The cortical neurophysiological signature of amyotrophic lateral sclerosis.

The progressive loss of motor function characteristic of amyotrophic lateral sclerosis is associated with widespread cortical pathology extending beyond primary motor regions. Increasing muscle weakness reflects a dynamic, variably compensated brain network disorder. In the quest for biomarkers to accelerate therapeutic assessment, the high temporal resolution of magnetoencephalography is uniquely able to non-invasively capture micro-magnetic fields generated by neuronal activity across the entire cortex simultaneously. This study examined task-free magnetoencephalography to characterize the cortical oscillatory signature of amyotrophic lateral sclerosis for having potential as a pharmacodynamic biomarker. Eight to ten minutes of magnetoencephalography in the task-free, eyes-open state was recorded in amyotrophic lateral sclerosis (n = 36) and healthy age-matched controls (n = 51), followed by a structural MRI scan for co-registration. Extracted magnetoencephalography metrics from the delta, theta, alpha, beta, low-gamma, high-gamma frequency bands included oscillatory power (regional activity), 1/f exponent (complexity) and amplitude envelope correlation (connectivity). Groups were compared using a permutation-based general linear model with correction for multiple comparisons and confounders. To test whether the extracted metrics could predict disease severity, a random forest regression model was trained and evaluated using nested leave-one-out cross-validation. Amyotrophic lateral sclerosis was characterized by reduced sensorimotor beta band and increased high-gamma band power. Within the premotor cortex, increased disability was associated with a reduced 1/f exponent. Increased disability was more widely associated with increased global connectivity in the delta, theta and high-gamma bands. Intra-hemispherically, increased disability scores were particularly associated with increases in temporal connectivity and inter-hemispherically with increases in frontal and occipital connectivity. The random forest model achieved a coefficient of determination (R2) of 0.24. The combined reduction in cortical sensorimotor beta and rise in gamma power is compatible with the established hypothesis of loss of inhibitory, GABAergic interneuronal circuits in pathogenesis. A lower 1/f exponent potentially reflects a more excitable cortex and a pathology unique to amyotrophic lateral sclerosis when considered with the findings published in other neurodegenerative disorders. Power and complexity changes corroborate with the results from paired-pulse transcranial magnetic stimulation. Increased magnetoencephalography connectivity in worsening disability is thought to represent compensatory responses to a failing motor system. Restoration of cortical beta and gamma band power has significant potential to be tested in an experimental medicine setting. Magnetoencephalography-based measures have potential as sensitive outcome measures of therapeutic benefit in drug trials and may have a wider diagnostic value with further study, including as predictive markers in asymptomatic carriers of disease-causing genetic variants.

Post-stroke upper limb recovery is correlated with dynamic resting-state network connectivity.

Motor recovery is still limited for people with stroke especially those with greater functional impairments. In order to improve outcome, we need to understand more about the mechanisms underpinning recovery. Task-unbiased, blood flow-independent post-stroke neural activity can be acquired from resting brain electrophysiological recordings and offers substantial promise to investigate physiological mechanisms, but behaviourally relevant features of resting-state sensorimotor network dynamics have not yet been identified. Thirty-seven people with subcortical ischaemic stroke and unilateral hand paresis of any degree were longitudinally evaluated at 3 weeks (early subacute) and 12 weeks (late subacute) after stroke. Resting-state magnetoencephalography and clinical scores of motor function were recorded and compared with matched controls. Magnetoencephalography data were decomposed using a data-driven hidden Markov model into 10 time-varying resting-state networks. People with stroke showed statistically significantly improved Action Research Arm Test and Fugl-Meyer upper extremity scores between 3 weeks and 12 weeks after stroke (both P < 0.001). Hidden Markov model analysis revealed a primarily alpha-band ipsilesional resting-state sensorimotor network which had a significantly increased life-time (the average time elapsed between entering and exiting the network) and fractional occupancy (the occupied percentage among all networks) at 3 weeks after stroke when compared with controls. The life-time of the ipsilesional resting-state sensorimotor network positively correlated with concurrent motor scores in people with stroke who had not fully recovered. Specifically, this relationship was observed only in ipsilesional rather in contralesional sensorimotor network, default mode network or visual network. The ipsilesional sensorimotor network metrics were not significantly different from controls at 12 weeks after stroke. The increased recruitment of alpha-band ipsilesional resting-state sensorimotor network at subacute stroke served as functionally correlated biomarkers exclusively in people with stroke with not fully recovered hand paresis, plausibly reflecting functional motor recovery processes.

Relationship between skill training and skill transfer through the example of bimanual motor learning.

Skill training aims to improve the performance of the task at hand and aims to transfer the acquired skill to related tasks. Both skill training and skill transfer are part of our everyday lives, and essential for survival, and their importance is reflected in years of research. Despite these enormous efforts, however, the complex relationship between skill training and skill transfer is not yet portrayed completely. Building upon two theories, we probed this relationship through the example of bimanual learning with a large cross-sectional design (N = 450) using an online framework. We designed five training tasks which differed in the variance of the training material (schema theory) and three transfer tasks differing in their similarity to the training task (identical elements theory). Theoretically, the five training tasks and the three transfer tasks varied approximately linearly from each other. Empirical data, however, suggested merely the presence of three statistically different training tasks and two significantly different transfer tasks, indicating a nonlinear relationship. Against our expectation, Bayesian statistics suggested that the type of skill training was not related to the type of skill transfer. However, the amount of skill training was positively related to the amount of skill transfer. Together, we showed that motor learning studies can be conducted online. Further, our results shed light on the complex relationship between skill training and skill transfer. Understanding this relationship has wide-ranging practical implications for the general population, particularly for musicians, athletes and patients recovering from injury.

A translational roadmap for transcranial magnetic and direct current stimulation in stroke rehabilitation: Consensus-based core recommendations from the third stroke recovery and rehabilitation roundtable.

BACKGROUND AND AIMS: The purpose of this Third Stroke Recovery and Rehabilitation Roundtable (SRRR3) was to develop consensus recommendations to address outstanding barriers for the translation of preclinical and clinical research using the non-invasive brain stimulation (NIBS) techniques Transcranial Magnetic Stimulation (TMS) and Transcranial Direct Current Stimulation (tDCS) and provide a roadmap for the integration of these techniques into clinical practice. METHODS: International NIBS and stroke recovery experts (N = 18) contributed to the consensus process. Using a nominal group technique, recommendations were reached via a five-stage process, involving a thematic survey, two priority ranking surveys, a literature review and an in-person meeting. RESULTS AND CONCLUSIONS: Results of our consensus process yielded five key evidence-based and feasibility barriers for the translation of preclinical and clinical NIBS research, which were formulated into five core consensus recommendations. Recommendations highlight an urgent need for (1) increased understanding of NIBS mechanisms, (2) improved methodological rigor in both preclinical and clinical NIBS studies, (3) standardization of outcome measures, (4) increased clinical relevance in preclinical animal models, and (5) greater optimization and individualization of NIBS protocols. To facilitate the implementation of these recommendations, the expert panel developed a new SRRR3 Unified NIBS Research Checklist. These recommendations represent a translational pathway for the use of NIBS in stroke rehabilitation research and practice.

A translational roadmap for transcranial magnetic and direct current stimulation in stroke rehabilitation: Consensus-based core recommendations from the third stroke recovery and rehabilitation roundtable.

BACKGROUND AND AIMS: The purpose of this Third Stroke Recovery and Rehabilitation Roundtable (SRRR3) was to develop consensus recommendations to address outstanding barriers for the translation of preclinical and clinical research using the non-invasive brain stimulation (NIBS) techniques Transcranial Magnetic Stimulation (TMS) and Transcranial Direct Current Stimulation (tDCS) and provide a roadmap for the integration of these techniques into clinical practice. METHODS: International NIBS and stroke recovery experts (N = 18) contributed to the consensus process. Using a nominal group technique, recommendations were reached via a five-stage process, involving a thematic survey, two priority ranking surveys, a literature review and an in-person meeting. RESULTS AND CONCLUSIONS: Results of our consensus process yielded five key evidence-based and feasibility barriers for the translation of preclinical and clinical NIBS research, which were formulated into five core consensus recommendations. Recommendations highlight an urgent need for (1) increased understanding of NIBS mechanisms, (2) improved methodological rigor in both preclinical and clinical NIBS studies, (3) standardization of outcome measures, (4) increased clinical relevance in preclinical animal models, and (5) greater optimization and individualization of NIBS protocols. To facilitate the implementation of these recommendations, the expert panel developed a new SRRR3 Unified NIBS Research Checklist. These recommendations represent a translational pathway for the use of NIBS in stroke rehabilitation research and practice.

Transcranial focused ultrasound-mediated neurochemical and functional connectivity changes in deep cortical regions in humans.

Low-intensity transcranial ultrasound stimulation (TUS) is an emerging non-invasive technique for focally modulating human brain function. The mechanisms and neurochemical substrates underlying TUS neuromodulation in humans and how these relate to excitation and inhibition are still poorly understood. In 24 healthy controls, we separately stimulated two deep cortical regions and investigated the effects of theta-burst TUS, a protocol shown to increase corticospinal excitability, on the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and functional connectivity. We show that theta-burst TUS in humans selectively reduces GABA levels in the posterior cingulate, but not the dorsal anterior cingulate cortex. Functional connectivity increased following TUS in both regions. Our findings suggest that TUS changes overall excitability by reducing GABAergic inhibition and that changes in TUS-mediated neuroplasticity last at least 50 mins after stimulation. The difference in TUS effects on the posterior and anterior cingulate could suggest state- or location-dependency of the TUS effect-both mechanisms increasingly recognized to influence the brain's response to neuromodulation.

The effect of pulse shape in theta-burst stimulation: Monophasic vs biphasic TMS.

BACKGROUND: Intermittent theta-burst stimulation (i) (TBS) is a transcranial magnetic stimulation (TMS) plasticity protocol. Conventionally, TBS is applied using biphasic pulses due to hardware limitations. However, monophasic pulses are hypothesised to recruit cortical neurons more selectively than biphasic pulses, predicting stronger plasticity effects. Monophasic and biphasic TBS can be generated using a custom-made pulse-width modulation-based TMS device (pTMS). OBJECTIVE: Using pTMS, we tested the hypothesis that monophasic iTBS would induce a stronger plasticity effect than biphasic, measured as induced increases in motor corticospinal excitability. METHODS: In a repeated-measures design, thirty healthy volunteers participated in three separate sessions, where monophasic and biphasic iTBS was applied to the primary motor cortex (M1 condition) or the vertex (control condition). Plasticity was quantified as increases in motor corticospinal excitability after versus before iTBS, by comparing peak-to-peak amplitudes of motor evoked potentials (MEP) measured at baseline and over 60 min after iTBS. RESULTS: Both monophasic and biphasic M1 iTBS led to significant increases in MEP amplitude. As predicted, linear mixed effects (LME) models showed that the iTBS condition had a significant effect on the MEP amplitude (χ2 (1) = 27.615, p < 0.001) with monophasic iTBS leading to significantly stronger plasticity than biphasic iTBS (t (693) = 2.311, p = 0.021). Control vertex iTBS had no effect. CONCLUSIONS: In this study, monophasic iTBS induced a stronger motor corticospinal excitability increase than biphasic within participants. This greater physiological effect suggests that monophasic iTBS may also have potential for greater functional impact, of interest for future fundamental and clinical applications of TBS.

An integrated measure of GABA to characterize post-stroke plasticity.

Stroke is a major cause of death and chronic neurological disability. Despite the improvements in stroke care, the number of patients affected by stroke keeps increasing and many stroke survivors are left permanently disabled. Current therapies are limited in efficacy. Understanding the neurobiological mechanisms underlying post-stroke recovery is therefore crucial to find new therapeutic options to address this medical burden. Long-lasting and widespread alterations of γ-aminobutyric acid (GABA) neurotransmission seem to play a key role in stroke recovery. In this review we first discuss a possible model of GABAergic modulation of post-stroke plasticity. We then overview the techniques currently available to non-invasively assess GABA in patients and the conclusions drawn from this limited body of work. Finally, we address the remaining open questions to clarify GABAergic changes underlying post-stroke recovery, we briefly review possible ways to modulate GABA post stroke and propose a novel approach to thoroughly quantify GABA in stroke patients, by integrating its concentration, the activity of its receptors and its link with microstructural changes.

Repeated unilateral handgrip contractions alter functional connectivity and improve contralateral limb response times.

In humans, motor learning is underpinned by changes in sensorimotor network functional connectivity (FC). Unilateral contractions increase FC in the ipsilateral primary motor cortex (M1) and supplementary motor area (SMA); areas involved in motor planning and execution of the contralateral hand. Therefore, unilateral contractions are a promising approach to augment motor performance in the contralateral hand. In a within-participant, randomized, cross-over design, 15 right-handed adults had two magnetic resonance imaging (MRI) sessions, where functional-MRI and MR-Spectroscopic Imaging were acquired before and after repeated right-hand contractions at either 5% or 50% maximum voluntary contraction (MVC). Before and after scanning, response times (RTs) were determined in both hands. Nine minutes of 50% MVC contractions resulted in decreased handgrip force in the contracting hand, and decreased RTs and increased handgrip force in the contralateral hand. This improved motor performance in the contralateral hand was supported by significant neural changes: increased FC between SMA-SMA and increased FC between right M1 and right Orbitofrontal Cortex. At a neurochemical level, the degree of GABA decline in left M1, left and right SMA correlated with subsequent behavioural improvements in the left-hand. These results support the use of repeated handgrip contractions as a potential modality for improving motor performance in the contralateral hand.

A mean-field model of glutamate and GABA synaptic dynamics for functional MRS.

Advances in functional magnetic resonance spectroscopy (fMRS) have enabled the quantification of activity-dependent changes in neurotransmitter concentrations in vivo. However, the physiological basis of the large changes in GABA and glutamate observed by fMRS (>10%) over short time scales of less than a minute remain unclear as such changes cannot be accounted for by known synthesis or degradation metabolic pathways. Instead, it has been hypothesized that fMRS detects shifts in neurotransmitter concentrations as they cycle from presynaptic vesicles, where they are largely invisible, to extracellular and cytosolic pools, where they are detectable. The present paper uses a computational modelling approach to demonstrate the viability of this hypothesis. A new mean-field model of the neural mechanisms generating the fMRS signal in a cortical voxel is derived. The proposed macroscopic mean-field model is based on a microscopic description of the neurotransmitter dynamics at the level of the synapse. Specifically, GABA and glutamate are assumed to cycle between three metabolic pools: packaged in the vesicles; active in the synaptic cleft; and undergoing recycling and repackaging in the astrocytic or neuronal cytosol. Computational simulations from the model are used to generate predicted changes in GABA and glutamate concentrations in response to different types of stimuli including pain, vision, and electric current stimulation. The predicted changes in the extracellular and cytosolic pools corresponded to those reported in empirical fMRS data. Furthermore, the model predicts a selective control mechanism of the GABA/glutamate relationship, whereby inhibitory stimulation reduces both neurotransmitters, whereas excitatory stimulation increases glutamate and decreases GABA. The proposed model bridges between neural dynamics and fMRS and provides a mechanistic account for the activity-dependent changes in the glutamate and GABA fMRS signals. Lastly, these results indicate that echo-time may be an important timing parameter that can be leveraged to maximise fMRS experimental outcomes.

Three-layer model with absorption for conservative estimation of the maximum acoustic transmission coefficient through the human skull for transcranial ultrasound stimulation.

Transcranial ultrasound stimulation (TUS) has been shown to be a safe and effective technique for non-invasive superficial and deep brain stimulation. Safe and efficient translation to humans requires estimating the acoustic attenuation of the human skull. Nevertheless, there are no international guidelines for estimating the impact of the skull bone. A tissue independent, arbitrary derating was developed by the U.S. Food and Drug Administration to take into account tissue absorption (0.3 dB/cm-MHz) for diagnostic ultrasound. However, for the case of transcranial ultrasound imaging, the FDA model does not take into account the insertion loss induced by the skull bone, nor the absorption by brain tissue. Therefore, the estimated absorption is overly conservative which could potentially limit TUS applications if the same guidelines were to be adopted. Here we propose a three-layer model including bone absorption to calculate the maximum pressure transmission through the human skull for frequencies ranging between 100 kHz and 1.5 MHz. The calculated pressure transmission decreases with the frequency and the thickness of the bone, with peaks for each thickness corresponding to a multiple of half the wavelength. The 95th percentile maximum transmission was calculated over the accessible surface of 20 human skulls for 12 typical diameters of the ultrasound beam on the skull surface, and varies between 40% and 78%. To facilitate the safe adjustment of the acoustic pressure for short ultrasound pulses, such as transcranial imaging or transcranial ultrasound stimulation, a table summarizes the maximum pressure transmission for each ultrasound beam diameter and each frequency.

Cerebellar GABA Change during Visuomotor Adaptation Relates to Adaptation Performance and Cerebellar Network Connectivity: A Magnetic Resonance Spectroscopic Imaging Study.

Motor adaptation is crucial for performing accurate movements in a changing environment and relies on the cerebellum. Although cerebellar involvement has been well characterized, the neurochemical changes in the cerebellum underpinning human motor adaptation remain unknown. We used a novel magnetic resonance spectroscopic imaging (MRSI) technique to measure changes in the inhibitory neurotransmitter GABA in the human cerebellum during visuomotor adaptation. Participants (n = 17, six female) used their right hand to adapt to a rotated cursor in the scanner, compared with a control task requiring no adaptation. We spatially resolved adaptation-driven GABA changes at the cerebellar nuclei and cerebellar cortex in the left and the right cerebellar hemisphere independently and found that simple right-hand movements increase GABA in the right cerebellar nuclei and decreases GABA in the left. When isolating adaptation-driven GABA changes, we found that GABA in the left cerebellar nuclei and the right cerebellar nuclei diverged, although GABA change from baseline at the right cerebellar nuclei was not different from zero at the group level. Early adaptation-driven GABA fluctuations in the right cerebellar nuclei correlated with adaptation performance. Participants showing greater GABA decrease adapted better, suggesting early GABA change is behaviorally relevant. Early GABA change also correlated with functional connectivity change in a cerebellar network. Participants showing greater decreases in GABA showed greater strength increases in cerebellar network connectivity. Results were specific to GABA, to adaptation, and to the cerebellar network. This study provides first evidence for plastic changes in cerebellar neurochemistry during motor adaptation. Characterizing these naturally occurring neurochemical changes may provide a basis for developing therapeutic interventions to facilitate human motor adaptation.SIGNIFICANCE STATEMENT Despite motor adaptation being fundamental to maintaining accurate movements, its neurochemical basis remains poorly understood, perhaps because measuring neurochemicals in the human cerebellum is technically challenging. Using a novel magnetic resonance spectroscopic imaging method, this study provides evidence for GABA changes in the left compared with the right cerebellar nuclei driven by both simple movement and motor adaptation. Although right cerebellar GABA changes were not significantly different from zero at the group level, the adaptation-driven GABA fluctuations in the right cerebellar nuclei correlated with adaptation performance and with functional connectivity change in a cerebellar network. These results show the first evidence for plastic changes in cerebellar neurochemistry during a cerebellar learning task. This provides the basis for developing therapeutic interventions that facilitate these naturally occurring changes to amplify cerebellar-dependent learning.

Non-invasive brain stimulation modulates GABAergic activity in neurofibromatosis 1.

Neurofibromatosis 1 (NF1) is a single-gene disorder associated with cognitive phenotypes common to neurodevelopmental conditions such as autism. GABAergic dysregulation underlies working memory impairments seen in NF1. This mechanistic experimental study investigates whether application of anodal transcranial direct current stimulation (atDCS) can modulate GABA and working memory in NF1. Thirty-one NF1 adolescents 11-18 years, were recruited to this single-blind sham-controlled cross-over randomized trial. AtDCS or sham stimulation was applied to the left Dorsolateral Prefrontal Cortex (DLPFC) and MR Spectroscopy was collected before and after intervention in the left DLPFC and occipital cortex. Task-related functional MRI was collected before, during, and after stimulation. Higher baseline GABA+ in the left DLPFC was associated with faster response times on baseline working memory measures. AtDCS was seen to significantly reduced GABA+ and increase brain activation in the left DLPFC as compared to sham stimulation. Task performance was worse in the aTDCS group during stimulation but no group differences in behavioural outcomes were observed at the end of stimulation. Although our study suggests aTDCS modulates inhibitory activity in the DLPFC, further work is needed to determine whether repeated sessions of atDCS and strategies such as alternating current stimulation offer a better therapeutic approach.

Classical and Learned MR to Pseudo-CT Mappings for Accurate Transcranial Ultrasound Simulation.

Model-based treatment planning for transcranial ultrasound therapy typically involves mapping the acoustic properties of the skull from an X-ray computed tomography (CT) image of the head. Here, three methods for generating pseudo-CT (pCT) images from magnetic resonance (MR) images were compared as an alternative to CT. A convolutional neural network (U-Net) was trained on paired MR-CT images to generate pCT T images from either T1-weighted or zero-echo time (ZTE) MR images (denoted tCT and zCT, respectively). A direct mapping from ZTE to pCT was also implemented (denoted cCT). When comparing the pCT and ground-truth CT images for the test set, the mean absolute error was 133, 83, and 145 Hounsfield units (HU) across the whole head, and 398, 222, and 336 HU within the skull for the tCT, zCT, and cCT images, respectively. Ultrasound simulations were also performed using the generated pCT images and compared to simulations based on CT. An annular array transducer was used targeting the visual or motor cortex. The mean differences in the simulated focal pressure, focal position, and focal volume were 9.9%, 1.5 mm, and 15.1% for simulations based on the tCT images; 5.7%, 0.6 mm, and 5.7% for the zCT; and 6.7%, 0.9 mm, and 12.1% for the cCT. The improved results for images mapped from ZTE highlight the advantage of using imaging sequences, which improves the contrast of the skull bone. Overall, these results demonstrate that acoustic simulations based on MR images can give comparable accuracy to those based on CT.

tDCS induced GABA change is associated with the simulated electric field in M1, an effect mediated by grey matter volume in the MRS voxel.

BACKGROUND AND OBJECTIVE: Transcranial direct current stimulation (tDCS) has wide ranging applications in neuro-behavioural and physiological research, and in neurological rehabilitation. However, it is currently limited by substantial inter-subject variability in responses, which may be explained, at least in part, by anatomical differences that lead to variability in the electric field (E-field) induced in the cortex. Here, we tested whether the variability in the E-field in the stimulated cortex during anodal tDCS, estimated using computational simulations, explains the variability in tDCS induced changes in GABA, a neurophysiological marker of stimulation effect. METHODS: Data from five previously conducted MRS studies were combined. The anode was placed over the left primary motor cortex (M1, 3 studies, N = 24) or right temporal cortex (2 studies, N = 32), with the cathode over the contralateral supraorbital ridge. Single voxel spectroscopy was performed in a 2x2x2cm voxel under the anode in all cases. MRS data were acquired before and either during or after 1 mA tDCS using either a sLASER sequence (7T) or a MEGA-PRESS sequence (3T). sLASER MRS data were analysed using LCModel, and MEGA-PRESS using FID-A and Gannet. E-fields were simulated in a finite element model of the head, based on individual structural MR images, using SimNIBS. Separate linear mixed effects models were run for each E-field variable (mean and 95th percentile; magnitude, and components normal and tangential to grey matter surface, within the MRS voxel). The model included effects of time (pre or post tDCS), E-field, grey matter volume in the MRS voxel, and a 3-way interaction between time, E-field and grey matter volume. Additionally, we ran a permutation analysis using PALM to determine whether E-field anywhere in the brain, not just in the MRS voxel, correlated with GABA change. RESULTS: In M1, higher mean E-field magnitude was associated with greater anodal tDCS-induced decreases in GABA (t(24) = 3.24, p = 0.003). Further, the association between mean E-field magnitude and GABA change was moderated by the grey matter volume in the MRS voxel (t(24) = -3.55, p = 0.002). These relationships were consistent across all E-field variables except the mean of the normal component. No significant relationship was found between tDCS-induced GABA decrease and E-field in the temporal voxel. No significant clusters were found in the whole brain analysis. CONCLUSIONS: Our data suggest that the electric field induced by tDCS within the brain is variable, and is significantly related to anodal tDCS-induced decrease in GABA, a key neurophysiological marker of stimulation. These findings strongly support individualised dosing of tDCS, at least in M1. Further studies examining E-fields in relation to other outcome measures, including behaviour, will help determine the optimal E-fields required for any desired effects.

A macroscopic link between interhemispheric tract myelination and cortico-cortical interactions during action reprogramming.

Myelination has been increasingly implicated in the function and dysfunction of the adult human brain. Although it is known that axon myelination shapes axon physiology in animal models, it is unclear whether a similar principle applies in the living human brain, and at the level of whole axon bundles in white matter tracts. Here, we hypothesised that in humans, cortico-cortical interactions between two brain areas may be shaped by the amount of myelin in the white matter tract connecting them. As a test bed for this hypothesis, we use a well-defined interhemispheric premotor-to-motor circuit. We combined TMS-derived physiological measures of cortico-cortical interactions during action reprogramming with multimodal myelin markers (MT, R1, R2* and FA), in a large cohort of healthy subjects. We found that physiological metrics of premotor-to-motor interaction are broadly associated with multiple myelin markers, suggesting interindividual differences in tract myelination may play a role in motor network physiology. Moreover, we also demonstrate that myelination metrics link indirectly to action switching by influencing local primary motor cortex dynamics. These findings suggest that myelination levels in white matter tracts may influence millisecond-level cortico-cortical interactions during tasks. They also unveil a link between the physiology of the motor network and the myelination of tracts connecting its components, and provide a putative mechanism mediating the relationship between brain myelination and human behaviour.

Neuroanatomical correlates of working memory performance in Neurofibromatosis 1.

Introduction: Neurofibromatosis 1 (NF1) is a single-gene disorder associated with cognitive impairments, particularly with deficits in working memory. Prior research indicates that brain structure is affected in NF1, but it is unclear how these changes relate to aspects of cognition. Methods: 29 adolescents aged 11-17 years were compared to age and sex-matched controls. NF1 subjects were assessed using detailed multimodal measurements of working memory at baseline followed by a 3T MR scan. A voxel-based morphometry approach was used to estimate the total and regional gray matter(GM) volumetric differences between the NF1 and control groups. The working memory metrics were subjected to a principal component analysis (PCA) approach. Results: The NF1 groups showed increased gray matter volumes in the thalamus, corpus striatum, dorsal midbrain and cerebellum bilaterally in the NF1 group as compared to controls. Principal component analysis on the working memory metrics in the NF1 group yielded three independent factors reflecting high memory load, low memory load and auditory working memory. Correlation analyses revealed that increased volume of posterior cingulate cortex, a key component of the default mode network (DMN) was significantly associated with poorer performance on low working memory load tasks. Conclusion: These results are consistent with prior work showing larger subcortical brain volumes in the NF1 cohort. The strong association between posterior cingulate cortex volume and performance on low memory load conditions supports hypotheses of deficient DMN structural development, which in turn may contribute to the cognitive impairments in NF1.

A checklist for assessing the methodological quality of concurrent tES-fMRI studies (ContES checklist): a consensus study and statement.

Low-intensity transcranial electrical stimulation (tES), including alternating or direct current stimulation, applies weak electrical stimulation to modulate the activity of brain circuits. Integration of tES with concurrent functional MRI (fMRI) allows for the mapping of neural activity during neuromodulation, supporting causal studies of both brain function and tES effects. Methodological aspects of tES-fMRI studies underpin the results, and reporting them in appropriate detail is required for reproducibility and interpretability. Despite the growing number of published reports, there are no consensus-based checklists for disclosing methodological details of concurrent tES-fMRI studies. The objective of this work was to develop a consensus-based checklist of reporting standards for concurrent tES-fMRI studies to support methodological rigor, transparency and reproducibility (ContES checklist). A two-phase Delphi consensus process was conducted by a steering committee (SC) of 13 members and 49 expert panelists through the International Network of the tES-fMRI Consortium. The process began with a circulation of a preliminary checklist of essential items and additional recommendations, developed by the SC on the basis of a systematic review of 57 concurrent tES-fMRI studies. Contributors were then invited to suggest revisions or additions to the initial checklist. After the revision phase, contributors rated the importance of the 17 essential items and 42 additional recommendations in the final checklist. The state of methodological transparency within the 57 reviewed concurrent tES-fMRI studies was then assessed by using the checklist. Experts refined the checklist through the revision and rating phases, leading to a checklist with three categories of essential items and additional recommendations: (i) technological factors, (ii) safety and noise tests and (iii) methodological factors. The level of reporting of checklist items varied among the 57 concurrent tES-fMRI papers, ranging from 24% to 76%. On average, 53% of checklist items were reported in a given article. In conclusion, use of the ContES checklist is expected to enhance the methodological reporting quality of future concurrent tES-fMRI studies and increase methodological transparency and reproducibility.