pathological gambling is defined in the current classification system of the world health organization ( 1992 ) ( icd10 ) as an impulse control disorder ( icd ) which causes excessive , uncontrollable gambling despite financial losses and social problems , while the latest version of the diagnostic and statistical manual ( dsm5 ) of the american psychiatric association ( 2013 ) grouped pathological gambling together with substancerelated and addictive disorders and renamed it to gambling disorder . despite this aetiological debate , in parkinson 's patients
it has been observed that pathological gambling occurs more frequently ( 3.46.1% ) than in the general population ( 0.252% ) , alongside with icds , such as binge eating , so called hypersexuality and compulsive shopping ( cox et  al . , 2005 ; avanzi et  al . , 2006 ; grosset et  al . , 2006 ; voon et  al . , 2006 ;
bondolfi et  al . , 2008 ; weintraub et  al . , 2010 ; santangelo et  al . ,
the aetiology of the development of pathological gambling in parkinson 's disease is still unclear , however , research suggests an association with dopamine replacement therapy , specifically with dopamine agonists ( voon et  al . , 2006 ;
weintraub et  al . , 2006 ; gallagher et  al . , 2007 ) .
this review summarizes evidence in this field of research attempting to reveal the relationship between parkinson therapy and pathological gambling , discusses the reasons why some patients react on them differently than others , what the relevant risk factors are and considers how impulsivity may contribute to the development of gambling symptoms .
( 2007 ) found that these patients are younger , earned a higher score in tests investigating noveltyseeking and impulsive behaviour , and were more likely to have a personal or family history of alcohol abuse .
being male and smoking in the past also seem to be risk factors ( gallagher et  al .
, 2007 ; valena et  al . , 2013 ) . in this respect , pathological gambling with and without
parkinson 's disease is rather similar : young age , male sex , impulsivity , noveltyseeking , smoking and alcoholism are also considered risk factors for pathological gambling in the general population ( johansson et  al . , 2009 ) .
observing the progress of their disease , in comparison to other parkinson 's patients , those who later develop pathological gambling tend to have an earlier onset of the illness and also suffer more frequently from manic or hypomanic episodes during the onperiod of dopaminergic medication ( voon et  al . , 2007 ) .
even in the first case reports about parkinson 's patients developing pathological gambling , a clear correlation has been observed with the initiation or dose escalation of dopaminergic medication ( molina et  al . , 2000 ;
seedat et  al . , 2000 ) . in further studies comparing the effect of different parkinson 's therapies , dopamine agonists emerged as the medication with the strongest association with the development of pathological gambling ( voon et  al . , 2006 ; weintraub et  al . , 2006 , 2010 ;
some studies claim that pramipexole could have the largest effect ( dodd et  al . , 2005 ) .
other studies systematically comparing different dopamine agonists have found no significant difference between each of them ( weintraub et  al . , 2006 ;
recent research also shows a strong effect of aripiprazole , prescribed for the treatment of mood disorders and schizophrenia , with stronger gamblingrelated cognition in comparison to other dopamine agonists ( grallbronnec et  al . , 2016 ) .
levodopa seems to play a less important role as only a few patients developed pathological gambling under levodopa monotherapy ( dodd et  al .
, 2005 ; voon et  al . , 2006 ; gallagher et  al . , 2007 ) , however , studies suggest that additionally prescribed levodopa raises the risk of the development of pathological gambling and icds ( dodd et  al . ,
particularly high doses and longterm use of levodopa and shortacting dopamine agonists are also associated with dopamine dysregulation syndrome and punding , that is , stereotypic behaviour ( gallagher et  al . , 2007 ) .
further , subthalamic nucleus deep brain stimulation ( stn dbs ) has a controversial role in the development of pathological gambling in parkinson 's disease .
it has been observed that after the initiation of stn dbs therapy , gambling symptoms resolved ( ardouin et  al . , 2006 ; bandini et  al .
these results could be explained by the significant reduction in the dosage of dopamine agonist medications .
however , in some individual cases , pathological gambling and/or impulsive behaviour only developed after stn dbs surgery ( funkiewiez et  al .
, 2003 ; contarino et  al . , 2007 ; smeding et  al . , 2007 ;
2011 ) ; although in these cases the symptoms resolved spontaneously or after the change in stimulation parameters and further reduction in dopaminergic therapy . this could be associated with the stimulation of the limbic subregion of the stn which has been shown to affect neurotransmission in the limbic basal gangliathalamocortical circuitry ( winter et  al . , 2008 ) .
evidence also shows that patients are more impulsive after activating stn dbs ( frank et  al .
2009 ) . as impulsivity is considered as a risk factor for developing pathological gambling in parkinson patients ( voon et  al . , 2007 ) , the contentious effects of stn dbs raise questions about the role of impulsivity in the development of gambling behaviour in general ( table  1 ) .
main results of studies on the association of pathological gambling with parkinson 's disease therapy bis , barratt impulsivity scale ; da , dopamine agonists ; icd , impulse control disorder ; igt , iowa gambling task ; ledd , ldopa equivalent daily dose ; pd , parkinson 's disease ; pg , pathological gambling ; stn dbs , subthalamic nucleus deep brain stimulation .
the fact that not all parkinson 's patients develop medicationassociated impulse control disorders or pathological gambling and that most of the patients solely developed pathological gambling under dopaminergic medication suggests an underlying genetic vulnerability mechanism ( voon et  al . ,
2006 ) . to analyse the genetic susceptibility of parkinson 's patients with pathological gambling , several genes have been examined that are relevant for the function of the mesolimbic reward system . the most obvious genes to investigate are the dopamine receptor genes , which could be affected by dopaminergic medications .
some studies suggest that a certain mutation of the drd2 gene ( taq1a ) is more frequent in pathological gamblers than in the general population ( lobo et  al . , 2010 ) .
this variation in the gene may be connected to a lower density of d2receptors in the striatum ( thompson et  al . , 1997 ) and to impulsivity ( eisenberg et  al . , 2007 ) , while the literature is inconclusive regarding its potential role in alcohol addiction ( heinz et  al . , 1996 ; heinz & goldman , 2000 ; munaf et  al . , 2007
however , no significant difference was found between the frequency of this mutation between parkinson 's patients with and without pathological gambling ( lee et  al . , 2009 ) .
interestingly , recent case reports suggest that not only dopamine agonists but also dopamine antagonists acting on the d2 receptors can trigger pathological gambling ( grtsch et  al . , 2015 ) , which underlines the role of this receptor . on the other hand ,
the homozygote genotype of a single nucleotide mutation ( p.s9 g ) of the drd3 gene has been shown to have a higher frequency in pathological gamblers with parkinson 's disease ( lee et  al . , 2009 ) .
this mutation is not associated with increased risk for pathological gambling in the general population ( lobo et  al . , 2010 ) .
however , the heterozygote genotype of this mutation has been reported to be linked to impulsivity ( retz et  al . , 2003 ; limosin et  al . ,
this mutation was also associated with decreased response rate to pramipexole in parkinson 's patients ( liu et  al . , 2009 ) , which could result in higher prescribed dosage .
according to our current knowledge , there has not been any study performed yet to assess the relationship between drd4 mutations and pathological gambling in parkinson 's patients .
however , the number of tandem repeats of a 48bp region in the drd4 gene is associated with pathological gambling , substance abuse and impulsivity , with discordant results of what number of repeats is relevant ( de castro et  al . , 1997 ; comings et  al . , 1999
healthy subjects with this genotype also presented an increased gambling behaviour after receiving ldopa ( eisenegger et  al . , 2010 ) .
another neurotransmitter system that has been shown to be affected in patients with pathological gambling is the serotoninergic system .
( 1999 ) have observed a significantly higher frequency of the short ( s ) allele of the promoter region of the serotonin transporter gene , 5httlpr , in male pathological gamblers compared to the general population .
the s allele of 5httlpr has also been associated with increased risk of developing depression under stress ( karg et  al . , 2011 ) , some aspects of impulsivity ( sakado et  al . ,
2003 ) , impulsive aggression and increased activity in the amygdala after negative affective visual stimuli ( heinz et  al . , 2011 ) .
an association between this mutation and pathological gambling has indeed been observed in patients with parkinson 's disease ( lee et  al . , 2009 ) .
another mutation that may be associated with pathological gambling in parkinson 's patients is the mutation of grin2b ( lee et  al . , 2009 ) .
grin2b is a gene from the 2b subunit of the nmda receptor , which is mainly expressed in the hippocampus , the striatum and also the cortex ( loftis & janowsky , 2003 ) .
the variation found to be more frequent in parkinson 's patients with pathological gambling is a single nucleotide polymorphism .
its specific role in the development of pathological gambling in parkinson 's disease is unclear , as this variation does not cause an amino acid change ( c.366c > g ) .
furthermore , it was also found to be associated with schizophrenia ( li & he , 2007 ) , as a different polymorphism of grin2b has been associated with obsessive compulsive disorder ( arnold et  al . , 2004 ) .
( 2011 ) found a different single nucleotide polymorphism of the grin2b gene to be related with risky decisionmaking , which might be considered as impulsive behaviour and therefore explain a link to pg in parkinson 's disease .
these research findings suggest that an underlying genetic susceptibility might facilitate the development of pathological gambling in parkinson 's patients .
however , some studies are inconsistent and there are some differences between pathological gamblers with and without parkinson 's disease .
altogether , these results and the observed connection to dopaminergic medication described above suggest that the vulnerability of parkinson patients towards pathological gambling may be triggered by dopamine agonists .
several studies have compared neuronal activation patterns of parkinson 's patients with and without pathological gambling . summarizing the results ,
differences have been found in the activity of regions associated with the mesolimbic reward system , mainly in the orbitofrontal cortex ( ofc ) and the ventral striatum ( cilia et  al . , 2008 ;
( 2008 ) compared the blood perfusion of different brain regions in parkinson 's patients with pathological gambling with patients who only have parkinson 's disease and a control group in a spect imaging study in a resting condition .
they have observed a generally increased blood flow in the ofc , hippocampus , parahippocampal gyrus , amygdala , ventral striatum and cuneus on the right hemisphere and in the insulae on both sides in parkinson 's patients with pathological gambling compared to both other groups .
( 2013 ) studied the function of the subthalamic nucleus by capturing local field potentials ( lfp ) in parkinson 's patients with and without pathological gambling on medication during an economic task .
the lfps were recorded with the aid of stn dbs electrodes that were implanted 4  days prior to the experiment .
the economic task included nonconflict and conflict decisions with stimuli pairs with the same probability vs. stimuli pairs with different probabilities of winning money . in conflict situations , risky choices could result in a higher reward , however , the task was overall designed to reward more nonrisky choices .
the results showed that during the economic decisionmaking task , lowfrequency oscillations synchronize in the subthalamic nucleus .
this synchronization was stronger during highconflict situations in comparison to lowconflict situations in patients with pathological gambling .
patients without pathological gambling showed no differences in the synchronization of lowfrequency oscillations during conflict or nonconflict situations .
the results of this experiment underline the role of the subthalamic nucleus in decisionmaking and might also explain why symptoms of pathological gambling resolve in some parkinson patients after stn dbs surgery .
however , the results do not explain why patients usually only improve after months of stn dbs therapy .
some studies focused more on the dopaminergic system and several differences were found between pathological gamblers with parkinson 's disease and parkinson 's patients without gambling .
the turnover of monoamines , including dopamine , in the ofc was found to be higher ( joutsa et  al . , 2012 ) ,
further the dopamine release during gambling tasks was found to be significantly increased in pathological gamblers ( steeves et  al . , 2009 ) .
these results suggest that the vulnerability to gambling problems is partly mediated by increased dopaminergic neurotransmisson the ofc and the ventral striatum .
pathological gambling in these patients may be caused by dopamine agonists in the mesolimbic dopaminergic system , particularly in the ventral striatum , which is less affected by the disease than the dorsal striatum . as dopamine agonist therapy seems to have a very strong association with the development of pathological gambling ( voon et  al .
2010 ) , imaging studies have been conducted to further understand the effect of this medication .
dopamine agonists have been shown to effect reward processing ; patients on this medication have a diminished reaction in the ofc after negative prediction errors compared to patients on levodopa therapy or off medication ( van eimeren et  al . , 2009 ) , suggesting a decreased learning effect after punishment .
parkinson 's patients with and without pathological gambling or compulsive shopping were compared in a prediction learning task on or off dopamine agonists .
patients with pathological gambling were faster and better at learning and had a higher activity in the ventral striatum and the ofc during rewardrelated learning while on medication . on the contrary , while learning through loss , the activity of these areas was lower in this group of patients than in the group with parkinson 's disease only under the same circumstances .
( 2012 ) suggest that these patients have an impaired activation of d2 and d3autoreceptors caused by tonic stimulation through dopamine agonists . through the absence of negative feedback ,
these findings could be used to propose that dopamine agonists cause a higher vulnerability to pathological gambling due to impaired learning processes . as a consequence of the impaired negative feedback
, the dopamine concentration would not decrease to the previous level after a rewardrelated dopamine release .
the high level of dopamine could also blunt the drop of dopamine concentration after punishment .
imaging studies with nonparkinson patients with pathological gambling also showed differences in the activation of the mesolimbic rewards system , however , the results are not consistent .
some studies showed a reduced activation of the prefrontal cortex and ventral striatum during loss and gain anticipation as well ( balodis et  al .
2012 ) , others showed higher activity in the striatum during gain anticipation ( romanczukseiferth et  al . , 2015 ) .
the activity of the prefrontal cortex and the ventral striatum also seems to be diminished after successful loss avoidance compared to healthy control subjects ( romanczukseiferth et  al .
neuronal activity during loss and gain anticipation and loss avoidance have not been researched yet in parkinson 's patients with pathological gambling .
as described above , impulsive behaviour is considered to be a general risk factor for developing pathological gambling in patients with parkinson 's disease ( voon et  al .
, 2007 ; johansson et  al . , 2009 ) . however , there are studies that indicate a more specific connection : frank et  al .
( 2007 ) compared two groups of patients with parkinson 's disease with a control group , assessing their learning ability in a probabilistic prediction task and their performance in a conflictbased decision task .
one of the groups of parkinson 's patients was treated with dopaminergic medication , the other group with stn dbs and lowdose dopaminergic therapy .
the first group 's performance was compared on and off medication , the second group 's performance on and off stn dbs without changing the dosage of their medication .
the results in the prediction task in the group taking dopaminergic medication only were similar to the findings of voon et  al .
( 2010 ) described above , that is , the learning ability of patients from negative outcome was impaired on medication .
the activation of deep brain stimulation showed no effect on the learning ability of the patients , neither after reward nor after punishment . on the other hand , in the conflictbased decision task , patients with activated stn dbs responded faster in high rather than in lowconflict conditions , while off deep brain stimulation , their response was slower during highconflict situations .
dopaminergic medication did not affect the difference in decisionmaking speed in high vs. lowconflict conditions .
this result is supported by other experiments assessing patients with stn dbs clinically with the barratt impulsiveness scale ( hlbig et  al . , 2009 ) and the simon task ( wylie et  al . , 2010 ) . if high impulsivity can promote pathological gambling , as suggested by the results of frank et  al .
( 2007 ) , there should be a higher risk for parkinson 's patients treated with stn dbs .
however , there are only individual cases of patients developing pathological gambling after initiation of deep brain stimulation ( smeding et  al . , 2007 ) , with no clear way of interpretation , because dopaminergic medication had also been changed postoperatively .
( 2009 ) found a higher frequency of impulse control disorders ( icds ) in parkinson 's patients treated with stn dbs .
however , the difference in prevalence of icds to the patient group only receiving drug therapy was not significant and it was not described when these patients developed icds and how long they had already received dbs therapy .
this information is relevant , as the recovery from icds after the initiation of dbs therapy can take up to 4  years and in some cases the symptoms initially worsen after the therapy ( ardouin et  al . , 2006 ) .
the effects on impulsive and compulsive behaviour of stn dbs can also depend on the localization of the electrodes .
the stimulation of the limbic subregion of the stn or the stimulation of adjacent structures can change the neurotransmission in limbic brain regions ( winter et  al . , 2008 ) .
these findings question the causal relationship between high impulsivity and pathological gambling in parkinson 's patients .
altogether , more research is needed for clarification of the effects of stn dbs . on the other hand , the results of those studies comparing the effect of stn dbs and dopamine agonist medication support the theory that parkinson 's patients with pathological gambling show impaired learning mechanisms modulated by dopamine agonists .
therefore , alterations of reward and punishment processing seem to play a prominent role in the development of pathological gambling in parkinson 's patients .
several genetic and neurofunctional findings suggest that individual differences in dopaminergic neurotransmission in the ventral striatum and associated brain areas contribute to pathological gambling in parkinson 's disease , and indicate complex interactions between such risk factors . taken together ,
altered learning processes in parkinson 's patients with pathological gambling appear to include increased baseline blood perfusion of mesolimbic brain areas , increased activation by reward and reduced activation by punishment in those brain areas , which are implicated in reinforcement learning ( schultz , 2002 ) , impulsivity ( horn et  al . , 2003 ) , addiction ( kalivas & volkow , 2005 ) and pathological gambling ( romanczukseiferth et  al . , 2015 )
. however , most of the studies performed in parkinson 's patients with pathological gambling are retrospective or crosssectional research , which makes the analysis of potentially causal factors more difficult .
for example , in crosssectional studies , impulsivity seems to be an important risk factor ( voon et  al . , 2007 ) ; however , these findings are not fully consistent with the results of experimental studies on the effects of dbs of the stn . prospective or longitudinal studies could broaden the perspective on the role of potential risk factors , that is , impulsivity or impaired learning . despite the obstacles in conducting such studies , the results of this research can play a crucial role in understanding the development of pathological gambling and icds not only in parkinson 's patients but also in the general population .
 abstractthe incidence of pathological gambling in parkinson 's patients is significantly greater than in the general population . 
 a correlation has been observed between dopamine agonist medication and the development of pathological gambling . 
 however , scientists conjecture that the affected patients have underlying risk factors . studies analysing parkinson 's patients have detected that patients who developed pathological gambling are younger , score higher on noveltyseeking tests , are more impulsive and are more likely to have a personal or family history of alcohol addiction . 
 in addition , some genetic variations have been associated with the susceptibility of developing pathological gambling , which include mutations of drd3 , 5httlpr and grin2b . 
 studies focusing on neurofunctional discrepancies between parkinson 's patients with and without pathological gambling have found increased functional activation and dopamine release in regions associated with the mesolimbic reward system . 
 furthermore , there is also evidence showing increased processing of reward and decreased activation elicited by punishment , suggesting altered learning processes . 
 furthermore , the role of deep brain stimulation of the nucleus subthalamicus ( stn dbs ) is controversial . in most parkinson 's patients , 
 pathological gambling resolved after the initiation of the stn dbs , which might be explained by discontinuation or decrease in dopamine agonist medication . 
 however , it has been also shown that some patients are more impulsive while the stn dbs is activated . 
 these differences may depend on the dbs localization in the more limbic or motor part of the stn and their regulative effects on impulsivity . 
 further research is needed to clarify susceptibility factors for the development of pathological gambling in parkinson 's patients . 
Introduction
Risk factors
Association with Parkinson's disease therapy
Genetic predisposition
Neurofunctional alterations
The role of impulsivity
Conclusions
Conflict of interests