Impulse Control Disorders in Parkinson's Disease. A Brief and Comprehensive Review

Impulse control and related disorders (ICDs-RD) encompasses a heterogeneous group of disorders that involve pleasurable behaviors performed repetitively, excessively, and compulsively. The key common symptom in all these disorders is the failure to resist an impulse or temptation to control an act or specific behavior, which is ultimately harmful to oneself or others and interferes in major areas of life. The major symptoms of ICDs include pathological gambling (PG), hypersexualtiy (HS), compulsive buying/shopping (CB) and binge eating (BE) functioning. ICDs and ICDs-RD have been included in the behavioral spectrum of non-motor symptoms in Parkinson's disease (PD) leading, in some cases, to serious financial, legal and psychosocial devastating consequences. Herein we present the prevalence of ICDs, the risk factors, its pathophysiological mechanisms, the link with agonist dopaminergic therapies and therapeutic managements.

ICDs and ICDs-RD have been included in the behavioral spectrum of non-motor symptoms in Parkinson's disease (PD), leading in some cases to serious financial, legal and psychosocially devastating consequences with a greater impact on the quality of life. Moreover, in recent years we have noticed that PD patients are at increased risk of developing more than one of the major ICDs.
Along these lines, although it is not the focus of the present paper, some authors have suggested that the increased drive or motivation to certain behaviors cannot be harmful but rather beneficial (1). Therefore, it remains under discussion whether artistic productivity or hypercreativity should be included in ICDs or in ICDs-RD, or if it might represent an innateskill that emerges in PD patients on dopaminergic therapy (8,12,13,23,24).

COMPONENT ASPECTS
Three main aspects that characterize ICDs groups and ICDrelated disorders in relation to reward-driven activities are: 1. The presence of impulsive aspects (lack of forethought or consideration of consequences) (1,3,9). 2. The presence of compulsive aspects (repetitive behaviors with a lack of self-control) (1,3,9). 3. A negative or harmful behavior to oneself or to others (1,3,6).
The four major ICDs include: Pathological Gambling (PG) characterized by an excessive and uncontrollable "preoccupation with gambling and the excitement that gambling with increasing risk provides" despite financial loss and social problems (3,7,22,(25)(26)(27). PG was one of the earliest recognized ICDs in PD (3). It was recently moved to the category of "Substance-related and addictive disorders" in the DMS-5, since substance abuse and PG activate brain reward areas and this bears similarities to drug addiction (7,28).
Hypersexual disorder (HS) included in "The Sexual and Gender Identity Disorders Workgroup" of DSM-5 (7). It could be described as an excessive amount of time consumed by sexual fantasies and by planning for engaging in sexual behavior which interferes with important activities and obligations in ordinary life (3,7). Other behaviors that might often occur are fetishism and voyeurism (7). As in substance abuse, patients with HS pursue a short-term reward and may develop tolerance and withdrawal-like syndromes (7). This condition is more common among adult men, and it may additionally occur with erectile failure (6,7,9,17,29).
Binge eating has been included in "Feeding and Eating Disorders" in DSM-5 (3,6,7). It is "a persistent disturbance of eating or eating-related behavior that results in the altered consumption of food, which significantly impairs physical health or psychosocial functioning" (7). The specific criteria proposed are: 1. Episodes of recurrent binge eating in the absence of any maladaptive compensatory behaviors. 2. Sense of lack of control over eating during the episodes. 3. Intake, in a discrete period of time (within any 2 h period), of an amount of food that is much larger than most people would eat in a similar period of time under normal circumstances.
The difference between binge eating and bulimia is that the former tends to be fluctuating while the latter is permanent (3,7). Compulsive buying (CB) is characterized by a constant urge to buy that leads to senseless contraction of debts with continuous delay of payment until a catastrophe clears the situation. As other ICDs, the repetitive loss of control over spending and the negative emotional state that emerges when not buying resemble substance use disorders (3,7).
A prevalence of 5.8% in the general population at risk of CB is described (1,3).

ICD-RELATED BEHAVIORS (ICDs-RD)
ICDs-RD are classified as related behaviors that have a contrast clinical presentation with respect to the four major ICDs. However, the biological link between both conditions may be identified in the dysregulation or inappropriate regulation of the reward pathways in the mesocorticolimbic network (22,30). ICDs-RD is characterized by repetitive perseverative behaviors that appear to be more closely linked to pulsatile drugs, such as levodopa or intermittent apomorphine therapy rather than dopaminergic agonist (DA) per se.

EPIDEMIOLOGY ICD in the General Population
The prevalence of ICDs in the general population, which has been underestimated, shows a wide range with variability according to different populations: from 0.2 to 5.3% (1). This enormous variability may be explained not only by different genetic, ethnic and cultural backgrounds, but also by the instruments used to assess these symptoms in the population (3,(18)(19)(20) (Table 1).
Although the ICDs were initially reported in PD patients on DA therapies, some studies report the occurrence of ICDs in the general population and in novo PD patients (10,11,34). It is still under discussion whether PD biology could be a risk factor for ICDs (35).

ICD in de novo PD
As mentioned above, it remains under discussion whether or not PD itself confers an increased risk for developing ICDs (35). Identifying the frequency of this disorder in novo PD patients could contribute to resolving these questions (1). A recent study analyzing data from the Parkinson's Progression Markers Initiative failed to demonstrate an increased risk for the development of ICDs or ICDs-RB in PD patients in the absence of treatment. Nevertheless, some symptoms suggestive of ICD have been reported in 20% of newly diagnosed, untreated PD patients with respect to the appropriately matched controls (36). In recent years, imaging studies have offered relevant insight to this debate (35). However, at the moment, results remain controversial over whether PD itself constitutes a risk factor for the development of ICDS or ICDs-RD (1, 3, 6).

ICDs-RD in PD in Different Populations
ICDRs continue to be under-recognized and under-managed in clinical practice. Determining the true frequency of ICDs in the health population, in PD de novo patients, and in PD patients with and without DA agonist therapies in different populations represents a significant challenge since a number of variables must be analyzed, including assessment tools, DA dose, DA formulations, years of disease, as well as cultural and other factors. Moreover, in many cases more than one ICD has been identified (29). In Table 2 we present a summary of various studies conducted to assess the presence of ICD behaviors over different periods of time and evaluate the risk factors and clinical characteristics.

Assessment Tools
Several instruments have been developed to assess and identify ICD symptoms in PD, some of which are summarized in Table 3.

Risk Factors
Several studies have been conducted to identify the risk factors for ICD development in PD patients (8). They include: + Demographic: young patient, male gender, unmarried (3-8, 14-21, 24, 27, 29, 59, 60). + Treatment related: although ICDs have been reported to be associated to different drugs, such as L-dopa, amantadine and rasagiline, DA intake appears as the major risk factor for ICDs (1-5, 7, 8, 13-15, 17-22, 27, 29, 59, 60). Prevalence of ICDs was compared among different DA drugs (pramipexole, ropirinole) and between extended releases or immediate formulations (1,3,6,29,60). However, controversial findings from preliminary reports suggest that long-acting DA and patch or pump formulations may reduce the risk for ICDs (8,15,61). It remains under discussion whether there is an association between ICDs and DA dose. The same controversial results were reported regarding DA treatment duration, higher daily dose and DA higher peak dose (3,7,29,60). + Personal or family history: history of cigarette smoking, drug abuse, depression, apathy, REM behavior disorders (RBD), tea, coffee and mate consumption, positive personal or family history of alcoholism or gambling, and impulsive or novelty-seeking traits increase the risk for ICDs and their predictors (2-8, 14, 16-18, 29, 59, 60). + PD onset and related ICDs: prevalence increases over time, while ICDs tend to occur in the first years of   the disease. Early PD onset and the presence of motor complications of PD may predict a higher risk for ICDs (4-8, 13, 14, 16-18, 21, 24, 29, 60). + Cultural factors: it remains to be determined if cultural factors may increase the risk for ICDs and ICRDs. Some authors suggest that cultural factors probably contribute not only to the prevalence of ICD but also the type of ICD (7,17). One classic example in this field was provided by the DOMINIO study that suggests that living in the United States of America may be an independent risk factor for ICD development (1,6,29). + Deep Brain Stimulation (DBS): the relationship between ICDs and DBS remain under discussion. Initial studies reported improvement in ICDs after DBS, while subsequent studies showed ICD exacerbation (1,6,22,60,62). DBS of the subthalamic nucleus (STN) is an effective, widely used treatment for motor fluctuations or disabling dyskinesias in PD (63). STN-DBS has been identified as an independent risk factor for ICRDs; however, the reduction of dopamine agonist dosage after STN-DBS could improve or decrease ICD occurrence (6,7,22,60,62).
On the other hand, several studies suggest that DBS may contribute to impulsivity, excessive reward seeking and ICDs. Consistent with this hypothesis, PD patients without ICDs showed impulsive decision making when DBS is turned on (7,60,62,64).
To explain these controversial findings, it has been hypothesized that STN stimulation plays a role in dynamic aspects of impulse and inhibitory control (22,60). + Personality, Neuropsychiatric symptoms and Cognition in ICDs: a higher level of neuroticism, ineffective coping skills, and lower levels of agreeableness and conscientiousness in PD patients with ICDs has been reported (3). Early onset PD patients constitute a high risk population for ICDs with a selfassertive/antisocial and reserved personality and somatization traits (22). A large constellation of comorbid affective symptoms and behavioral traits have been reported in PD with/or at risk for ICDs including depression, anxiety, novelty seeking, impulsivity symptoms and anhedonia (2,62,65,66). Interestingly, in PD patients with ICDs, apathy could be noticed during withdrawal from dopamine replacement therapy (DRT). Impulsivity and apathy are two major comorbid syndromes of PD that may represent two extremes of a dysexecutive and behavioral spectrum involving dopamine-dependent cortico-striatothalamo-cortical networks (64). + Cognition: controversial data have been identified in cognitive battery tests between PD patients with and without ICD (8,36); the first group presents values lowered in some tests that evaluate the frontal lobe, but did not find significant differences in executive functioning (14,67). Cognitive flexibility and ability to plan is altered in patients with ICD (8).
Visuo-spatial working memory and reward-punishment learning impairments have been reported in different studies; however, many results could not be replicated (6,17). To rate severity of ICD in PD patients. A brief, clinician-rated screening tool that assess the intensity and impact of a wide range of ICBs common in PD  Stronger predictor f ICDs (2,6,8,9,16,18) Interestingly, patients with ICDs showed a more immediate reward response and greater choice impulsivity leading to increased risk behavior (6). When the cognitive performance was compared according to the type of ICD it was found that patients with HS showed greater general cognitive impairment, including lower performances on learning tests and were more impaired on the Stroop test and memory tasks than were patients with PG (8,68). However, another study found no differences in the executive functions of patients with PD and PG (69). + Genetics: genetic factors have been involved in ICDs in PD.
Although heritability was estimated to be 57%, consensus remains a challenge and data need to be replicated in large cohorts from different populations (16). A large number of single nucleotide polymorphisms (SNP) in dopaminergic, glutamatergic, serotonergic, and opioid neurotransmitter systems has been reported as a candidate that improved predictability of ICDs when compared with clinical risk factors (2,6,9,16,21,70). Recently, an association of OPRM1 rs1799971 was identified, a gene encoding the mu opioid receptor with ICDs. This gene is central to pain control as well as drug reward and addictive behaviors (70).
In Table 4 we present the genetic factors reported to be related to ICDs. Interestingly, the ICARUS study, the largest prospective observational study in an Italian population, contributes to the identification of additional risk factors that include nonmotor symptoms (mood and sexual function), mood symptoms (depression), sleep disorders and a low level of quality of life (19).

+Other Risk Factors
Recently, the overexpression of FosB, a transcriptional regulator involved in addiction induced by drugs of abuse and in many types of compulsive behaviors has been reported to be associated with L-dopa induced dyskinesia and to be triggered by pramipexole (60).
The FosB overexpression was identified in the nucleus accumbens (NA) and the striatum (brain regions important for addiction) of healthy and DA-lesioned rats exposed to pramipexole and found to be NMDA receptor dependent. These findings suggest that enhanced FosB expression may represent the strongest predictor of PD patients at risk of ICDs (27,60).

PATHOPHYSIOLOGY
Although an extensive number of studies have focused on the pathophysiologic mechanisms of ICDs in PD, these remain to be clarified (2,9). Classically, the appearance of impulsivity in PD has been attributed to neuronal dopaminergic degeneration, facilitating ICD occurrence in dopamine replacement therapies (8).
Nevertheless, in recent years, evidence has suggested a complex multifactorial mechanism beyond the dopaminergic corticostriatal networks, including a complex serotoninergic and noradrenergic interaction. Further investigation is required (9).

DOPAMINERGIC THEORY
Dopaminergic receptors, Dopamine 1 receptor 1 (D1R) (D1 and D5) and Dopamine 2 receptor (D2R) (D2, D3, D4) types possess contrasting roles with inhibitory and excitatory signaling, respectively. These contrasting roles are present not only in the nigro-striatal pathway but also in the mesolimbic and mesocortical circuits. The pathways link cortical and subcortical regions [prefrontal cortex (PFC), ventral striatum, VTA and amygdala]; both circuits are implicated in reward learning and executive decision making or reinforcement behaviors, respectively (6,22,74). To measure brain cortical thickness and subcortical volumes, and to assess their relationship with presence and severity of symptoms, in PD patients with and without ICDs.
To assess whether a functional dysregulation of the habenula and amygdala (modulators of the reward brain circuit), contributes to PD punding.
X Punding x x Cortical thinning of right inferior frontal gyrus compared to controls and PD-without punding (87) To investigate structural abnormalities in mesocortical, limbic cortices and subcortical structures in PD ICDs.
x x x Volume loss in the nucleus accumbens of PD patients. PD-ICD showed significant increased cortical thickness in rostral anterior cingulte cortex and frontal pole compared to PD-without ICD. Increased cortical thickness in medial prefrontal regions in PD-ICD To determine morphometric changes as predictors of ICB in de novo PD x x x No significant morphometric changes in PD-ICD and PD-without ICD before and after onset of ICD.
To better understand the neural basis of ICDs in PD x x x PD-ICD patients showed a reduced gray mater volume in External Globus Pallidus compared to PD-without ICD (90) To investigate gray matter (GM) and cortical thickness (CTh) changes in PD with and without ICDs.
x x x Increased cortical thickness in anterior cingulate cortex, orbitofrontal cortex in PD-ICD.  Anatomical regions involved in ICDs: In PD with ICDs a marked decrease ventrostriatal D3Rbinding has been reported, while experimental PD models have shown an increase in DA levels in the NA associated to bilateral nigrostriatal DA denervation (64,76). These findings, of a diminished striatal D2/D3 receptor level and an increase in mesolimbic DA tone, lead to an imbalance in the cortico-accumbens network implicated in reward signaling and behavioral changes (64,77,78). Moreover, the dopaminergic mesocorticolimbic system provides a role for shift behavior in response to changing stimulus-reward contingencies (64).
In this scenario, the tonic "overdosed" by D2/D3 receptor agonists in the mesocorticolimbic circuit could contribute to suppress, through the impairment of top-down inhibitory control from prefrontal cortical area (PFC) inputs to the To determine the changes in DTI associated with medication-related ICD in PD patients undergoing chronic dopamine-replacement therapy.  ventral striatum, reward-related learning and induce compulsive, perseverative behavior through the direct D1 receptor pathway (6,9,22). Dopaminergic agonists (DA) show a high D3R affinity in the mesolimbic system (6,7,9,60). In effect, DA therapy, acting on the depleted dorsal striatum (involved in the sensorymotor circuit) and a relatively intact ventral striatum, induces a reduction of inhibitory response and impulse control by the reduction of activity in the lateral orbitofrontal cortex, the rostral cingulated zone, the amygdala, and in the external pallidum (6,7). Therefore, PD patients on DA are not only at high risk for ICDs but also demonstrate greater choice impulsivity, shorter reaction time and increased risk taking (6,79).
The D1 receptor family localize in the direct pathway of reward-based behaviors. Stimulation increases the activity of striatal projections to the nucleus accumbens/ventral striatum, while D2 receptors elicit suppression of the cortico-accumbens network (6,22,80).

NEUROIMAGING IN PD PATIENTS WITH ICDS
In recent years neuroimaging, particularly that which is focused on the dopaminergic system, has significantly contributed to the knowledge of neurobiological factors for ICDs (2,7,8,81,82) (see Tables 5A-D).

Structural MRI changes have been reported in PD patients
with ICDs with a selective atrophy in the orbitofrontal and anterior cingulate cortices (areas involved in behavioral modulation). Atrophy in the orbitofrontal cortex has been reported in PD patients with ICDs (85, 91). 2. Functional brain resonance (fMRI) studies have reported an abnormal metabolism on the frontostriatal and cingulate cortices, the nucleus accumbens and the amygdala (2, 120).

A connectivity dysfunction between the striatal and limbic
areas has been proposed. Brain connectivity was impaired in PD patients with ICDs with respect to the PD individuals without ICDs involving the neurocognitive network. A decreased connectivity has been identified in the central executive networks (mediofrontal areas, anterior cingulate and para-cingulate cortices), while an increased connectivity has been identified in the salience network (limbic-paralimbic network) and in the default mode network (pre-cuneus and posterior cingulate, bilateral inferior-lateral-parietal and ventromedial frontal cortices) (95,97).
Single photon emission computed tomography (SPECT) of the dopamine transporter (DAT). DAT regulates dopamine turnover. A reduced DAT binding in PD patients with PG and ICDs has been identified in PD patients To investigate brain network connectivity at baseline in a cohort of drug-naive PD patients who successively developed ICDs over a 36-month follow-up period compared with patients who did not.
Drug Naive PD X Increased baseline connectivity in subtantia nigra (SN) and decreased baseline connectivity in default mode network and central executive network in PD patients who develop ICD after chronic dopaminergic treatment compared to those who did not (96) To investigate intrinsic neural networks connectivity changes in PD with and without ICD. Effects Questionnaire Exposure to drug-cues increase subjective feeling of being "ON" during both "ON" and "OFF" medication scans, which corresponds to significantly increased activation in ventral striatum (VS) in PD-DDS.
Frontiers in Neurology | www.frontiersin.org To demonstrate that DA would be associated with greater risk taking and lower ventral striatal activity in PD with ICD vs. PD without ICD X X X Risk task with "Gain" and "Loss" condition. ON and OFF medication states. ON state associated with lower bilateral ventral striatal activity compared to the OFF state in patients with ICD with the reverse finding in PD control group. Greater correlation between BOLD activity and risk in PD-ICD compared to PD-without ICD in bilateral ACC and caudate, and left OFC.
To compare dopaminergic function during gambling in PD patients, with and without pathological gambling (PG), following dopamine agonists.
To investigate resting state brain perfusion in PD PG compared with matched PD controls and healthy controls.
X X X 99mTc-ECD (rCBF/SPECT) PD-PG showed a disconnection between the ACC and the striatum, which was not observed in PD patients without PG and HC groups. with ICD compared to PD patients without ICD or healthy controls. This reduced binding of DAT has been suggested as a potential biomarker for risk of developing ICD symptoms (2,36,60). The binding reduction was not uniformly reproduced in different studies: some reported a reduction in right ventral striatum (2,102), while others in the left putamen and left inferior frontal gyrus. These data could reflect a mesolimbic projection and frontostriatal disconnection, suggesting a vulnerability or maladaptive synaptic plasticity under non-physiological DA stimulation (2).

POSITRON EMISSION TOMOGRAPHY (PET) WITH 11C-RACLOPRIDE
Positron emission tomography (PET) neuroimaging with 11Craclopride explores the DA fluxes within the basal ganglia. The 11C-raclopride is a reversible binding to the postsynaptic D2/3 receptor that competes with endogenous DA (2,8,22,106,107). Decreased 11C-raclopride binding is an indirect measure of increased endogenous dopamine release or "hyperdopaminergic state." A significant reduction of 11C-raclopride binding has been reported in ventral striatum, but not in dorsal striatum, in PD with ICDs (single or multiple) as compared to PD individuals without ICDs, following generic reward-related vs. neutral visual stimuli.
All of these findings contribute to support a mesocorticolimbic imbalance in PD with ICDs (108).

PD-ICDs TREATMENT
The first approach for ICD is prevention, and a key element is patient and family education concerning potential risks of different dopaminergic therapies. Physicians should be aware of predisposing risk factors and balance cost/benefit before DA prescriptions, excluding genetic factors and taking into consideration clinical findings, such as young age, early PD onset, lengthy disease duration, personal history of addictive behaviors, male gender, short-acting DA drugs, behavior and mood disorders (apathy, depression), DBS and certain cultural factors that require attention before prescription.
When ICDs appear, treatment continues to be a challenge. Individualized treatment must be conducted, identifying potential variables, such as motor status, comorbidities, other non-motor symptoms and quality of life (27,122,123).
The relevance of prevention is supported by NICE guidance that includes written information, or verbal information recorded in writing, at DA initiation of treatment. The authors emphasize the relevance of communicating to patients, relatives and carers the risk of ICDs due to the potential impact on their lives and for early detection (124).
The first approach for the treatment of ICD symptoms is the reduction or discontinuation of DAs. However, it should be considered that neuropsychiatric traits may persist for at least 12 weeks after drug withdrawal (60,61,123).
Nonetheless, in certain cases this strategy is not feasible, and some patients are at risk of developing DA withdrawal syndrome and worsening motor symptoms (21,61,123).
Although animal PD models have identified serotonin (5HT) depletion as a higher risk for impulsivity and risk behaviors, the serotonin reuptake inhibitors (SSRIs) used to treat ICDs had controversial results (22,123).
Atypical antipsychotics, such as clozapine and quetiapine have been used to treat ICDs in PD, but no randomized trials have been conducted and evidence is limited (2,7).
Taking into consideration that specific SNP opioid receptors have been identified as stronger risk factors for ICDs, opioid antagonists employed in the treatment of PG have produced controversial results (naltrexone, nalmefene) (2,7,16,22,60,123).
A number of drugs administered to increase Gabaergic inhibition (valproate, topiramate), as well as new drugs to preserve ventral striatal DA system (zonisamide, donepezil, noradrenaline reuptake inhibitor) have been essayed (2).
As previously mentioned, controversial data are available concerning DBS and ICD treatment. A favorable response through reduction in dopaminergic requirements has been noted. It has been suggested that STN stimulation could reduce the risk for ICDs by increased reward-driven behaviors by inhibitor effect in the indirect dopaminergic pathway. However, some patients may develop transient de novo ICDs after STN DBS, and selective patients may develop ICDs a long time after DBS (123,125).
A non-pharmacologic approach includes cognitive behavioral therapy and patient and caregiver education (7,60).

CONCLUSIONS
The treatment used for PD, particularly DA, is associated with the development of ICDs and related behaviors. Susceptibility to these disorders depends on the associated risk factors.
ICDs can have serious personal, family, psychosocial, financial, and medical consequences. However, in contrast, artistic activities have been described in patients with PD while undergoing treatment with DA. These patients are compulsive but report a positive influence on quality of life.
These findings highlight the need for a very critical approach at the moment of Dopaminergic Replacement therapy choice.

AUTHOR CONTRIBUTIONS
EG: study concept, design, and editing. VA: study concept and editing of manuscript.