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Inhibitory control has been linked to beta oscillations in the fronto-basal ganglia network. Here we aim to investigate the functional role of the phase of this oscillatory beta rhythm for successful motor inhibition. We applied 20 Hz transcranial alternating current stimulation (tACS) to the pre-supplementary motor area (pre-SMA) while presenting stop signals at 4 (Experiment 1) and 8 (Experiment 2) equidistant phases of the tACS entrained beta oscillations. Participants showed better inhibitory performance when stop signals were presented at the trough of the beta oscillation whereas their inhibitory control performance decreased with stop signals being presented at the oscillatory beta peak. These results are consistent with the communication through coherence theory, in which postsynaptic effects are thought to be greater when an input arrives at an optimal phase within the oscillatory cycle of the target neuronal population. The current study provides mechanistic insights into the neural communication principles underlying successful motor inhibition and may have implications for phase-specific interventions aimed at treating inhibitory control disorders such as PD or OCD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

We are in the midst of a mental health crisis with major depressive disorder being the most prevalent among mental health disorders and up to 30% of patients not responding to first-line treatments. Noninvasive Brain Stimulation (NIBS) techniques have proven to be effective in treating depression. However, there is a fundamental problem of scale. Currently, any type of NIBS treatment requires patients to repeatedly visit a clinic to receive brain stimulation by trained personnel. This is an often-insurmountable barrier to both patients and healthcare providers in terms of time and cost. In this perspective, we assess to what extent Transcranial Electrical Stimulation (TES) might be administered with remote supervision in order to address this scaling problem and enable neuroenhancement of mental resilience at home. Social, ethical, and technical challenges relating to hardware- and software-based solutions are discussed alongside the risks of stimulation under- or over-use. Solutions to provide users with a safe and transparent ongoing assessment of aptitude, tolerability, compliance, and/or misuse are proposed, including standardized training, eligibility screening, as well as compliance and side effects monitoring. Looking into the future, such neuroenhancement could be linked to prevention systems which combine home-use TES with digital sensor and mental monitoring technology to index decline in mental wellbeing and avoid relapse. Despite the described social, ethical legal, and technical challenges, the combination of remotely supervised, at-home TES setups with dedicated artificial intelligence systems could be a powerful weapon to combat the mental health crisis by bringing personalized medicine into people's homes., Competing Interests: BO is the Founder and CEO of PlatoScience ApS, Copenhagen, Denmark. MJ is the Research Manager at PlatoScience ApS. AS is scientific advisor for PlatoScience ApS. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Paneva, Leunissen, Schuhmann, de Graaf, Jønsson, Onarheim and Sack.)

The stop-signal paradigm has become ubiquitous in investigations of inhibitory control. Tasks inspired by the paradigm, referred to as stop-signal tasks, require participants to make responses on go trials and to inhibit those responses when presented with a stop-signal on stop trials. Currently, the most popular version of the stop-signal task is the 'choice-reaction' variant, where participants make choice responses, but must inhibit those responses when presented with a stop-signal. An alternative to the choice-reaction variant of the stop-signal task is the 'anticipated response inhibition' task. In anticipated response inhibition tasks, participants are required to make a planned response that coincides with a predictably timed event (such as lifting a finger from a computer key to stop a filling bar at a predefined target). Anticipated response inhibition tasks have some advantages over the more traditional choice-reaction stop-signal tasks and are becoming increasingly popular. However, currently, there are no openly available versions of the anticipated response inhibition task, limiting potential uptake. Here, we present an open-source, free, and ready-to-use version of the anticipated response inhibition task, which we refer to as the OSARI (the Open-Source Anticipated Response Inhibition) task., (© 2021. Crown.)

To investigate whether beta oscillations are causally related to motor inhibition, thirty-six participants underwent two concurrent transcranial alternating current stimulation (tACS) and electroencephalography (EEG) sessions during which either beta (20 Hz) or gamma (70 Hz) stimulation was applied while participants performed a stop-signal task. In addition, we acquired magnetic resonance images to simulate the electric field during tACS. 20 Hz stimulation targeted at the pre-supplementary motor area enhanced inhibition and increased beta oscillatory power around the time of the stop-signal in trials directly following stimulation. The increase in inhibition on stop trials followed a dose-response relationship with the strength of the individually simulated electric field. Computational modeling revealed that 20 and 70 Hz stimulation had opposite effects on the braking process. These results highlight that the effects of tACS are state-dependent and demonstrate that fronto-central beta activity is causally related to successful motor inhibition, supporting its use as a functional biomarker., Competing Interests: The authors declare no competing interests., (© 2022 The Authors.)

Suboptimal inhibitory control is a major factor contributing to motor/cognitive deficits in older age and pathology. Here, we provide novel insights into the neurochemical biomarkers of inhibitory control in healthy young and older adults and highlight putative neurometabolic correlates of deficient inhibitory functions in normal aging. Age-related alterations in levels of glutamate-glutamine complex (Glx), N -acetylaspartate (NAA), choline (Cho), and myo-inositol (mIns) were assessed in the right inferior frontal gyrus (RIFG), pre-supplementary motor area (preSMA), bilateral sensorimotor cortex (SM1), bilateral striatum (STR), and occipital cortex (OCC) with proton magnetic resonance spectroscopy ( 1 H-MRS). Data were collected from 30 young (age range 18-34 years) and 29 older (age range 60-74 years) adults. Associations between age-related changes in the levels of these metabolites and performance measures or reactive/proactive inhibition were examined for each age group. Glx levels in the right striatum and preSMA were associated with more efficient proactive inhibition in young adults but were not predictive for reactive inhibition performance. Higher NAA/mIns ratios in the preSMA and RIFG and lower mIns levels in the OCC were associated with better deployment of proactive and reactive inhibition in older adults. Overall, these findings suggest that altered regional concentrations of NAA and mIns constitute potential biomarkers of suboptimal inhibitory control in aging., (© The Author(s) 2020. Published by Oxford University Press.)

Response inhibition is essential for navigating everyday life. Its derailment is considered integral to numerous neurological and psychiatric disorders, and more generally, to a wide range of behavioral and health problems. Response-inhibition efficiency furthermore correlates with treatment outcome in some of these conditions. The stop-signal task is an essential tool to determine how quickly response inhibition is implemented. Despite its apparent simplicity, there are many features (ranging from task design to data analysis) that vary across studies in ways that can easily compromise the validity of the obtained results. Our goal is to facilitate a more accurate use of the stop-signal task. To this end, we provide 12 easy-to-implement consensus recommendations and point out the problems that can arise when they are not followed. Furthermore, we provide user-friendly open-source resources intended to inform statistical-power considerations, facilitate the correct implementation of the task, and assist in proper data analysis., Competing Interests: FV, GB, PB, AB, JB, CC, HC, LC, BC, JC, AD, DE, HG, IG, AH, RH, SJ, JK, IL, CL, GL, DM, SM, AM, MP, RP, KR, MR, JS, AS, KT, Mv, LV, MV, JW, RW, BZ, CB No competing interests declared, AA, NS Reviewing editor, eLife, CB has received payment for consulting and speaker's honoraria from GlaxoSmithKline, Novartis, Genzyme, and Teva. He has recent research grants with Novartis and Genzyme, SC consults for Shire, Ieso Digital Health, Cambridge Cognition, and Promentis. Dr Chamberlain's research is funded by Wellcome Trust (110049/Z/15/Z), TR consults for Cambridge Cognition, Mundipharma and Unilever. He receives royalties from Cambridge Cognition (CANTAB) and has recent research grants with Shionogi and SmallPharma, KR has received speaker's honoraria and grants for other projects from Eli Lilly and Shire, RS has consulted to Highland Therapeutics, Eli Lilly and Co., and Purdue Pharma. He has commercial interest in a cognitive rehabilitation software company, eHave, (© 2019, Verbruggen et al.)

In the present study we examined the effect of bihemispheric in-phase synchronization of motor cortical rhythms on complex bimanual coordination. Twenty young healthy volunteers received 10 Hz or 20 Hz tACS in a double-blind crossover design while performing a bimanual task-set switching paradigm. We used a bilateral high-density montage centred over the hand knob representation within the primary motor cortices to apply tACS time-locked to the switching events. Online tACS in either frequency led to faster but more erroneous switching transitions compared to trials without active stimulation. When comparing stimulation frequencies, 10 Hz stimulation resulted in higher error rates and slower switching transitions than 20 Hz stimulation. Furthermore, the stimulation frequencies showed distinct carry-over effects in trials following stimulation trains. Non-stimulated switching transitions were generally faster but continuous performance became more erroneous over time in the 20 Hz condition. We suggest that the behavioural effects of bifocal in-phase tACS are explained by online synchronization of long-range interhemispheric sensorimotor oscillations, which impacts on interhemispheric information flow and the top-down control required for flexible control of complex bimanual actions. Different stimulation frequencies may lead to distinct offline effects, which potentially accumulate over time and therefore need to be taken into account when evaluating subsequent performance.

We investigated the effect of age on the ability to modulate GABA A -ergic and GABA B -ergic inhibitory activity during stopping of action (reactive inhibition) and preparation to stop (proactive inhibition). Twenty-five young and twenty-nine older adults performed an anticipated response version of the stop-signal task with varying levels of stop-signal probability. Paired-pulse transcranial magnetic stimulation was applied to left primary motor cortex to assess the modulation of GABA A -mediated short-interval intracortical inhibition (SICI) during stopping and GABA B -mediated long-interval intracortical inhibition (LICI) during the anticipation of a stop-signal. At the behavioral level, reactive inhibition was affected by aging as indicated by longer stop-signal reaction times in older compared to young adults. In contrast, proactive inhibition was preserved at older age as both groups slowed down their go response to a similar degree with increasing stop-signal probability. At the neural level, the amount of SICI was higher in successful stop relative to go trials in young but not in older adults. LICI at the start of the trial was modulated as a function of stop-signal probability in both young and older adults. Our results suggest that specifically the recruitment of GABA A -mediated intracortical inhibition during stopping of action is affected by aging.

Aging is typically associated with substantial declines in motor functioning as well as robust changes in the functional organization of brain networks. Previous research has investigated the link between these 2 age-varying factors but examinations were predominantly limited to the functional organization within motor-related brain networks. Little is known about the relationship between age-related behavioral impairments and changes in functional organization at the whole brain (i.e., multiple network) level. This knowledge gap is surprising given that the decreased segregation of brain networks (i.e., increased internetwork connectivity) can be considered a hallmark of the aging process. Accordingly, we investigated the association between declines in motor performance across the adult lifespan (20-75 years) and age-related modulations of functional connectivity within and between resting state networks. Results indicated that stronger internetwork resting state connectivity observed as a function of age was significantly related to worse motor performance. Moreover, performance had a significantly stronger association with the strength of internetwork as compared with intranetwork connectivity, including connectivity within motor networks. These findings suggest that age-related declines in motor performance may be attributed to a breakdown in the functional organization of large-scale brain networks rather than simply age-related connectivity changes within motor-related networks.

Healthy aging is accompanied by motor inhibition deficits that involve a slower process of stopping a prepotent motor response (i.e., reactive inhibition) rather than a diminished ability to anticipate stopping (i.e., proactive inhibition). Some studies suggest that efficient motor inhibition is related to GABAergic function. Since age-related alterations in the GABA system have also been reported, motor inhibition impairments might be linked to GABAergic alterations in the cortico-subcortical network that mediates motor inhibition. Thirty young human adults (mean age, 23.2 years; age range, 18-34 years; 14 men) and 29 older human adults (mean age, 67.5 years; age range, 60-74 years; 13 men) performed a stop-signal task with varying levels of stop-signal probability. GABA + levels were measured with magnetic resonance spectroscopy (MRS) in right inferior frontal cortex, pre-supplementary motor area (pre-SMA), left sensorimotor cortex, bilateral striatum, and occipital cortex. We found that reactive inhibition was worse in older adults compared with young adults, as indicated by longer stop-signal reaction times (SSRTs). No group differences in proactive inhibition were observed as both groups slowed down their response to a similar degree with increasing stop-signal probability. The MRS results showed that tissue-corrected GABA + levels were on average lower in older as compared with young adults. Moreover, older adults with lower GABA + levels in the pre-SMA were slower at stopping (i.e., had longer SSRTs). These findings suggest a role for the GABA system in reactive inhibition deficits. SIGNIFICANCE STATEMENT Inhibitory control has been shown to diminish as a consequence of aging. We investigated whether the ability to stop a prepotent motor response and the ability to prepare to stop were related to GABA levels in different regions of the network that was previously identified to mediate inhibitory control. Overall, we found lower GABA levels in older adults compared with young adults. Importantly, those older adults who were slower at stopping had less GABA in the pre-supplementary motor area, a key node of the inhibitory control network. We propose that deficits in the stop process in part depend on the integrity of the GABA system., (Copyright © 2018 the authors 0270-6474/18/387844-08$15.00/0.)

Levels of GABA, the main inhibitory neurotransmitter in the brain, can be regionally quantified using magnetic resonance spectroscopy (MRS). Although GABA is crucial for efficient neuronal functioning, little is known about age-related differences in GABA levels and their relationship with age-related changes in brain structure. Here, we investigated the effect of age on GABA levels within the left sensorimotor cortex and the occipital cortex in a sample of 85 young and 85 older adults using the MEGA-PRESS sequence. Because the distribution of GABA varies across different brain tissues, various correction methods are available to account for this variation. Considering that these correction methods are highly dependent on the tissue composition of the voxel of interest, we examined differences in voxel composition between age groups and the impact of these various correction methods on the identification of age-related differences in GABA levels. Results indicated that, within both voxels of interest, older (as compared to young adults) exhibited smaller gray matter fraction accompanied by larger fraction of cerebrospinal fluid. Whereas uncorrected GABA levels were significantly lower in older as compared to young adults, this age effect was absent when GABA levels were corrected for voxel composition. These results suggest that age-related differences in GABA levels are at least partly driven by the age-related gray matter loss. However, as alterations in GABA levels might be region-specific, further research should clarify to what extent gray matter changes may account for age-related differences in GABA levels within other brain regions., (© 2018 Wiley Periodicals, Inc.)

Edited magnetic resonance spectroscopy (MRS) and transcranial magnetic stimulation (TMS) have often been used to study the integrity of the GABAergic neurotransmission system in healthy aging. To investigate whether the measurement outcomes obtained with these 2 techniques are associated with each other in older human adults, gamma-aminobutyric acid (GABA) levels in the left sensorimotor cortex were assessed with edited MRS in 28 older (63-74 years) and 28 young adults (19-34 years). TMS at rest was then used to measure intracortical inhibition (short-interval intracortical inhibition/long-interval intracortical inhibition), intracortical facilitation, interhemispheric inhibition from left to right primary motor cortex (M1) and recruitment curves of left and right M1. Our observations showed that short-interval intracortical inhibition and long-interval intracortical inhibition in the left M1 were reduced in older adults, while GABA levels did not significantly differ between age groups. Furthermore, MRS-assessed GABA within left sensorimotor cortex was not correlated with TMS-assessed cortical excitability or inhibition. These observations suggest that healthy aging gives rise to altered inhibition at the postsynaptic receptor level, which does not seem to be associated with MRS-assessed GABA+ levels., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The cerebellum appears to undergo late maturation in children and early decline at older age. Whether these age-related changes affect bimanual coordination performance remains unclear at best. Here, we identified the ages at which bimanual coordination performance stops improving and starts declining. In an independent cohort, we defined brain regions of interest involved in bimanual coordination using functional magnetic resonance imaging. We used these regions of interest to investigate the extent to which the gray matter of cerebellar and other brain regions explains bimanual coordination performance from 10- to 80-year-olds. Results showed that bimanual coordination performance starts declining from the age of 40 years. In participants aged 10-20 years, cerebellar lobule VI was the only significant brain predictor of bimanual coordination performance. In participants aged 60-80 years, this cerebellar region, together with the primary sensorimotor cortex, formed a group of strongest predictors. These results from 2 independent samples (10-20 and 60-80 years) suggest that cerebellar lobule VI is critical for the development and preservation of bimanual coordination skills in children and older adults, respectively. In addition, post hoc analyses suggested that the primary motor cortex mediated the adverse effect of age on bimanual coordination performance in older adults., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The ability to learn new motor skills is crucial for activities of daily living, especially in older adults. Previous work in younger adults has indicated fast and slow stages for motor learning that were associated with changes in functional interactions within and between brain hemispheres. However, the impact of the structural scaffolds of these functional interactions on different stages of motor learning remains elusive. Using diffusion-weighted imaging and probabilistic constrained spherical deconvolution-based tractography, we reconstructed transcallosal white matter pathways between the left and right primary motor cortices (M1-M1), left dorsal premotor cortex and right primary motor cortex (LPMd-RM1) and right dorsal premotor cortex and left primary motor cortex (RPMd-LM1) in younger and older adults trained in a set of bimanual coordination tasks. We used fractional anisotropy (FA) to assess microstructural organisation of the reconstructed white matter pathways. Older adults showed lower behavioural performance than younger adults and improved their performance more in the fast but less in the slow stage of learning. Linear mixed models predicted that individuals with higher FA of M1-M1 pathways improve more in the fast but less in the slow stage of bimanual learning. Individuals with higher FA of RPMd-LM1 improve more in the slow but less in the fast stage of bimanual learning. These predictions did not differ significantly between younger and older adults suggesting that, in both younger and older adults, the M1-M1 and RPMd-LM1 pathways are important for the fast and slow stage of bimanual learning, respectively., (© 2018 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Response inhibition is an important executive process studied by clinical and experimental psychologists, neurophysiologists and cognitive neuroscientists alike. Stop-signal paradigms are popular because they are grounded in a theory that provides methods to estimate the latency of an unobservable process: the stop-signal reaction time (SSRT). Critically, SSRT estimates can be biased by skew of the response time distribution and gradual slowing over the course of the experiment. Here, we present a series of experiments that directly compare three common stop-signal paradigms that differ in the distribution of response times. The results show that the widely used choice response (CR) and simple response (SR) time versions of the stop-signal paradigm are particularly susceptible to skew of the response time distribution and response slowing, and that using the anticipated response (AR) paradigm based on the Slater-Hammel task offers a viable alternative to obtain more reliable SSRT estimates., (© 2017 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Background: Traumatic brain injury (TBI) has been associated with impairments in inhibiting prepotent motor responses triggered by infrequent external signals (ie, reactive inhibition). It is unclear whether proactive preparation to inhibit upcoming responses is also affected (ie, proactive inhibition). Successful inhibition relies on frontosubcortical interactions; therefore, impairments might be linked with gray matter atrophy in subcortical structures., Objective: We investigated reactive and proactive inhibition in TBI and control groups, and their relationship with subcortical gray matter., Methods: Participants performed a response inhibition task in which the probability of stopping was manipulated. Reactive inhibition was measured as the stop-signal reaction time (SSRT) when the probability of stopping was low. Proactive inhibition was measured as the change in SSRT and in go response time with increasing probability of stopping. Subcortical gray matter structures were automatically segmented with FSL-FIRST. Group differences in subregional volume and associations with reactive and proactive inhibition efficiency were investigated using shape analysis., Results: Reactive inhibition was impaired in TBI, as indicated by longer SSRTs. Moreover, the degree of atrophy in subregions of subcortical structures was predictive for SSRT in TBI. In contrast, proactive inhibition was not affected because both groups showed no response time slowing as a function of stopping probability. Proactive inhibition efficiency could be predicted by local volume in the anterior left putamen, bilateral pallidum, and right thalamus in controls but not in TBI., Conclusions: Our results reveal that proactive inhibition seems unaffected in TBI and that volume of subregions of subcortical nuclei is predictive for response inhibition proficiency and of clinical relevance in TBI.

It remains unclear which specific brain regions are the most critical for human postural control and balance, and whether they mediate the effect of age. Here, associations between postural performance and corticosubcortical brain regions were examined in young and older adults using multiple structural imaging and linear mixed models. Results showed that of the regions involved in posture, the brainstem was the strongest predictor of postural control and balance: lower brainstem volume predicted larger center of pressure deviation and higher odds of balance loss. Analyses of white and gray matter in the brainstem showed that the pedunculopontine nucleus area appeared to be critical for postural control in both young and older adults. In addition, the brainstem mediated the effect of age on postural control, underscoring the brainstem's fundamental role in aging. Conversely, lower basal ganglia volume predicted better postural performance, suggesting an association between greater neural resources in the basal ganglia and greater movement vigor, resulting in exaggerated postural adjustments. Finally, results showed that practice, shorter height and heavier weight (i.e., higher body mass index), higher total physical activity, and larger ankle active (but not passive) range of motion were predictive of more stable posture, irrespective of age., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Increasing a participant's ability to prepare for response inhibition is known to result in longer Go response times and is thought to engage a "top-down fronto-striatal inhibitory task set." This premise is supported by the observation of anterior striatum activation in functional magnetic resonance imaging (fMRI) analyses that focus on uncertain versus certain Go trials. It is assumed that setting up a proactive inhibitory task set also influences how participants subsequently implement stopping. To assess this assumption, we aimed to manipulate the degree of proactive inhibition in a modified stop-signal task to see how this manipulation influences activation when reacting to the Stop cue. Specifically, we tested whether there is differential activity of basal ganglia nuclei, namely the subthalamic nucleus (STN) and anterior striatum, on Stop trials when stop-signal probability was relatively low (20%) or high (40%). Successful stopping was associated with increased STN activity when Stop trials were infrequent and increased caudate head activation when Stop trials were more likely, suggesting a different implementation of reactive response inhibition by the basal ganglia for differing degrees of proactive response control. Hum Brain Mapp 37:4706-4717, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

There is a convergence in the literature toward a critical role for the basal ganglia in action selection. However, which substructures within the basal ganglia fulfill this role is still unclear. Here we used shape analyses of structural magnetic resonance imaging data to determine the extent to which basal ganglia structures predict performance in easy and complex multilimb reaction-time tasks in young and old adults. Results revealed that inward deformation (i.e., local atrophy) of the nucleus accumbens and caudate were predictive of longer action selection times in complex conditions, but not in easy conditions. Additionally, when assessing the relation between behavioral performance and the shape of the left nucleus accumbens in the two age groups separately, we found a significant performance-structure association in old, but not young adults. This result suggests that the relevance of the nucleus accumbens for the process of action selection increases with age. Hum Brain Mapp 37:4629-4639, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Successfully switching between tasks is critical in many daily activities. Age-related slowing of this switching behavior has been documented extensively, but the underlying neural mechanisms remain unclear. Here, we investigated the contribution of brain white matter changes associated with myelin alterations to age-related slowing of switching performance. Diffusion tensor imaging derived radial diffusivity (RD) and magnetization transfer imaging derived magnetization transfer ratio (MTR) were selected as myelin sensitive measures. These metrics were studied in relation to mixing cost (i.e., the increase in reaction time during task blocks that require task switching) on a local-global switching task in young (n = 24) and older (n = 22) adults. Results showed that higher age was associated with widespread increases in RD and decreases in MTR, indicative of white matter deterioration, possibly due to demyelination. Older adults also showed a higher mixing cost, implying slowing of switching performance. Finally, mediation analyses demonstrated that decreases in MTR of the bilateral superior corona radiata contributed to the observed slowing of switching performance with increasing age. These findings provide evidence for a role of cortico-subcortical white matter changes in task switching performance deterioration with healthy aging. Hum Brain Mapp 37:4084-4098, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Background Even though lower-limb motor disorders are core features of spastic cerebral palsy (sCP), the relationship with brain lesions remains unclear. Unraveling the relation between gait pathology, lower-limb function, and brain lesions in sCP is complex for several reasons; wide heterogeneity in brain lesions, ongoing brain maturation, and gait depends on a number of primary motor functions/deficits (eg, muscle strength, spasticity). Objective To use a comprehensive approach combining conventional MRI and diffusion tensor imaging (DTI) in children with sCP above 3 years old to relate quantitative parameters of brain lesions in multiple brain areas to gait performance. Methods A total of 50 children with sCP (25 bilateral, 25 unilateral involvement) were enrolled. The investigated neuroradiological parameters included the following: (1) volumetric measures of the corpus callosum (CC) and lateral ventricles (LVs), and (2) DTI parameters of the corticospinal tract (CST). Gait pathology and primary motor deficits, including muscle strength and spasticity, were evaluated by 3D gait analysis and clinical examination. Results In bilateral sCP (n = 25), volume of the LV and the subparts of the CC connecting frontal, (pre)motor, and sensory areas were most related to lower-limb functioning and gait pathology. DTI measures of the CST revealed additional relations with the primary motor deficits (n = 13). In contrast, in unilateral sCP, volumetric (n = 25) and diffusion measures (n = 14) were only correlated to lower-limb strength. Conclusions These results indicate that the combined influence of multiple brain lesions and their impact on the primary motor deficits might explain a large part of the gait pathology in sCP., (© The Author(s) 2016.)

Background and Objectives: The postural instability and gait disorder (PIGD) and tremor dominant (TD) subtypes of Parkinson's disease (PD) show different patterns of alterations in functional connectivity (FC) between specific brain regions. This study aimed to investigate the relation between symptomatic heterogeneity in PD and structural alterations underlying these FC changes., Methods: 68 PD patients classified as PIGD (n = 41) or TD (n = 19) and 19 age-matched controls underwent Magnetic Resonance Imaging (MRI). Diffusion-weighted images were used to assess fractional anisotropy (FA) and mean diffusivity (MD) at the whole-brain level using tract-based spatial statistics (TBSS). In addition, structural connectivity was assessed between regions that previously showed altered FC using probabilistic tractography. Anatomical images were used to determine shape and volume of the putamen, caudate and pallidum., Results: TBSS revealed widespread FA reductions in PIGD compared to controls involving the superior longitudinal fasciculi and corpus callosum. No such differences were found in TD. Both PD subgroups had increased MD compared to controls in tracts connecting the left caudate with the bilateral ventral putamen. TD patients additionally showed increased MD compared to PIGD and controls in tracts connecting the right inferior parietal lobule with the right premotor and primary motor cortex, which previously showed altered FC. We also found grey matter atrophy in the rostrodorsal head of the caudate in PIGD compared to controls., Conclusion: Microstructural changes in white matter tracts, particularly in those connecting striatal sub-areas, partly underlie FC alterations in PD subtypes. Caudate shape alterations further implicate the striatum in PIGD pathophysiology.

Changes in both brain structure and neurophysiological function regulating homotopic as well as heterotopic interhemispheric interactions (IHIs) are assumed to be responsible for the bimanual performance deficits in older adults. However, how the structural and functional networks regulating bimanual performance decline in older adults, as well as the interplay between brain structure and function remain largely unclear. Using a dual-site transcranial magnetic stimulation paradigm, we examined the age-related changes in the interhemispheric effects from the dorsolateral prefrontal cortex and dorsal premotor cortex onto the contralateral primary motor cortex (M1) during the preparation of a complex bimanual coordination task in human. Structural properties of these interactions were assessed with diffusion-based fiber tractography. Compared with young adults, older adults showed performance declines in the more difficult bimanual conditions, less optimal brain white matter (WM) microstructure, and a decreased ability to regulate the interaction between dorsolateral prefrontal cortex and M1. Importantly, we found that WM microstructure, neurophysiological function, and bimanual performance were interrelated in older adults, whereas only the task-related changes in IHI predicted bimanual performance in young adults. These results reflect unique interactions between structure and function in the aging brain, such that declines in WM microstructural organization likely lead to dysfunctional regulation of IHI, ultimately accounting for bimanual performance deficits., Significance Statement: The structural and functional changes in the aging brain are associated with a decline in movement control, compromising functional independence. We used MRI and noninvasive brain stimulation techniques to investigate white matter microstructural organization and neurophysiological function in the aging brain, in relation to bimanual movement control. We found that less optimal brain microstructural organization and task-related modulations in neurophysiological function resulted in poor bimanual performance in older adults. By interrelating brain structure, neurophysiological function, and behavior, the current study provides a comprehensive picture of biological alterations in the aging brain that underlie declines in bimanual performance., (Copyright © 2016 the authors 0270-6474/16/361808-15$15.00/0.)

In young adults, canceling an initiated action depends on the right inferior frontal cortex (IFC), presupplementary motor area (preSMA), and the basal ganglia. Older adults show response inhibition deficits, but how this relates to functional brain activation remains unclear. Using event-related functional magnetic resonance imaging, we tested whether older adults (N = 20) exhibit overactivation during stop-signal inhibition as shown for attentional control tasks, or reduced activity compared with young adults (N = 20). We used a modified stop-signal task involving coupled bimanual responses and manipulated whether both or just one hand was cued to stop. Stop-task difficulty was matched across groups. We found a group by condition interaction in supramarginal gyrus, anterior insula, rIFC, and preSMA, with activation increasing for successful Stop versus Go trials in the young adults only. Comparing the groups on Stop trials revealed preSMA and striatum hypoactivity for older adults. White matter tracts connecting rIFC, preSMA, and the subthalamic nuclei were associated with stronger activation of preSMA in older adults, suggesting that maintenance of the brain's structure has positive implications for brain function., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Many patients with traumatic brain injury (TBI) suffer from postural control impairments that can profoundly affect daily life. The cerebellum and brain stem are crucial for the neural control of posture and have been shown to be vulnerable to primary and secondary structural consequences of TBI. The aim of this study was to investigate whether morphometric differences in the brain stem and cerebellum can account for impairments in static and dynamic postural control in TBI. TBI patients (n = 18) and healthy controls (n = 30) completed three challenging postural control tasks on the EquiTest® system (Neurocom). Infratentorial grey matter (GM) and white matter (WM) volumes were analyzed with cerebellum-optimized voxel-based morphometry using the spatially unbiased infratentorial toolbox. Volume loss in TBI patients was revealed in global cerebellar GM, global infratentorial WM, middle cerebellar peduncles, pons and midbrain. In the TBI group and across both groups, lower postural control performance was associated with reduced GM volume in the vermal/paravermal regions of lobules I-IV, V and VI. Moreover, across all participants, worse postural control performance was associated with lower WM volume in the pons, medulla, midbrain, superior and middle cerebellar peduncles and cerebellum. This is the first study in TBI patients to demonstrate an association between postural impairments and reduced volume in specific infratentorial brain areas. Volumetric measures of the brain stem and cerebellum may be valuable prognostic markers of the chronic neural pathology, which complicates rehabilitation of postural control in TBI., (© 2015 Wiley Periodicals, Inc.)

Even though declines in sensorimotor performance during healthy aging have been documented extensively, its underlying neural mechanisms remain unclear. Here, we explored whether age-related subcortical atrophy plays a role in sensorimotor performance declines, and particularly during bimanual manipulative performance (Purdue Pegboard Test). The thalamus, putamen, caudate and pallidum of 91 participants across the adult lifespan (ages 20-79 years) were automatically segmented. In addition to studying age-related changes in the global volume of each subcortical structure, local deformations within these structures, indicative of subregional volume changes, were assessed by means of recently developed shape analyses. Results showed widespread age-related global and subregional atrophy, as well as some notable subregional expansion. Even though global atrophy failed to explain the observed performance declines with aging, shape analyses indicated that atrophy in left and right thalamic subregions, specifically subserving connectivity with the premotor, primary motor and somatosensory cortical areas, mediated the relation between aging and performance decline. It is concluded that subregional volume assessment by means of shape analyses offers a sensitive tool with high anatomical resolution in the search for specific age-related associations between brain structure and behavior., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

In Parkinson's disease (PD), freezing of gait (FOG) is associated with widespread functional and structural gray matter changes throughout the brain. Previous study of freezing-related white matter changes was restricted to brainstem and cerebellar locomotor tracts. This study was undertaken to determine the spatial distribution of white matter damage associated with FOG by combining whole brain and striatofrontal seed-based diffusion tensor imaging. Diffusion-weighted images were collected in 26 PD patients and 16 age-matched controls. Parkinson's disease groups with (n = 11) and without freezing of gait (n = 15) were matched for age and disease severity. We applied tract-based spatial statistics to compare fractional anisotropy and mean diffusivity of white matter structure across the whole brain between groups. Probabilistic tractography was used to evaluate fractional anisotropy and mean diffusivity of key subcortico-cortical tracts. Tract-based spatial statistics revealed decreased fractional anisotropy in PD with FOG in bilateral cerebellar and superior longitudinal fascicle clusters. Increased mean diffusivity values were apparent in the right internal capsule, superior frontal cortex, anterior corona radiata, the left anterior thalamic radiation, and cerebellum. Tractography showed consistent white matter alterations in striatofrontal tracts through the putamen, caudate, pallidum, subthalamic nucleus, and in connections of the cerebellar peduncle with subthalamic nucleus and pedunculopontine nucleus bilaterally. We conclude that FOG is associated with diffuse white matter damage involving major cortico-cortical, corticofugal motor, and several striatofrontal tracts in addition to previously described cerebello-pontine connectivity changes. These distributed white matter abnormalities may contribute to the motor and non-motor correlates of FOG., (© 2015 International Parkinson and Movement Disorder Society.)

We investigated whether balance control in young TBI patients can be promoted by an 8-week balance training program and whether this is associated with neuroplastic alterations in brain structure. The cerebellum and cerebellar peduncles were selected as regions of interest because of their importance in postural control as well as their vulnerability to brain injury. Young patients with moderate to severe TBI and typically developing (TD) subjects participated in balance training using PC-based portable balancers with storage of training data and real-time visual feedback. An additional control group of TD subjects did not attend balance training. Mean diffusivity and fractional anisotropy were determined with diffusion MRI scans and were acquired before, during (4 weeks) and at completion of training (8 weeks) together with balance assessments on the EquiTest® System (NeuroCom) which included the Sensory Organization Test, Rhythmic Weight Shift and Limits of Stability protocols. Following training, TBI patients showed significant improvements on all EquiTest protocols, as well as a significant increase in mean diffusivity in the inferior cerebellar peduncle. Moreover, in both training groups, diffusion metrics in the cerebellum and/or cerebellar peduncles at baseline were predictive of the amount of performance increase after training. Finally, amount of training-induced improvement on the Rhythmic Weight Shift test in TBI patients was positively correlated with amount of change in fractional anisotropy in the inferior cerebellar peduncle. This suggests that training-induced plastic changes in balance control are associated with alterations in the cerebellar white matter microstructure in TBI patients.

Suppressing and flexibly adapting actions are a critical part of our daily behavioral repertoire. Traumatic brain injury (TBI) patients show clear impairments in this type of action control; however, the underlying mechanisms are poorly understood. Here, we tested whether white matter integrity of cortico-subcortical pathways could account for impairments in task switching, an important component of executive functioning. Twenty young adults with TBI and eighteen controls performed a switching task requiring attention to global versus local stimulus features. Diffusion weighted images were acquired and whole brain tract-based spatial statistics (TBSS) were used to explore where white matter damage was associated with switching impairment. A crossing fiber model and probabilistic tractography further identified the specific fiber populations. Relative to controls, patients with a history of TBI had a higher switch cost and were less accurate. The TBI group showed a widespread decline in fractional anisotropy (FA) throughout the TBSS skeleton. FA in the superior corona radiata showed a negative relationship with switch cost. More specifically, this involved cortico-subcortical loops with the (pre-)supplementary motor area and superior frontal gyrus. These findings provide evidence for damage to frontal-subcortical projections in TBI, which is associated with task switching impairments., (Copyright © 2013 Wiley Periodicals, Inc.)

Traumatic brain injury (TBI) is associated with neuronal loss, diffuse axonal injury and executive dysfunction. Whereas executive dysfunction has traditionally been associated with prefrontal lesions, ample evidence suggests that those functions requiring behavioral flexibility critically depend on the interaction between frontal cortex, basal ganglia and thalamus. To test whether structural integrity of this fronto-striato-thalamic circuit can account for executive impairments in TBI we automatically segmented the thalamus, putamen and caudate of 25 patients and 21 healthy controls and obtained diffusion weighted images. We assessed components of executive function using the local-global task, which requires inhibition, updating and switching between actions. Shape analysis revealed localized atrophy of the limbic, executive and rostral-motor zones of the basal ganglia, whereas atrophy of the thalami was more global in TBI. This subcortical atrophy was related to white matter microstructural organization in TBI, suggesting that axonal injuries possibly contribute to subcortical volume loss. Global volume of the nuclei showed no clear relationship with task performance. However, the shape analysis revealed that participants with smaller volume of those subregions that have connections with the prefrontal cortex and rostral motor areas showed higher switch costs and mixing costs, and made more errors while switching. These results support the idea that flexible cognitive control over action depends on interactions within the fronto-striato-thalamic circuit., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Despite an increasing amount of specific correlation studies between structural and functional connectivity, there is still a need for combined studies, especially in pathological conditions. Impairments of brain white matter (WM) and diffuse axonal injuries are commonly suspected to be responsible for the disconnection hypothesis in traumatic brain injury (TBI) patients. Moreover, our previous research on TBI patients shows a strong relationship between abnormalities in topological organization of brain networks and behavioral deficits. In this study, we combined task-related functional connectivity (using event-related fMRI) with structural connectivity (derived from fiber tractography using diffusion MRI data) estimates in the same participants (17 adults with TBI and 16 controls), allowing for direct comparison between graph metrics of the different imaging modalities. Connectivity matrices were computed covering the switching motor network, which includes the basal ganglia, anterior cingulate cortex/supplementary motor area, and anterior insula/inferior frontal gyrus. The edges constituting this network consisted of the partial correlations between the fMRI time series from each node of the switching motor network. The interregional anatomical connections between the switching-related areas were determined using the fiber tractography results. We found that graph metrics and hubs obtained showed no agreement in both groups. The topological properties of brain functional networks could not be solely accounted for by the properties of the underlying structural networks. However, combining complementary information from both imaging modalities could improve accuracy in prediction of switching performance. Direct comparison between functional task-related and anatomical structural connectivity, presented here for the first time in TBI patients, links two powerful approaches to map the patterns of brain connectivity that may underlie behavioral deficits in brain-injured patients.

The ability to suppress and flexibly adapt motor behavior is a fundamental mechanism of cognitive control, which is impaired in traumatic brain injury (TBI). Here, we used a combination of functional magnetic resonance imaging and diffusion weighted imaging tractography to study changes in brain function and structure associated with motor switching performance in TBI. Twenty-three young adults with moderate-severe TBI and twenty-six healthy controls made spatially and temporally coupled bimanual circular movements. A visual cue signaled the right hand to switch or continue its circling direction. The time to initiate the switch (switch response time) was longer and more variable in the TBI group and TBI patients exhibited a higher incidence of complete contralateral (left hand) movement disruptions. Both groups activated the basal ganglia and a previously described network for task-set implementation, including the supplementary motor complex and bilateral inferior frontal cortex (IFC). Relative to controls, patients had significantly increased activation in the presupplementary motor area (preSMA) and left IFC, and showed underactivation of the subthalamic nucleus (STN) region. This altered functional engagement was related to the white matter microstructural properties of the tracts connecting preSMA, IFC, and STN. Both functional activity in preSMA, IFC, and STN, and the integrity of the connections between them were associated with behavioral performance across patients and controls. We suggest that damage to these key pathways within the motor switching network because of TBI, shifts the patients toward the lower end of the existing structure-function-behavior spectrum., (Copyright © 2012 Wiley Periodicals, Inc.)

Bimanual actions are ubiquitous in daily life. Many coordinated movements of the upper extremities rely on precise timing, which requires efficient interhemispheric communication via the corpus callosum (CC). As the CC in particular is known to be vulnerable to traumatic brain injury (TBI), furthering our understanding of its structure-function association is highly valuable for TBI diagnostics and prognosis. In this study, 21 young adults with TBI and 17 controls performed object manipulation tasks (insertion of pegs with both hands and bilateral daily life activities) and cognitive control tasks (i.e., switching maneuvers during spatially and temporally coupled bimanual circular motions). The structural organization of 7 specific subregions of the CC (prefrontal, premotor/supplementary motor, primary motor, primary sensory, parietal, temporal, and occipital) was subsequently investigated in these subjects with diffusion tensor imaging (DTI). Findings revealed that bimanual coordination was impaired in TBI patients as shown by elevated movement time values during daily life activities, a decreased number of peg insertions, and slower response times during the switching task. Furthermore, the DTI analysis demonstrated a significantly decreased fractional anisotropy and increased radial diffusivity in prefrontal, primary sensory, and parietal regions in TBI patients versus controls. Finally, multiple regression analyses showed evidence of the high specificity of callosal subregions accounting for the variance associated with performance of the different bimanual coordination tasks. Whereas disruption in commissural pathways between occipital areas played a role in performance on the clinical tests of bimanual coordination, deficits in the switching task were related to disrupted interhemispheric communication in prefrontal, sensory, and parietal regions. This study provides evidence that structural alterations of several subregional callosal fibers in adults with TBI are associated with differential behavioral manifestations of bimanual motor functioning.