Mateusz Zurowski

Increased striatal dopamine release in Parkinsonian patients with pathological gambling: a [11C] raclopride PET study

Pathological gambling is an impulse control disorder reported in association with dopamine agonists used to treat Parkinsons disease. Although impulse control disorders are conceptualized as lying within the spectrum of addictions, little neurobiological evidence exists to support this belief. Functional imaging studies have consistently demonstrated abnormalities of dopaminergic function in patients with drug addictions, but to date no study has specifically evaluated dopaminergic function in Parkinsons disease patients with impulse control disorders. We describe results of a [(11)C] raclopride positron emission tomography (PET) study comparing dopaminergic function during gambling in Parkinsons disease patients, with and without pathological gambling, following dopamine agonists. Patients with pathological gambling demonstrated greater decreases in binding potential in the ventral striatum during gambling (13.9%) than control patients (8.1%), likely reflecting greater dopaminergic release. Ventral striatal bindings at baseline during control task were also lower in patients with pathological gambling. Although prior imaging studies suggest that abnormality in dopaminergic binding and dopamine release may be markers of vulnerability to addiction, this study presents the first evidence of these phenomena in pathological gambling. The emergence of pathological gambling in a number of Parkinsons disease patients may provide a model into the pathophysiology of this disorder.

Prevalence of repetitive and reward-seeking behaviors in Parkinson disease

We surveyed 297 patients with Parkinson disease (PD) with systematic screens and rigorous definitional criteria. Pathologic hypersexuality lifetime prevalence was 2.4%. Compulsive shopping was 0.7%. Combined with our pathologic gambling data, the lifetime prevalence of these behaviors was 6.1% and increases to 13.7% in patients on dopamine agonists.

Prospective prevalence of pathologic gambling and medication association in Parkinson disease

The authors prospectively screened 297 patients with Parkinson disease (PD), who attended a tertiary clinic, using a modified South Oaks Gambling Scale. Lifetime prevalence of pathologic gambling (PG) was 3.4% and on any dopamine agonist was 7.2%. PG was associated with earlier PD onset and with dopamine agonists but not with agonist subtype or doses. We found no association with a potent D3 receptor agonist.

Serotonin 2A Receptors and Visual Hallucinations in Parkinson Disease

BACKGROUND Complex visual hallucinations (VHs) occur in several pathologic conditions; however, the neural mechanisms underlying these symptoms remain unclear. Although dopamine may have a role, indirect evidence indicates that serotonin may also contribute to the pathogenesis of complex VHs, probably via involvement of the serotonin 2 receptor. OBJECTIVE To examine for the first time in vivo changes in serotonin 2A receptor neurotransmission among patients having Parkinson disease (PD) with VHs. DESIGN Case-control study. SETTING Academic research. PATIENTS Seven patients having PD with VHs and 7 age-matched patients having PD without VHs were recruited. MAIN OUTCOME MEASURES We used the selective serotonin 2A receptor ligand setoperone F 18 during positron emission tomography among nondemented patients having PD with VHs. RESULTS Patients having PD with VHs demonstrate increased serotonin 2A receptor binding in the ventral visual pathway (including the bilateral inferooccipital gyrus, right fusiform gyrus, and inferotemporal cortex) as well as the bilateral dorsolateral prefrontal cortex, medial orbitofrontal cortex, and insula. CONCLUSIONS This pilot study provides the first in vivo evidence suggesting a role for serotonin 2A receptors in mediating VHs via the ventral visual pathway in PD. Treatment studies should be performed using selective serotonin 2A receptor antagonists, which have important implications for the clinical management of VHs and psychosis in PD.

Drug-induced deactivation of inhibitory networks predicts pathological gambling in PD

Objective: Some patients with Parkinson disease (PD) develop pathological gambling when treated with dopamine agonists (DAs). However, little is known about DA-induced changes in neuronal networks that may underpin this drug-induced change in behavior in vulnerable individuals. In this case-control study, we aimed to investigate DA-induced changes in brain activity that may differentiate patients with PD with DA-induced pathological gambling (gamblers) from patients with PD without such a history (controls). Methods: Following overnight withdrawal of antiparkinsonian medication, patients were studied with H215O PET before and after administration of DA (3 mg apomorphine) to measure changes in regional cerebral blood flow as an index of regional brain activity during a card selection game with probabilistic feedback. Results: We observed that the direction of DA-related activity change in brain areas that are implicated in impulse control and response inhibition (lateral orbitofrontal cortex, rostral cingulate zone, amygdala, external pallidum) distinguished gamblers from controls. DA significantly increased activity in these areas in controls, while gamblers showed a significant DA-induced reduction of activity. Conclusions: We propose that in vulnerable patients with PD, DAs produce an abnormal neuronal pattern that resembles those found in nonparkinsonian pathological gambling and drug addiction. DA-induced disruption of inhibitory key functions—outcome monitoring (rostral cingulate zone), acquisition and retention of negative action-outcome associations (amygdala and lateral orbitofrontal cortex)—together with restricted access of those areas to executive control (external pallidum)—may well explain loss of impulse control and response inhibition in vulnerable patients with PD, thereby fostering the development of pathological gambling.

Extrastriatal dopaminergic abnormalities of DA homeostasis in Parkinson’s patients with medication-induced pathological gambling: A [11C] FLB-457 and PET study

Impulse control disorders such as pathological gambling (PG) are a serious and common adverse effect of dopamine (DA) replacement medication in Parkinsons disease (PD). Patients with PG have increased impulsivity and abnormalities in striatal DA, in common with behavioural and substance addictions in the non-PD population. To date, no studies have investigated the role of extrastriatal dopaminergic abnormalities in PD patients with PG. We used the PET radiotracer, [11C] FLB-457, with high-affinity for extrastriatal DA D2/3 receptors. 14 PD patients on DA agonists were imaged while they performed a gambling task involving real monetary reward and a control task. Trait impulsivity was measured with the Barratt Impulsivity Scale (BIS). Seven of the patients had a history of PG that developed subsequent to DA agonist medication. Change in [11C] FLB-457 binding potential (BP) during gambling was reduced in PD with PG patients in the midbrain, where D2/D3 receptors are dominated by autoreceptors. The degree of change in [11C] FLB-457 binding in this region correlated with impulsivity. In the cortex, [11C] FLB-457 BP was significantly greater in the anterior cingulate cortex (ACC) in PD patients with PG during the control task, and binding in this region was also correlated with impulsivity. Our findings provide the first evidence that PD patients with PG have dysfunctional activation of DA autoreceptors in the midbrain and low DA tone in the ACC. Thus, altered striatal and cortical DA homeostasis may incur vulnerability for the development of PG in PD, linked with the impulsive personality trait.

Deep Brain Stimulation and the Search for Identity

Ethical evaluation of deep brain stimulation as a treatment for Parkinson’s disease is complicated by results that can be described as involving changes in the patient’s identity. The risk of becoming another person following surgery is alarming for patients, caregivers and clinicians alike. It is one of the most urgent conceptual and ethical problems facing deep brain stimulation in Parkinson’s disease at this time. In our paper we take issue with this problem on two accounts. First, we elucidate what is meant by “becoming another person” from a conceptual point of view. After critically discussing two broad approaches we concentrate on the notion of “individual identity” which centers on the idea of “core attitudes”. Subsequently we discuss several approaches to determine what distinguishes core attitudes from those that are more peripheral. We argue for a “foundational-function model” highlighting the importance of specific dependency relations between these attitudes. Our second aim is to comment on the possibility to empirically measure changes in individual identity and argue that many of the instruments now commonly used in selecting and monitoring DBS-patients are inappropriate for this purpose. Future research in this area is advised combining a conceptual and an empirical approach as a basis of sound ethical appraisal.

Sympathetic denervation impairs epidermal healing in cutaneous wounds

The involvement of peripheral nerves in dermal wound healing, particularly in the inflammatory response has not been extensively studied. Therefore, this study was performed to examine the role of peripheral nerves in the healing of rat skin linear incisions. We report that chemical sympathectomy with 6‐hydroxydopamine significantly impaired wound healing as measured on days 7, 11, and 14 postsurgery (by day 14, 48% of the sympathectomized rats were healed in contrast with 84% of the controls; p = 0.0104). In contrast, neonatal capsaicin treatment, which predominantly destroys sensory afferents, had no effect on wound healing (p > 0.05 on all days). These results support the hypothesis that sympathetic efferents are important for wound healing. Unlike previous research, which showed that peripheral nerves influence ischemic skin flaps, we are the first to demonstrate a role for peripheral nerves in the healing of skin incisions. Because inflammation is an important step in cutaneous wound healing, we propose that a reduction of neurogenic inflammation caused by sympathectomy may explain the impaired wound healing that we observed in our study.

Patients’ expectations of deep brain stimulation, and subjective perceived outcome related to clinical measures in Parkinson's disease: a mixed-method approach

Objective To study patients’ expectations of subthalamic deep brain stimulation (STN-DBS) and their subjective perceived outcome, by using qualitative and quantitative methods in Parkinsons disease (PD). Methods PD patients were prospectively examined before and 3 months after surgery. Semistructured interviews regarding preoperative expectations and postsurgical subjective perceived outcome were conducted. These were analysed using content analysis. For statistical analyses, patients were classified according to their subjective perceived outcome, resulting in three different subjective outcome groups (negative, mixed, positive outcome). The groups were used for multiple comparisons between and within each group regarding motor impairment, quality of life (QoL), neuropsychiatric status and cognitive functioning, using standard instruments. A logistic regression analysis was conducted to find predictors of subjective negative outcome. Receiver operating characteristic curves were used to analyse cut-off scores for predictive tests. Results Of the 30 PD patients participating, 8 had a subjective negative outcome, 8 a mixed and 14 a positive outcome. All groups significantly improved in motor functioning. Patients with subjective negative outcome were characterised by preoperative unrealistic expectations, no postsurgical improvement in QoL, and significantly higher presurgical and postsurgical apathy and depression scores. Higher preoperative apathy and depression scores were significant predictors of negative subjective outcome. Cut-off scores for apathy and depression were identified. Conclusions The mixed-method approach proved useful in examining a patients subjective perception of STN-DBS outcome. Our results show that significant motor improvement does not necessarily lead to a positive subjective outcome. Moreover, PD patients should be screened carefully before surgery regarding apathy and depression. (DRKS-ID: DRKS00003221).

Pain characteristics and demographics of patients attending a university-affiliated pain clinic in Toronto, Ontario

BACKGROUND Pain clinics tend to see more complex chronic pain patients than primary care settings, but the types of patients seen may differ among practices. OBJECTIVE The aim of the present observational study was to describe the pain and demographic characteristics of patients attending a university-affiliated tertiary care pain clinic in Toronto, Ontario. METHODS Data were collected on 1242 consecutive new patients seen over a three-year period at the Comprehensive Pain Program in central Toronto. RESULTS Musculoskeletal problems affecting large joints and the spine were the predominant cause of pain (more prevalent in women), followed by neuropathic disorders (more prevalent in men) in patients with recognizable physical pathology. The most affected age group was in the 35- to 49-year age range, with a mean pain duration of 7.8 years before the consultation. While 77% of the Comprehensive Pain Program patients had relevant and detectable physical pathology for pain complaints, three-quarters of the overall study population also had significant associated psychological or psychiatric comorbidity. Women, in general, attended the pain clinic in greater numbers and had less apparent physical pathology than men. Finally, less than one in five patients was employed at the time of referral. CONCLUSIONS The relevance of the data in relation to other pain clinics is discussed, as well as waiting lists and other barriers faced by chronic pain patients, pain practitioners and pain facilities in Ontario and Canada.