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July 2, 2010 (Buenos Aires, Argentina) — A new imaging study using perfusion single-photon emission computed tomography (SPECT) has turned up a disconnect between brain regions involved in risk estimation and inhibition of inappropriate reward-seeking behavior that appears to differentiate Parkinson's disease (PD) patients with pathological gambling behavior from both those without this problem and healthy control subjects. The work, led by Roberto Cilia, MD, was a collaboration between the Parkinson Institute and the IRCCS-Ospedale Maggiore in Milan, Italy, and colleagues from the Toronto Western Research Institute and Hospital, University of Toronto, Ontario, Canada. Their connectivity analyses showed a disconnect between the anterior cingulate cortex (ACC) and the striatum that they speculate may underlie the inability of PD patients with pathological gambling behavior to process negative outcomes and disengage from reward-seeking behaviors. "When a normal subject performs a task, such as a gambling task, and he accumulates more and more errors, the negative feedback increases activity in the ACC," Dr. Cilia told Medscape Medical News. "After many errors, the activity of the ACC reaches a threshold and engages the striatum to induce a shift in behavior, a change in strategy," he explains. "This shifting strategy is selectively impaired in patients with Parkinson's disease and pathological gambling," he added, but was found to be robust in PD patients without pathological gambling behaviors or in healthy subjects. They presented their findings recently at the Movement Disorder Society (MDS) 14th International Conference of Parkinson's Disease and Movement Disorders. Dr. Cilia won a junior award for excellence in clinical research and presented these findings during a plenary session at the meeting. The truly new aspect of this work is more the method than the result, Dr. Cilia adds. They used 3 connectivity analyses — correlation analysis, functional connectivity analysis, and then finally effective connectivity analysis. With this latter analysis, they were able to establish the interaction of these brain regions, he said, as well as the direction of the information flow between regions and the significance of the connections. In addition, theirs is unusual in that it conducted this kind of analysis using perfusion SPECT. "Usually, connectivity is performed using functional [magnetic resonance imaging]," Dr. Cilia explained. "This is the first study using just SPECT, which is widely available, so that different hospitals and centers can use this approach for research." Complications of Treatment Impulse control disorders (ICDs), such as pathological gambling or shopping, or hypersexuality are known to be induced by dopaminergic medications in some vulnerable patients with PD. Risk factors underlying this vulnerability are still under study, Dr. Cilia noted, but previous imaging studies have suggested abnormal dopamine transmission in the mesolimbic reward system. In this study, they performed perfusion SPECT in 30 patients with PD, 15 with pathological gambling on the South Oaks Gambling Scale (SOGS), and 15 controls matched on demographics and clinical features, such as age, disease duration and severity, and daily dosage of PD medications (levodopa and dopamine agonists). None of the patients had dementia or cognitive impairment. Perfusion SPECT was performed in the subjects at rest. In the PD patients with pathological gambling, they used covariance analysis in statistical parametric mapping (SPM5) to identify brain regions where perfusion correlated with gambling severity. These regions in turn were used as "seed-volumes-of- interest" to identify interconnected regions in a functional connectivity analysis. Next, they created a path model using effective connectivity analysis. They found that increasing gambling severity in the PD patients with pathological gambling correlated negatively with the right ventrolateral prefrontal cortex, anterior and posterior cingulate cortices, medial prefrontal cortex, insula, parahippocampal gyrus, and left striatum. Positive correlations were also found in the fusiform gyrus and cerebellum, the study authors note. "The main finding of the connectivity analyses was the disconnection between striatum and ACC in PD gamblers, an interaction that was very robust in both control groups," they write. Reduced DAT Density In a separate analysis, Dr. Cilia and colleagues report reduced presynaptic dopamine transporter (DAT) density in PD patients with pathological gambling and other ICDs. Previous imaging studies have suggested increased dopamine transmission from the ventral striatum in these patients. Striatal DAT regulates synaptic dopamine through active reuptake into the presynaptic neuron, they note. In this study, 8 patients with pathological gambling, 5 with compulsive sexual behavior, 3 with binge eating, and 2 with compulsive shopping, as well as 21 matched PD controls and 14 healthy subjects, underwent DAT SPECT using FP-CIT (fluoropropyl-carbomethoxy-Iodophenyl-tropane) tracer. SPM5 was then applied for voxelwise analysis. Analysis of variance showed the 3 groups displayed differences in the bilateral dorsal and ventral striatum, the researchers report. In a post hoc analysis, they found reduced FP-CIT binding in the ventral striatum of the PD patients with pathological gambling compared with control subjects with PD. PD patients, with or without pathological gambling, showed bilateral tracer reduction in the dorsal putamen compared with the healthy subjects. In addition, there was no correlation between DAT binding and severity of gambling on the SOGS. "Reduced DAT density in the ventral 'limbic' striatum may explain the increased synaptic dopamine availability previously shown in PD patients with pathological gambling," Dr. Cilia and colleagues conclude. "Low DAT expression has been previously associated with high impulsivity and addictive disorders in mice and non-PD individuals, and we believe that our finding might reflect either functional down-regulation or allelic polymorphisms." "There is no obvious relationship between the reduced DAT binding in the ventral striatum and the functional disconnection between ACC and striatum," Dr. Cilia noted. "We are currently working on this." Highly Refined Technology Asked for comment on these findings, Christopher G. Goetz, MD, from Rush University, Chicago, Illinois, and chair of the MDS Congress Scientific Program Committee, pointed out that in the past few years ICDs have become a well- recognized problem in patients with chronic PD. "It has not, however, been clear what area of the brain is activated or altered in relationship to the emergence of this problem," Dr. Goetz told Medscape Medical News. "This study uses highly refined technology to identify functional alterations that characterize patients with impulse control disorder," he said. "Knowledge of the anatomy and neurochemical changes seen in association with this clinical problem will allow for chemical engineers to initiate treatments that can target involved areas. "Impulse control disorders account for clinically pertinent problems faced by patients and caregivers, he concludes, and at this point, the primary treatment for ICDs is to withdraw medications that otherwise are beneficial for the motor control of Parkinson's disease." In a statement from the MDS featuring the DAT finding, Andrew Evans, MD, of the Royal Melbourne Hospital in Australia, said, "Cilia et al report that PD patients have reduced striatal DAT binding but only those impulse control behaviors (ICBs) show reduced ventral striatal DAT binding although it is not clear whether the results remain significant when corrected for dopaminergic drug exposure. "The role of DAT in determining the amount of dopamine available for receptor stimulation after its release from the presynaptic terminal may therefore underlie the heightened release of endogenous dopamine reported in PD patients with ICBs in response to gambling reward," Dr. Evans notes. "Less effective clearance of synaptic dopamine may further render these individuals more sensitive to drug-induced dopamine surges and lead to a range of other reward based behaviors." To these latter comments, Dr. Cilia responded that the 2 groups of patients with PD with and without ICBs were taking similar daily doses of levodopa and dopamine agonists "and therefore there was no need to correct this data for drug exposure." Dr. Cilia reports that he performed this study in Toronto during a Research Fellowship that was partially funded by the Grigioni Foundation for Parkinson’s Disease in Milan, Italy. Movement Disorder Society (MDS) 14th International Congress of Parkinson's Disease and Movement Disorders: Abstract 581. Presented June 16, 2010. ---------------------------------------------------------------------- To sign-off Parkinsn send a message to: mailto:[log in to unmask] In the body of the message put: signoff parkinsn