Although etiological models of substance use disorders (SUDs) differ from one another at the level of neurobiological and social cognitive explanations, the overall picture is that there are at least two semi-dependent behavioral systems in the brain involved– a fast associative impulsive system and a slower reflective system. Both of these systems are susceptible to change through substance use (alcohol & cocaine) [
1,
2]. Substance dependence and the specific lack of behavioral autonomy associated with substance intake is primarily guided by direct reward, high impulsivity, difficulty in foreseeing the consequences of actions, and difficulties in planning behavior [
3‐
8]. Research suggests that difficulties in delaying gratification, impulsivity and inhibition may be caused by temporal processing deficits [
9,
10]. The dopaminergic system and its target neural substrates (striatum and prefrontal cortex), which neuroanatomically and neurophysiologically underpin SUDs [
5,
8,
11], are important neural systems for the timing of motor acts [
12,
13].
Motor timing, cognitive deficits and SUD
Timing is crucial when individual outcomes are considered and decisions are made [
10]. A recent review of the literature on time perception, impulsivity and decision making found that impulsive individuals perceive time differently [
9,
10]. Time is perceived at a higher cost, leading to overestimation of the duration of time intervals and consequently discounting the value of delayed rewards more strongly than low-impulsive individuals. Additionally, an increased state of arousal, possibly driven by emotional distress, is arguably the main factor that alters the way in which impulsive individuals take time into account when making decisions (for a detailed review please see [
10]). A recent review of the literature on impulsivity concluded that many tasks confound timing abilities (e.g., motor impulsivity, time estimation deficiencies, and reward discrimination features). These factors are all known to cause an individual to act impulsively [
9] and the question that arises is whether timing should be considered as a contributory cause of impulsive behaviour [
12]. As such, it may be necessary to consider timing confounds in new research paradigms since timing deficits could be a precipitating factor for impulsivity [
9].
Whereas existing theories of the effects of DA highlight its crucial role in reward learning and disinhibition, they do not offer an account of the pathological hypersensitivity to temporal delay which is one of the phenotypes of SUDs [
12]. This hypersensitivity has been examined. Timing aspects of impulsivity were tested through either pharmacological enhancement of dopamine or placebo using an intertemporal choice task and functional magnetic resonance scanning. The results showed that by explicitly probing the relationship between the utility of rewards and their timing, independently of feedback and learning, DA increased impulsivity by enhancing the diminutive influence of increasing delay on reward value and its corresponding neural representation in the striatum [
12]. These findings reveal a novel mechanism by which DA influences human decision making by controlling the relationship between
the timing of future rewards and their subjective value. DA, therefore, selectively impacts the discounting of future rewards (time till reward is received) and it does this without any significant effect on the value of the utility of this reward [
12].
There are no neurological disorders that are characterized by temporal deficits [
14]. It is thus difficult to tease apart if the observed temporal processing deficits in actual fact reflect increased sustained attention or working memory demands (which are required by timing tasks). Thus timing deficits may actually reflect cognitive deficits [
14] and vice versa. Deficits in attention and working memory are thought to impair the ability to plan ahead and consider all information available before choices are made without considering all alternatives [
9]. Individuals with SUDs show deficits in attention and working memory [
13]. Timing deficits have been associated with attention and working memory. A number of human timing studies have indicated that sustained attention and working memory are crucial in accurate estimations of intervals in the seconds range [
13]. Further, the inability to retain several alternatives to be evaluated in memory or the inability to foresee the future all lead to increased impulsivity [
9]. One of the few studies to date that attempted to examine motor timing in stimulant dependent individuals, whilst controlling for possible confounds, found that motor timing deficits are present in this population [
13]. The stimulus dependent group showed abnormal motor timing abilities on all timing tasks, except sensorimotor synchronisation. With regard to neuropsychological deficits other than timing, only the overestimation of a relatively long time interval could be explained by impulsivity. These results indicate that stimulant dependent individuals exhibit motor timing deficits that cannot be explained by cognitive deficits [
13].
Evolutionary and developmental perspectives on SUDs
In line with the literature on dual circuitry deficits in SUD [
1], van Hoof has argued that SUDs can be explained through evolutionary and developmental processes. SUDs result from an imbalance between a stimulus-driven mode of action (Drive Mechanism) and a more cognitive-predictive mode of action (Guidance Mechanism). At the core of van Hoof’s model [
2,
15], is the hypothesis that during phylogenesis, as during ontogenesis, these two distinguishable mechanisms, relevant for grasping stationary and moving objects, are implemented in a repetitive way from the motoric area into the limbic area of the brain, resulting in the capacity to organize intentional behaviour. Individual personality differences shape the development of both of these mechanisms in an innate bimodal distribution (e.g., manifesting as personality traits such as extroversion or introversion). Extroverts show a bimodal distribution of personality traits; sensitive for punishment (negative feedback) resulting in avoiding neurotics, or insensitive for punishment (negative feedback), resulting in blunted antisocial or narcissistic personality traits.
The Drive Mechanism, a feedback mechanism, is hypothesized to be effected and implemented through a ventral circuitry that runs through the orbitofrontal cortex which includes the parietal cortex, the ventral premotor cortex and the basal ganglia. The Drive Mechanism is based upon a compilation of stimulus–response rules specifying the motor routines that objects habitually require (sensorimotor learning). The Guidance Mechanism, a dorsally located feed-forward control mechanism, runs through the dorsolateral prefrontal cortex. This is a more cognitive-predictive mode of action based on a compilation of action–effect rules specifying the actions and the effects produced in the future and is mediated by fronto-striatal circuits. For this mechanism to work properly the timing of motor movements is crucial [
2,
15]. Both circuitries circumnavigate the same anatomical structures, namely the cortex, striatum, globus pallidus and thalamus [
2,
15].
This bimodal distribution and evolutionary neurobiological model may provide a useful pathogenic framework for the classification of major psychiatric disorders, including SUDs [
2,
15]. Indeed, most psychiatric disorders are believed to be defined by some level of dysfunction in ventral and/or dorsal systems and there is a body of literature to support this [
5,
16‐
20].
Rationale
Attention, impulsivity and working memory deficits are commonly found in SUDs [
4,
10,
21,
22] and are predictors of poor SUD treatment outcomes and relapse in alcohol and cocaine dependence specifically [
22‐
25]. These deficits are in line with van Hoof’s [
15] model of imbalances in Drive and Guidance Mechanisms (a stronger Drive relative to the Guidance mechanism). According to van Hoof, the ability to time actions is a crucial factor for a well-functioning Guidance mechanism. Motor timing deficits correlate with attention, working memory deficits and impulsivity [
14,
26] and have been found in individuals with SUDs [
13]. To our knowledge, these timing deficits have not been investigated with regard to treatment outcome and relapse in SUDs. Early detection of motor timing deficits may be predictive of treatment outcome and relapse risk. Cognitive training of motor timing as well as alternative activities that function as distractors to inhibit premature responses may be potentially useful interventions [
9].
Study aims
This is a prospective, ongoing study that aims to examine the prognostic value of motor timing deficits in SUDs. These deficits are thought to reflect deficits in the Drive Mechanism and Guidance Mechanisms. We hypothesize that motor timing pre-treatment will be correlated with treatment response and relapse rates after treatment (which forms part of the standard care at the participating centre). Second, we will assess whether different subtypes of substance dependence (alcohol and/or cocaine) can be distinguished by task performance on a variety of tasks. We will compare task performance in patients with SUDs and healthy controls (HC) at pre- and post- completion of the treatment programme to avoid possible test-retest confounds. Third, we will test if motor timing performances correlate with impulsivity and attention and working memory functions. Fourth, we aim to find support for the model of van Hoof [
2,
15].
Three contrasting motor tasks will be used. All patients will be pair-matched with healthy controls for age, sex and ethnicity. The tested sensitivity values of the motor timing parameters will be compared to a carefully selected battery of neurocognitive tests. This is necessary due to the novelty of the motor task battery, the confounding effects of attention and working memory on motor timing paradigms [
14], and the high impulsivity levels found in SUDs [
22]. This study does not only have the potential to make a valuable contribution to both the SUD and motor timing literature but could further provide knowledge of the mechanisms at play in SUDs. If motor timing has prognostic value in the treatment of SUDs, simple motor timing measures can be incorporated in the management of patients and in the monitoring of outcomes.
Hypotheses
This prospective study will test the theoretical basis for prognostic indicators in SUD and its subtypes with regards to motor timing (measured in terms of treatment response and relapse). We hypothesise to find deficits in motor timing in SUD patients (alcohol and/or cocaine) compared with age-, gender-, and education-, ethnicity- and handedness- matched HC. We expect to find; i) a higher internal clock rate (higher spontaneous rhythms on condition 1 of the Flexibility Task [Task 2]); ii) a lower capacity to structure, organise and plan an action directly towards a visual target (higher reaction times and lower movement times on the motor reaction task [Task 1]); ii), lower inhibitory capacities (higher reaction times on the Go stimuli in the NoGo trail, more errors on the NoGo stimuli in the NoGo trail, and lower cognitive flexibility Go-NoGo Task [task 3]) in addicted individuals compared to HC. With regards to van Hoof’s model we expect to find; iii) a comparatively high activity of the Drive Mechanism and a comparatively low activity of the Guidance Mechanism. High activity in the Drive Mechanism will be reflected by hypotheses i and ii. We expect to find that the above hypotheses will; iv) correlate with lower treatment response and higher relapse in addicted patients (alcohol and/or cocaine), v) that timing deficits will correlate with measures of impulsivity (higher impulsivity reflecting higher degree of timing deficits) and, vii) that timing deficits will not be better explained by attention and working memory deficits.