AND HYPOTHESES: Impaired executive control is a potential prognostic and endophenotypic marker of schizophrenia (SZ) and bipolar disorder (BP). Assessing children with familial high-risk (FHR) of SZ or BP enables characterization of early risk markers and we hypothesize that they express impaired executive control as well as aberrant brain activation compared to population-based control (PBC) children. STUDY DESIGN: Using a flanker task, we examined executive control together with functional magnetic resonance imaging (fMRI) in 11- to 12-year-old children with FHR of SZ (FHR-SZ) or FHR of BP (FHR-BP) and PBC children as part of a register-based, prospective cohort-study; The Danish High Risk and Resilience study-VIA 11. STUDY RESULTS: We included 85 (44% female) FHR-SZ, 63 (52% female) FHR-BP and 98 (50% female) PBC in the analyses. Executive control effects, caused by the spatial visuomotor conflict, showed no differences between groups. Bayesian ANOVA of reaction time (RT) variability, quantified by the coefficient of variation (CVRT), revealed a group effect with similarly higher CVRT in FHR-BP and FHR-SZ compared to PBC (BF10 = 6.82). The fMRI analyses revealed no evidence for between-group differences in task-related brain activation. Post hoc analyses excluding children with psychiatric illness yielded same results. CONCLUSION: FHR-SZ and FHR-BP at age 11-12 show intact ability to resolve a spatial visuomotor conflict and neural efficacy. The increased variability in RT may reflect difficulties in maintaining sustained attention. Since variability in RT was independent of existing psychiatric illness, it may reflect a potential endophenotypic marker of risk.

Evaluating the influence of anatomical accuracy and electrode positions on EEG forward solutions.

Generating realistic volume conductor models for forward calculations in electroencephalography (EEG) is not trivial and several factors contribute to the accuracy of such models, two of which are its anatomical accuracy and the accuracy with which electrode positions are known. Here, we investigate effects of anatomical accuracy by comparing forward solutions from SimNIBS, a tool which allows state-of-the-art anatomical modeling, with well-established pipelines in MNE-Python and FieldTrip. We also compare different ways of specifying electrode locations when digitized positions are not available such as transformation of measured positions from standard space and transformation of a manufacturer layout. Substantial effects of anatomical accuracy were seen throughout the entire brain both in terms of field topography and magnitude with SimNIBS generally being more accurate than the pipelines in MNE-Python and FieldTrip. Topographic and magnitude effects were particularly pronounced for MNE-Python which uses a three-layer boundary element method (BEM) model. We attribute these mainly to the coarse representation of the anatomy used in this model, in particular differences in skull and cerebrospinal fluid (CSF). Effects of electrode specification method were evident in occipital and posterior areas when using a transformed manufacturer layout whereas transforming measured positions from standard space generally resulted in smaller errors. We suggest modeling the anatomy of the volume conductor as accurately possible and we hope to facilitate this by making it easy to export simulations from SimNIBS to MNE-Python and FieldTrip for further analysis. Likewise, if digitized electrode positions are not available, a set of measured positions on a standard head template may be preferable to those specified by the manufacturer.

Dynamic involvement of premotor and supplementary motor areas in bimanual pinch force control.

Many activities of daily living require quick shifts between symmetric and asymmetric bimanual actions. Bimanual motor control has been mostly studied during continuous repetitive tasks, while little research has been carried out in experimental settings requiring dynamic changes in motor output generated by both hands. Here, we performed functional magnetic resonance imaging (MRI) while healthy volunteers performed a visually guided, bimanual pinch force task. This enabled us to map functional activity and connectivity of premotor and motor areas during bimanual pinch force control in different task contexts, requiring mirror-symmetric or inverse-asymmetric changes in discrete pinch force exerted with the right and left hand. The bilateral dorsal premotor cortex showed increased activity and effective coupling to the ipsilateral supplementary motor area (SMA) in the inverse-asymmetric context compared to the mirror-symmetric context of bimanual pinch force control while the SMA showed increased negative coupling to visual areas. Task-related activity of a cluster in the left caudal SMA also scaled positively with the degree of synchronous initiation of bilateral pinch force adjustments, irrespectively of the task context. The results suggest that the dorsal premotor cortex mediates increasing complexity of bimanual coordination by increasing coupling to the SMA while SMA provides feedback about motor actions to the sensory system.

Safety, Feasibility, and Potential Clinical Efficacy of 40 Hz Invisible Spectral Flicker versus Placebo in Patients with Mild-to-Moderate Alzheimer's Disease: A Randomized, Placebo-Controlled, Double-Blinded, Pilot Study.

BACKGROUND: Recent studies suggested induction of 40 Hz neural activity as a potential treatment for Alzheimer's disease (AD). However, prolonged exposure to flickering light raises adherence and safety concerns, encouraging investigation of tolerable light stimulation protocols. OBJECTIVE: To investigate the safety, feasibility, and exploratory measures of efficacy. METHODS: This two-stage randomized placebo-controlled double-blinded clinical trial, recruited first cognitive healthy participants (n = 3/2 active/placebo), and subsequently patients with mild-to-moderate AD (n = 5/6, active/placebo). Participants were randomized 1:1 to receive either active intervention with 40 Hz Invisible Spectral Flicker (ISF) or placebo intervention with color and intensity matched non-flickering white light. RESULTS: Few and mild adverse events were observed. Adherence was above 86.1% of intended treatment days, with participants remaining in front of the device for >51.3 min (60 max) and directed gaze >34.9 min. Secondary outcomes of cognition indicate a tendency towards improvement in the active group compared to placebo (mean: -2.6/1.5, SD: 6.58/6.53, active/placebo) at week 6. Changes in hippocampal and ventricular volume also showed no tendency of improvement in the active group at week 6 compared to placebo. At week 12, a potential delayed effect of the intervention was seen on the volume of the hippocampus in the active group compared to placebo (mean: 0.34/-2.03, SD: 3.26/1.18, active/placebo), and the ventricular volume active group (mean: -0.36/2.50, SD: 1.89/2.05, active/placebo), compared to placebo. CONCLUSION: Treatment with 40 Hz ISF offers no significant safety or adherence concerns. Potential impact on secondary outcomes must be tested in larger scale clinical trials.

Get to grips with motivation: Slipping and gripping movements are biased by approach-avoidance context.

People are better at approaching appetitive cues signaling reward and avoiding aversive cues signaling punishment than vice versa. This action bias has previously been shown in approach-avoidance tasks involving arm movements in response to appetitive or aversive cues. It is not known whether appetitive or aversive stimuli also bias more distal dexterous actions, such as gripping and slipping, in a similar manner. To test this hypothesis, we designed a novel task involving grip force control (gripping and slipping) to probe gripping-related approach and avoidance behavior. 32 male volunteers, aged 18-40 years, were instructed to either grip ("approach") or slip ("avoid") a grip-force device with their right thumb and index finger at the sight of positive or negative images. In one version of this pincer grip task, participants were responding to graspable objects and in another version of the task they were responding to happy or angry faces. Bayesian repeated measures Analysis of variance revealed extreme evidence for an interaction between response type and cue valence (Bayes factor = 296). Participants were faster to respond in affect-congruent conditions ("approach appetitive," "avoid aversive") than in affect-incongruent conditions ("approach aversive," "avoid appetitive"). This bias toward faster response times for affect-congruent conditions was present regardless of whether it was a graspable object or a face signaling valence. Since our results mirror the approach and avoidance effects previously observed for arm movements, we conclude that a tendency favoring affectively congruent cue-response mappings is an inherent feature of motor control and thus also includes precision grip.

Novel Invisible Spectral Flicker Induces 40 Hz Neural Entrainment with Similar Spatial Distribution as 40 Hz Stroboscopic Light.

BACKGROUND: Exposure to 40 Hz stroboscopic light, for one hour a day, has previously been published as a potential treatment option for Alzheimer's disease in animal models. However, exposure for an hour a day to 40 Hz stroboscopic light can be strenuous and examining other types of 40 Hz inducing stimuli is paramount if chronic treatment is wanted. OBJECTIVE: A core assumption behind ensuring a therapeutic outcome is that the visual stimuli can induce 40 Hz gamma entrainment. Here, we examine whether a specific visual stimulus, 40 Hz invisible spectral flicker (ISF), can induce gamma entrainment and how it differs from both continuous light (CON) and 40 Hz stroboscopic light (STROBE). METHODS: The study included non-simultaneous EEG-fMRI neuroimaging of 13 young healthy volunteers during light exposure. Each light condition (i.e., CON, ISF, or STROBE) was active for 30 seconds followed immediately by the next. RESULTS: Entrainment of 40 Hz neural activity were significantly higher signal-to-noise ratio during exposure to ISF (mean: 3.03, 95% CI 2.07 to 3.99) and STROBE (mean: 12.04, 95% CI 10.18 to 13.87) compared to CON. Additionally STROBE had a higher entrainment than ISF (mean: 9.01, 95% CI 7.16 to 12.14). CONCLUSION: This study presents a novel method of 40 Hz entrainment using ISF. This enables the possibility of future randomized placebo-controlled clinical trials with acceptable double blinding due to the essentially imperceivable flicker, which is expected to substantially reduce discomfort compared to interventions with stroboscopic flicker.

Uncovering the genetic profiles underlying the intrinsic organization of the human cerebellum.

The functional diversity of the human cerebellum is largely believed to be derived more from its extensive connections rather than being limited to its mostly invariant architecture. However, whether and how the determination of cerebellar connections in its intrinsic organization interact with microscale gene expression is still unknown. Here we decode the genetic profiles of the cerebellar functional organization by investigating the genetic substrates simultaneously linking cerebellar functional heterogeneity and its drivers, i.e., the connections. We not only identified 443 network-specific genes but also discovered that their co-expression pattern correlated strongly with intra-cerebellar functional connectivity (FC). Ninety of these genes were also linked to the FC of cortico-cerebellar cognitive-limbic networks. To further discover the biological functions of these genes, we performed a "virtual gene knock-out" by observing the change in the coupling between gene co-expression and FC and divided the genes into two subsets, i.e., a positive gene contribution indicator (GCI+) involved in cerebellar neurodevelopment and a negative gene set (GCI-) related to neurotransmission. A more interesting finding is that GCI- is significantly linked with the cerebellar connectivity-behavior association and many recognized brain diseases that are closely linked with the cerebellar functional abnormalities. Our results could collectively help to rethink the genetic substrates underlying the cerebellar functional organization and offer possible micro-macro interacted mechanistic interpretations of the cerebellum-involved high order functions and dysfunctions in neuropsychiatric disorders.

Does pericentral mu-rhythm "power" corticomotor excitability? - A matter of EEG perspective.

BACKGROUND: Electroencephalography (EEG) and single-pulse transcranial magnetic stimulation (spTMS) of the primary motor hand area (M1-HAND) have been combined to explore whether the instantaneous expression of pericentral mu-rhythm drives fluctuations in corticomotor excitability, but this line of research has yielded diverging results. OBJECTIVES: To re-assess the relationship between the mu-rhythm power expressed in left pericentral cortex and the amplitude of motor potentials (MEP) evoked with spTMS in left M1-HAND. METHODS: 15 non-preselected healthy young participants received spTMS to the motor hot spot of left M1-HAND. Regional expression of mu-rhythm was estimated online based on a radial source at motor hotspot and informed the timing of spTMS which was applied either during epochs belonging to the highest or lowest quartile of regionally expressed mu-power. Using MEP amplitude as dependent variable, we computed a linear mixed-effects model, which included mu-power and mu-phase at the time of stimulation and the inter-stimulus interval (ISI) as fixed effects and subject as a random effect. Mu-phase was estimated by post-hoc sorting of trials into four discrete phase bins. We performed a follow-up analysis on the same EEG-triggered MEP data set in which we isolated mu-power at the sensor level using a Laplacian montage centered on the electrode above the M1-HAND. RESULTS: Pericentral mu-power traced as radial source at motor hot spot did not significantly modulate the MEP, but mu-power determined by the surface Laplacian did, showing a positive relation between mu-power and MEP amplitude. In neither case, there was an effect of mu-phase on MEP amplitude. CONCLUSION: The relationship between cortical oscillatory activity and cortical excitability is complex and minor differences in the methodological choices may critically affect sensitivity.

The Myelin Content of the Human Precentral Hand Knob Reflects Interindividual Differences in Manual Motor Control at the Physiological and Behavioral Level.

The primary motor cortex hand area (M1HAND) and adjacent dorsal premotor cortex (PMd) form the so-called motor hand knob in the precentral gyrus. M1HAND and PMd are critical for dexterous hand use and are densely interconnected via corticocortical axons, lacking a sharp demarcating border. In 24 young right-handed volunteers, we performed multimodal mapping to delineate the relationship between structure and function in the right motor hand knob. Quantitative structural magnetic resonance imaging (MRI) at 3 tesla yielded regional R1 maps as a proxy of cortical myelin content. Participants also underwent functional MRI (fMRI). We mapped task-related activation and temporal precision, while they performed a visuomotor synchronization task requiring visually cued abduction movements with the left index or little finger. We also performed sulcus-aligned transcranial magnetic stimulation of the motor hand knob to localize the optimal site (hotspot) for evoking a motor evoked potential (MEP) in two intrinsic hand muscles. Individual motor hotspot locations varied along the rostrocaudal axis. The more rostral the motor hotspot location in the precentral crown, the longer were corticomotor MEP latencies. "Hotspot rostrality" was associated with the regional myelin content in the precentral hand knob. Cortical myelin content also correlated positively with task-related activation of the precentral crown and temporal precision during the visuomotor synchronization task. Together, our results suggest a link among cortical myelination, the spatial cortical representation, and temporal precision of finger movements. We hypothesize that the myelination of cortical axons facilitates neuronal integration in PMd and M1HAND and, hereby, promotes the precise timing of movements.SIGNIFICANCE STATEMENT Here we used magnetic resonance imaging and transcranial magnetic stimulation of the precentral motor hand knob to test for a link among cortical myelin content, functional corticomotor representations, and manual motor control. A higher myelin content of the precentral motor hand knob was associated with more rostral corticomotor presentations, with stronger task-related activation and a higher precision of movement timing during a visuomotor synchronization task. We propose that a high precentral myelin content enables fast and precise neuronal integration in M1 (primary motor cortex) and dorsal premotor cortex, resulting in higher temporal precision during dexterous hand use. Our results identify the degree of myelination as an important structural feature of the neocortex that is tightly linked to the function and behavior supported by the cortical area.

A Bayesian reanalysis of the effects of hydroxychloroquine and azithromycin on viral carriage in patients with COVID-19.

Gautret and colleagues reported the results of a non-randomised case series which examined the effects of hydroxychloroquine and azithromycin on viral load in the upper respiratory tract of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patients. The authors reported that hydroxychloroquine (HCQ) had significant virus reducing effects, and that dual treatment of both HCQ and azithromycin further enhanced virus reduction. In light of criticisms regarding how patients were excluded from analyses, we reanalysed the original data to interrogate the main claims of the paper. We applied Bayesian statistics to assess the robustness of the original paper's claims by testing four variants of the data: 1) The original data; 2) Data including patients who deteriorated; 3) Data including patients who deteriorated with exclusion of untested patients in the comparison group; 4) Data that includes patients who deteriorated with the assumption that untested patients were negative. To ask if HCQ monotherapy was effective, we performed an A/B test for a model which assumes a positive effect, compared to a model of no effect. We found that the statistical evidence was highly sensitive to these data variants. Statistical evidence for the positive effect model ranged from strong for the original data (BF+0 ~11), to moderate when including patients who deteriorated (BF+0 ~4.35), to anecdotal when excluding untested patients (BF+0 ~2), and to anecdotal negative evidence if untested patients were assumed positive (BF+0 ~0.6). The fact that the patient inclusions and exclusions are not well justified nor adequately reported raises substantial uncertainty about the interpretation of the evidence obtained from the original paper.

Functional and Structural Plasticity Co-express in a Left Premotor Region During Early Bimanual Skill Learning.

Introduction: Motor skill learning already triggers the functional reorganization of regional brain activity after short periods of training. Recent studies suggest that microstructural change may emerge at similar timescales, but the spatiotemporal profiles of functional and structural plasticity have rarely been traced in parallel. Recently, we demonstrated that 5 days of endoscopic skill training induces changes in task-related brain activity in the ventral premotor cortex (PMv) and other areas of the frontoparietal grasping network. Here, we analyzed microstructural data, collected during the same experiment to investigate if microstructural plasticity overlaps temporally and spatially with the training-induced changes in task-related brain activity. Materials and Methods: Thirty-nine students were divided into a full-routine group (n = 20), that underwent three endoscopy training sessions in the MR-scanner as well as a 5-day virtual reality (VR)-endoscopy training and a brief-routine group (n = 19), that only performed the in-scanner endoscopy training sessions. Diffusion Tensor Imaging (DTI)-derived fractional anisotropy (FA) and resting-state functional magnetic resonance imaging (rs-fMRI) were collected at baseline, after the first and after the last VR-training session. Results: The full-routine group showed significant FA changes in a left-hemispheric subcortical cluster underlying the PMv region, for which we previously demonstrated functional plasticity during endoscopy training in the same sample. Functional (task-related fMRI) and structural (FA) changes showed the largest change from the first to the second scan, suggesting similar temporal dynamics. In the full-routine group, the FA change in the subcortical cluster underlying the left PMv scaled positively with the individual improvement in endoscopic surgery. Conclusion: Microstructural white-matter plasticity mirrors the spatiotemporal profile of task-dependent plasticity during a 5-day course of endoscopy skill training. The observed similarities motivate future research on the interplay between functional and structural plasticity during early skill acquisition.

Migraine with aura in women is not associated with structural thalamic abnormalities.

Migraine with aura is a highly prevalent disorder involving transient neurological disturbances associated with migraine headache. While the pathophysiology is incompletely understood, findings from clinical and basic science studies indicate a potential key role of the thalamus in the mechanisms underlying migraine with and without aura. Two recent, clinic-based MRI studies investigated the volumes of individual thalamic nuclei in migraine patients with and without aura using two different data analysis methods. Both studies found differences of thalamic nuclei volumes between patients and healthy controls, but the results of the studies were not consistent. Here, we investigated whether migraine with aura is associated with changes in thalamic volume by analysing MRI data obtained from a large, cross-sectional population-based study which specifically included women with migraine with aura (N = 156), unrelated migraine-free matched controls (N = 126), and migraine aura-free co-twins (N = 29) identified from the Danish Twin Registry. We used two advanced, validated analysis methods to assess the volume of the thalamus and its nuclei; the MAGeT Brain Algorithm and a recently developed FreeSurfer-based method based on a probabilistic atlas of the thalamic nuclei combining ex vivo MRI and histology. These approaches were very similar to the methods used in each of the two previous studies. Between-group comparisons were corrected for potential effects of age, educational level, BMI, smoking, alcohol, and hypertension using a linear mixed model. Further, we used linear mixed models and visual inspection of data to assess relations between migraine aura frequency and thalamic nuclei volumes in patients. In addition, we performed paired t-tests to compare volumes of twin pairs (N = 29) discordant for migraine with aura. None of our analyses showed any between-group differences in volume of the thalamus or of individual thalamic nuclei. Our results indicate that the pathophysiology of migraine with aura does not involve alteration of thalamic volume.

Probing Context-Dependent Modulations of Ipsilateral Premotor-Motor Connectivity in Relapsing-Remitting Multiple Sclerosis.

Objective: We employed dual-site TMS to test whether ipsilateral functional premotor-motor connectivity is altered in relapsing-remitting Multiple Sclerosis (RR-MS) and is related to central fatigue. Methods: Twelve patients with RR-MS and 12 healthy controls performed a visually cued Pinch-NoPinch task with their right hand. During the reaction time (RT) period of Pinch and No-Pinch trials, single-site TMS was applied to the left primary motor cortex (M1) or dual-site TMS was applied to the ipsilateral dorsal premotor cortex (PMd) and to M1. We traced context-dependent changes of corticospinal excitability and premotor-motor connectivity by measuring Motor-Evoked Potentials (MEPs) in the right first dorsal interosseus muscle. Central fatigue was evaluated with the Fatigue Scale for Motor and Cognitive Functions (FSMS). Results: In both groups, single-pulse TMS revealed a consistent increase in mean MEP amplitude during the Reaction Time (RT) period relative to a resting condition. Task-related corticospinal facilitation increased toward the end of the RT period in Pinch trials, while it decreased in No-Pinch trials. Again, this modulation of MEP facilitation by trial type was comparable in patients and controls. Dual-site TMS showed no significant effect of a conditioning PMd pulse on ipsilateral corticospinal excitability during the RT period in either group. However, patients showed a trend toward a relative attenuation in functional PMd-M1 connectivity at the end of the RT period in No-Pinch trials, which correlated positively with the severity of motor fatigue (r = 0.69; p = 0.007). Conclusions: Dynamic regulation of corticospinal excitability and ipsilateral PMd-M1 connectivity is preserved in patients with RR-MS. MS-related fatigue scales positively with an attenuation of premotor-to-motor functional connectivity during cued motor inhibition. Significance: The temporal, context-dependent modulation of ipsilateral premotor-motor connectivity, as revealed by dual-site TMS of ipsilateral PMd and M1, constitutes a promising neurophysiological marker of fatigue in MS.

Associations of neural processing of reward with posttraumatic stress disorder and secondary psychotic symptoms in trauma-affected refugees.

Background: Psychological traumatic experiences can lead to posttraumatic stress disorder (PTSD). Secondary psychotic symptoms are not common but may occur. Objectives: Since psychotic symptoms of schizophrenia have been related to aberrant reward processing in the striatum, using the same paradigm we investigate whether the same finding extends to psychotic and anhedonic symptoms in PTSD. Methods: A total of 70 male refugees: 18 PTSD patients with no secondary psychotic symptoms (PTSD-NSP), 21 PTSD patients with secondary psychotic symptoms (PTSD-SP), and 31 healthy controls (RHC) were interviewed and scanned with functional magnetic resonance imaging (fMRI) during a monetary incentive delay task. Using region of interest analysis of the prefrontal cortex and ventral striatum, we investigated reward-related activity. Results: Compared to RHC, participants with PTSD had decreased neural activity during monetary reward. Also, participants with PTSD-SP exhibited decreased activity in the associative striatum relative to participants with PTSD-NSP during processing of motivational reward anticipation which correlated with severity of psychotic symptoms. However, the difference between the two PTSD groups disappeared when PTSD severity and trauma exposure were accounted for. Conclusions: Anhedonia and secondary psychotic symptoms in PTSD are characterized by dysfunctional reward consumption and anticipation processing, respectively. The latter may reflect a mechanism by which abnormal reward signals in the basal ganglia facilitates psychotic symptoms across psychiatric conditions.

Antecedentes: Las experiencias traumáticas psicológicas pueden conducir al trastorno de estrés postraumático (TEPT). Los síntomas psicóticos secundarios no son comunes, pero pueden ocurrir.Objetivos: Dado que los síntomas psicóticos de la esquizofrenia se han relacionado con el procesamiento aberrante de recompensas en el cuerpo estriado, utilizando el mismo paradigma, investigamos si el mismo hallazgo se extiende a los síntomas psicóticos y anhedónicos en el TEPT.Método: Un total de 70 refugiados varones: 18 pacientes con TEPT sin síntomas psicóticos secundarios (TEPT-NSP), 21 pacientes con TEPT con síntomas psicóticos secundarios (TEPT-SP) y 31 controles sanos (RHC) fueron entrevistados y escaneados con Imagen por resonancia magnética funcional (fMRI en su sigla en inglés) durante una tarea de retraso de incentivo monetario. Mediante el análisis de la región de interés de la corteza prefrontal y el estriado ventral, investigamos la actividad relacionada con la recompensa.Resultados: En comparación con los RHC, los participantes con TEPT habían disminuido la actividad neuronal durante la recompensa monetaria. Además, los participantes con TEPT-SP exhibieron disminución de la actividad en el estriado asociativo en relación con los participantes con TEPT-NSP durante el procesamiento de la anticipación de recompensa motivacional, lo cual estuvo correlacionado con la gravedad de los síntomas psicóticos. Sin embargo, la diferencia entre los dos grupos de TEPT desapareció cuando se controlaron la gravedad del TEPT y la exposición al trauma.Conclusiones: La anhedonia y los síntomas psicóticos secundarios en el TEPT se caracterizan por un consumo de recompensa disfuncional y un procesamiento de anticipación, respectivamente. Este último puede reflejar un mecanismo por el cual las señales de recompensa anormales en los ganglios basales facilitan los síntomas psicóticos a través de afecciones psiquiátricas.