Brain mapping across 16 autism mouse models reveals a spectrum of functional connectivity subtypes.

Autism Spectrum Disorder (ASD) is characterized by substantial, yet highly heterogeneous abnormalities in functional brain connectivity. However, the origin and significance of this phenomenon remain unclear. To unravel ASD connectopathy and relate it to underlying etiological heterogeneity, we carried out a bi-center cross-etiological investigation of fMRI-based connectivity in the mouse, in which specific ASD-relevant mutations can be isolated and modeled minimizing environmental contributions. By performing brain-wide connectivity mapping across 16 mouse mutants, we show that different ASD-associated etiologies cause a broad spectrum of connectional abnormalities in which diverse, often diverging, connectivity signatures are recognizable. Despite this heterogeneity, the identified connectivity alterations could be classified into four subtypes characterized by discrete signatures of network dysfunction. Our findings show that etiological variability is a key determinant of connectivity heterogeneity in ASD, hence reconciling conflicting findings in clinical populations. The identification of etiologically-relevant connectivity subtypes could improve diagnostic label accuracy in the non-syndromic ASD population and paves the way for personalized treatment approaches.

Improving the quality of combined EEG-TMS neural recordings: Introducing the coil spacer.

BACKGROUND: In the last decade, interest in combined transcranial magnetic stimulation (TMS) and electroencephalography (EEG) approaches has grown substantially. Aside from the obvious artifacts induced by the magnetic pulses themselves, separate and more sinister signal disturbances arise as a result of contact between the TMS coil and EEG electrodes. NEW METHOD: Here we profile the characteristics of these artifacts and introduce a simple device - the coil spacer - to provide a platform allowing physical separation between the coil and electrodes during stimulation. RESULTS: EEG data revealed high amplitude signal disturbances when the TMS coil was in direct contact with the EEG electrodes, well within the physiological range of viable EEG signals. The largest artifacts were located in the Delta and Theta frequency range, and standard data cleanup using independent components analysis (ICA) was ineffective due to the artifact's similarity to real brain oscillations. COMPARISON WITH EXISTING METHOD: While the current best practice is to use a large coil holding apparatus to fixate the coil 'hovering' over the head with an air gap, the spacer provides a simpler solution that ensures this distance is kept constant throughout testing. CONCLUSIONS: The results strongly suggest that data collected from combined TMS-EEG studies with the coil in direct contact with the EEG cap are polluted with low frequency artifacts that are indiscernible from physiological brain signals. The coil spacer provides a cheap and simple solution to this problem and is recommended for use in future simultaneous TMS-EEG recordings.

Revealing the quality of movement: A meta-analysis review to quantify the thresholds to pathological variability during standing and walking.

Neuromotor processes are inherently noisy, which results in variability during movement and fluctuations in motor control. Although controversial, low levels of variability are traditionally considered healthy, while increased levels are thought to be pathological. This systematic review and meta-analysis of the literature investigates the thresholds between healthy and pathological task variability. After examining 13,195 publications, 109 studies were included. Results from over 3000 healthy subjects and 2775 patients revealed an overall positive effect size of pathology on variability of 0.59 for walking and 0.80 for sway. For the coefficient of variation of stride time (ST) and sway area (SA), upper thresholds of 2.6% and 265mm(2) discriminated pathological from asymptomatic performance, while 1.1% and 62mm(2) identified the lower thresholds for pathological variability. This window of healthy performance now provides science based evidence for the discrimination of both extremely low and extremely high levels of variability in the identification as well as standardised monitoring of functional status in neurological cases.

A technical guide to tDCS, and related non-invasive brain stimulation tools.

Transcranial electrical stimulation (tES), including transcranial direct and alternating current stimulation (tDCS, tACS) are non-invasive brain stimulation techniques increasingly used for modulation of central nervous system excitability in humans. Here we address methodological issues required for tES application. This review covers technical aspects of tES, as well as applications like exploration of brain physiology, modelling approaches, tES in cognitive neurosciences, and interventional approaches. It aims to help the reader to appropriately design and conduct studies involving these brain stimulation techniques, understand limitations and avoid shortcomings, which might hamper the scientific rigor and potential applications in the clinical domain.

The autism brain imaging data exchange: towards a large-scale evaluation of the intrinsic brain architecture in autism.

Autism spectrum disorders (ASDs) represent a formidable challenge for psychiatry and neuroscience because of their high prevalence, lifelong nature, complexity and substantial heterogeneity. Facing these obstacles requires large-scale multidisciplinary efforts. Although the field of genetics has pioneered data sharing for these reasons, neuroimaging had not kept pace. In response, we introduce the Autism Brain Imaging Data Exchange (ABIDE)-a grassroots consortium aggregating and openly sharing 1112 existing resting-state functional magnetic resonance imaging (R-fMRI) data sets with corresponding structural MRI and phenotypic information from 539 individuals with ASDs and 573 age-matched typical controls (TCs; 7-64 years) (http://fcon_1000.projects.nitrc.org/indi/abide/). Here, we present this resource and demonstrate its suitability for advancing knowledge of ASD neurobiology based on analyses of 360 male subjects with ASDs and 403 male age-matched TCs. We focused on whole-brain intrinsic functional connectivity and also survey a range of voxel-wise measures of intrinsic functional brain architecture. Whole-brain analyses reconciled seemingly disparate themes of both hypo- and hyperconnectivity in the ASD literature; both were detected, although hypoconnectivity dominated, particularly for corticocortical and interhemispheric functional connectivity. Exploratory analyses using an array of regional metrics of intrinsic brain function converged on common loci of dysfunction in ASDs (mid- and posterior insula and posterior cingulate cortex), and highlighted less commonly explored regions such as the thalamus. The survey of the ABIDE R-fMRI data sets provides unprecedented demonstrations of both replication and novel discovery. By pooling multiple international data sets, ABIDE is expected to accelerate the pace of discovery setting the stage for the next generation of ASD studies.

The neural correlates of upper limb motor blocks in Parkinson's disease and their relation to freezing of gait.

Due to basal ganglia dysfunction, bimanual motor performance in Parkinson patients reportedly relies on compensatory brain activation in premotor-parietal-cerebellar circuitries. A subgroup of Parkinson's disease (PD) patients with freezing of gait (FOG) may exhibit greater bimanual impairments up to the point that motor blocks occur. This study investigated the neural mechanisms of upper limb motor blocks and explored their relation with FOG. Brain activation was measured using functional magnetic resonance imaging during bilateral finger movements in 16 PD with FOG, 16 without FOG (PD + FOG and PD - FOG), and 16 controls. During successful movement, PD + FOG showed decreased activation in right dorsolateral prefrontal cortex (PFC), left dorsal premotor cortex (PMd), as well as left M1 and bilaterally increased activation in dorsal putamen, pallidum, as well as subthalamic nucleus compared with PD - FOG and controls. On the contrary, upper limb motor blocks were associated with increased activation in right M1, PMd, supplementary motor area, and left PFC compared with successful movement, whereas bilateral pallidum and putamen activity was decreased. Complex striatofrontal activation changes may be involved in the difficulties of PD + FOG to perform bimanual movements, or sequential movements in general. These novel results suggest that, whatever the exact underlying cause, PD + FOG seem to have reached a saturation point of normal neural compensation and respond belatedly to actual movement breakdown.

Age-related neural correlates of cognitive task performance under increased postural load.

Behavioral studies suggest that postural control requires increased cognitive control and visuospatial processing with aging. Consequently, performance can decline when concurrently performing a postural and a demanding cognitive task. We aimed to identify the neural substrate underlying this effect. A demanding cognitive task, requiring visuospatial transformations, was performed with varying postural loads. More specifically, old and young subjects performed mental rotations of abstract figures in a seated position and when standing on a force platform. Additionally, functional magnetic resonance imaging (fMRI) was used to identify brain regions associated with mental rotation performance. Old as compared to young subjects showed increased blood oxygenation level-dependent (BOLD) responses in a frontoparietal network as well as activations in additional areas. Despite this overall increased activation, they could still modulate BOLD responses with increasing task complexity. Importantly, activity in left lingual gyrus was highly predictive (r = -0.83, adjusted R(2) = 0.65) of the older subjects' degree of success in mental rotation performance when shifting from a sitting to a standing position. More specifically, increased activation in this area was associated with better performance, once postural load increased.

[Scientific monitoring of the visitation procedure in inpatient rehabilitation centres of the German statutory pension insurance fund--the "Visit II" Project]. / Wissenschaftliche Begleitung der Weiterentwicklung des Visitationsverfahrens für Reha-Kliniken der Deutschen Rentenversicherung Bund--Das Projekt "Visit II".

Visitation procedures are an established method of external quality assurance. They have been conducted for many years in the German statutory pension insurance's medical rehabilitation centres and have continuously been refined and standardized. The overall goal of the visitation procedure implemented by the German statutory pension fund is to ensure compliance with defined quality standards as well as information exchange and counselling of rehabilitation centres. In the context of advancing the visitation procedure in the German statutory pension funds' medical rehabilitation centres, the "Visit II" Project was initiated to evaluate the perspectives and expectations of the various professional groups involved in the visitations and to modify the materials used during visitations (documentation form and manual). Evaluation data from the rehabilitation centres visited in 2008 were gathered using both written surveys (utilization analysis) and telephone-based interviews with administration managers and chief physicians. The utilization analysis procedure was evaluated with regard to its methodological quality. In addition, the pension insurance physicians in charge of patient allocation during socio-medical assessment were surveyed with regard to potential needs for revision of the visitation procedure. Data collection was complemented by expert panels with auditors. Interviews with users as part of the formative evaluation of the visitation procedure showed positive results regarding acceptance and applicability of the visitations as well as of the utilization analysis procedures. Various suggestions were made with regard to modification and revision of the visitation materials, that could be implemented in many cases. Documentation forms were supplemented by current scientifically-based topics in rehabilitation (e. g., vocationally oriented measures), whereas items with minor relevance were skipped. The manual (for somatic indications) was thoroughly revised. The transparent presentation of visitation processes and visitation criteria has proven to be a useful basis for strengthening the cooperation between the statutory pension insurance funds and the rehabilitation centres. Moreover, it is a helpful tool for the systematic and continuous advancement of this complex method by including all parties involved.

Age-related changes in brain activation underlying single- and dual-task performance: visuomanual drawing and mental arithmetic.

Depending on task combination, dual-tasking can either be performed successfully or can lead to performance decrements in one or both tasks. Interference is believed to be caused by limitations in central processing, i.e. structural interference between the neural activation patterns associated with each task. In the present study, single- and dual-task effects were addressed in the context of aging. Increasing evidence from research on motor and cognitive tasks has shown that aging is associated with an expansion of brain activation and an increased BOLD-signal. This may result in increased structural interference and higher dual-task interference in older adults. Functional magnetic resonance imaging was used to measure the BOLD-response in 20 old and 20 young healthy adults while performing tasks separately, or combined. Single tasks consisted of mental arithmetic cued by auditory tones, and a visuomotor task, drawing a circular shape with spatiotemporal constraints. Age-related brain activation increases were only apparent during performance of the visuomotor task. Elderly showed higher BOLD-responses in a frontoparietal network, pointing to an increased reliance on sensory feedback processing. However, no increased structural interference was found for the elderly during performance of the dual-task. Region of interest analysis involving a functional cluster within the (pre-) supplementary motor area, active during performance of both single-tasks, revealed that both groups were able to upregulate their brain activity for dual-as compared to single-task performance. We assume that this allowed both groups to maintain performance under dual-task conditions, leading to minimal dual-task interference.

Shared neural resources between left and right interlimb coordination skills: the neural substrate of abstract motor representations.

Functional magnetic resonance imaging was used to reveal the shared neural resources between movements performed with effectors of the left versus right body side. Prior to scanning, subjects extensively practiced a complex coordination pattern involving cyclical motions of the ipsilateral hand and foot according to a 90 degrees out-of-phase coordination mode. Brain activity associated with this (nonpreferred) coordination pattern was contrasted with pre-existing isodirectional (preferred) coordination to extract the learning-related brain networks. To identify the principal candidates for effector-independent movement encoding, the conjunction of training-related activity for left and right limb coordination was determined. A dominantly left-lateralized parietal-to-(pre)motor activation network was identified, with activation in inferior and superior parietal cortex extending into intraparietal sulcus and activation in the premotor areas, including inferior frontal gyrus (pars opercularis). Similar areas were previously identified during observation of complex coordination skills by expert performers. These parietal-premotor areas are principal candidates for abstract (effector-independent) movement encoding, promoting motor equivalence, and they form the highest level in the action representation hierarchy.

Age-related reduction in the differential pathways involved in internal and external movement generation.

Age-related differences in regional brain activation during two different movement generation modes were examined. Old and young volunteers were scanned while performing cyclical hand-foot flexion-extension movements in the presence and the absence of augmented visual feedback, referring to external and internal movements generation, respectively. Performing the coordination task under both conditions resulted in the activation of two distinct neural networks in the young adults, i.e., the hMT/V5+, and parietal and premotor cortices were typically involved during the visually guided mode, whereas the supplementary motor area (SMA), cingulate motor area (CMA), frontal operculum (FO) and secondary somatosensory area (S2) were typically involved during internally guided movements. Remarkably, much less differentiation between both feedback dependent networks was observed in the seniors, i.e., they exhibited high activity in the SMA, CMA, FO and S2 during both modes, suggesting that the typical network differentiation was largely diminished. This is hypothesized to reflect a general increase in processing resources within areas contributing to motor control and associated sensory processing, supporting motor performance in the elderly.

Conceptual binding: integrated visual cues reduce processing costs in bimanual movements.

In discrete reaction time (RT) tasks, it has been shown that nonsymmetric bimanual movements are initiated slower than symmetric movements in response to symbolic cues. By contrast, no such RT differences are found in response to direct cues ("direct cue effect"). Here, we report three experiments showing that the direct cue effect generalizes to rhythmical bimanual movements and that RT cost depends on different cue features: 1) symbolic versus direct or 2) integrated (i.e., action of both hands is indicated as one entity) versus dissociated (i.e., action of each hand is indicated separately). Our main finding was that dissociated symbolic cues were most likely processed serially, resulting in the longest RTs, which were substantially reduced with integrated symbolic cues. However, extra RT costs for switching to nonsymmetrical bimanual movements were overcome only when the integrated cues were direct. We conclude that computational resources might have been exceeded when the response needs to be determined for each hand separately, but not when a common response for both hands is selected. This supports the idea that bimanual control benefits from conceptual binding.

Neural correlates of motor dysfunction in children with traumatic brain injury: exploration of compensatory recruitment patterns.

Traumatic brain injury (TBI) is a common form of disability in children. Persistent deficits in motor control have been documented following TBI but there has been less emphasis on changes in functional cerebral activity. In the present study, children with moderate to severe TBI (n = 9) and controls (n = 17) were scanned while performing cyclical movements with their dominant and non-dominant hand and foot according to the easy isodirectional (same direction) and more difficult non-isodirectional (opposite direction) mode. Even though the children with TBI were shown to be less successful on various items of a clinical motor test battery than the control group, performance on the coordination task during scanning was similar between groups, allowing a meaningful interpretation of their brain activation differences. fMRI analysis revealed that the TBI children showed enhanced activity in medial and anterior parietal areas as well as posterior cerebellum as compared with the control group. Brain activation generally increased during the non-isodirectional as compared with the isodirectional mode and additional regions were involved, consistent with their differential degree of difficulty. However, this effect did not interact with group. Overall, the findings indicate that motor impairment in TBI children is associated with changes in functional cerebral activity, i.e. they exhibit compensatory activation reflecting increased recruitment of neural resources for attentional deployment and somatosensory processing.

Directional constraints during bimanual coordination: the interplay between intrinsic and extrinsic directions as revealed by head motions.

The role of directional compatibility was investigated during the production of in-phase and anti-phase coordination patterns involving both arms as well as the head. Our first aim was to compare the quality of coordination between both arms when symmetrical arm posture manipulations were used to disentangle muscle homology from the mutual direction of limb motions in extrinsic space. Findings revealed that in-phase coordination, characterized by the simultaneous activation of homologous muscle groups, was resistant to posture manipulations. Conversely, during anti-phase coordination, the influence of extrinsic direction became more prevalent whereby isodirectionality in extrinsic space contributed to stabilization of anti-phase coordination patterns. The second aim was to study the effect of periodic head movements upon the assembling of a coordinative synergy among the body segments. The findings demonstrated that the in-phase patterns were hardly affected by directionality of head motion. Conversely, the anti-phase patterns were more vulnerable to the directional influence of head movements, showing less accurate and stable coordination during non-isodirectional than isodirectional head motions. These observations underscore the robust nature of coordination patterns based on muscle homology, even in the absence of symmetric arm positions. Moreover, isodirectional head movements became easily integrated with the overall coordination pattern, whereas head-limb coupling was poor when the head moved anti-directional with the limbs.

The coalition of constraints during coordination of the ipsilateral and heterolateral limbs.

Previous work on the coordination between the upper and lower limbs has invariably shown that its accuracy/stability is primarily determined by the mutual direction between limbs in extrinsic space and not by muscle relationships. Here we show that muscle grouping does play a critical role in coordination of the arm and leg, in addition to direction. More specifically, the simultaneous activation of isofunctional muscles and/or limb movements proceeding in the same direction, results in more successful performance than the alternated activation of isofunctional muscles and/or movements occurring in different directions. In the absence of isofunctional muscle coupling, the mutual direction between the limbs plays a more prominent role in determining coordinative accuracy. These coordination constraints can largely account for the observed differences between ipsilateral and heterolateral limb coordination. The findings are discussed in view of the coalition of coordination constraints.

The role of directional compatibility in assembling coordination patterns involving the upper and lower limb girdles and the head.

The role of directional compatibility was investigated during the production of in-phase and anti-phase coordination patterns involving the four limbs as well as the head. Our first aim was to compare the quality of interlimb coordination between concordant and discordant coordination patterns across girdles at different cycling frequencies. Concordant implied adoption of either the in-phase or anti-phase coordination mode across both girdles whereas discordant implied a combination of both modes. The second aim was to study the effect of periodic head movements upon the assembling of a coordinative synergy among the limbs. Findings revealed that concordant coordination modes were produced with higher accuracy and consistency than discordant coordination modes and this effect was more distinct at higher cycling frequencies. Inclusion of head movements was found to destabilize in-phase coordination but stabilize anti-phase coordination patterns, particularly during discordant conditions at higher cycling frequencies. This observation contrasts with previous findings in which anti-phase modes have invariably been shown to be more vulnerable to experimental perturbations than in-phase modes. The findings are discussed within the context of the coalition of egocentric and allocentric constraints during multilimb coordination and the role of direction as an organizing principle in movement control.

Cerebellar and premotor function in bimanual coordination: parametric neural responses to spatiotemporal complexity and cycling frequency.

In the present functional magnetic resonance imaging (fMRI) study, we assessed the neural network governing bimanual coordination during manipulations of spatiotemporal complexity and cycling frequency. A parametric analysis was applied to determine the effects of each of both factors as well as their interaction. Subjects performed four different cyclical movement tasks of increasing spatiotemporal complexity (i.e., unimanual left-right hand movements, bimanual in-phase movements, bimanual anti-phase movements, and bimanual 90 degrees out-of-phase movements) across four frequency levels (0.9, 1.2, 1.5, and 1.8 Hz). Results showed that, within the network involved in bimanual coordination, functional subcircuits could be distinguished: Activation in the supplementary motor area, superior parietal cortex (SPS), and thalamic VPL Nc was mainly correlated with increasing spatiotemporal complexity of the limb movements, suggesting that these areas are involved in higher-order movement control. By contrast, activation within the primary motor cortex, cingulate motor cortex (CMC), globus pallidus, and thalamic VLo Nc correlated mainly with movement frequency, indicating that these areas play an important role during movement execution. Interestingly, the cerebellum and the dorsal premotor cortex were identified as the principal regions responding to manipulation of both parameters and exhibiting clear interaction effects. Therefore, it is concluded that both areas represent critical sites for the control of bimanual coordination.

Dynamical changes in corticospinal excitability during imagery of unimanual and bimanual wrist movements in humans: a transcranial magnetic stimulation study.

This study explored the dynamical changes in corticospinal excitability during the imagination of cyclical unimanual and bimanual wrist flexion-extension movements. Transcranial magnetic stimulation was applied over the left motor cortex to evoke motor evoked potentials in the right wrist flexor and extensor muscles. Findings provided evidence for increased reciprocal excitability changes during imagery of symmetrical in-phase movements as compared to asymmetrical (anti-phase) or unimanual movements. This suggests that in-phase movements may reinforce whereas anti-phase movements may reduce the temporal representation of the task in the corticospinal motor networks of the brain.

Changes in brain activation during the acquisition of a new bimanual coodination task.

Motor skill acquisition is associated with the development of automaticity and induces neuroplastic changes in the brain. Using functional magnetic resonance imaging (fMRI), the present study traced learning-related activation changes during the acquisition of a new complex bimanual skill, requiring a difficult spatio-temporal relationship between the limbs, i.e., cyclical flexion-extension movements of both hands with a phase offset of 90 degrees. Subjects were scanned during initial learning and after the coordination pattern was established. Kinematics of the movements were accurately registered and showed that the new skill was acquired well. Learning-related decreases in activation were found in right dorsolateral prefrontal cortex (DLPFC), right premotor, bilateral superior parietal cortex, and left cerebellar lobule VI. Conversely, learning-related increases in activation were observed in bilateral primary motor cortex, bilateral superior temporal gyrus, bilateral cingulate motor cortex (CMC), left premotor cortex, cerebellar dentate nuclei/lobule III/IV/Crus I, putamen/globus pallidus and thalamus. Accordingly, bimanual skill learning was associated with a shift in activation among cortico-subcortical regions, providing further evidence for the existence of differential cortico-subcortical circuits preferentially involved during the early and advanced stages of learning. The observed activation changes account for the transition from highly attention-demanding task performance, involving processing of sensory information and corrective action planning, to automatic performance based on memory representations and forward control.