Background: This review article integrates findings from published behavioural and neuroimaging studies of impulsive-compulsive behaviours (ICBs) in Parkinson’s disease, with the aim of identifying the basic correlates of these problematic and distressing behaviours. The underlying premise is that for any feature to be a reliable marker of ICBs, it should be evident across multiple levels of analyses. When changes are evident only at one level, but not in the others, their reliability as indicators of ICBs should be questioned. Summary: To this end, we draw on the conclusions from three published systematic reviews of dopamine metabolic processes in the striatum, functional magnetic resonance imaging and cognitive, affective, and motivational assessments of medicated Parkinson’s patients with and without ICBs (ICB+ and ICB−, respectively). The key findings are as follows: ICB+ showed abnormal dopaminergic of the striatum, including the brain network supporting reward processing. Fronto-striatal connectivity was also reduced. These findings are consistent with the broader evidence of psychological dysfunction, evident on assessments of cognitive control (goal-driven behaviour, impulsivity), reward-driven decision-making (temporal discounting, gambling), and elevated rates of self-report negative affect (anxiety, depression, anhedonia). The implications of these findings are discussed with reference to the research domain criteria and, relatedly, directions for future research. Key Messages: The identification of markers of ICB that allow early diagnosis, monitoring, and optimisation of therapy is an ambitious goal. And whilst we have pulled together a number of convergent findings identified using different paradigms, we are still some distance off understanding the mechanism(s) that increase vulnerability to ICB. It is our hope that this review spurs future studies to further investigate the interaction between motivation and cognition with the twin aims of identifying markers of ICB that have both clinical utility and function as outcome measures in therapeutic clinical trials.

© 2023 S. Karger AG, Basel

Introduction

Impulsive compulsive behaviours (ICBs) are present in medicated Parkinson’s, with hypersexuality disorder, compulsive shopping disorder, compulsive eating disorder, and pathological gambling disorder are amongst the most prevalent (∼40% of medicated PD). ICBs are experienced as an irresistible and overpowering urge to engage in hedonistic activities in spite of negative consequences [1]. ICBs are associated with greater functional impairment; decreased quality of life; place strain on interpersonal relationships, financial stability; increase care-giver burden and psychiatric comorbidity more broadly [2, 3].

ICBs are a recognised side effect of the dopamine replacement therapies (DRT) that provide symptomatic relief from the motor symptoms. Despite this knowledge, ICBs are rarely seen in clinic. Reasons for this include (but are not limited to) the following: clinic appointments are usually short and therefore focused on managing motor and non-motor symptoms; lack of awareness amongst people affected by Parkinson’s that ICBs are a DRT side-effect; reluctance to disclose ICBs, due to feelings of shame, or because they lack insight their ICB is problematic [4].

Economic Burden of Parkinson’s

Parkinson’s is the second most common neurodegenerative condition after Alzheimer’s and is one of the most expensive neurological diseases treated in outpatients [5, 6]. A cost of illness study suggests ICBs contribute as much as 3% to the economic impact of Parkinson’s [7]. Thus, the rise in prevalence of Parkinson’s brings into the focus the need for a sustainable, personalised-medicine approach to ICBs [8].

Improving the health and wellbeing of individuals with ICBs will reduce the burden on the wider health economy and ensure sustainable resource utilization and reduce the burden on services. This claim is supported by economic studies showing a strong correlation between disease severity and treatment cost evidence in the USA. Evaluation studies show that for every $1 spent on delivering a targeted system of monitoring, detection and early treatment of substance misuse saves $4 in health care costs [9].

Unmet Need

Even when ICBs are identified or disclosed, treatment options are limited. Clinical advice is to stop or reduce DRTs, but this leaves motor symptoms exposed increasing physical disability and does not always alleviate ICBs. Changing DRTs is another option, but risks destabilising the condition, and again, once ICBs have become entrenched they are more resistant to treatment [1]. These approaches fall far short of evidence based practice showing that the most effective way to help someone who is at risk of developing a behavioural addiction such as Gambling Disorder is to intervene early, before the disorder can progress with brief motivational interventions and/or supportive monitoring. In contrast, severe, complex, and chronic disorders often require specialty treatment and continued post-treatment support and even then, full remission is rarely achieved [9].

Aim and Approach of Narrative Review

The overarching aim is to identify biological and psychological markers risk factors and prognostic indicators for medicated-related ICB. The first step towards meeting this aim is deliver meticulous summaries of all the available primary research. To this end, we integrate the findings from three of our published systematic reviews of Parkinson’s, which separately examined metabolic brain imaging studies of medicated ICB [10] and resting state functional imaging studies of medicated ICB [11]. The third systematic review investigated cognitive, motivational, and affective correlates of medicated ICB [12].

This “integrative” approach is predicated on the Research Domain Criteria (RDoC) framework that conceives of mental illnesses as brain disorders, which can be studied at the level of brain circuits using the tools of clinical neuroscience [13]. From this initial set of data, further bio and psychological signatures can be examined from the measures of circuitry: “upwards” to clinically relevant variation in psychological correlates or “downwards” to the genetic and molecular/cellular factors that ultimately influence such function. Importantly, all of these levels of analysis are seen as affecting both the biology and psychology of mental illness [14].

The Systematic Reviews

The first systematic review examined metabolic imaging studies using Positron Emission Tomography (PET) or Single Photon Emission Tomography (SPECT) which allowed for the visualization and quantification of the function and metabolism of the dopaminergic striatum. A meta-analysis was also conducted.

Our decision to focus on the dopaminergic striatum was informed by an extensive literature showing that manipulations of dopamine levels in the dorsal and ventral striatum affect the activation of behaviour in distinct, yet parallel ways. Whereas dopamine in the dorsal striatum contributes to the sensorimotor coordination of consummatory behaviour and the development of a “response set” in motor preparatory processes for skilled responses, dopamine in the ventral striatum influences the impact of reward-related stimuli on appetitive aspects of behaviour.

Because of the importance of neural circuits to the RDoC approach, a (very) brief overview of the anatomy of the striatum is provided before we discuss the findings. The striatum is the input module to the basal ganglia and is subdivided into the dorsal striatum which is composed of the caudate nucleus and the putamen, and the ventral striatum which contains the nucleus accumbens. The striatum received afferent input from (mostly ipsilateral) temporal, parietal, and frontal areas, topographically arranged in the medio-lateral and dorsal-ventral axes. Afferents are also received from all elements of the reward circuit that includes the dorsal anterior cingulate cortex, the dorsal prefrontal cortex, the ventromedial prefrontal cortex, the ventral pallidum, the lateral habenula, the hypothalamus, the subthalamic nucleus, the midbrain (the substantia nigra pars compacta and the ventral tegmental area), and the brain stem (the pedunculopontine tegmentum [15].

Our search revealed a total of 238 studies published from database inception until 2018, of which 19 full texts were assessed. Nine studies, reporting a total of 117 Parkinson’s patients with a confirmed ICB (ICB+) and 175 Parkinson’s patients without an ICB (ICB–), met the inclusion criteria of data reported for at least one striatal region based on reports of dopamine transporter (DAT) level using radiotracers tracers ([123I]FP-CIT radiotracer, [18F]FP-CIT radiotracer, or [18F]fluorodopa), presynaptic dopamine release using [11C]raclopride, which is a competitive D2/3 antagonist sensitive to changes in endogenous dopamine levels, and post-synaptic D2/3 receptors availability ([11C]-(+)-PHNO, [18F] fallypride or [11C]raclopride). A meta-analysis of the ICB− and the ICB+ data revealed evidence of dorsal and ventral striatal dysfunction in ICB. Specifically, dopamine transporter binding in the putamen and the caudate nucleus was significantly reduced; whereas of dopamine transporter binding in the putamen and the caudate nucleus of the dorsal striatum, and increased dopamine release to reward-related stimuli/gambling tasks in the ventral striatum. There was no difference in dopamine receptor availability.

The aim of the second systematic review was to extend the modular findings of abnormal dopaminergic modulation of the striatum, to provide a broader network representation of neural circuits in ICB. To this end, we included studies reporting resting state functional connectivity using PET, SPECT, and functional magnetic resonance imaging techniques. The underlying assumption is that areas whose spontaneous activity correlates, form functional networks. Our search revealed a total of 299 studies published from database inception until 2018, of which 39 full texts were assessed. Nine cross-sectional studies met the inclusion criteria of data reporting resting state functional connectivity imaging (5 studies used MRI, 1 study used SPECT, and 3 studies used PET). Whilst the small number of studies precluded a meaningful meta-analysis from taking place, a narrative interpretation of the resting-state studies showed abnormal ventral striatal connectivity in ICB+. Specifically, the ventral striatum showed increased connectivity with frontal areas and limbic structures (e.g., habenula, amygdala, thalamus, insula) and decreased connectivity with the anterior cingulate cortex.

Having identified a putative set of neural structures and brain circuits in ICB, the next step, according to the RDoC framework, is to integrate findings with clinically relevant markers of psychological (dys)function and the genetic signature. Our third systematic review and meta-analysis adopted an “upward” direction and examined the cognitive, motivation, and affective correlates of ICB. The decision to progress in this direction rather than the more fine grained molecular approach, was based on the small number of candidate genes investigated, and the broader view that the traditional candidate gene approach is out-of-touch with the current understanding of the genetic architecture of complex behavioural traits [16].

A total of 10,200 studies published between 2000 and 2018 were screened. A total of 79 full-texts were assessed, of which 25 studies, reporting n = 625 patients with an ICB+ and n = 938 ICB−. The meta-analysis showed ICB+ was marked by significantly elevated rates of disadvantageous decision-making on reward-related tasks such as the Iowa Gambling Task, The Kirby delay discounting questionnaire, the Monetary Risk-Taking Task. ICB was also marked by significantly elevated self-report rated negative affect (Beck Depression Inventory, Centre for Epidemiological Studies-Depression scale; Geriatric depression scale; Hospital anxiety and depression Scale), anhedonia (Snaith-Hamilton pleasure scale) and impulsivity (Barratt impulsiveness scale-11; Brief self-control scale). Finally, ICB was associated with cognitive rigidity (using the Trails A and B test). Part A of the test requires participants to connect a series of numbers (1–25) in sequential order. In the second part (B) the targets comprise numbers (from 1 to 13) and letters (from A to L), and the requirement is to connect the targets whilst alternating letters and numbers, as in 1-A-2-B-3-C, in the shortest time possible. The dependent variable is the discrepancy in time between completing part B and A.

Conclusions and Implications

Data from the systematic reviews converge on an association between ICB and the brain reward system [17]. Whilst this aligns with a primordial view of ICB, the RDoC approach as implemented here point to a much richer understanding of the systems involved in ICB. We are now at a point where we can leverage knowledge of neurobiological circuit maps of behavioural and cognitive functioning from the wider cognitive neuroscience literature to elucidate the ways in which activity in these circuits becomes dysregulated in ICB. The intention here is not to “explain” ICB in terms of abnormal modulation of the constructs of reward, impulsivity, negative affect or cognitive inflexibility. Instead, having identified that ICB is likely to reflect the confluence of changes in a number of different neural systems, future research should investigate the multiple constituent mechanisms [18]. So, in relation to reward, this might include, reward responsiveness, reward learning and reward valuation [19].

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

Martini was supported by a Keele University PhD scholarship.

Author Contributions

Edelstyn and De Rosa formulated the conceptual structure for the narrative review. Martini conducted the 3 systematic reviews on which the narrative review was based, and writing the initial draft. De Rosa and contributed to the preparation of the manuscript. Edelstyn was responsible for addressing reviewer comments and drafting the revised manuscript.

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