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.

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