Matthijs Vink

Deep brain stimulation restores frontostriatal network activity in obsessive-compulsive disorder

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.

On the Role of the Striatum in Response Inhibition

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.

Function of striatum beyond inhibition and execution of motor responses.

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. Hum Brain Mapp, 2005.

Dysfunctional Reward Circuitry in Obsessive-Compulsive Disorder

BACKGROUND Obsessive-compulsive disorder (OCD) is primarily conceived as an anxiety disorder but has features resembling addictive behavior. Patients with OCD may develop dependency upon compulsive behaviors because of the rewarding effects following reduction of obsession-induced anxiety. Reward processing is critically dependent on ventral striatal-orbitofrontal circuitry and brain imaging studies in OCD have consistently shown abnormal activation within this circuitry. This is the first functional imaging study to investigate explicitly reward circuitry in OCD. METHODS Brain activity during reward anticipation and receipt was compared between 18 OCD patients and 19 healthy control subjects, using a monetary incentive delay task and functional magnetic resonance imaging. Reward processing was compared between OCD patients with predominantly contamination fear and patients with predominantly high-risk assessment. RESULTS Obsessive-compulsive disorder patients showed attenuated reward anticipation activity in the nucleus accumbens compared with healthy control subjects. Reduced activity of the nucleus accumbens was more pronounced in OCD patients with contamination fear than in patients with high-risk assessment. Brain activity during reward receipt was similar between patients and control subjects. A hint toward more dysfunctional reward processing was found in treatment-resistant OCD patients who subsequently were successfully treated with deep brain stimulation of the nucleus accumbens. CONCLUSIONS Obsessive-compulsive disorder patients may be less able to make beneficial choices because of altered nucleus accumbens activation when anticipating rewards. This finding supports the conceptualization of OCD as a disorder of reward processing and behavioral addiction.

Chronic effects of cannabis use on the human reward system: An fMRI study

Cannabis is one of the most used drugs of abuse. It affects the brain reward system in animals, and has proven rewarding and addictive potential in humans. We used functional MRI to measure brain activity during reward anticipation in a monetary reward task. Long-term cannabis users were compared to healthy controls. An additional control group consisting of nicotine users was included. Cannabis users showed attenuated brain activity during reward anticipation in the nucleus accumbens compared to non-smoking controls, but not compared to smoking controls. Cannabis users showed decreased reward anticipation activity in the caudate nucleus, compared to both non-smoking and smoking controls. These data suggest that nicotine may be responsible for attenuated reward anticipation activity in the accumbens, but that differences in the caudate are associated with the use of cannabis. Our findings imply that chronic cannabis use as well as nicotine, may cause an altered brain response to rewarding stimuli.

Test-retest reliability of fMRI activation during prosaccades and antisaccades

Various studies have investigated reproducibility of fMRI results. Whereas group results can be highly reproducible, individual activity maps tend to vary across sessions. Individual reliability is of importance for the application of fMRI in endophenotype research, where brain activity is linked to genetic polymorphisms. In this study, the test-retest reliability of activation maps during the antisaccade paradigm was assessed for individual and group results. Functional MRI images were acquired during two sessions of prosaccades and antisaccades in twelve healthy subjects using an event-related fMRI design. Reliability was assessed for both individual and group-wise results. In addition, the reliability of differences between subjects was established in predefined regions of interest. The reliability of group activation maps was high for prosaccades and antisaccades, but only moderate for antisaccades vs. prosaccades, probably as a result of low statistical power of individual results. Reproducibility of individual subject maps was highly variable, indicating that reliable results can be obtained in some but not all subjects. Reliability of individual activity maps was largely explained by individual differences in the global temporal signal to noise ratio (SNR). As the global SNR was stable over sessions, it explained a large portion of the differences between subjects in regional brain activation. A low SNR in some subjects may be dealt with either by improving the statistical sensitivity of the fMRI procedure or by subject exclusion. Differences in the global SNR between subjects should be addressed before using regional brain activation as phenotype in genetic studies.

Expectations and violations: Delineating the neural network of proactive inhibitory control

The ability to stop a prepared response (reactive inhibition) appears to depend on the degree to which stopping is expected (proactive inhibition). Functional MRI studies have shown that activation during proactive and reactive inhibition overlaps, suggesting that the whole neural network for reactive inhibition becomes already activated in anticipation of stopping. However, these studies measured proactive inhibition as the effect of stop‐signal probability on activation during go trials. Therefore, activation could reflect expectation of a stop‐signal (evoked by the stop‐signal probability cue), but also violation of this expectation because stop‐signals do not occur on go trials. We addressed this problem, using a stop‐signal task in which the stop‐signal probability cue and the go‐signal were separated in time. Hence, we could separate activation during the cue, reflecting expectation of the stop‐signal, from activation during the go‐signal, reflecting expectation of the stop‐signal or violation of that expectation. During the cue, the striatum, the supplementary motor complex (SMC), and the midbrain activated. During the go‐signal, the right inferior parietal cortex (IPC) and the right inferior frontal cortex (IFC) activated. These findings suggest that the neural network previously associated with proactive inhibition can be subdivided into two components. One component, including the striatum, the SMC, and the midbrain, activated during the cue, implicating this network in proactive inhibition. Another component, consisting of the right IPC and the right IFC, activated during the go‐signal. Rather than being involved in proactive inhibition, this network appears to be involved in processes associated with violation of expectations. Hum Brain Mapp 34:2015–2024, 2013.

Striatal dysfunction in schizophrenia and unaffected relatives.

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.

Cardiorespiratory Effects on Default-Mode Network Activity as Measured With fMRI

The default‐mode network (DMN) consists of areas showing more activation during rest than during a task. Several authors propose some form of cognitive processing to underlie BOLD signal changes in the DMN as activity within the network is modulated by the level of effort required by the task and is positively correlated with self‐referential processing. Alternatively, BOLD signal changes within the DMN may be caused by cardiorespiratory processes (CR) affecting BOLD signal measurements independent of neuronal activity. The goal of this study is to investigate whether BOLD signal changes within the DMN can be explained by CR effects. To this aim, brain activity, heartbeat, and respiration are measured during resting‐state and while subjects perform a cognitive task with a high‐ and low‐demand condition. To correct for CR effects we used RETROICOR (Glover et al., [ 2000 ]: Magn Reson Med 44:162–167) in combination with additive linear modeling of changes due to respiration volume, heart rate and heart rate variability. CR effects were present within the frequency‐range of the DMN and were located in areas of the DMN, but equally so in other areas. After removal of CR effects, deactivation and resting‐state connectivity between the areas of the DMN remained significant. In addition, DMN deactivation was still modulated by task demand. The same CR correction method did remove activation in task‐related areas. We take these results to indicate that the BOLD signal within the DMN cannot be explained by CR effects alone and is possibly related to some form of cognitive neuronal processing. Hum Brain Mapp, 2009.

Reduced Proactive Inhibition in Schizophrenia Is Related to Corticostriatal Dysfunction and Poor Working Memory

BACKGROUND Inhibitory control is central to executive functioning and appears deficient in schizophrenia. However, it is unclear how inhibitory control is affected, what the underlying neural mechanisms are, whether these deficits are related to the illness itself or to increased risk for the illness, and whether there is a relation to impairments in other executive functions. METHODS We used functional magnetic resonance imaging to investigate two forms of inhibitory control: proactive inhibition (anticipation of stopping) and reactive inhibition (outright stopping). Twenty-four schizophrenia patients, 24 unaffected siblings, and 24 healthy control subjects performed a modified version of the stop-signal paradigm. To assess the relation between performance on inhibitory control and other executive functions, we correlated inhibitory control indices with working memory span. RESULTS Compared with control subjects, proactive inhibition was reduced in patients and siblings. Reactive inhibition was unaffected. Reduced proactive inhibition was associated with a failure to activate the right striatum, the right inferior frontal cortex, and the left and right temporoparietal junction. Activation during reactive inhibition was unaffected. Those patients with the least proactive inhibition also showed the shortest working memory span. CONCLUSIONS These results suggest that schizophrenia is associated with reduced proactive inhibition, probably resulting from corticostriatal dysfunction. This deficit is related to an increased risk for schizophrenia and likely reflects a general executive function deficit rather than a specific inhibitory control impairment.