Performance on the balloon analogue risk task and anticipatory response inhibition task is associated with severity of impulse control behaviours in people with Parkinson's disease.

Dopamine agonist medication is one of the largest risk factors for development of problematic impulse control behaviours (ICBs) in people with Parkinson's disease. The present study investigated the potential of dopamine gene profiling and individual performance on impulse control tasks to explain ICB severity. Clinical, genetic and task performance data were entered into a mixed-effects linear regression model for people with Parkinson's disease taking (n = 50) or not taking (n = 25) dopamine agonist medication. Severity of ICBs was captured via the Questionnaire for Impulsive-compulsive disorders in Parkinson's disease Rating Scale. A cumulative dopamine genetic risk score (DGRS) was calculated for each participant from variance in five dopamine-regulating genes. Objective measures of impulsive action and impulsive choice were measured on the Anticipatory Response Inhibition Task and Balloon Analogue Risk Task, respectively. For participants on dopamine agonist medication, task performance reflecting greater impulsive choice (p = 0.014), and to a trend level greater impulsive action (p = 0.056), as well as a longer history of DA medication (p < 0.001) all predicted increased ICB severity. DGRS however, did not predict ICB severity (p = 0.708). No variables could explain ICB severity in the non-agonist group. Our task-derived measures of impulse control have the potential to predict ICB severity in people with Parkinson's and warrant further investigation to determine whether they can be used to monitor ICB changes over time. The DGRS appears better suited to predicting the incidence, rather than severity, of ICBs on agonist medication.

Exploring stop signal reaction time over two sessions of the anticipatory response inhibition task.

Various behavioural tasks measure response inhibition encompassing the ability to cancel unwanted actions, evaluated via stop signal reaction time (SSRT). It is unclear whether SSRT is an unchangeable inherent measure of inhibitory network integrity or whether it can improve with repetition. The current study explored if and how SSRT changed over two sessions for the Anticipatory Response Inhibition Task (ARIT), and how this compared with the Stop Signal Task (SST). Forty-four participants repeated the ARIT and SST over two sessions. SSRT and its constituent measures (Go trial reaction time, stop signal delay) were calculated. SSRT reflecting non-selective response inhibition was consistent between sessions in the ARIT and SST (both p > 0.293). Reaction time and stop signal delay also remained stable across sessions in the ARIT (all p > 0.063), whereas in the SST, reaction time (p = 0.013) and stop signal delay (p = 0.009) increased. SSRT reflecting behaviourally selective stopping on the ARIT improved (p < 0.001) over two sessions, which was underpinned by changes to reaction time (p < 0.001) and stop signal delay (p < 0.001). Overall, the maximal efficiency of non-selective inhibition remained stable across two sessions in the ARIT. Results of the SST confirmed that non-selective inhibition can, however, be affected by more than inhibitory network integrity. Behaviourally selective stopping on the ARIT changed across sessions, suggesting the sequential neural process captured by the SSRT occurred more quickly in session two. These findings have implications for future studies that necessitate behavioural measures over multiple sessions.

OSARI, an Open-Source Anticipated Response Inhibition Task.

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

Dopamine genetic risk score predicts impulse control behaviors in Parkinson's disease.

INTRODUCTION: Up to 40% of Parkinson's disease patients taking dopamine agonist medication develop impulse control behaviors which can have severe negative consequences. The current study aimed to utilize dopamine genetics to identify patients most at risk of developing these behaviors. METHODS: Demographic, clinical, and genetic data were obtained from the Parkinson's Progression Markers Initiative for de novo patients (n = 327), patients taking dopamine agonists (n = 146), and healthy controls (n = 160). Impulsive behaviors were identified using the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease. A dopamine genetic risk score was calculated for each patient according to polymorphisms in genes coding for dopamine D1, D2 and D3 receptors, and catechol-O-methyltransferase. A higher score reflected higher central dopamine neurotransmission. RESULTS: Patients on agonists with a low dopamine genetic risk score were over 18 times more likely to have an impulsive behavior compared to higher scores (p = 0.04). The 38% of patients taking agonists who had at least one impulsive behavior were more likely to be male and report higher Unified Parkinson's Disease Rating Scale I&II scores. With increasing time on dopamine agonists (range 92-2283 days, mean 798 ± 565 standard deviation), only patients with a high dopamine genetic risk score showed an increase in number of impulsive behaviors (p = 0.033). Predictive effects of the gene score were not present in de novo or healthy control. CONCLUSIONS: A dopamine genetic risk score can identify patients most at risk of developing impulsive behaviors on dopamine agonist medication and predict how these behaviors may worsen over time.

The role of interhemispheric communication during complete and partial cancellation of bimanual responses.

Precise control of upper limb movements in response to external stimuli is vital to effectively interact with the environment. Accurate execution of bimanual movement is known to rely on finely orchestrated interhemispheric communication between the primary motor cortices (M1s). However, relatively little is known about the role of interhemispheric communication during sudden cancellation of prepared bimanual movement. The current study investigated the role of interhemispheric interactions during complete and partial cancellation of bimanual movement. In two experiments, healthy young human participants received transcranial magnetic stimulation to both M1s during a bimanual response inhibition task. The increased corticomotor excitability in anticipation of bimanual movement was accompanied by a release of inhibition from both M1s. After a stop cue, inhibition was reengaged onto both hemispheres to successfully cancel the complete bimanual response. However, when the stop cue signaled partial cancellation (stopping of one digit only), inhibition was reengaged with regard to the cancelled digit, but the responding digit representation was facilitated. This bifurcation in interhemispheric communication between M1s occurred 75 ms later in the more difficult condition when the nondominant, as opposed to dominant, hand was still responding. Our results demonstrate that interhemispheric communication is integral to response inhibition once a bimanual response has been prepared. Interestingly, M1-M1 interhemispheric circuitry does not appear to be responsible for the nonselective suppression of all movement components that has been observed during partial cancellation. Instead such interhemispheric communication enables uncoupling of bimanual response components and facilitates the selective initiation of just the required unimanual movement.NEW & NOTEWORTHY We provide the first evidence that interhemispheric communication plays an important role during sudden movement cancellation of two-handed responses. Simultaneously increased inhibition onto both hemispheres assists with two-handed movement cancellation. However, this network is not responsible for the widespread suppression of motor activity observed when only one of the two hands is cancelled. Instead, communication between hemispheres enables the separation of motor activity for the two hands and helps to execute the required one-handed response.

Memory deficits in Parkinson's disease are associated with reduced beta power modulation.

There is an increasing recognition of the significant non-motor symptoms that burden people with Parkinson's disease. As such, there is a pressing need to better understand and investigate the mechanisms underpinning these non-motor deficits. The electrical activity within the brains of people with Parkinson's disease is known to exhibit excessive power within the beta range (12-30 Hz), compared with healthy controls. The weight of evidence suggests that this abnormally high level of beta power is the cause of bradykinesia and rigidity in Parkinson's disease. However, less is known about how the abnormal beta rhythms seen in Parkinson's disease impact on non-motor symptoms. In healthy adults, beta power decreases are necessary for successful episodic memory formation, with greater power decreases during the encoding phase predicting which words will subsequently be remembered. Given the raised levels of beta activity in people with Parkinson's disease, we hypothesized that the necessary decrease in power during memory encoding would be diminished and that this would interfere with episodic memory formation. Accordingly, we conducted a cross-sectional, laboratory-based experimental study to investigate whether there was a direct relationship between decreased beta modulation and memory formation in Parkinson's disease. Electroencephalography recordings were made during an established memory-encoding paradigm to examine brain activity in a cohort of adults with Parkinson's disease (N = 28, 20 males) and age-matched controls (N = 31, 18 males). The participants with Parkinson's disease were aged 65 ± 6 years, with an average disease duration of 6 ± 4 years, and tested on their normal medications to avoid the confound of exacerbated motor symptoms. Parkinson's disease participants showed impaired memory strength (P = 0.023) and reduced beta power decreases (P = 0.014) relative to controls. Longer disease duration was correlated with a larger reduction in beta modulation during encoding, and a concomitant reduction in memory performance. The inability to sufficiently decrease beta activity during semantic processing makes it a likely candidate to be the central neural mechanism underlying this type of memory deficit in Parkinson's disease. These novel results extend the notion that pathological beta activity is causally implicated in the motor and (lesser appreciated) non-motor deficits inherent to Parkinson's disease. These findings provide important empirical evidence that should be considered in the development of intelligent next-generation therapies.

Response inhibition activates distinct motor cortical inhibitory processes.

We routinely cancel preplanned movements that are no longer required. If stopping is forewarned, proactive processes are engaged to selectively decrease motor cortex excitability. However, without advance information there is a nonselective reduction in motor cortical excitability. In this study we examined modulation of human primary motor cortex inhibitory networks during response inhibition tasks with informative and uninformative cues using paired-pulse transcranial magnetic stimulation. Long- (LICI) and short-interval intracortical inhibition (SICI), indicative of GABAB- and GABAA-receptor mediated inhibition, respectively, were examined from motor evoked potentials obtained in task-relevant and task-irrelevant hand muscles when response inhibition was preceded by informative and uninformative cues. When the participants (10 men and 8 women) were cued to stop only a subcomponent of the bimanual response, the remaining response was delayed, and the extent of delay was greatest in the more reactive context, when cues were uninformative. For LICI, inhibition was reduced in both muscles during all types of response inhibition trials compared with the pre-task resting baseline. When cues were uninformative and left-hand responses were suddenly canceled, task-relevant LICI positively correlated with response times of the responding right hand. In trials where left-hand responding was highly probable or known (informative cues), task-relevant SICI was reduced compared with that when cued to rest, revealing a motor set indicative of responding. These novel findings indicate that the GABAB-receptor-mediated pathway may set a default inhibitory tone according to task context, whereas the GABAA-receptor-mediated pathways are recruited proactively with response certainty. NEW & NOTEWORTHY We examined how informative and uninformative cues that trigger both proactive and reactive processes modulate GABAergic inhibitory networks within human primary motor cortex. We show that GABAB inhibition was released during the task regardless of cue type, whereas GABAA inhibition was reduced when responding was highly probable or known compared with rest. GABAB-receptor-mediated inhibition may set a default inhibitory tone, whereas GABAA circuits may be modulated proactively according to response certainty.

An Activation Threshold Model for Response Inhibition.

Reactive response inhibition (RI) is the cancellation of a prepared response when it is no longer appropriate. Selectivity of RI can be examined by cueing the cancellation of one component of a prepared multi-component response. This substantially delays execution of other components. There is debate regarding whether this response delay is due to a selective neural mechanism. Here we propose a computational activation threshold model (ATM) and test it against a classical "horse-race" model using behavioural and neurophysiological data from partial RI experiments. The models comprise both facilitatory and inhibitory processes that compete upstream of motor output regions. Summary statistics (means and standard deviations) of predicted muscular and neurophysiological data were fit in both models to equivalent experimental measures by minimizing a Pearson Chi-square statistic. The ATM best captured behavioural and neurophysiological dynamics of partial RI. The ATM demonstrated that the observed modulation of corticomotor excitability during partial RI can be explained by nonselective inhibition of the prepared response. The inhibition raised the activation threshold to a level that could not be reached by the original response. This was necessarily followed by an additional phase of facilitation representing a secondary activation process in order to reach the new inhibition threshold and initiate the executed component of the response. The ATM offers a mechanistic description of the neural events underlying RI, in which partial movement cancellation results from a nonselective inhibitory event followed by subsequent initiation of a new response. The ATM provides a framework for considering and exploring the neuroanatomical constraints that underlie RI.

Proactive modulation of long-interval intracortical inhibition during response inhibition.

Daily activities often require sudden cancellation of preplanned movement, termed response inhibition. When only a subcomponent of a whole response must be suppressed (required here on Partial trials), the ensuing component is markedly delayed. The neural mechanisms underlying partial response inhibition remain unclear. We hypothesized that Partial trials would be associated with nonselective corticomotor suppression and that GABAB receptor-mediated inhibition within primary motor cortex might be responsible for the nonselective corticomotor suppression contributing to Partial trial response delays. Sixteen right-handed participants performed a bimanual anticipatory response inhibition task while single- and paired-pulse transcranial magnetic stimulation was delivered to elicit motor evoked potentials in the left first dorsal interosseous muscle. Lift times, amplitude of motor evoked potentials, and long-interval intracortical inhibition were examined across the different trial types (Go, Stop-Left, Stop-Right, Stop-Both). Go trials produced a tight distribution of lift times around the target, whereas those during Partial trials (Stop-Left and Stop-Right) were substantially delayed. The modulation of motor evoked potential amplitude during Stop-Right trials reflected anticipation, suppression, and subsequent reinitiation of movement. Importantly, suppression was present across all Stop trial types, indicative of a "default" nonselective inhibitory process. Compared with blocks containing only Go trials, inhibition increased when Stop trials were introduced but did not differ between trial types. The amount of inhibition was positively correlated with lift times during Stop-Right trials. Tonic levels of inhibition appear to be proactively modulated by task context and influence the speed at which unimanual responses occur after a nonselective "brake" is applied.

Dopamine Gene Profiling to Predict Impulse Control and Effects of Dopamine Agonist Ropinirole.

Dopamine agonists can impair inhibitory control and cause impulse control disorders for those with Parkinson disease (PD), although mechanistically this is not well understood. In this study, we hypothesized that the extent of such drug effects on impulse control is related to specific dopamine gene polymorphisms. This double-blind, placebo-controlled study aimed to examine the effect of single doses of 0.5 and 1.0 mg of the dopamine agonist ropinirole on impulse control in healthy adults of typical age for PD onset. Impulse control was measured by stop signal RT on a response inhibition task and by an index of impulsive decision-making on the Balloon Analogue Risk Task. A dopamine genetic risk score quantified basal dopamine neurotransmission from the influence of five genes: catechol-O-methyltransferase, dopamine transporter, and those encoding receptors D1, D2, and D3. With placebo, impulse control was better for the high versus low genetic risk score groups. Ropinirole modulated impulse control in a manner dependent on genetic risk score. For the lower score group, both doses improved response inhibition (decreased stop signal RT) whereas the lower dose reduced impulsiveness in decision-making. Conversely, the higher score group showed a trend for worsened response inhibition on the lower dose whereas both doses increased impulsiveness in decision-making. The implications of the present findings are that genotyping can be used to predict impulse control and whether it will improve or worsen with the administration of dopamine agonists.

Does response inhibition have pre- and postdiagnostic utility in Parkinson's disease?

Parkinson's disease (Pd) is the second most prevalent degenerative neurological condition worldwide. Improving and sustaining quality of life is an important goal for Parkinson's patients. Key areas of focus to achieve this goal include earlier diagnosis and individualized treatment. In this review the authors discuss impulse control in Pd and examine how measures of impulse control from a response inhibition task may provide clinically useful information (a) within an objective test battery to aid earlier diagnosis of Pd and (b) in postdiagnostic Pd, to better identify individuals at risk of developing impulse control disorders with dopaminergic medication.

Uncoupling response inhibition.

The ability to prevent unwanted movement is fundamental to human behavior. When healthy adults must prevent a subset of prepared actions, execution of the remaining response is markedly delayed. We hypothesized that the delay may be sensitive to the degree of similarity between the prevented and continued actions. Fifteen healthy participants performed an anticipatory response inhibition task that required bilateral index finger extension or thumb abduction with homogeneous digit pairings, or a heterogeneous pairing of a combination of the two movements. We expected that the uncoupling of responses required for selective movement prevention would be more difficult with homogeneous (same digit, homologous muscles) than heterogeneous pairings (different digits, nonhomologous muscles). Measures of response times (and asynchrony between digits) during action execution, stopping performance, and electromyography from EIP (index finger extension) and APB (thumb abduction) were analyzed. As expected, selective trials produced a delay in the remaining movement compared with execution trials. Successful performance in the selective condition occurred via suppression of the entire prepared response and subsequent selective reinitiation of the remaining component. Importantly, the delayed reinitiation of motor output was sensitive to the degree of similarity between responses, occurring later but at a faster rate with homogeneous digits. There were persistent aftereffects from the selective condition on the motor system, which indicated greater levels of inhibition and a higher gain were necessary to successfully perform selective trials with homogeneous pairings. Overall, the results support a model of inhibition of a unitary response and selective reinitiation, rather than selective inhibition.