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Abstract

The subthalamic nucleus (STN) is a small but vitally important structure in the basal ganglia. Because of its small volume, and its localization in the basal ganglia, the STN can best be visualized using ultra-high resolution 7 Tesla (T) magnetic resonance imaging (MRI). In the present study, first we individually segmented 7 T MRI STN masks to generate atlas probability maps. Secondly, the individually segmented STN masks and the probability maps were used to derive cortico-subthalamic white matter tract strength. Tract strength measures were then taken to test two functional STN hypotheses which account for the efficiency in stopping a motor response: the right inferior fronto-subthalamic (rIFC-STN) hypothesis and the posterior medial frontal cortex-subthalamic (pMFC-STN) hypothesis. Results of two independent experiments show that increased white matter tract strength between the pMFC and STN results in better stopping behaviour.

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... There is converging evidence from animal models (Eagle and Baunez, 2010;Bari et al., 2011) and human psychopharmacology (Chamberlain et al., 2006(Chamberlain et al., , 2009, that the noradrenergic system facilitates inhibitory control for action cancellation. A prefrontal cortical network is also implicated in such response inhibition, including the right inferior frontal gyrus (rIFG) and presupplementary motor area (preSMA; Chambers et al., 2006;Duann et al., 2009;Forstmann et al., 2012;Rae et al., 2015). ...
... Phasic and tonic activities in the locus coeruleus have been proposed to afford behavioral flexibility and inhibitory control (Aston-Jones and Cohen, 2005;Bouret and Sara, 2005;Dayan and Yu, 2006). This might be achieved by modulation of connectivity within the prefrontal network (Chambers et al., 2006;Duann et al., 2009;Forstmann et al., 2012;Ye et al., 2014;Rae et al., 2016). Here, we tested this hypothesis by linking locus coeruleus integrity to functional connectivity between rIFG and preSMA, as a predictor of behavior. ...
... The influence of noradrenaline may also be understood in terms of its effect on task-related connectivity between regions (Rae et al., 2016;Holland et al., 2021). For inhibitory control, connectivity between the rIFG and preSMA are of particular relevance: lesion studies, transient interference by magnetic or electrical stimulation, and neuroimaging work provide converging evidence that interactions between these regions are crucial for successful response inhibition (Chambers et al., 2006;Duann et al., 2009;Forstmann et al., 2012;Rae et al., 2015). We found that the effect of locus coeruleus integrity on response inhibition is partly mediated by changes in functional connectivity between the rIFG and preSMA. ...
Article
Response inhibition is a core executive function enabling adaptive behavior in dynamic environments. Human and animal models indicate that inhibitory control and control networks are modulated by noradrenaline, arising from the locus coeruleus. The integrity (i.e., cellular density) of the locus coeruleus noradrenergic system can be estimated from magnetization transfer (MT)-sensitive magnetic resonance imaging (MRI), in view of neuromelanin present in noradrenergic neurons of older adults. Noradrenergic psychopharmacological studies indicate noradrenergic modulation of prefrontal and frontostriatal stopping-circuits in association with behavioral change. Here, we test the noradrenergic hypothesis of inhibitory control, in healthy adults. We predicted that locus coeruleus integrity is associated with age-adjusted variance in response inhibition, mediated by changes in connectivity between frontal inhibitory control regions. In a preregistered analysis, we used MT MRI images from N = 63 healthy humans aged above 50 years (of either sex) who performed a Stop-Signal Task (SST), with atlas-based measurement of locus coeruleus contrast. We confirm that better response inhibition is correlated with locus coeruleus integrity and stronger connectivity between presupplementary motor area (preSMA) and right inferior frontal gyrus (rIFG), but not volumes of the prefrontal cortical regions. We confirmed a significant role of prefrontal connectivity in mediating the effect of individual differences in the locus coeruleus on behavior, where this effect was moderated by age, over and above adjustment for the mean effects of age. Our results support the hypothesis that in normal populations, as in clinical settings, the locus coeruleus noradrenergic system regulates inhibitory control.SIGNIFICANCE STATEMENT We show that the integrity of the locus coeruleus, the principal source of cortical noradrenaline, is related to the efficiency of response inhibition in healthy older adults. This effect is in part mediated by its effect on functional connectivity in a prefrontal cortical stopping-network. The behavioral effect, and its mediation by connectivity, are moderated by age. This supports the psychopharmacological and genetic evidence for the noradrenergic regulation of behavioral control, in a population-based normative cohort. Noradrenergic treatment strategies may be effective to improve behavioral control in impulsive clinical populations, but age, and locus coeruleus integrity, are likely to be important stratification factors.
... In order to identify STN, we referenced a FSL based probabilistic MNI atlas with a resolution of 0.5 x 0.5 x 0.5 mm 3 [Forstmann et al. 2012]. The atlas-based ROI mask was thresholded at 35-50%. ...
... The atlas-based ROI mask was thresholded at 35-50%. This range was chosen for determining the region with the maximum percentage of participant overlap used for creating that atlas [Forstmann et al. 2012]. The STN mask was warped to the MNI atlas with 2 mm 3 isotropic resolution as shown in Figure 1. ...
... In order to ensure the validity of our methods, we also estimated the size of all ROIs in the basal ganglia and thalamus for all subjects. Figure 4, shows that our estimated structural volumes were close to those reported in the literature [Anastasi et al., 2006;Harman et al., 1950;Von Bonin et al., 1951;Yelnik, 2002;Chaddock et al., 2010;Ziegler et al., 2013;Menke et al., 2010;Chowdhury et al., 2013;Bagary et al., 2002;Spoletini et al., 2011], with the exception the of STN, which was different from the values documented, for example, in [Forstmann et al., 2012;Massey et al., 2012;Lambert et al., 2012;Nowinski et al., 2005;Colpan et al., 2010]. This may be due to our selective probabilistic thresholding used for STN localization, which is different from previous methods [Lambert et al., 2012], where STN was localized as one large region containing iron. ...
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The basal ganglia and thalamus play an important role in cognition, procedural learning, eye movements, control of voluntary motor movements, emotional control, habit development, and are structures that are severely impacted by neurological disorders such as Alzheimer's disease, Parkinson's disease, or Tourette syndrome. To understand the structural connectivity of cortical and subcortical circuits in the healthy human brain could thus be of pivotal importance for detecting changes in this circuitry and to start early intervention, to assess the progress of movement rehabilitation, or the effectiveness of therapeutic approaches in neuropsychiatry. While conventional magnetic resonance imaging (MRI), positron emission tomography, or magnetoencephalography are able to provide detailed information about connectivity at the macro level, the sensitivity and specificity these imaging techniques put limits on the amount of detail one can obtain when measuring in vivo connectivity of human basal ganglia and thalamus. In contrast, the multiband diffusion echo planar imaging MRI sequence, which acquires multiple slices of the brain simultaneously, enables high resolution imaging of these brain structures with only short acquisition times at 3-Tesla field strength. Here, we introduce a novel protocol that allows us to generate comprehensive in vivo participant-specific probabilistic patterns and visualizations of the structural connections that exist within basal ganglia and thalamic nuclei. Moreover, we are able to map specific parcellations of these nuclei into sub-territories based on their connectivity with primary motor-, and somatosensory cortex. The detailed subcortical structural connectivity mapping introduced in this work could benefit early intervention and therapy methods for human movement rehabilitation and for treating neuropsychiatric disorders.
... The STN is a key site of functional convergence of motor circuits 27 : it receives excitatory signals directly from cortical regions and sends excitatory signals to the internal globus pallidus, which in turn inhibits the thalamus (Fig. 1a), thereby resulting in the rapid stopping of a planned action 25 . Although it has been hypothesized that successful stopping requires increased functional engagement of the STN, few studies in adults have found these predicted effects 10,11,14 , likely due to inherent difficulties of noninvasively imaging the STN 28 . Consequently, the extent to which the developing brain deploys canonical cortical-basal ganglia systems is not well understood. ...
... Regions of Interest (ROIs) were defined by a previous meta-analysis of neuroimaging studies of inhibitory control in adults 17 , including rAI, rIFG, rPreSMA, rMFG, rSMG, and rCau ( Fig. 5a, Supplementary Table 9). We also included ROIs in the rSTN and lSTN, based on a previous ultra-high-resolution 7T MRI study 28 , which provided more accurate localization of this small subcortical structure. We examined whether these independently defined ROIs have significantly greater activation during SuccStop than Go trials in children. ...
... Consistent with this model we found that the strength of SST-modulated connectivity between the rAI and rSTN was correlated with inhibitory control abilities in children. This result held after FDR-correction for multiple comparison, which included two other prefrontal cortex regions that have also been implicated in stopping and have extensive connections with the STN 10,28,43,44 .: rIFG, and rPreSMA, highlighting the specificity of the STN-AI connection during stopping. Structural imaging studies in adults have revealed that the strength of white matter pathways between prefrontal regions, including IFG and preSMA, and STN during inhibitory control is related to SSRT 24,28 . ...
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Inhibitory control is fundamental to children’s self-regulation and cognitive development. Here we investigate cortical-basal ganglia pathways underlying inhibitory control in children and their adult-like maturity. We first conduct a comprehensive meta-analysis of extant neurodevelopmental studies of inhibitory control and highlight important gaps in the literature. Second, we examine cortical-basal ganglia activation during inhibitory control in children ages 9–12 and demonstrate the formation of an adult-like inhibitory control network by late childhood. Third, we develop a neural maturation index (NMI), which assesses the similarity of brain activation patterns between children and adults, and demonstrate that higher NMI in children predicts better inhibitory control. Fourth, we show that activity in the subthalamic nucleus and its effective connectivity with the right anterior insula predicts children’s inhibitory control. Fifth, we replicate our findings across multiple cohorts. Our findings provide insights into cortical-basal ganglia circuits and global brain organization underlying the development of inhibitory control. Late childhood is an important period for the development of inhibitory control underlying self-regulation and impulse control behavior. Here, the authors identify brain mechanisms and functional cortical-basal ganglia circuits that predict inhibitory control in children.
... Reductions in the proficiency to inhibit actions are reported in several neurological and neuropsychiatric disorders with altered function of the neural circuitry linked to inhibitory action control: the frontal-basal ganglia network (Alderson et al. 2007;Wylie et al. 2016;Manza et al. 2017). The subthalamic nucleus (STN) is a key structure in the broader frontal-striatal network that may be directly involved in regulating inhibitory control (Aron and Poldrack 2006;Aron et al. 2007; van den Zandbelt and Vink 2010;Forstmann et al. 2012;Jahanshahi et al. 2015;Aron et al. 2016), including the striatum, the globus pallidus, the cerebellum, primary motor cortex, and premotor cortex (Coxon et al. 2006;Li et al. 2008;Zandbelt and Vink 2010;Mirabella et al. 2011;Mattia et al. 2012;Brunamonti et al. 2014;Mallet et al. 2016). Current models propose that the STN suppresses the basal ganglia output to the cortex, which functionally stops response-generating signals from activating motor actions (Nambu et al. 2002;Bogacz and Gurney 2007;Wiecki and Frank 2013). ...
... Moving ventrally from the dorsal motor subregion toward the center of the STN nucleus reveals a different pattern of cortical afferents characterized by converging projections from preSMA, IFC, and dorsolateral prefrontal cortex (DLPFC) (Haynes and Haber 2013). Imaging studies suggest that the preSMA, IFC, and STN form a network involved in inhibitory stopping control (Aron et al. 2004;Forstmann et al. 2012;Zandbelt et al. 2013;Aron et al. 2014). Supporting this hypothesis are neurophysiological studies showing increased power in the beta frequency (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) in the STN coincident with stopping (Kuhn et al. 2004;Ray et al. 2012;Alegre et al. 2013;Bastin et al. 2014) and increased spiking activity in STN with successfully stopped responses (Isoda and Hikosaka 2008;Bastin et al. 2014). ...
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Patients with Parkinson’s disease (PD) often experience reductions in the proficiency to inhibit actions. The motor symptoms of PD can be effectively treated with deep brain stimulation (DBS) of the Subthalamic nucleus (STN), a key structure in the frontal-striatal network that may be directly involved in regulating inhibitory control. However, the precise role of the STN in stopping control is unclear. The STN consists of functional sub-territories linked to dissociable cortical networks although the boundaries of the subregions are still under debate. We investigated whether stimulating dorsal and ventral subregions of the STN would show dissociable effects on the ability to stop. We studied 12 PD patients with STN DBS. Patients with two adjacent contacts positioned within the bounds of the dorsal and ventral STN completed two testing sessions (off medication) with low amplitude stimulation (0.4mA) at either the dorsal or ventral contacts bilaterally while performing the stop task. Ventral, but not dorsal, DBS improved stopping latencies. Go reactions were similar between dorsal and ventral DBS STN. Stimulation in the ventral, but not dorsal, subregion of the STN improved stopping speed, confirming the involvement of the STN in stopping control and supporting STN functional subregions.
... This is especially true for small structures, like the STN. Several previous studies that derived STN volumes from low-resolution data sets and/or template approaches have yielded values that were higher and lower than the values obtained in the present study [27][28][29][30] . However, the STN volumes obtained in this study were consistent (within two standard deviations) with those reported in other high-resolution 7T datasets 10,12,31 , 9.4T datasets 32 as well as values reported from postmortem histology studies [33][34][35][36][37] . ...
... Last, despite the fact that the median time since diagnosis in our PD study cohort was 1.4 years, there was considerable heterogeneity in the expression of motor symptoms. One half of the cohort had MDS-UPDRS III scores in the mild motor severity range (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32) while the other half were assessed in the moderate range (33-58) 41 . The majority of the subjects were receiving oral dopamine replacement therapy and/ or dopamine agonist. ...
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This project investigated whether structural changes are present in the subthalamic nucleus (STN) of people with mild-to-moderate severity of Parkinson’s disease (PD). Within-subject measures of STN volume and fractional anisotropy (FA) were derived from high-resolution 7Tesla magnetic resonance imaging (MRI) for 29 subjects with mild-to-moderate PD (median disease duration = 2.3±1.9 years) and 18 healthy matched controls. Manual segmentation of the STN was performed on 0.4 mm in-plane resolution images. FA maps were generated and FA values were averaged over the left and right STN separately for each subject. Motor sign severity was assessed using the Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS). Linear effects models showed that STN volume was significantly smaller in the PD subjects compared to controls (p = 0.01). Further, after controlling for differences in STN volumes within or between groups, the PD group had lower FA values in the STN compared to controls (corrected p ≤ 0.008). These findings demonstrate that morphological changes occur in the STN, which likely impact the function of the hyperdirect and indirect pathways of the basal ganglia and movement control.
... Our results show that CST integrity after stroke is crucial for both excitation and inhibition, enabling voluntary modulation and release of grip force.contribution of cortico-striatal pathways for motor inhibition, likely to be important for both force modulation (Tracking error) and release. White matter tracts connecting the posterior medial frontal cortex and the subthalamic nucleus have been identified as important for stopping an ongoing action.78 Cortico-subthalamic connection strength in ageing has also been association between interhemispheric M1-M1 connectivity at T1 and a decrease in Release duration over time (change scores) (SupplementaryTable 5). ...
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Recovery of dexterous hand use is critical for functional outcome after stroke. Grip force recordings can inform on maximal motor output and modulatory and inhibitory cerebral functions, but how these actually contribute to recovery of dexterous hand use is unclear. This cohort study used serially assessed measures of hand kinetics to test the hypothesis that behavioural measures of motor modulation and inhibition explain dexterity recovery beyond that explained by measures of motor output alone. We also investigated the structural and functional connectivity correlates of grip force control recovery. Eighty-nine adults (median age=54 years, 26% females) with first-ever ischemic or hemorrhagic stroke and persistent arm and hand paresis were assessed longitudinally, at 3 by guest on 30 September 2022 2 weeks, and at 3 and 6 months after stroke. Kinetic measures included: maximal grip force, accuracy of precision and power grip force control, and ability to release force abruptly. Dexterous hand use was assessed clinically with the Box and Block Test =and motor impairment with the upper extremity Fugl-Meyer Assessment. Structural and functional MRI was used to assess weighted cortico-spinal tract lesion load, voxel-based lesion symptom mapping and interhemispheric resting-state functional connectivity. Fifty-three percent of patients had severe initial motor impairment and a majority still had residual force control impairments at 6 months. Force release at 3 weeks explained 11% additional variance of Box and Block Test outcome at 6 months, above that explained by initial scores (67%). Other kinetic measures did not explain additional variance of recovery. The predictive value of force release remained significant when controlling for cortico-spinal tract lesion load and clinical measures. Cortico-spinal tract lesion load correlated with recovery in grip force control measures. Lesions involving the parietal operculum, insular cortex, putamen and fronto-striatal tracts were also related to poorer force modulation and release. Lesions to fronto-striatal tracts explained an additional 5% of variance in force release beyond the 43% explained by cortico-spinal injury alone. Interhemispheric functional connectivity did not relate to force control recovery. We conclude that not only voluntary force generation but also force release (reflecting motor inhibition) are important for recovery of dexterous hand use after stroke. Although cortico-spinal injury is a main determinant of recovery, lesions to integrative somatosensory areas and fronto-parietal white matter (involved in motor inhibition) explain additional variance in post-stroke force release recovery. Our findings indicate that post-stroke upper limb motor impairment profiling, which is essential for targeted treatment, should consider both voluntary grasp generation and inhibition. Running title: Motor inhibition and dexterous hand use
... Aron et al., 2007;Aron and Poldrack, 2006;Jahfari et al., 2011;Rae et al., 2015). Further, efficiency of inhibitory control is dependent on the strength of fronto-basal ganglia connectivity (Chavan et al., 2017;Forstmann et al., 2012;Jahfari et al., 2012;Matar et al., 2019). Motor output through the thalamus (THAL) is thought to be under the direction of signals originating from frontal regions via three pathways through the basal ganglia (BG); the direct, indirect and hyperdirect pathways (see figure 2; Albin et al., 1989;Alexander and Crutcher, 1990;DeLong, 1990;Nambu et al., 2002). ...
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Is motor response inhibition is supported by a specialised neuronal inhibitory control mechanism, or by a more general system of action updating? This pre-registered study employed a context-cueing paradigm requiring both inhibitory and non-inhibitory action updating in combination with functional magnetic resonance imaging to test the specificity of responses under different updating conditions, including the cancellation of actions. Cortical regions of activity were found to be common to multiple forms of action updating. However, functional specificity during response inhibition was observed in the anterior right inferior frontal gyrus. In addition, fronto-subcortical activity was explored using a novel contrast method. These exploratory results indicate that the specificity for response inhibition observed in right prefrontal cortex continued downstream and was observed in right hemisphere subcortical activity, while left hemisphere activity was associated with right-hand response execution. Overall, our findings reveal both common and distinct correlates of response inhibition in prefrontal cortex, with exploratory analyses supporting putative models of subcortical pathways and extending them through the demonstration of lateralisation.
... For putamen, we used the common second-level main effect of "continue" trials thresholded at p<0.001 (uncorrected) and applied an inclusive mask which included the bilateral putamen (AAL's putamen.nii). For STN, we used a probabilistic STN template derived from high-resolution 7T structural scans 46 which was combined into a bilateral mask. For all ROI analyses, statistical threshold was set at p<0.05 after small-volume correction, using voxel-level FWE correction (FWE SVC ). ...
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Dopaminergic treatment may impair the ability to suppress impulsive behaviours in patients with Parkinson's disease, triggering impulse control disorders. It is unclear how dopaminergic medication affects the neural networks that contribute to withholding inappropriate actions. To address this question, we mapped brain activity with whole-brain functional magnetic resonance imaging at 3 Tesla, while 26 patients with Parkinson’s disease performed a sequential gambling task while being ON and OFF their regular dopaminergic treatment. During a gambling round, patients repeatedly decided between the option to continue with gambling and accumulate more monetary reward under increasing risk or the option to bank the current balance and start a new round. 13 patients had an impulse control disorder (ICD+ group). These patients did not differ in risk-taking attitude during sequential gambling from 13 patients without impulse control disorder (ICD group–), but they displayed differences in gambling-related activity in cortico-subcortical brain areas supporting inhibitory control. First, the ICD+ group showed reduced “continue-to-gamble” activity in right inferior frontal gyrus and subthalamic nucleus. Second, the individual risk-attitude scaled positively with “continue-to-gamble” activity in right subthalamic nucleus and striatum in the ICD- group only. Third, ICD+ patients differed in their functional neural responses to dopaminergic treatment from ICD- patients: dopaminergic therapy reduced functional connectivity between inferior frontal gyrus and subthalamic nucleus during “continue-to-gamble” decisions and attenuated striatal responses towards accumulating reward and risk. Together, the medication-independent (trait) and medication-related (state) differences in neural activity may set a permissive stage for the emergence of impulse control disorders during dopamine replacement therapy in Parkinsońs disease.
... Previous studies examining the intersection of tractography and fMRI are suggestive of a similar overlap of structural and functional connectivity within hyperdirect connections during stopping behaviour 10,42 with the strength of hyperdirect connections also correlating with the efficacy of stopping 43 . More broadly, the relationship between functional and structural connectivity in brain networks is highly complex 44 and also limited by the pitfalls of the modalities used to assess these measures. ...
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Parkinson’s disease (PD) is characterised by the emergence of pathological patterns of oscillatory synchronisation across the cortico-basal-ganglia circuit. The relationship between anatomical connectivity and oscillatory synchronisation within this system remains poorly understood. We address this by integrating evidence from invasive electrophysiology, magnetoencephalography, tractography and computational modelling in patients. Coupling between supplementary motor area (SMA) and subthalamic nucleus (STN) within the high beta frequency (21-30 Hz) range correlated with fibre tract densities between these two structures. Additionally within the STN, non-linear waveform features suggestive of cortical synchronisation correlated with cortico-STN fibre densities. Finally, computational modelling revealed that exaggerated hyperdirect cortical inputs to the STN in the upper beta frequency range can provoke the generation of widespread pathological synchrony at lower beta (13-20 Hz) frequencies. These observations reveal a spectral signature of the hyperdirect pathway at high beta frequencies and provide evidence for its pathophysiological role in oscillatory network dysfunction in PD. One sentence summary Signatures of the hyperdirect pathway and its likely role in pathological network disruption in Parkinson’s disease are identified.
... Previous studies investigating the association between regional white matter structure and inhibition have almost exclusively focused on typicallydeveloping children and adults. These studies found that better inhibition performance was associated with higher FA in the corpus callosum, the anterior corona radiata, and in connections serving the inferior frontal gyrus, the pre-supplementary motor area and the subthalamic nucleus [49][50][51][126][127][128][129]. Surprisingly, in the present analyses, associations of FA mean in tracts serving the aforementioned brain areas and inhibition performance were not found. ...
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Inhibition abilities are often impaired in children born very preterm. In typically-developing individuals, inhibition has been associated with structural brain connectivity (SC). As SC is frequently altered following preterm birth, this study investigated whether aberrant SC underlies inhibition deficits in school-aged children born very preterm. In a group of 67 very preterm participants aged 8 to 13 years and 69 term-born peers, inhibition abilities were assessed with two tasks. In a subgroup of 50 very preterm and 62 term-born participants, diffusion tensor imaging (DTI) data were collected. Using network-based statistics (NBS), mean fractional anisotropy (FAmean) was compared between groups. Associations of FAmean and inhibition abilities were explored through linear regression. The composite score of inhibition abilities was lower in the very preterm group (M = -0.4, SD = 0.8) than in the term-born group (M = 0.0, SD = 0.8) but group differences were not significant when adjusting for age, sex and socio-economic status (β = -0.13, 95%-CI [-0.30, 0.04], p = .13). In the very preterm group, FAmean was significantly lower in a network comprising thalamo-frontal, thalamo-temporal, frontal, cerebellar and intra-hemispheric connections than in the term-born group (t = 5.21, lowest p-value = 0.001). Irrespective of birth status, a network comprising parietal, cerebellar and subcortical connections was positively associated with inhibition abilities (t = 4.23, lowest p-value = 0.02). Very preterm birth results in long-term alterations of SC at network-level. As networks underlying inhibition abilities do not overlap with those differing between the groups, FAmean may not be adequate to explain inhibition problems in very preterm children. Future studies should combine complementary measures of brain connectivity to address neural correlates of inhibition abilities.
... Second, to further test the specificity of the association between dFPN connectivity and evidence accumulation rate, we delineated four additional networks (the salience, default mode and visual and basal ganglia networks) based in the fronto-insular, posterior cingulate/precuneus, primary visual cortex (V1) and subthalamic nucleus seed regions, respectively (Supplementary Table 3 and Fig. 3b) [119][120][121][122] . ...
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Animal neurophysiological studies have identified neural signals within dorsal frontoparietal areas that trace a perceptual decision by accumulating sensory evidence over time and trigger action upon reaching a threshold. Although analogous accumulation-to-bound signals are identifiable on extracranial human electroencephalography, their cortical origins remain unknown. Here neural metrics of human evidence accumulation, predictive of the speed of perceptual reports, were isolated using electroencephalography and related to dorsal frontoparietal network (dFPN) connectivity using diffusion and resting-state functional magnetic resonance imaging. The build-up rate of evidence accumulation mediated the relationship between the white matter macrostructure of dFPN pathways and the efficiency of perceptual reports. This association between steeper build-up rates of evidence accumulation and the dFPN was recapitulated in the resting-state networks. Stronger connectivity between dFPN regions is thus associated with faster evidence accumulation and speeded perceptual decisions. Our findings identify an integrated network for perceptual decisions that may be targeted for neurorehabilitation in cognitive disorders. How efficiently humans make perceptual decisions varies between people. Based on EEG and structural and functional MRI data, Brosnan et al. suggest a role for dorsal frontoparietal network connectivity in the speed of perceptual decisions.
... Response inhibition succeeds when the stop signal comes soon enough after the onset of the go stimulus but fails when it comes later-too close to the moment of response execution. The stop-signal paradigm has been used in numerous studies, with both healthy and clinical populations, to examine the cognitive, developmental, and neural underpinning of response inhibition (e.g., Aron and Poldrack 2006;Badcock et al. 2002;Bissett and Logan 2011;Fillmore et al. 2002;Forstmann et al. 2012;Hughes et al. 2012;Matzke et al. 2017a;Schachar et al. 2000;Schachar and Logan 1990;Verbruggen et al. 2014;Williams et al. 1999). ...
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The stop-signal paradigm is a popular procedure to investigate response inhibition—the ability to stop ongoing responses. It consists of a choice response time (RT) task that is occasionally interrupted by a stop stimulus signaling participants to withhold their response. Performance in the stop-signal paradigm is often formalized as race between a set of go runners triggered by the choice stimulus and a stop runner triggered by the stop signal. We investigated whether evidence-accumulation processes, which have been widely used in choice RT analysis, can serve as the runners in the stop-signal race model and support the estimation of psychologically meaningful parameters. We examined two types of the evidence-accumulation architectures: the racing Wald model (Logan et al. 2014) and a novel proposal based on the lognormal race (Heathcote and Love 2012). Using a series of simulation studies and fits to empirical data, we found that these models are not measurement models in the sense that the data-generating parameters cannot be recovered in realistic experimental designs.
... Rae et al. [41]). The latter is based on the probability maps provided by Forstmann et al. [42]; in the current study, the downloaded maps were smoothed with a Gaussian kernel of 2 mm (original resolution was 0.5 mm) using SPM12, then thresholded at 0.1 to produce left and right STN masks. These masks were combined and the resultant image binarized. ...
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Previous neuroimaging studies have reported differences in regional brain activation between males and females during stop signal task performance, suggesting the presence of sex-linked differences in brain network organization of inhibitory ability. Despite a growing literature on sex differences during stop signal task performance, a consensus still has not been reached due to variations in task design and analysis methods. Due to these disparate findings we used up to date stop signal task methods to compare behavioral performance and associated brain activation between males and females using an event-related functional magnetic resonance imaging design. We observed that males were faster in inhibiting their responses, but females exhibited marked increased in stopping network activation, in addition to increased activation of the anterior insula and left amygdala. These findings suggest that males and females process stop signals differently.
... After, we adopted the intra-class correlation coefficient (ICC) for the absolute agreement between raters concerning the volume of the segmentation and the shared voxels overlap rate to quantify the reliability of defining the STN. Here, the overlap rate was defined as the percentage of the overlapped region compared with the segmentation of the first operator (Forstmann et al., 2012;Keuken et al., 2013). ...
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A connection between the subthalamic nucleus (STN) and the cerebellum which has been shown to exist in non-human primates, was recently identified in humans. However, its anatomical features, network properties and function have yet to be elucidated in humans. In the present study, we quantified the STN-cerebellum pathway in humans and explored its function based on structural observations. Anatomical features and asymmetry index (AI) were explored using high definition fiber tractography data of 30 individuals from the Massachusetts General Hospital - Human Connectome Project adult diffusion database. Pearson's correlation analysis was performed to determine the interrelationship between the subdivisions of the STN-cerebellum and the global cortical-STN connections. The pathway was visualized bilaterally in all the subjects. Typically, after setting out from the STN, the STN-cerebellum projections incorporated into the nearby corticopontine tracts, passing through the cerebral peduncle, mediated by the pontine nucleus and then connecting in two opposite directions to join the bilateral middle cerebellar peduncle. On the group averaged level, 78.03% and 62.54% of fibers from the right and left STN respectively, distributed to Crus I in the cerebellum, part of the remaining fibers projected to Crus II, with most of the fibers crossing contralaterally. According to the AI evaluation, 60% of the participants were right STN dominant, 23% were left STN dominant, and 17% were relatively symmetric. Pearson's correlation analysis further indicated that the number of pathways from mesial Brodmann area 8 to the STN (hyperdirect pathway associated with decision making) was positively correlated with the number of fibers from the right STN to Crus I. The insertion and termination, the right-side dominance, and the positive correlation with the hyperdirect pathway all suggest that the STN-cerebellum pathway might be involved in decision-making processes.
... A standardized brain atlas consisting of the Automated Anatomical Labeling (AAL) atlas (Tzourio-Mazoyer et al., 2002) and a bilateral binarized mask of the STN (Forstmann et al., 2012) were used to outline 92 brain regions across both hemispheres. The preSMA and SMA were not separated due to tracts ending in the border of preSMA and SMA (Catani et al., 2012), and will collectively make up a region to be referred to as SMA complex (SMAc). ...
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The right inferior frontal gyrus (rIFG) has most strongly, although not exclusively, been associated with response inhibition, not least based on covariations of behavioral performance measures and local grey matter characteristics. However, the white matter microstructure of the rIFG as well as its connectivity has been less in focus, especially when it comes to the consideration of potential subdivisions within this area. The present study reconstructed the structural connections of the three main subregions of the rIFG (i.e. pars opercularis, pars triangularis and pars orbitalis) using diffusion tensor imaging, and further assessed their associations with behavioral measures of inhibitory control. The results revealed a marked heterogeneity of the three subregions with respect to the pattern and extent of their connections, with the pars orbitalis showing the most widespread inter-regional connectivity, while the pars opercularis showed the least amount of connections. When relating behavioral performance measures of a stop signal task to brain structure, the data indicated a differential association of dorsal and ventral opercular connectivity with the go reaction time and the stopping accuracy, respectively.
... We used diffusion tensor imaging (DTI) and characterized the locations and trajectories of the VTA connections to these brain regions. To index the strength of brain connectivity, we computed fractional anisotropy (FA) from DTI. FA in cortico-cortical or subcorticocortical brain connections is related to a variety of cognitive functions and learning skills in children and adults (Klingberg et al., 2000;Tuch et al., 2005;Keller and Just, 2009;Forstmann et al., 2010Forstmann et al., , 2012Yeatman et al., 2012;Qi et al., 2015;Mamiya et al., 2016Mamiya et al., , 2018. It is heavily influenced by the structural properties of brain connections, including the coherence of neural pathways, the organization of fiber crossing in a local environment and the amount of myelination (Douaud et al., 2011). ...
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Successful learning requires the control of attention to monitor performance and compare actual versus expected outcomes. Neural activity in the ventral tegmental area (VTA) has been linked to attention control in animals. However, it is unknown whether the strength of VTA connections is related to conflict monitoring in humans. To study the relationship between VTA connections and conflict monitoring, we acquired diffusion tensor imaging (DTI) data on 50 second language learners who we have previously studied. We performed probabilistic tractography to document VTA connections with the dorsal striatum and the anterior cingulate cortex (ACC), and administered the Flanker task in which subjects were required to monitor and report conflicts in visual stimuli. Reaction times (RTs) indexed students’ conflict monitoring. Probabilistic tractography revealed distinct neural connections between the VTA and the dorsal striatum and ACC. Correlational analyses between tractography and flanker RTs revealed that the strength of VTA connections with the left caudate nucleus was negatively correlated with RTs recorded in the presence of conflicts. This provides the first evidence to suggest that VTA connections with the left caudate nucleus are related to conflict monitoring in humans.
... The STN exerts an excitatory influence on the output nuclei of the basal ganglia which in turn inhibit the thalamus and the cortex. Activation of the STN during inhibition of movement has been found in many fMRI, local field potential (LFP) and single unit studies in both animals and humans (Aron and Poldrack, 2006;Forstmann et al., 2012;Ray et al., et al., 2015;Fischer et al., 2017a). The STN is also involved in response inhibition of non-motor modalities such as working memory and decision making Zaghloul et al., 2012;Wessel et al., 2016b;Herz et al., 2018). ...
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The subthalamic nucleus (STN), a preferred target for treating movement disorders, has a crucial role in inhibition and execution of movement. To better understand the mechanism of movement regulation in the STN of Parkinson's disease patients, we compared the same movement with different context, facilitation vs. inhibition context. We recorded subthalamic multiunit activity intra-operatively while parkinsonian patients (off medications, n = 43 patients, 173 recording sites) performed increasingly complex oddball paradigms with frequent and deviant tones: first, passive listening to tone series with no movement (‘None-Go’ task, n = 7, 28 recording sites); second, pressing a button after every tone (‘All-Go’ task, n = 7, 26 recording sites); and third, pressing a button only for frequent tones, thus adding inhibition of movement following deviant tones (‘Go-NoGo’ task, n = 29, 119 recording sites). The STN responded mainly to movement-involving tasks. In the limbic-associative STN, evoked response to the deviant tone (inhibitory cue) was not significantly different between the Go-NoGo and the All-Go task. However, the evoked response to the frequent tone (go cue) in the Go-NoGo task was significantly reduced. The reduction was mainly prominent in the negative component of the evoked response amplitude aligned to the press. Successful movement inhibition was correlated with higher baseline activity. We suggest that the STN in Parkinson's disease patients adapts to movement inhibition context by selectively decreasing the amplitude of neuronal activity. Thus, the STN enables movement inhibition not by increasing responses to the inhibitory cue but by reducing responses to the release cue. The negative component of the evoked response probably facilitates movement and a higher baseline activity enables successful inhibition of movement. These discharge modulations were found in the ventromedial, non-motor domain of the STN and therefore suggest a significant role of the limbic- associative STN domains in movement planning and in global movement regulation.
... Thus, all the main pathways, including direct, indirect and hyperdirect pathways, plus the pallidothalamic, nigropallidal and thalamo-striatal projections, have all been successfully characterized to allow an in vivo, comprehensive reconstruction of the basal ganglia connectome (Lehéricy et al., 2004;Draganski et al., 2008;Verstynen et al., 2011;Forstmann et al., 2012;Lenglet et al., 2012). ...
Article
The current model of the basal ganglia system based on the 'direct', 'indirect' and 'hyperdirect' pathways provides striking predictions about basal ganglia function that have been used to develop deep brain stimulation approaches for Parkinson's disease and dystonia. The aim of this review is to challenge this scheme in light of new tract tracing information that has recently become available from the human brain using MRI-based tractography, thus providing a novel perspective on the basal ganglia system. We also explore the implications of additional direct pathways running from cortex to basal ganglia and between basal ganglia and cerebellum in the pathophysiology of movement disorders.
... There is evidence that the efficiency of response inhibition (i.e. SSRT) correlates with the microstructural white-matter properties of these tracts (e.g., fractional anisotropy, fiber length, and mean diffusivity) [38,50,52,53]. However, it should be pointed out that, due to the electrode montage employed in our study and the non-focal nature of tDCS, we cannot rule out that the observed results reflect a combined effect of stimulation of the rIFC and other regions of the frontal cortex such as the frontopolar region. ...
Article
Background: Response inhibition refers to the ability to stop an on-going action quickly when it is no longer appropriate. Previous studies showed that transcranial direct current stimulation (tDCS) applied with the anode over the right inferior frontal cortex (rIFC), a critical node of the fronto-basal ganglia inhibitory network, improved response inhibition. However, the tDCS effects on brain activity and network connectivity underlying this behavioral improvement are not known. Objective: This study aimed to address the effects of tDCS applied with the anode over the rIFC on brain activity and network functional connectivity underlying the behavioral change in response inhibition. Methods: Thirty participants performed a stop-signal task in a typical laboratory setting as a baseline during the first study visit (i.e., Session 1). In the second visit (at least 24 h after Session 1), all participants underwent resting-state functional magnetic resonance imaging (rsfMRI) scans before and after 1.5 mA tDCS (Anodal or Sham). Immediately following the post-tDCS rsfMRI, participants performed the same stop-signal task as in Session 1 during an event-related fMRI (efMRI) scan in a 3T scanner. Changes in task performance, i.e., the stop-signal response time (SSRT), a measure of response inhibition efficiency, was determined relative to the participants' own baseline performance in Session 1. Results: Consistent with previous findings, Anodal tDCS facilitated the SSRT. efMRI results showed that Anodal tDCS strengthened the functional connectivity between right pre-supplementary motor area (rPreSMA) and subthalamic nuclei during Stop responses. rsfMRI revealed changes in intrinsic connectivity between rIFC and caudate, and between rIFC, rPreSMA, right inferior parietal cortex (rIPC), and right dorsolateral prefrontal cortex (rDLPFC) after Anodal tDCS. In addition, corresponding to the regions of rsfMRI connectivity change, the efMRI BOLD signal in the rDLPFC and rIPC during Go responses accounted for 74% of the variance in SSRT after anodal tDCS, indicating an effect of tDCS on the Go-Stop process. Conclusion: These results indicate that tDCS with the anode over the rIFC facilitates response inhibition by modulating neural activity and functional connectivity in the fronto-basal ganglia as well as rDLPFC and rIPC as an integral part of the response inhibition network.
... As for the reactive inhibition, we found activation in the right IFG, the left SMA, left M1, as well as bilateral activation of STN (Figure 4B; Supplementary Table 2). Because the volume of STN is about 240 mm 3 in humans that means the activation of STN is only eight voxels (Hardman et al., 2002;Hamani et al., 2004), we chose the coordinate of the STN described in Forstmann et al. (2012) as a reference to confirm the STN activated significantly. ...
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Successful behavioral inhibition involves both proactive and reactive inhibition, allowing people to prepare for restraining actions, and cancel their actions if the response becomes inappropriate. In the present study, we utilized the stop-signal paradigm to examine whole-brain contrasts and functional connectivity for proactive and reactive inhibition. The results of our functional magnetic resonance imaging (fMRI) data analysis show that the inferior frontal gyrus (IFG), the supplementary motor area (SMA), the subthalamic nucleus (STN), and the primary motor cortex (M1) were activated by both proactive and reactive inhibition. We then created 70 dynamic causal models (DCMs) representing the alternative hypotheses of modulatory effects from proactive and reactive inhibition in the IFG-SMA-STN-M1 network. Bayesian model selection (BMS) showed that causal connectivity from the IFG to the SMA was modulated by both proactive and reactive inhibition. To further investigate the possible brain circuits involved in behavioral control, including proactive inhibitory processes, we compared 13 DCMs representing the alternative hypotheses of proactive modulation in the dorsolateral prefrontal cortex (DLPFC)-caudate-IFG-SMA neural circuits. BMS revealed that the effective connectivity from the caudate to the IFG is modulated only in the proactive inhibition condition but not in the reactive inhibition. Together, our results demonstrate how fronto-basal ganglia pathways are commonly involved in proactive and reactive inhibitory control, with a "longer" pathway (DLPFC-caudate-IFG-SMA-STN-M1) playing a modulatory role in proactive inhibitory control, and a "shorter" pathway (IFG-SMA-STN-M1) involved in reactive inhibition. These results provide causal evidence for the roles of indirect and hyperdirect pathways in mediating proactive and reactive inhibitory control.
... Additional to the D1 and D2 system further satellite systems have been posited to explain clinical manifestations in Parkinson's disease like tremor and non-motor symptoms (Obeso et al., 2010): (i) a striatonigro-striatal loop (Haber et al., 2000), (ii) a 'hyperdirect' projection system as well as additional projections to the STN (Forstmann et al., 2012) and (ii) multisynaptic connections from the cerebellum, exerting influence on the indirect projection system (Bostan et al., 2010;Hoshi et al., 2005). Next to the above proposed nigro-striatal system, also the dentato-pallidal projection influences the motor output in Parkinson's disease (Wu and Hallett, 2013). ...
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Basal ganglia (BG) circuitry plays a crucial role in the control of movement. Degeneration of its pathways and imbalance of dopaminergic signalling goes along with movement disorders such as Parkinson's disease. In this study, we explore the interaction of degeneration in two BG pathways (the nigro-striatal and dentato-pallidal pathway) with D2 receptor signalling to elucidate an association to motor impairment and medication response.Included in the study were 24 parkinsonian patients [male, 62 years (± 9.3 SD)] compared to 24 healthy controls [male, 63 years (± 10.2 SD)]; each participant passed through three phases of the study (i) acquisition of metadata/clinical testing, (ii) genotyping and (iii) anatomical/diffusion MRI.We report a decline in nigro-striatal (p
... This becomes especially problematic with the investigation of very small structures such as the STN. Moreover, the interpretation for ROI analyses is dependent on the atlas used for the analysis [40], we repeated the ROI analyses with a box (10x10x10 mm) at the coordinates identified by Forstmann, Keuken [41] which lead to the same null effect found in the previous analysis. Accordingly, the null effect of STN activation can be understood as an indicator for no or less involvement of the STN in selective changing. ...
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Selective inhibition describes the stopping of an action while other actions are further executed. It can be differentiated between two strategies to stop selectively: the fast but global stop all, then discriminate strategy and the slower but more selective first discriminate, then stop strategy. It is assumed that the first discriminate, then stop strategy is especially used when information regarding which action might have to be stopped is already available beforehand. Moreover, it is supposed that both strategies differ in matters of basal ganglia pathways used for their execution. Aim of the present study was to investigate the use of the two strategies in situations requiring selective changing of an action. Eighteen healthy male participants performed a selective stop-change task with informative and uninformative cues during fMRI. Behavioral results show that informative cues led to a benefit in both inhibition times and selectivity. FMRI data revealed that the same cortico-subcortical pathway was used with informative and uninformative cues. Behavioral and neuronal results indicate that participants used the first discriminate, then stop strategy for selective inhibition irrespective of the amount of previously available information. Moreover, the neural activity data indicate that the benefit in the informed condition was produced by an efficient preparation for the concrete change process. Possible factors that might affect which strategy is used for selective stopping are the level of previously available information (foreknowledge) and the experimental set-up, as e.g. task complexity.
... 0.2 x 0.2mm and 1.0 x 1.0mm). For clarity, comparisons are only done for the labeled volumes by the joint rater, which aligns with our previously published studies (e.g., [31][32][33][34][35][36][37]. As can be seen in Fig 6, the effect of anisotropy on the deviation in volume and shape similarity is moderate when resolutions are relatively high (0.1mm anisotropic vs. 0.2mm isotropic). ...
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How, and to what extent do size and shape of a voxel measured with magnetic resonance imaging (MRI) affect the ability to visualize small brain nuclei? Despite general consensus that voxel geometry affects volumetric properties of regions of interest, particularly those of small brain nuclei, no quantitative data on the influence of voxel size and shape on labeling accuracy is available. Using simulations, we investigated the selective influence of voxel geometry by reconstructing simulated ellipsoid structures with voxels varying in shape and size. For each reconstructed ellipsoid, we calculated differences in volume and similarity between the labeled volume and the predefined dimensions of the ellipsoid. Probability functions were derived from one or two individual raters and a simulated ground truth for reference. As expected, larger voxels (i.e., coarser resolution) and increasing anisotropy results in increased deviations of both volume and shape measures, which is of particular relevance for small brain structures. Our findings clearly illustrate the anatomical inaccuracies introduced by the application of large and/or anisotropic voxels. To ensure deviations occur within the acceptable range (Dice coefficient scores; DCS > 0.75, corresponding to < 57% volume deviation), the volume of isotropic voxels should not exceed 5% of the total volume of the region of interest. When high accuracy is required (DCS > 0.90, corresponding to a < 19% volume deviation), the volumes of isotropic voxels should not exceed 0.08%, of the total volume. Finally, when large anisotropic factors (>3) are used, and the ellipsoid is orthogonal to the slice axes, having its long axis in the imaging plane, the voxel volume should not exceed 0.005% of the total volume. This allows sufficient compensation of anisotropy effects, in order to reach accuracy in the acceptable range (DCS > 0.75, corresponding to >57% volume deviation).
... Despite our small sample of patients, Spearman correlations show that surgical disruption of connectivity of CCx is associated with improvement of symptoms of extremities contralateral to Raprl lesions, which is in line with previous reports 3-6 and with similar effects to DBS in this area. 7,8,10,12,[34][35][36][37][38] Lesions of fibers connecting contralateral DCNs are in turn associated with posture and gait improvements. ...
Article
BACKGROUND Prelemniscal radiations (Raprl) are composed of different fiber tracts, connecting the brain stem and cerebellum with basal ganglia and cerebral cortex. In Parkinson disease (PD), lesions in Raprl induce improvement of tremor, rigidity, and bradykinesia in some patients, while others show improvement of only 1 or 2 symptoms, suggesting different fiber tracts mediate different symptoms. OBJECTIVE To search for correlations between improvements of specific symptoms with surgical lesions of specific fiber tract components of Raprl in patients with PD. METHODS A total of 10 patients were treated with unilateral radiofrequency lesions directed to Raprl. The improvement for tremor, rigidity, bradykinesia, posture, and gait was evaluated at 24 to 33 mo after operation through the Unified Parkinson's Disease Rating Scale (UPDRS) score, and the precise location and extension of lesions through structural magnetic resonance imaging and probabilistic tractography at 6 to 8 mo postsurgery. Correlation between percentage of fiber tract involvement and percentage of UPDRS-III score improvement was evaluated through Spearman's correlation coefficient. RESULTS Group average improvement was 86% for tremor, 62% for rigidity, 56% for bradykinesia, and 45% for gait and posture. Improvement in global UPDRS score correlated with extent of lesions in fibers connecting with contralateral cerebellar cortex and improvement of posture and gait with fibers connecting with contralateral deep cerebellar nuclei. Lesion of fibers connecting the globus pallidum with pedunculopontine nucleus induced improvement of gait and posture over other symptoms. CONCLUSION Partial lesion of Raprl fibers resulted in symptom improvement at 2-yr follow-up. Lesions of selective fiber components may result in selective improvement of specific symptoms.
... Age and sex were regressed out from the connectivity maps as described in the statistical analysis section. We used the Harvard-Oxford subcortical atlas and the subthalamic nucleus atlas [15] provided by FSL (https:// fsl.fmrib.ox.ac.uk/fsl/fslwiki/Atlases). Since all image preprocessing were performed using SPM, we manually checked that these atlases have a good overlap with the corresponding regions in the template used by SPM ( Supplementary Fig. S1). ...
Article
Introduction: The role of the cerebellum in Parkinson's disease (PD) has attracted increasing attention; however, the role of functional connectivity (FC) between the basal ganglia and particular cerebellar subregions remains to be elucidated. We aimed to clarify the FC and its contribution to motor and cognitive performances in patients with PD. Methods: We included 99 patients with PD and 99 age- and sex-matched healthy controls in this study. We created a cerebellar functional parcellation by performing cerebellum-only independent component analysis. Using the functional parcellation map, we performed seed-based connectivity analysis using each region as a seed and extracted the mean correlation coefficients within the thalamus and basal ganglia, including the caudate, pallidum, putamen and subthalamic nucleus. We examined the group differences and correlations with the motor and general cognitive scores. In addition, we conducted a mediation analysis to clarify the relationship among FC, motor severity, and cognition. Results: The PD group showed decreased FC between a wide range of cerebellar subregions and the basal ganglia. Motor severity was correlated with FC between the subthalamic nucleus and posterior Crus I/II, and general cognitive performance scores correlated with FC between the caudate nucleus and medial-posterior part of the Crus I/II (p < 0.05, corrected for multiple comparisons). The cerebello-caudate network had a direct effect on cognitive performance (p = 9.0 × 10-3), although partially mediated by motor performance (p = 8.2 × 10-3). Conclusion: FC between cerebellar Crus I/II and divergent basal ganglia related to motor and cognitive performance in PD.
... Our results show that CST integrity after stroke is crucial for both excitation and inhibition, enabling voluntary modulation and release of grip force.contribution of cortico-striatal pathways for motor inhibition, likely to be important for both force modulation (Tracking error) and release. White matter tracts connecting the posterior medial frontal cortex and the subthalamic nucleus have been identified as important for stopping an ongoing action.78 Cortico-subthalamic connection strength in ageing has also been association between interhemispheric M1-M1 connectivity at T1 and a decrease in Release duration over time (change scores) (SupplementaryTable 5). ...
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Recovery of dexterous hand use is critical for functional outcome after stroke. Grip force recordings can inform on maximal motor output and modulatory and inhibitory cerebral functions, but how these actually contribute to recovery of dexterous hand use is unclear. This cohort study used serially assessed measures of hand kinetics to test the hypothesis that behavioural measures of motor modulation and inhibition explain dexterity recovery beyond that explained by measures of motor output alone. We also investigated the structural and functional connectivity correlates of grip force control recovery. Eighty-nine adults (median age = 54 years, 26% females) with first-ever ischemic or hemorrhagic stroke and persistent arm and hand paresis were assessed longitudinally, at 3 weeks, and at 3 and 6 months after stroke. Kinetic measures included: maximal grip force, accuracy of precision and power grip force control, and ability to release force abruptly. Dexterous hand use was assessed clinically with the Box and Block Test = and motor impairment with the upper extremity Fugl-Meyer Assessment. Structural and functional MRI was used to assess weighted cortico-spinal tract lesion load, voxel-based lesion symptom mapping and interhemispheric resting-state functional connectivity. Fifty-three percent of patients had severe initial motor impairment and a majority still had residual force control impairments at 6 months. Force release at 3 weeks explained 11% additional variance of Box and Block Test outcome at 6 months, above that explained by initial scores (67%). Other kinetic measures did not explain additional variance of recovery. The predictive value of force release remained significant when controlling for cortico-spinal tract lesion load and clinical measures. Cortico-spinal tract lesion load correlated with recovery in grip force control measures. Lesions involving the parietal operculum, insular cortex, putamen and fronto-striatal tracts were also related to poorer force modulation and release. Lesions to fronto-striatal tracts explained an additional 5% of variance in force release beyond the 43% explained by cortico-spinal injury alone. Interhemispheric functional connectivity did not relate to force control recovery. We conclude that not only voluntary force generation but also force release (reflecting motor inhibition) are important for recovery of dexterous hand use after stroke. Although cortico-spinal injury is a main determinant of recovery, lesions to integrative somatosensory areas and fronto-parietal white matter (involved in motor inhibition) explain additional variance in post-stroke force release recovery. Our findings indicate that post-stroke upper limb motor impairment profiling, which is essential for targeted treatment, should consider both voluntary grasp generation and inhibition.
... Of particular relevance to our findings is the strong theoretical relationship between functional and effective-and implicitly also structural-connectivity in networks such as the hyperdirect pathway with unidirectional information transfer 40 . Previous studies examining the intersection of tractography and fMRI are suggestive of a similar overlap of structural and functional connectivity within hyperdirect connections during stopping behavior 10,41 with the strength of hyperdirect connections also correlating with the efficacy of stopping 42 . More broadly, the relationship between functional and structural connectivity in brain networks is highly complex 43 and also limited by the pitfalls of the modalities used to assess these measures. ...
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Parkinson’s disease (PD) is characterised by the emergence of beta frequency oscillatory synchronisation across the cortico-basal-ganglia circuit. The relationship between the anatomy of this circuit and oscillatory synchronisation within it remains unclear. We address this by combining recordings from human subthalamic nucleus (STN) and internal globus pallidus (GPi) with magnetoencephalography, tractography and computational modelling. Coherence between supplementary motor area and STN within the high (21–30 Hz) but not low (13-21 Hz) beta frequency range correlated with ‘hyperdirect pathway’ fibre densities between these structures. Furthermore, supplementary motor area activity drove STN activity selectively at high beta frequencies suggesting that high beta frequencies propagate from the cortex to the basal ganglia via the hyperdirect pathway. Computational modelling revealed that exaggerated high beta hyperdirect pathway activity can provoke the generation of widespread pathological synchrony at lower beta frequencies. These findings suggest a spectral signature and a pathophysiological role for the hyperdirect pathway in PD.
... A standardized brain atlas consisting of the Automated Anatomical Labeling (AAL) atlas (Tzourio-Mazoyer et al., 2002) and a bilateral binarized mask of the STN (Forstmann et al., 2012) were used to outline 92 brain regions across both hemispheres. The AAL atlas does not separate the preSMA and SMA proper region, and there are short frontal tracts that connects the IFG to both the preSMA and SMA proper region (Catani et al., 2012), without a clear separation between the two regions. ...
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The right inferior frontal gyrus (rIFG) has most strongly, although not exclusively, been associated with response inhibition, not least based on covariations of behavioral performance measures and local gray matter characteristics. However, the white matter microstructure of the rIFG as well as its connectivity has been less in focus, especially when it comes to the consideration of potential subdivisions within this area. The present study reconstructed the structural connections of the three main subregions of the rIFG (i.e., pars opercularis, pars triangularis, and pars orbitalis) using diffusion tensor imaging, and further assessed their associations with behavioral measures of inhibitory control. The results revealed a marked heterogeneity of the three subregions with respect to the pattern and extent of their connections, with the pars orbitalis showing the most widespread inter-regional connectivity, while the pars opercularis showed the lowest number of interconnected regions. When relating behavioral performance measures of a stop signal task to brain structure, the data indicated an association between the dorsal opercular connectivity and the go reaction time and the stopping accuracy.
... For the putamen, thalamus and caudate nucleus, the left and right parts of each hemisphere were extracted from the images using Freesurfer. The substantia nigra and sub-thalamic nucleus were segmented using in-house software that implements an atlas-based approach for the substantia nigra atlas 31 and the sub-thalamic nucleus atlas 32 . The results were checked visually and corrected as appropriate. ...
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There is a growing need for surrogate biomarkers for Parkinson’s disease (PD). Structural analysis using magnetic resonance imaging with T1-weighted sequences has the potential to quantify histopathological changes. Degeneration is typically measured by the volume and shape of morphological changes. However, these changes appear late in the disease, preventing their use as surrogate markers. We investigated texture changes in 108 individuals, divided into three groups, matched in terms of sex and age: (1) healthy controls (n = 32); (2) patients with early-stage PD (n = 39); and (3) patients with late-stage PD and severe L-dopa-related complications (n = 37). All patients were assessed in off-treatment conditions. Statistical analysis of first- and second-order texture features was conducted in the substantia nigra, striatum, thalamus and sub-thalamic nucleus. Regions of interest volumetry and voxel-based morphometry were performed for comparison. Significantly different texture features were observed between the three populations, with some showing a gradual linear progression between the groups. The volumetric changes in the two PD patient groups were not significantly different. Texture features were significantly associated with clinical scores for motor handicap. These results suggest that texture features, measured in the nigrostriatal pathway at PD diagnosis, may be useful in predicting clinical progression of motor handicap.
... The globus pallidus masks were divided into the globus pallidus externus (GPe) and internus (GPi) by a probabilistic atlas 10 . The substantia nigra (SN), the subthalamic nucleus (STN), the ventral tegmental area (VTA), and the cerebellar hemisphere were also extracted using the probabilistic atlas [11][12][13] . The deep cerebellar nuclei (DCN) were manually extracted based on the hypointensity region of the cerebellar white matter from individual diffusion tensor images. ...
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Aromatic l-amino acid decarboxylase (AADC) is an essential dopamine-synthesizing enzyme. In children with AADC deficiency, the gene delivery of AADC into the putamen, which functionally interacts with cortical regions, was found to improve motor function and ameliorate dystonia. However, how the restoration of dopamine in the putamen in association with cortico-putaminal networks leads to therapeutic effects remains unclear. Here, we examined neuroimaging data of eight patients with AADC deficiency (five males and three females, age range 4–19 years) who received the AADC gene therapy of the bilateral putamen in an open-label phase 1/2 study. Using high-resolution positron emission tomography with a specific AADC tracer, 6-[18F]fluoro-l-m-tyrosine (FMT), we showed that FMT uptake increased in the broad area of the putamen over the years. Then, with the structural connectivity-based parcellation of the putaminal area, we found that motor improvement is associated with dopaminergic restoration of the putaminal area that belongs to the prefrontal cortico-putaminal network. The prefrontal area dominantly belongs to the frontoparietal control network, which contributes to cognitive-motor control function, including motor initiation and planning. The results suggest that putaminal dopamine promotes the development of an immature motor control system, particularly in the human prefrontal cortex that is primarily affected by AADC deficiency.
... 27 This network is thought to involve hyperdirect pathway input to the STN, 28 with the strength of hyperdirect connections correlating with the efficacy of stopping. 29,30 Impulsivity is a key component in a number of other neuropsychiatric disorders, and it is therefore interesting that, among these, elevated α band power at rest has been reported in the ventralis oralis complex of the thalamus of patients with Tourette's syndrome, 31 in the bed nucleus of stria terminalis or in subgenual cingulate area in patients with major depression, 32 and in the nucleus accumbens in patients with addiction or substance use disorders. 33 This raises the possibility that α activity might serve as a biomarker for behavioral impulsivity across neuropsychiatric disorders. ...
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Background: Impulsivity is common in people with Parkinson's disease (PD), with many developing impulsive compulsive behavior disorders (ICB). Its pathophysiological basis remains unclear. Objectives: We aimed to investigate local field potential (LFP) markers of trait impulsivity in PD and their relationship to ICB. Methods: We recorded subthalamic nucleus (STN) LFPs in 23 PD patients undergoing deep brain stimulation implantation. Presence and severity of ICB were assessed by clinical interview and the Questionnaire for Impulsive-Compulsive Disorders in PD-Rating Scale (QUIP-RS), whereas trait impulsivity was estimated with the Barratt Impulsivity Scale (BIS-11). Recordings were obtained during the off dopaminergic states and the power spectrum of the subthalamic activity was analyzed using Fourier transform-based techniques. Assessment of each electrode contact localization was done to determine the topography of the oscillatory activity recorded. Results: Patients with (n = 6) and without (n = 17) ICB had similar LFP spectra. A multiple regression model including QUIP-RS, BIS-11, and Unified PD Rating Scale-III scores as regressors showed a significant positive correlation between 8-13 Hz power and BIS-11 score. The correlation was mainly driven by the motor factor of the BIS-11, and was irrespective of the presence or absence of active ICB. Electrode contact pairs with the highest α power, which also correlated most strongly with BIS-11, tended to be more ventral than contact pairs with the highest beta power, which localize to the dorsolateral motor STN. Conclusions: Our data suggest a link between α power and trait impulsivity in PD, irrespective of the presence and severity of ICB. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
... Maintenance is considered to reflect how well a brain is preserved 85 in structural and functional terms, and compensation is the capacity to recruit existing 86 resources with greater efficiency or to employ alternative neural networks in response to 87 cognitive demand. These two sub-components are therefore measured in different ways 88 [8]. First, an index of brain maintenance has been developed to assess the degree of brain 89 deterioration relative to chronological age (Brain Predicted Age Difference -BrainPAD or 90 Brain Gap Estimation -BrainAGE) in order to address a more precise value of mainte-91 nance than just brain volume alone [10,11,12]. ...
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The noradrenergic theory of Cognitive Reserve (Robertson, 2013-2014) postulates that the upregulation of the Locus Coeruleus - Noradrenergic System (LC-NA) originating in the Brainstem might facilitate cortical networks involved in attention, and protracted activation of this system throughout the lifespan may enhance cognitive stimulation contributing to Reserve. To test the above-mentioned theory, a study was conducted on a sample of 686 participants (395 controls, 156 Mild Cognitive Impairment, 135 Alzheimer’s Disease) investigating the relationship between LC volume, attentional performance and a biological index of brain maintenance (BrainPAD – an objective measure which compares an individual’s structural brain health, reflected by their voxel-wise grey matter density, to the state typically expected at that individual’s age). Further analyses were carried out on Reserve indices including education and occupational attainment. Volumetric variation across groups was also explored along with gender differences. Control analyses on the Serotoninergic (5-HT), Dopaminergic (DA) and Cholinergic (Ach) systems were contrasted with the Noradrenergic (NA) hypothesis. The antithetic relationships were also tested across the neuromodulatory subcortical systems.Results supported by bayesian modelling showed that LC volume disproportionately predicted higher attentional performance as well as biological brain maintenance across the three groups. These findings lend support to the role of the noradrenergic system as a key mediator underpinning the neuropsychology of Reserve, and they suggest that early prevention strategies focused on the noradrenergic system (e.g. cognitive-attentive training, physical exercise, pharmacological and dietary interventions) may yield important clinical benefits to mitigate cognitive impairment with age and disease.
... These two sub-components are therefore measured in different ways [8]. First, an 88 index of brain maintenance has been developed to assess the degree of brain deterioration 89 relative to chronological age (Brain Predicted Age Difference -BrainPAD or Brain Gap 90 Estimation -BrainAGE) in order to address a more precise value of maintenance than just 91 brain volume alone [10,11,12]. Based on the brain deterioration in optimal normal ageing, 92 BrainPAD is a cross-sectional measure which compares an individual's structural brain 93 health, reflected by their voxel-wise grey matter density, to the state typically expected at 94 that individual's age. ...
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The noradrenergic theory of Cognitive Reserve (Robertson, 2013-2014) postulates that the upregulation of the Locus Coeruleus - Noradrenergic System (LC-NA) originating in the Brainstem might facilitate cortical networks involved in attention, and protracted activation of this system throughout the lifespan may enhance cognitive stimulation contributing to Reserve. To test the above-mentioned theory, a study was conducted on a sample of 686 participants (395 controls, 156 Mild Cognitive Impairment, 135 Alzheimer’s Disease) investigating the relationship between LC volume, attentional performance and a biological index of brain maintenance (BrainPAD – an objective measure which compares an individual’s structural brain health, reflected by their voxel-wise grey matter density, to the state typically expected at that individual’s age). Further analyses were carried out on Reserve indices including education and occupational attainment. Volumetric variation across groups was also explored along with gender differences. Control analyses on the Serotoninergic (5-HT), Dopaminergic (DA) and Cholinergic (Ach) systems were contrasted with the Noradrenergic (NA) hypothesis. The antithetic relationships were also tested across the neuromodulatory subcortical systems.Results supported by bayesian modelling showed that LC volume disproportionately predicted higher attentional performance as well as biological brain maintenance across the three groups. These findings lend support to the role of the noradrenergic system as a key mediator underpinning the neuropsychology of Reserve, and they suggest that early prevention strategies focused on the noradrenergic system (e.g. cognitive-attentive training, physical exercise, pharmacological and dietary interventions) may yield important clinical benefits to mitigate cognitive impairment with age and disease.
... Tracking was performed by seeding from 210 bilateral cortical regions and 36 bilateral subcortical regions obtained from the Brainnetome Atlas . Adding to this set, the subthalamic nucleus and the bed nucleus of the stria terminalis were obtained from the Subthalamic Nucleus Atlas (Forstmann et al., 2012) and from a probabilistic map of the National Institute of Mental Health (https:// afni.nimh.nih.gov), respectively. ...
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Rich-club organization is key to efficient global neuronal signaling and integration of information. Alterations interfere with higher-order cognitive processes, and are common to several psychiatric and neurological conditions. A few studies examining the structural connectome in obsessive-compulsive disorder (OCD) suggest lower efficiency of information transfer across the brain. However, it remains unclear whether this is due to alterations in rich-club organization. In the current study, the structural connectome of 28 unmedicated OCD patients, 8 of their unaffected siblings and 28 healthy controls was reconstructed by means of diffusion-weighted imaging and probabilistic tractography. Topological and weighted measures of rich-club organization and connectivity were computed, alongside global and nodal measures of network integration and segregation. The relationship between clinical scores and network properties was explored. Compared to healthy controls, OCD patients displayed significantly lower topological and weighted rich-club organization, allocating a smaller fraction of all connection weights to the rich-club core. Global clustering coefficient, local efficiency, and clustering of nonrich club nodes were significantly higher in OCD patients. Significant three-group differences emerged, with siblings displaying highest and lowest values in different measures. No significant correlation with any clinical score was found. Our results suggest weaker structural connectivity between rich-club nodes in OCD patients, possibly resulting in lower network integration in favor of higher network segregation. We highlight the need of looking at network-based alterations in brain organization and function when investigating the neurobiological basis of this disorder, and stimulate further research into potential familial protective factors against the development of OCD.
... This parcellation comprised the 116 parcels of the automated anatomical labeling (AAL) atlas ( Tzourio-Mazoyer et al., 2002 ) with node location set to the center of mass of each AAL parcel, and 32 additional nodes chosen from the literature for their specific role in memory and motor processes (e.g. Beckmann et al. 2009 ;Cooper and Ritchey 2019 ;Forstmann et al. 2012 andHoffstaedter et al., 2014 ). The addition of these regions allowed to ensure the presence of nodes known to be involved in motor and memory functions since the AAL atlas is based on a purely anatomical parcellation. ...
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This magnetoencephalography (MEG) study investigates how procedural sequence learning performance is related to prior brain resting-state functional connectivity (rsFC), and to what extent sequence learning induces rapid changes in brain rsFC in school-aged children. Procedural learning was assessed in 30 typically developing children (mean age ± SD: 9.99 years ± 1.35) using a serial reaction time task (SRTT). During SRTT, participants touched as quickly and accurately as possible a stimulus sequentially or randomly appearing in one of the quadrants of a touchscreen. Band-limited power envelope correlation (brain rsFC) was applied to MEG data acquired at rest pre- and post-learning. Correlation analyses were performed between brain rsFC and sequence-specific learning or response time indices. Stronger pre-learning interhemispheric rsFC between inferior parietal and primary somatosensory/motor areas correlated with better subsequent sequence learning performance and faster visuomotor response time. Faster response time was associated with post-learning decreased rsFC within the dorsal extra-striate visual stream and increased rsFC between temporo-cerebellar regions. In school-aged children, variations in functional brain architecture at rest within the sensorimotor network account for interindividual differences in sequence learning and visuomotor performance. After learning, rapid adjustments in functional brain architecture are associated with visuomotor performance but not sequence learning skills.
... However, the probabilistic map referring to the SI/NBM (4ch.nii) defined by Zaborszky et al. (2008) [119] overlaps several subcortical nuclei delineated in other atlases [118,[120][121][122][123][124][125][126]. Therefore, the "4ch.nii" was used as main reference to delineate the SI/NBM, but was adjusted by excluding the subcortical nuclei identified by other atlases while accounting for the probabilistic localisation of the SI/NBM delineated in previous works [81,82,[127][128][129]. ...
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The noradrenergic theory of Cognitive Reserve (Robertson, 2013–2014) postulates that the upregulation of the locus coeruleus—noradrenergic system (LC–NA) originating in the brainstem might facilitate cortical networks involved in attention, and protracted activation of this system throughout the lifespan may enhance cognitive stimulation contributing to reserve. To test the above-mentioned theory, a study was conducted on a sample of 686 participants (395 controls, 156 mild cognitive impairment, 135 Alzheimer’s disease) investigating the relationship between LC volume, attentional performance and a biological index of brain maintenance (BrainPAD—an objective measure, which compares an individual’s structural brain health, reflected by their voxel-wise grey matter density, to the state typically expected at that individual’s age). Further analyses were carried out on reserve indices including education and occupational attainment. Volumetric variation across groups was also explored along with gender differences. Control analyses on the serotoninergic (5-HT), dopaminergic (DA) and cholinergic (Ach) systems were contrasted with the noradrenergic (NA) hypothesis. The antithetic relationships were also tested across the neuromodulatory subcortical systems. Results supported by Bayesian modelling showed that LC volume disproportionately predicted higher attentional performance as well as biological brain maintenance across the three groups. These findings lend support to the role of the noradrenergic system as a key mediator underpinning the neuropsychology of reserve, and they suggest that early prevention strategies focused on the noradrenergic system (e.g., cognitive-attentive training, physical exercise, pharmacological and dietary interventions) may yield important clinical benefits to mitigate cognitive impairment with age and disease.
... Another aspect possibly explaining the correlation between visual and cognitive functions is that both processes rely on neuronal transmissions like neurotransmitters and white matter pathways (Forstmann et al., 2012;Jitsuishi et al., 2020) propagating chemical or electrical signals for the transduction of visual or cognitive information. Thus, a more efficient neuronal processing resulting in lower energy usage is linked to better visual and cognitive performance (Babiloni et al., 2010;Leisman et al., 2016). ...
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Visual and cognitive skills are key to successful functioning in highly demanding settings such as elite sports. However, their mutual influence and interdependencies are not sufficiently understood yet. This cross-sectional study examined in a cross-sectional study design the relationship of between visual skills and executive functions in elite soccer players. Fifty-nine male elite soccer players (age: 18-34 years) performed tests assessing visual clarity (left-, right- and both eyes), contrast sensitivity, near-far quickness, and hand-eye coordination. Executive functions measures included working memory capacity, cognitive flexibility, inhibition and selective attention. Overall, visual abilities were largely correlated with the executive functions. Near-far quickness performance showed a large correlation with an executive function total score as well as with cognitive flexibility, working memory, and especially selective attention. Visual clarity and contrast sensitivity were moderately correlated with the cognition total score. Most consistent correlations of the executive functionswith the visual functions were present for working memory. , specifically with the visual clarity of the right- and both eyes and near-far quickness. These findings present an overall vision-cognition relationship but also very specific linkages among subcategories of these functions, especially by indicating meaningful relations between near-far quickness, selective attention and cognitive flexibility. Further studies are needed to investigate the neuropsychological mechanisms accounting for the correlations and possible improvements of the executive functions by training specific visual skills.
... Experimental studies in patients have helped to define the contribution of subcortical structures to response inhibition, specifically fronto-basal interactions (Whelan et al., 2012). Evidence from these studies suggest that the connection between supplementary motor area/inferior frontal gyrus and sub-thalamic nucleus (Inase et al., 1999;Aron et al., 2007) is crucial in controlling response inhibition (Aron and Poldrack, 2006;Frank, 2006;Li et al., 2008;Hikosaka and Isoda, 2010;Munakata et al., 2011;Forstmann et al., 2012) The stop-signal paradigm is well-suited for laboratory investigation of response inhibition. Participants perform a reaction time (RT) task in response to a Go cue. ...
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Introduction: The ability to stop the execution of a movement in response to an external cue requires intact executive function. The effect of psychotropic drugs on movement inhibition is largely unknown. Movement stopping can be estimated by the Stop Signal Reaction Time (SSRT). In a recent publication, we validated an improved measure of SSRT (optimum combination SSRT, ocSSRT). Here we explored how diazepam, which enhances transmission at GABAA receptors, affects ocSSRT. Methods: Nine healthy individuals were randomized to receive placebo, 5 mg or 10 mg doses of diazepam. Each participant received both the dosage of drug and placebo orally on separate days with adequate washout. The ocSSRT and simple reaction time (RT) were estimated through a stop-signal task delivered via a battery-operated box incorporating green (Go) and red (Stop) light-emitting diodes. The task was performed just before and 1 h after dosing. Result: The mean change in ocSSRT after 10 mg diazepam was significantly higher (+27 ms) than for placebo (−1 ms; p = 0.012). By contrast, the mean change in simple response time remained comparable in all three dosing groups (p = 0.419). Conclusion: Our results confirm that a single therapeutic adult dose of diazepam can alter motor inhibition in drug naïve healthy individuals. The selective effect of diazepam on ocSSRT but not simple RT suggests that GABAergic neurons may play a critical role in movement-stopping.
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Stopping an inappropriate response requires the involvement of the prefrontal-subthalamic hyperdirect pathway. However, how the prefrontal-striatal indirect pathway contributes to stopping is poorly understood. In this study, transcranial ultrasound stimulation is used to perform interventions in a task-related region in the striatum. Functional magnetic resonance imaging (MRI) reveals activation in the right anterior part of the putamen during response inhibition, and ultrasound stimulation to the anterior putamen, as well as the subthalamic nucleus, results in significant impairments in stopping performance. Diffusion imaging further reveals prominent structural connections between the anterior putamen and the right anterior part of the inferior frontal cortex (IFC), and ultrasound stimulation to the anterior IFC also shows significant impaired stopping performance. These results demonstrate that the right anterior putamen and right anterior IFC causally contribute to stopping and suggest that the anterior IFC-anterior putamen circuit in the indirect pathway serves as an essential route for stopping.
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Magnetic resonance imaging studies typically use standard anatomical atlases for identification and analyses of (patho-)physiological effects on specific brain areas; these atlases often fail to incorporate neuroanatomical alterations that may occur with both age and disease. The present study utilizes Parkinson's disease and age-specific anatomical atlases of the subthalamic nucleus for diffusion tractography, assessing tracts that run between the subthalamic nucleus and a-priori defined cortical areas known to be affected by Parkinson's disease. The results show that the strength of white matter fiber tracts appear to remain structurally unaffected by disease. Contrary to that, Fractional Anisotropy values were shown to decrease in Parkinson's disease patients for connections between the subthalamic nucleus and the pars opercularis of the inferior frontal gyrus, anterior cingulate cortex, the dorsolateral prefrontal cortex and the pre-supplementary motor, collectively involved in preparatory motor control, decision making and task monitoring. While the biological underpinnings of fractional anisotropy alterations remain elusive, they may nonetheless be used as an index of Parkinson's disease. Moreover, we find that failing to account for structural changes occurring in the subthalamic nucleus with age and disease reduce the accuracy and influence the results of tractography, highlighting the importance of using appropriate atlases for tractography.
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The current study aims to examine the effect of material properties on implanted leads used for deep brain stimulation (DBS) using finite element (FE) analysis to investigate brain deformation around an implanted DBS lead in response to daily head accelerations. FE analysis was used to characterize the relative motion of the DBS lead in a suite of fifteen cases sampled from a previously derived kinematic envelope representative of everyday activities describing translational and rotational pulse shape, magnitude, and duration. Load curves were applied to the atlas-based brain model (ABM) with a scaled Haversine acceleration pulse in four directions of rotation: + X, − Y, + Y, and + Z. In addition to the fifteen sampled cases, six experimental cases taken from a previous literature review were also simulated for comparison. The current investigation found that there was very little difference in brain response for the DBS leads with two different material properties. In general, the brain and DBS lead experienced the greatest deformation during rotation about the Z axis for similar load cases. In conclusion, this study showed that there was no significant difference in implanted DBS lead deformation based on lead material properties.
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The pre-supplementary motor area (pre-SMA) is central for the initiation and inhibition of voluntary action. For the execution of action, the pre-SMA optimises the decision of which action to choose by adjusting the thresholds for the required evidence for each choice. However, it remains unclear how the pre-SMA contributes to action inhibition. Here, we use computational modelling of a stop/no-go task, performed by an adult with a focal lesion in the pre-SMA, and 52 age-matched controls. We show that the patient required more time to successfully inhibit an action (longer stop-signal reaction time) but was faster in terms of go reaction times. Computational modelling revealed that the patient’s failure to stop was explained by a significantly lower response threshold for initiating an action, as compared to controls, suggesting that the patient needed less evidence before committing to an action. A similarly specific impairment was also observed for the decision of which action to choose. Together, our results suggest that dynamic threshold modulation may be a general mechanism by which the pre-SMA exerts its control over voluntary action.
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Background To investigate the relative contributions of cerebral cortex and basal ganglia to movement stopping, we tested the optimum combination Stop Signal Reaction Time (ocSSRT) and median visual reaction time (RT) in patients with Alzheimer’s disease (AD) and Parkinson’s disease (PD) and compared values with data from healthy controls. Methods Thirty-five PD patients, 22 AD patients, and 29 healthy controls were recruited to this study. RT and ocSSRT were measured using a hand-held battery-operated electronic box through a stop signal paradigm. Result The mean ocSSRT was found to be 309 ms, 368 ms, and 265 ms in AD, PD, and healthy controls, respectively, and significantly prolonged in PD compared to healthy controls ( p = 0.001). The ocSSRT but not RT could separate AD from PD patients ( p = 0.022). Conclusion Our data suggest that subcortical networks encompassing dopaminergic pathways in the basal ganglia play a more important role than cortical networks in movement-stopping. Combining ocSSRT with other putative indices or biomarkers of AD (and other dementias) could increase the accuracy of early diagnosis.
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Age-related characteristics of motivational inductors of behavior and internal control, which contribute to “successful” aging, are studied. University students and elderly women (20 ± 1.1 and 65.1 ± 5.8 years, respectively) are involved in the study. The dominance of cognitive activity in the profile of motivational inductors regardless of the age and time period of self-appraisal is established. Age differences are found for the “future” situation: increased importance of physical activity for the elderly and significantly greater importance of the “emotional state” components both in the present and in the future for young female students. However, the recognition of the priority of cognitive activity does not correspond to the practical implementation of the cognitive training program, presumably due to the age-related weakening of executive control in initiating new activities.
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Dopaminergic medication is widely used to alleviate motor symptoms of Parkinson’s disease, but these medications also impact cognition with significant variability across patients. It is hypothesized that dopaminergic medication impacts cognition and working memory in Parkinson’s disease by modulating frontoparietal-basal ganglia cognitive control circuits, but little is known about the underlying causal signalling mechanisms and their relation to individual differences in response to dopaminergic medication. Here we use a novel state-space computational model with ultra-fast (490 ms resolution) functional MRI to investigate dynamic causal signalling in frontoparietal-basal ganglia circuits associated with working memory in 44 Parkinson’s disease patients ON and OFF dopaminergic medication, as well as matched 36 healthy controls. Our analysis revealed aberrant causal signalling in frontoparietal-basal ganglia circuits in Parkinson’s disease patients OFF medication. Importantly, aberrant signalling was normalized by dopaminergic medication and a novel quantitative distance measure predicted individual differences in cognitive change associated with medication in Parkinson’s disease patients. These findings were specific to causal signalling measures, as no such effects were detected with conventional non-causal connectivity measures. Our analysis also identified a specific frontoparietal causal signalling pathway from right middle frontal gyrus to right posterior parietal cortex that is impaired in Parkinson’s disease. Unlike in healthy controls, the strength of causal interactions in this pathway did not increase with working memory load and the strength of load-dependent causal weights was not related to individual differences in working memory task performance in Parkinson’s disease patients OFF medication. However, dopaminergic medication in Parkinson’s disease patients reinstated the relation with working memory performance. Our findings provide new insights into aberrant causal brain circuit dynamics during working memory and identify mechanisms by which dopaminergic medication normalizes cognitive control circuits.
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Tourette disorder (TD) is characterized by tics, which are sudden repetitive involuntary movements or vocalizations. Deficits in inhibitory control in TD patients remain inconclusive from the traditional method of estimating the ability to stop an impending action, which requires careful interpretation of a metric derived from race model. One possible explanation for these inconsistencies is that race model’s assumptions of independent and stochastic rise of GO and STOP process to a fixed threshold are often violated, making the classical metric to assess inhibitory control less robust. Here, we used a pair of metrics derived from a recent alternative model to address why stopping performance in TD is unaffected despite atypical neural circuitry. These new metrics distinguish between proactive and reactive inhibitory control and estimate them separately. When these metrics in adult TD group were contrasted with healthy controls (HC), we identified robust deficits in reactive control, but not in proactive control in TD. The TD group exhibited difficulty in slowing down the speed of movement preparation, which they rectified by their intact ability to postpone the movement.
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Interacting with our environment requires the selection of appropriate responses and the inhibition of others. Such effortful inhibition is achieved by a number of interference resolution and global inhibition processes. This meta-analysis including 57 studies and 73 contrasts revisits the overlap and differences in brain areas supporting interference resolution and global inhibition in cortical and subcortical brain areas. Activation likelihood estimation was used to discern the brain regions subserving each type of cognitive control. Individual contrast analysis revealed a common activation of the bilateral insula and supplementary motor areas. Subtraction analyses demonstrated the voxel-wise differences in recruitment in a number of areas including the precuneus in the interference tasks and the frontal pole and dorsal striatum in the inhibition tasks. Our results display a surprising lack of subcortical involvement within these types of cognitive control, a finding that is likely to reflect a systematic gap in the field of functional neuroimaging.
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Previous Diffusion Tensor Imaging (DTI) studies in children suggest that developmental improvements in inhibitory control is largely mediated by the degree of white matter organisation within a right-lateralised network of fronto-basal-ganglia regions. Recent advances in diffusion imaging analysis now permit greater biological specificity, both in identifying specific fibre populations within a voxel, as well as in the underlying microstructural properties of that white matter. In the present work, employing a novel fixel-based analysis (FBA) framework, we aimed to comprehensively investigate microstructure within the fronto-basal-ganglia circuit in childhood, and its contribution to inhibition performance. Diffusion MRI data were obtained from 43 healthy children and adolescents age 9–11 years (10.42 ± .41 years, 18 females). Response inhibition for each participant was assessed using the Stop-signal Task (SST) and quantified as a Stop–Signal Reaction Time (SSRT). All steps relevant to FBA were implemented in MRtrix3Tissue, a fork of the MRtrix3 software library. Tracts of the fronto-basal-ganglia circuit were delineated using probabilistic tractography to identify the tracts connecting the subthalamic nucleus, pre-supplementary motor area and the inferior frontal gyrus. Connectivity-based fixel enhancement (CFE) was then used to assess the association between fibre density (FD) and fibre cross-section (FC) with inhibitory ability. Significant negative associations were identified for FD in both the right and left fronto-basal-ganglia circuit whereby greater FD was associated with better inhibition performance. This effect was specifically localised to clusters of fixels within white matter proximal to the right subthalamic nucleus. We did not report any meaningful associations between SSRT and FC. Whilst findings are broadly consistent with prior DTI evidence, current results suggest that SSRT is predominantly facilitated by subcortical microstructure of the connections projecting from the subthalamic nucleus to the cortical regions of the network. Our findings extend current understanding of the role of white matter in childhood response inhibition.
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The flexibility of behavioral control is a testament to the brain’s capacity for dynamically resolving uncertainty during goal-directed actions. This ability to select actions and learn from immediate feedback is driven by the dynamics of basal ganglia (BG) pathways. A growing body of empirical evidence conflicts with the traditional view that these pathways act as independent levers for facilitating (i.e., direct pathway) or suppressing (i.e., indirect pathway) motor output, suggesting instead that they engage in a dynamic competition during action decisions that computationally captures action uncertainty. Here we discuss the utility of encoding action uncertainty as a dynamic competition between opposing control pathways and provide evidence that this simple mechanism may have powerful implications for bridging neurocomputational theories of decision making and reinforcement learning.
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The subthalamic nucleus (STN) is thought to be a central regulator of behavioral inhibition, which is thought to be a major determinant of impulsivity. Thus, it would be reasonable to hypothesize that STN function is related to impulsivity. However, it has been difficult to test this hypothesis because of the challenges in noninvasively and accurately measuring this structure's signal in humans. We utilized a novel approach for STN signal localization that entails identifying this structure directly on fMRI images for each individual participant in native space. Using this approach, we measured STN responses during the stop signal task in a sample of healthy adult participants. We confirmed that the STN exhibited selective activation during "Stop" trials. Furthermore, the magnitude of STN activation during successful Stop trials inversely correlated with individual differences in trait impulsivity as measured by a personality inventory. Time course analysis revealed that early STN activation differentiated successful from unsuccessful Stop trials, and individual differences in the magnitude of STN activation inversely correlated with stop signal RT, an estimate of time required to stop. These results are consistent with the STN playing a central role in inhibition and related behavioral proclivities, with implications for both normal range function and clinical syndromes of inhibitory dyscontrol. Moreover, the methods utilized in this study for measuring STN fMRI signal in humans may be gainfully applied in future studies to further our understanding of the role of the STN in regulating behavior and neuropsychiatric conditions.
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A challenge associated with deep brain stimulation (DBS) in treating advanced Parkinson disease (PD) is the direct visualization of brain nuclei, which often involves indirect approximations of stereotactic targets. In the present study, the authors compared T2*-weighted images obtained using 7-T MR imaging with those obtained using 1.5- and 3-T MR imaging to ascertain whether 7-T imaging enables better visualization of targets for DBS in PD. The authors compared 1.5-, 3-, and 7-T MR images obtained in 11 healthy volunteers and 1 patient with PD. With 7-T imaging, distinct images of the brain were obtained, including the subthalamic nucleus (STN) and internal globus pallidus (GPi). Compared with the 1.5- and 3-T MR images of the STN and GPi, the 7-T MR images showed marked improvements in spatial resolution, tissue contrast, and signal-to-noise ratio. Data in this study reveal the superiority of 7-T MR imaging for visualizing structures targeted for DBS in the management of PD. This finding suggests that by enabling the direct visualization of neural structures of interest, 7-T MR imaging could be a valuable aid in neurosurgical procedures.
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Models of natural action selection implicate fronto-striatal circuits in both motor and cognitive ‘actions’. Dysfunction of these circuits leads to decision-making deficits in various populations. We review how computational models provide insights into the mechanistic basis for these deficits in Parkinson's patients and individuals with ventromedial frontal damage. We then consider implications of the models for understanding behaviour and cognition in attention deficit/hyperactivity disorder (ADHD). Incorporation of cortical norepinephrine function into the model improves action selection in noisy environments and accounts for response variability in ADHD. We close with more general clinical implications. Fronto-striatal dysfunction can lead to dramatic changes in cognition and action, as evidenced by various disorders with disturbances to this circuitry, including Parkinson's disease (PD), schizophrenia, attention deficit/hyperactivity disorder (ADHD), obsessive–compulsive disorder, Tourrette's syndrome, Huntington's disease and addiction (Nieoullon 2002). One might wonder how adaptive evolution of a brain system could lead to the complexity and diversity of behaviours associated with these disorders, especially since these behaviours generally do not occur spontaneously in animals. However, we could also turn this question on its ear and ask: how elegant must a neural system be to lead to more rational human behaviour? It may be an unfortunate but necessary corollary that the complexity required to produce adaptive thought and behaviour may be vulnerable to all manner of issues with the ‘plumbing’, which would have compounding effects on the overall system. Thus the trade-offs that come with adaptive human behaviour may be akin to those associated with a car that has electronic seat position control and GPS navigation – these luxurious amenities come with increased risk of something breaking in an unpredictable fashion.
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A new method for rapid NMR imaging dubbed FLASH (fast low-angle shot) imaging is described which, for example, allows measuring times of the order of 1s (64×128 pixel resolution) or 6s (256×256 pixels). The technique takes advantage of excitation pukes with small hip angles eliminating the need of waiting periods in between successive experiments. It is based on the acquisition of the free induction decay in the form of a gradient echo generated by reversal of the read gradient. The entire imaging time is only given by the number of projections desired times the duration of slice selection and data acquisition. The method results in about a 100-fold reduction in measuring time without sacrificing spatial resolution. Further advantages are an optimized signal-to-noise ratio, the applicability of commercial gradient systems, and the deposition of extremely low rf power. FLASH imaging is demonstrated on phantoms, animals, and human extremities using a 2.3T 40cm bore magnet system. (1)H NMR images are obtained with variable relaxation time contrasts and without motional artifacts.
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Fronto-basal ganglia pathways play a crucial role in voluntary action control, including the ability to inhibit motor responses. Response inhibition might be mediated via a fast hyperdirect pathway connecting the right inferior frontal gyrus (rIFG) and the presupplementary motor area (preSMA) with the subthalamic nucleus or, alternatively, via the indirect pathway between the cortex and caudate. To test the relative contribution of these two pathways to inhibitory action control, we applied an innovative quantification method for effective brain connectivity. Functional magnetic resonance imaging data were collected from 20 human participants performing a Simon interference task with an occasional stop signal. A single right-lateralized model involving both the hyperdirect and indirect pathways best explained the pattern of brain activation on stop trials. Notably, the overall connection strength of this combined model was highest on successfully inhibited trials. Inspection of the relationship between behavior and connection values revealed that fast inhibitors showed increased connectivity between rIFG and right caudate (rCaudate), whereas slow inhibitors were associated with increased connectivity between preSMA and rCaudate. In compliance, connection strengths from the rIFG and preSMA into the rCaudate were correlated negatively. If participants failed to stop, the magnitude of experienced interference (Simon effect), but not stopping latency, was predictive for the hyperdirect-indirect model connections. Together, the present results suggest that both the hyperdirect and indirect pathways act together to implement response inhibition, whereas the relationship between performance control and the fronto-basal ganglia connections points toward a top-down mechanism that underlies voluntary action control.
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Extraction of the brain-i.e. cerebrum, cerebellum, and brain stem-from T1-weighted structural magnetic resonance images is an important initial step in neuroimage analysis. Although automatic algorithms are available, their inconsistent handling of the cortical mantle often requires manual interaction, thereby reducing their effectiveness. This paper presents a fully automated brain extraction algorithm that incorporates elastic registration, tissue segmentation, and morphological techniques which are combined by a watershed principle, while paying special attention to the preservation of the boundary between the gray matter and the cerebrospinal fluid. The approach was evaluated by comparison to a manual rater, and compared to several other leading algorithms on a publically available data set of brain images using the Dice coefficient and containment index as performance metrics. The qualitative and quantitative impact of this initial step on subsequent cortical surface generation is also presented. Our experiments demonstrate that our approach is quantitatively better than six other leading algorithms (with statistical significance on modern T1-weighted MR data). We also validated the robustness of the algorithm on a very large data set of over one thousand subjects, and showed that it can replace an experienced manual rater as preprocessing for a cortical surface extraction algorithm with statistically insignificant differences in cortical surface position.
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When people make decisions they often face opposing demands for response speed and response accuracy, a process likely mediated by response thresholds. According to the striatal hypothesis, people decrease response thresholds by increasing activation from cortex to striatum, releasing the brain from inhibition. According to the STN hypothesis, people decrease response thresholds by decreasing activation from cortex to subthalamic nucleus (STN); a decrease in STN activity is likewise thought to release the brain from inhibition and result in responses that are fast but error-prone. To test these hypotheses-both of which may be true-we conducted two experiments on perceptual decision making in which we used cues to vary the demands for speed vs. accuracy. In both experiments, behavioral data and mathematical model analyses confirmed that instruction from the cue selectively affected the setting of response thresholds. In the first experiment we used ultra-high-resolution 7T structural MRI to locate the STN precisely. We then used 3T structural MRI and probabilistic tractography to quantify the connectivity between the relevant brain areas. The results showed that participants who flexibly change response thresholds (as quantified by the mathematical model) have strong structural connections between presupplementary motor area and striatum. This result was confirmed in an independent second experiment. In general, these findings show that individual differences in elementary cognitive tasks are partly driven by structural differences in brain connectivity. Specifically, these findings support a cortico-striatal control account of how the brain implements adaptive switches between cautious and risky behavior.
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The right inferior frontal gyrus (rIFG) and the presupplementary motor area (pre-SMA) have been identified with cognitive control-the top-down influence on other brain areas when nonroutine behavior is required. It has been argued that they "inhibit" habitual motor responses when environmental changes mean a different response should be made. However, whether such "inhibition" can be equated with inhibitory physiological interactions has been unclear, as has the areas' relationship with each other and the anatomical routes by which they influence movement execution. Paired-pulse transcranial magnetic stimulation (ppTMS) was applied over rIFG and primary motor cortex (M1) or over pre-SMA and M1 to measure their interactions, at a subsecond scale, during either inhibition and reprogramming of actions or during routine action selection. Distinct patterns of functional interaction between pre-SMA and M1 and between rIFG and M1 were found that were specific to action reprogramming trials; at a physiological level, direct influences of pre-SMA and rIFG on M1 were predominantly facilitatory and inhibitory, respectively. In a subsequent experiment, it was shown that the rIFG's inhibitory influence was dependent on pre-SMA. A third experiment showed that pre-SMA and rIFG influenced M1 at two time scales. By regressing white matter fractional anisotropy from diffusion-weighted magnetic resonance images against TMS-measured functional connectivity, it was shown that short-latency (6 ms) and longer latency (12 ms) influences were mediated by cortico-cortical and subcortical pathways, respectively, with the latter passing close to the subthalamic nucleus.
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Stopping an action in response to an unexpected event requires both that the event is attended to, and that the action is inhibited. Previous neuroimaging investigations of stopping have failed to adequately separate these cognitive elements. Here we used a version of the widely used Stop Signal Task that controls for the attentional capture of stop signals. This allowed us to fractionate the contributions of frontal regions, including the right inferior frontal gyrus and medial frontal cortex, to attentional capture, response inhibition, and error processing. A ventral attentional system, including the right inferior frontal gyrus, has been shown to respond to unexpected stimuli. In line with this evidence, we reasoned that lateral frontal regions support attentional capture, whereas medial frontal regions, including the presupplementary motor area (pre-SMA), actually inhibit the ongoing action. We tested this hypothesis by contrasting the brain networks associated with the presentation of unexpected stimuli against those associated with outright stopping. Functional MRI images were obtained in 26 healthy volunteers. Successful stopping was associated with activation of the right inferior frontal gyrus, as well as the pre-SMA. However, only activation of the pre-SMA differentiated stopping from a high-level baseline that controlled for attentional capture. As expected, unsuccessful attempts at stopping activated the anterior cingulate cortex. In keeping with work in nonhuman primates these findings demonstrate that successful motor inhibition is specifically associated with pre-SMA activation.
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