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Successful response inhibition relies on the suppression of motor cortex activity. The striatum has previously been linked to motor cortex suppression during the act of inhibition (reactive), but activation was also seen during anticipation of stop signals (proactive). More specifically, striatal activation increased with a higher stop probability. Using functional magnetic resonance imaging with specific regions of interest, we investigate for the first time whether activation in the striatum during reactive inhibition is related to previously formed expectations. We used a modified stop-signal response task in which subjects were asked trial by trial, after being presented a stop-signal probability cue, whether they actually expected a stop to occur. This enabled us to investigate the subjective expectation of a stop signal during each trial. We found that striatal activity during reactive inhibition was higher when subjects expected stop signals. These results help explain conflicting findings of previous studies on the association between striatal activation and inhibition, since we demonstrate a crucial role of the subjects' expectation of a stop signal and thus their ability to prepare for a stop in advance. In conclusion, the current results show for the first time that striatal contributions to reactive response inhibition are, in part, related to subjective anticipation., (Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.)

Schizophrenia is associated with frontostriatal network impairments underlying clinical and cognitive symptoms. We previously found disruptions in anatomical pathways, including the tract connecting the left nucleus accumbens and left dorsolateral prefrontal cortex (DLPFC). Similar deficits are observed in unaffected siblings of schizophrenia patients, indicating that these deficits are linked to a genetic vulnerability for the disorder. Frontostriatal tract disruptions may arise during adolescence, preceding the clinical manifestation of the disorder. However, to date, no studies have been performed to investigate frontostriatal tract connections in adolescents who are at increased familial risk for schizophrenia. In this study, we investigate the impact of familial risk on frontostriatal tract connections using diffusion tensor imaging in 27 adolescent offspring of schizophrenia patients and 32 matched control adolescents, aged 10-18 years. Mean fractional anisotropy (FA) was calculated for the tracts connecting the striatum (caudate nucleus, putamen, nucleus accumbens) and frontal cortex regions (DLPFC, medial orbital frontal cortex, inferior frontal gyrus). As expected, based on siblings data, we found an impact of familial risk on frontostriatal development: schizophrenia offspring showed increased FA in the tracts connecting nucleus accumbens and DLPFC as compared with control adolescents. Moreover, while FA increased across age in control adolescents, it did not in schizophrenia offspring. We did not find differences in FA in other frontostriatal tracts. These results indicate altered development of white matter in subjects who are at familial risk for schizophrenia and may precede frontostriatal white matter alterations in adult schizophrenia patients and siblings.

Inhibitory control, like most cognitive processes, is subject to an age-related decline. The effect of age on neurofunctional inhibition processing remains uncertain, with age-related increases as well as decreases in activation being reported. This is possibly because reactive (i.e., outright stopping) and proactive inhibition (i.e., anticipation of stopping) have not been evaluated separately. Here, we investigate the effects of aging on reactive as well as proactive inhibition, using functional MRI in 73 healthy subjects aged 30-70years. We found reactive inhibition to slow down with advancing age, which was paralleled by increased activation in the motor cortex. Behaviorally, older adults did not exercise increased proactive inhibition strategies compared to younger adults. However, the pattern of activation in the right inferior frontal gyrus (rIFG) showed a clear age-effect on proactive inhibition: rather than flexibly engaging the rIFG in response to varying stop-signal probabilities, older subjects showed an overall hyperactivation. Whole-brain analyses revealed similar hyperactivations in various other frontal and parietal brain regions. These results are in line with the neural compensation hypothesis of aging: processing becomes less flexible and efficient with advancing age, which is compensated for by overall enhanced activation. Moreover, by disentangling reactive and proactive inhibition, we can show for the first time that the age-related increase in activation during inhibition that is reported generally by prior studies may be the result of compensation for reduced neural flexibility related to proactive control strategies., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Schizophrenia is a severe psychiatric disorder associated with impaired fronto-striatal functioning. Similar deficits are observed in unaffected siblings of patients, indicating that these deficits are linked to a familial risk for the disorder. Fronto-striatal deficits may arise during adolescence and precede clinical manifestation of the disorder. However, the development of the fronto-striatal network in adolescents at increased familial risk for schizophrenia is still poorly understood. In this cross-sectional study, we investigate the impact of familial risk on fronto-striatal functioning across age related to reward anticipation and receipt in 25 adolescent offspring of schizophrenia patients (SZ offspring) and 36 age-matched healthy controls (range 10-19years). Subjects performed a reward task while being scanned with functional MRI. Overall response times and the amount of money won did not differ between the groups. Striatal activation during reward anticipation decreased across age in the SZ offspring, while it did not in the healthy controls. Activation in the orbitofrontal cortex during reward receipt did not differ between the groups. These results, taken together with data from adult schizophrenia patients and their siblings, indicate that the diminishing striatal activation across adolescence may signify a familial vulnerability for schizophrenia., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The aim of the present study was to investigate the effect of HIV infection on cortical and subcortical regions of the frontal-striatal system involved in the inhibition of voluntary movement. Functional MRI (fMRI) studies suggest that human immunodeficiency virus (HIV) infection is associated with frontostriatal dysfunction. While frontostriatal systems play a key role in behavioral inhibition, there are to our knowledge no fMRI studies investigating the potential impact of HIV on systems involved during the inhibition of voluntary movement. A total of 17 combined antiretroviral therapy (cART) naïve HIV+ participants as well as 18 age, gender, ethnic, education matched healthy controls performed a modified version of the stop-signal paradigm. This paradigm assessed behavior as well as functional brain activity associated with motor execution, reactive inhibition (outright stopping) and proactive inhibition (anticipatory response slowing before stopping). HIV+ participants showed significantly slower responses during motor execution compared to healthy controls, whereas they had normal proactive response slowing. Putamen hypoactivation was evident in the HIV+ participants based on successful stopping, indicating subcortical dysfunction during reactive inhibition. HIV+ participants showed normal cortical functioning during proactive inhibition. Our data provide evidence that HIV infection is associated with subcortical dysfunction during reactive inhibition, accompanied by relatively normal higher cortical functioning during proactive inhibition. This suggests that HIV infection may primarily involve basic striatal-mediated control processes in cART naïve participants.

Healthy aging is associated with a progressive decline across a range of cognitive functions. An important factor underlying this decline may be the age-related impairment in stimulus-reward processing. Several studies have investigated age-related effects, but compared young versus old subjects. This is the first study to investigate the effect of aging on brain activation during reward processing within a continuous segment of the adult life span. We scanned 49 healthy adults aged 40-70 years, using functional MRI. We adopted a simple reward task, which allowed separate evaluation of neural responses to reward anticipation and receipt. The effect of reward on performance accuracy and speed was not related to age, indicating that all subjects could perform the task correctly. We identified a whole-brain significant age-related decline of ventral striatum activation during reward anticipation as compared to neutral anticipation. Importantly, the specificity of this finding was underscored by the observation that there was no general decline in activation during anticipation. Activation in the ventral striatum increased with age during reward receipt as compared to receiving neutral outcome. Finally, activation in the ventromedial prefrontal cortex during outcome was not affected by age. Our data demonstrate that the typical shift in striatal activation from reward receipt to reward anticipation in young adults disappears with healthy aging. These changes are consistent the well-ocumented age-related decline of striatal dopamine availability, and may provide a stepping stone for further research of age-related neurodegenerative diseases., (© 2015 Wiley Periodicals, Inc.)

During adolescence, functional and structural changes in the brain facilitate the transition from childhood to adulthood. Because the cortex and the striatum mature at different rates, temporary imbalances in the frontostriatal network occur. Here, we investigate the development of the subcortical and cortical components of the frontostriatal network from early adolescence to early adulthood in 60 subjects in a cross-sectional design, using functional MRI and a stop-signal task measuring two forms of inhibitory control: reactive inhibition (outright stopping) and proactive inhibition (anticipation of stopping). During development, reactive inhibition improved: older subjects were faster in reactive inhibition. In the brain, this was paralleled by an increase in motor cortex suppression. The level of proactive inhibition increased, with older subjects slowing down responding more than younger subjects when anticipating a stop-signal. Activation increased in the right striatum, right ventral and dorsal inferior frontal gyrus, and supplementary motor area. Moreover, functional connectivity during proactive inhibition increased between striatum and frontal regions with age. In conclusion, we demonstrate that developmental improvements in proactive inhibition are paralleled by increases in activation and functional connectivity of the frontostriatal network. These data serve as a stepping stone to investigate abnormal development of the frontostriatal network in disorders such as schizophrenia and attention-deficit hyperactivity disorder., (Copyright © 2014 Wiley Periodicals, Inc.)

Background: Impaired working memory (WM) is a hallmark of schizophrenia. In addition to classical WM regions such as the dorsolateral prefrontal cortex (DLPFC) and the striatum, dysfunctions in the default-mode network (DMN) contribute to these WM deficits. Unaffected siblings of patients also show WM impairments. However, the nature of the functional deficits underlying these impairments is unclear, mainly because of impaired performance confounding neuroimaging results., Methods: Here, we investigated WM and DMN activity in 23 unaffected siblings of schizophrenia patients and 24 healthy volunteers using fMRI and a Sternberg WM task. WM load was determined prior to scanning to ensure 90% accuracy for all subjects., Results: Siblings showed hyperactivation during the encoding phase of WM in the right medial prefrontal cortex (MPFC) which is the anterior part of the DMN. No differences were found during the maintenance phase. During the retrieval phase, siblings showed hyperactivation in WM regions: DLPFC, inferior parietal cortex and the striatum. Siblings who showed hyperactivity in the MPFC during encoding showed DLPFC and striatum hyperactivation during retrieval., Conclusions: Our finding of hyperactivation in WM and DMN areas indicates that siblings fail to adequately inhibit DMN activity during demanding cognitive tasks and subsequently hyperactivate WM areas. This failure may reflect dopamine hyperactivity in the striatum which prevents adequate DMN suppression needed for effective WM. This study provides support for the notion that aberrant WM and DMN activation patterns may represent candidate endophenotypes for schizophrenia., (© 2013 Elsevier B.V. All rights reserved.)

Little is known about the underlying neural mechanism of deep brain stimulation (DBS). We found that DBS targeted at the nucleus accumbens (NAc) normalized NAc activity, reduced excessive connectivity between the NAc and prefrontal cortex, and decreased frontal low-frequency oscillations during symptom provocation in patients with obsessive-compulsive disorder. Our findings suggest that DBS is able to reduce maladaptive activity and connectivity of the stimulated region.

Stopping an action requires suppression of the primary motor cortex (M1). Inhibitory control over M1 relies on a network including the right inferior frontal cortex (rIFC) and the supplementary motor complex (SMC), but how these regions interact to exert inhibitory control over M1 is unknown. Specifically, the hierarchical position of the rIFC and SMC with respect to each other, the routes by which these regions control M1, and the causal involvement of these regions in proactive and reactive inhibition remain unclear. We used off-line repetitive TMS to perturb neural activity in the rIFC and SMC followed by fMRI to examine effects on activation in the networks involved in proactive and reactive inhibition, as assessed with a modified stop-signal task. We found repetitive TMS effects on reactive inhibition only. rIFC and SMC stimulation shortened the stop-signal RT (SSRT) and a shorter SSRT was associated with increased M1 deactivation. Furthermore, rIFC and SMC stimulation increased right striatal activation, implicating frontostriatal pathways in reactive inhibition. Finally, rIFC stimulation altered SMC activation, but SMC stimulation did not alter rIFC activation, indicating that rIFC lies upstream from SMC. These findings extend our knowledge about the functional organization of inhibitory control, an important component of executive functioning, showing that rIFC exerts reactive control over M1 via SMC and right striatum.

Background: Stopping a manual response requires suppression of the primary motor cortex (M1) and has been linked to activation of the striatum. Here, we test three hypotheses regarding the role of the striatum in stopping: striatum activation during successful stopping may reflect suppression of M1, anticipation of a stop-signal occurring, or a slower response build-up., Methodology/principal Findings: Twenty-four healthy volunteers underwent functional magnetic resonance imaging (fMRI) while performing a stop-signal paradigm, in which anticipation of stopping was manipulated using a visual cue indicating stop-signal probability, with their right hand. We observed activation of the striatum and deactivation of left M1 during successful versus unsuccessful stopping. In addition, striatum activation was proportional to the degree of left M1 deactivation during successful stopping, implicating the striatum in response suppression. Furthermore, striatum activation increased as a function of stop-signal probability and was to linked to activation in the supplementary motor complex (SMC) and right inferior frontal cortex (rIFC) during successful stopping, suggesting a role in anticipation of stopping. Finally, trial-to-trial variations in response time did not affect striatum activation., Conclusions/significance: The results identify the striatum as a critical node in the neural network associated with stopping motor responses. As striatum activation was related to both suppression of M1 and anticipation of a stop-signal occurring, these findings suggest that the striatum is involved in proactive inhibitory control over M1, most likely in interaction with SMC and rIFC.

Background: Schizophrenia has been frequently associated with impaired inhibitory control. Such control is known to involve the striatum. Here, we investigate whether impaired inhibitory control is associated with abnormal striatal activation in schizophrenia. First-degree relatives of patients were also tested to examine whether striatal abnormality is associated with schizophrenia, or with the risk for the illness., Methods: Both functional MRI and behavioral data were acquired during a task designed to invoke inhibitory control in 21 patients, 15 unaffected siblings, and 36 matched controls. Subjects must refrain from responding to designated stop cues occurring within a series of motor cues. Subjects could anticipate the occurrence of stop cues as the likelihood of these cues increased in a linear fashion throughout the task., Results: Control subjects showed striatal activation while responding to motor cues. This activation increased in a linear fashion when the likelihood of having to inhibit the response was increased. Both patients siblings did not show anticipation-related increase in either striatal activation. However, only patients showed behavioral impairments., Conclusions: Striatal abnormalities occur in schizophrenia patients and unaffected siblings. Thus striatal abnormalities may be related to an increased (genetic) risk to develop schizophrenia.

We used functional magnetic resonance imaging (fMRI) to study the role of the striatum in inhibitory motor control. Subjects had to refrain from responding to designated items (STOP trials) within a similar series of motor stimuli. Striatal activation was increased significantly compared to that when responding to all targets within a series of motor stimuli, indicating that the striatum is more active when inhibitory motor control over responses is required. The likelihood of a STOP trial was varied parametrically by varying the number of GO trials before a STOP trial. We could thus measure the effect of expecting a STOP trial on the fMRI response in the striatum. We show for the first time in humans that the striatum becomes more active when the likelihood of inhibiting a planned motor response increases. Our findings suggest that the striatum is critically involved in inhibitory motor control, most likely by controlling the execution of planned motor responses.