Edited by: Patrick Anselme, University of Liège, Belgium
Reviewed by: Damien Brevers, Université Libre de Bruxelles, Belgium; Bryan F. Singer, University of Michigan, USA
*Correspondence: Ruud van den Bos, Department of Organismal Animal Physiology, Faculty of Science, Radboud University Nijmegen, Heyendaalseweg 135, NL-6524 AJ Nijmegen, Netherlands e-mail:
This article was submitted to the journal Frontiers in Behavioral Neuroscience.
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Huntington’s disease (HD) is a genetic, neurodegenerative disorder, which specifically affects striatal neurons of the indirect pathway, resulting in a progressive decline in muscle coordination and loss of emotional and cognitive control. Interestingly, predisposition to pathological gambling and other addictions involves disturbances in the same cortico-striatal circuits that are affected in HD, and display similar disinhibition-related symptoms, including changed sensitivity to punishments and rewards, impulsivity, and inability to consider long-term advantages over short-term rewards. Both HD patients and pathological gamblers also show similar performance deficits on risky decision-making tasks, such as the Iowa Gambling Task (IGT). These similarities suggest that HD patients are a likely risk group for gambling problems. However, such problems have only incidentally been observed in HD patients. In this review, we aim to characterize the risk of pathological gambling in HD, as well as the underlying neurobiological mechanisms. Especially with the current rise of easily accessible Internet gambling opportunities, it is important to understand these risks and provide appropriate patient support accordingly. Based on neuropathological and behavioral findings, we propose that HD patients may not have an increased tendency to seek risks and start gambling, but that they do have an increased chance of developing an addiction once they engage in gambling activities. Therefore, current and future developments of Internet gambling possibilities and related addictions should be regarded with care, especially for vulnerable groups like HD patients.
Huntington’s disease (HD) is a genetic neurodegenerative disorder, inherited in an autosomal dominant fashion. The disease is characterized by progressive motor, cognitive and behavioral symptoms, which usually become apparent between 30 and 50 years of age, and lead to premature death in 10–20 years after disease onset. HD is caused by a mutation in the Huntingtin gene (HTT), which leads to protein aggregation, deregulation of several cellular processes, and eventually cell death. Neuronal degeneration initially occurs selectively in the striatum (caudate nucleus and putamen), where it affects cortico-striatal pathways that serve to control motor and cognitive functions (Reiner et al.,
In this review we will argue that HD patients may be a risk group for developing problematic gambling. Firstly, problematic gambling is characterized by subjects’ inability to stop gambling despite financial, personal or professional problems. Based on neurobiological disturbances and behavioral symptoms the capacity to stop gambling behavior seems diminished or absent in HD patients. Secondly, due to the more liberal attitudes towards gambling and increasing possibilities of legal and illegal Internet gambling (see e.g., Griffiths,
In general, changing external conditions and treatment methods can have unexpected and undesirable effects on patient behavior, especially in complex neurological diseases. Such effects are easily missed when behavioral symptoms are not regularly reevaluated. This may be best illustrated by the case of Parkinson’s disease, where the introduction of drug treatment with dopamine agonists led to impulse control disorders such as compulsive gambling, shopping, eating, and hypersexuality, caused by overstimulation of the mesolimbic dopaminergic system (Dodd et al.,
Here, we will explore the disease profile of HD in relation to addiction, gambling problems, and decision-making deficits. In Section
HD is caused by an unstable CAG (trinucleotide; cytosine-adenine-guanine) repeat in the coding region of the HTT gene, which leads to the production of mutant huntingtin protein (Htt) with an expanded polyglutamine (polyQ) stretch (MacDonald et al.,
Neuronal degeneration is initially restricted to the basal ganglia, where the medium spiny neurons in the striatum (caudate nucleus and putamen) are specifically affected (Vonsattel and DiFiglia,
Cortico-basal ganglia circuits, encompassing connections between cortical areas, striatal areas, pallidal areas and thalamic areas, are organized in a parallel fashion subserving different functions in the organization of behavior. As many excellent reviews exist on the anatomy and function of these circuits (e.g., Alexander et al.,
Pathology in HD is observed in both the putamen and caudate nucleus (Vonsattel and DiFiglia,
In sum, HD is characterized by a specific degeneration of striatal neurons belonging to the indirect pathway. As the disease progresses, atrophy of the striatum spreads along a caudal-rostral and dorsal-ventral gradient causing a sequential disturbance of cortico-striatal circuits. The resulting loss of inhibitory control in these circuits is directly related to the progression of motor, cognitive and behavioral symptoms in HD, as discussed below.
HD is characterized by a variety of progressive motor, cognitive and behavioral symptoms. The first symptoms usually arise at mid-age, with an average onset age of 40, although a small percentage of patients suffer from juvenile-onset HD, which starts before the age of 20. As the symptoms and progression of juvenile-onset HD are somewhat distinct from adult-onset disorder, we will focus on the latter patient group in this review. One of the first symptoms to become apparent in HD is chorea (involuntary movement disorder), and a clinical diagnosis is usually made after onset of movement abnormalities (Shannon,
Motor symptoms start to become apparent in the early stages of HD, and are usually the first symptoms to be noticed in laboratory settings and by first-degree relatives of HD patients (de Boo et al.,
Behavioral disorders in HD can be complex and difficult to classify, and their occurrence and onset is highly variable between individuals. Moreover, it can sometimes be difficult to distinguish behavioral disorders from normal coping with a distressing disease (Caine and Shoulson,
Other, less commonly observed psychiatric symptoms and disorders in HD are anxiety, obsessive-compulsive disorder, mania, schizophrenia-like psychotic symptoms, such as paranoia, hallucinations, and delusions (Caine and Shoulson,
It is suggested that most psychiatric symptoms in HD are in fact part of a broad, ill-defined “frontal lobe syndrome” or “executive dysfunction syndrome”, which includes symptoms such as apathy, irritability, disinhibition, impulsivity, obsessiveness, and perseveration (Lyketsos et al.,
Cognitive decline is another important aspect of HD pathology. Many studies have focused specifically on the occurrence of cognitive symptoms in preclinical and early clinical stages of HD, in the hope to discover early clinical biomarkers of the disease (reviewed in Papp et al.,
Studies with animal models of HD show similar cognitive impairments to those observed in human patients. Although not all studies find robust cognitive deficits (Fielding et al.,
Motor, behavioral and cognitive symptoms in HD have been studied extensively in the past, and continue to be a topic of interest due to the wide variety and variability in the occurrence and onset of these symptoms across patients. In general, behavioral and cognitive symptoms are related to three frontal behavioral categories: apathy, executive dysfunction, and disinhibition. The combination of these symptoms is sometimes referred to as “executive dysfunction syndrome”. All of these symptoms are related to deficits in the cortico-striatal circuits involving the orbitofrontal cortex, dorsolateral prefrontal cortex and anterior cingulate cortex. As discussed above, neuropathological studies have observed a gradual degeneration of the striatum in a dorsal to ventral direction in HD patients. Although the behavioral and cognitive observations partly agree with a progressive impairment of cortico-striatal circuits, the symptomatic findings appear to be more diffuse than expected based on pathological observations. Onset and progression of behavioral and cognitive symptoms in HD is highly heterogeneous, indicating that damage to striatal regions may be more variable and widespread in early stages of HD than previously thought. This view is supported by evidence from several structural imaging studies (Thieben et al.,
While many people are able to gamble recreationally, it may become an overt problem for some, as they develop pathological forms of this behavior. Pathological gambling is characterized by an excessive urge to gamble despite clear negative financial, personal and professional consequences. It has recently been classified as an addiction in DSM-V, as it closely resembles substance abuse disorders in both diagnostic criteria and neuropathology (van Holst et al.,
The underlying neurobiological mechanisms of gambling are complex and involve many different brain regions and neurotransmitter systems (reviewed in Raylu and Oei,
Pathological gamblers perform poorly compared to controls on formal reward-related risky decision-making tasks (e.g., Cavedini et al.,
From these studies it is clear that neurobiological predisposition for developing pathological gambling behavior involves disturbances in both the associative/cognitive control circuit and the limbic circuit (van den Bos et al.,
With the increasing amount of possibilities offered by the Internet, there has also been a rise in both legal and illegal online gambling opportunities in recent years. These easily accessible and often uncontrolled gambling activities may pose a risk to anyone who has an increased susceptibility to gambling addiction, but may otherwise not become involved in such activities (Griffiths,
In view of these similarities between pathological gamblers and HD patients, we may expect the incidence of gambling problems to be increased among HD patients compared to the normal population. Nevertheless, only one study so far has reported cases of pathological gambling in an Italian family with HD (De Marchi et al.,
Laboratory tasks are commonly used to assess cognitive and behavioral abnormalities in neurological disorders. To gain insight into the processes and impairments involved in decision-making and risk-taking behavior, several tasks have been developed, including the IGT (Bechara et al.,
HD patients have been tested on both the Iowa and Cambridge Gambling Task. In a study with intermediate-stage patients, Stout et al. (
A limited number of other studies have tested risky decision-making in early stages of HD, but did not find performance difficulties in these patients on either the IGT or the CGT (Watkins et al.,
The neurobiological mechanisms underlying decision-making processes in the IGT have been well studied and described (see e.g., Bechara et al.,
Since decision-making processes in the IGT involve an interaction of limbic and associative/cognitive control cortico-striatal circuits, it is not surprising that HD patients are impaired in the performance of this task. One of the observations by Stout and colleagues is that the impact of loss on decision-making is reduced in HD patients (Campbell et al.,
The typical array of motor, emotional, and cognitive symptoms of HD is caused by progressive striatal atrophy that affects the different cortico-striatal circuits. Although onset and progression of behavioral and cognitive symptoms appear to be highly heterogeneous, motor and cognitive circuits are typically affected early in the disease, while the limbic circuit is affected at a later stage. Interestingly, neurobiological predisposition to pathological gambling and other addictions involves disturbances in the same cortico-striatal circuits that are affected in HD. Despite these striking similarities, however, in the medical literature HD has not been associated with pathological gambling or other addictive behaviors. Only one study so far has described a family in which gambling problems occurred in several HD-affected family members (De Marchi et al.,
Nevertheless, disturbances in the limbic cortico-striatal circuit of HD patients may still promote risky decision-making in situations with uncertain outcome, as demonstrated in the IGT (Doya,
If HD patients indeed have an increased risk of developing pathological gambling behavior when presented with the appropriate situation, the rise of easily accessible Internet gambling opportunities may pose a specific risk for this patient group. Even if they do not actively seek out these situations, HD patients are now much more likely to come across gambling opportunities than they were in the past. This is especially true for patients who spend most of their time at home due to their symptoms, where the Internet may be an important means to occupy them. A higher probability of engaging in gambling behavior may therefore cause a disproportionate increase in related problems in the HD population. We suggest that caretakers should be aware of these possible risks, and preferably try to prevent HD patients from engaging in (online) gambling activities. Moreover, we argue that clinicians should regularly assess the risk and prevalence of gambling-related problems in the HD population, to be able to provide appropriate treatment and guidance to patients and caretakers.
Besides epidemiological studies to assess the prevalence of pathological gambling and other addictions in HD, several lines of research can be suggested to increase our understanding of the issues discussed in this paper. First of all, it would be interesting to link performance deficits on the IGT directly to disturbances in cortico-striatal activity in HD patients. To this end, HD patients’ brain activation patterns can be studied with functional magnetic resonance imaging while performing the IGT, and compared to activity in normal subjects. Activity in the striatum, dorsolateral prefrontal cortex and orbitofrontal cortex is expected to be decreased in HD patients during decision-making on the IGT.
To study the behavioral and neurobiological aspects of gambling-behavior in HD in more detail, currently available rodent disease models can be utilized. On a behavioral level, these animals can be expected to show decreased performance on the IGT, similar to human patients. Rodent versions of the IGT are available (review: de Visser et al.,
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.