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1.  Serotonin Transporter Occupancy and the Functional Neuroanatomic Effects of Citalopram in Geriatric Depression 
The functional neuroanatomic changes associated with selective serotonin reuptake inhibitor (SSRI) treatment have been the focus of positron emission tomography (PET) studies of cerebral glucose metabolism in geriatric depression.
To evaluate the underlying neurochemical mechanisms, the present study measured both cerebral glucose metabolism and serotonin transporter (SERT) availability prior to and during treatment with the SSRI, citalopram. It was hypothesized that SERT occupancy would be observed in cortical and limbic brain regions that have shown metabolic effects, as well as striatal and thalamic regions that have been implicated in prior studies in mid-life patients.
Psychiatric Outpatient Clinic.
Seven depressed patients who met DSM-IV criteria for current major depressive episode were enrolled.
Patients underwent a twelve week open-label trial of the SSRI, citalopram.
Patients underwent high resolution research tomography (HRRT) PET scans to measure changes in cerebral glucose metabolism and SERT occupancy by citalopram treatment (after 8–10 weeks of treatment).
Three different tracer kinetic models were applied to the [11C]-DASB region of interest data and yielded similar results of an average of greater than 70% SERT occupancy in the striatum and thalamus during citalopram treatment. Voxel-wise analyses showed significant SERT occupancy in these regions, as well as cortical (e.g. anterior cingulate, superior and middle frontal, precuneus, and limbic (parahippocampal gyrus) areas that also showed reductions in glucose metabolism.
The findings suggest that cortical and limbic SERT occupancy may be an underlying mechanism for the regional cerebral metabolic effects of citalopram in geriatric depression.
PMCID: PMC3968900  PMID: 21841458
selective serotonin reuptake inhibitors; citalopram; serotonin; Positron Emission Tomography (PET); glucose metabolism; serotonin transporter; depression; aging
2.  The Functional Anatomy of Impulse Control Disorders 
Impulsive–compulsive disorders such as pathological gambling, hypersexuality, compulsive eating, and shopping are side effects of the dopaminergic therapy for Parkinson’s disease. With a lower prevalence, these disorders also appear in the general population. Research in the last few years has discovered that these pathological behaviors share features similar to those of substance use disorders (SUD), which has led to the term “behavioral addictions”. As in SUDs, the behaviors are marked by a compulsive drive toward and impaired control over the behavior. Furthermore, animal and medication studies, research in the Parkinson’s disease population, and neuroimaging findings indicate a common neurobiology of addictive behaviors. Changes associated with addictions are mainly seen in the dopaminergic system of a mesocorticolimbic circuit, the so-called reward system. Here we outline neurobiological findings regarding behavioral addictions with a focus on dopaminergic systems, relate them to SUD theories, and try to build a tentative concept integrating genetics, neuroimaging, and behavioral results.
PMCID: PMC3779310  PMID: 23963609
Behavioral addictions; Pathological gambling; Binge eating; Compulsive buying; Hypersexuality; Substance use disorders; Mesocorticolimbic circuit; Reward system; Dopamine; Parkinson; Parkinson’s disease; Neurobiology; Risk factors; Impulse control disorders; Functional anatomy
3.  Continuous theta burst stimulation of right dorsolateral prefrontal cortex induces changes in impulsivity level 
Brain stimulation  2009;3(3):170-176.
There is evidence that the right dorsolateral prefrontal cortex (DLPFC) may play a certain role in decision making related to reward value and time perception and, in particular, in the inhibitory control of impulsive decision making. Using the theta burst stimulation (TBS) and a delay discounting (DD) task, we investigated the potential role of right DLPFC in impulsive decision making defined by the rate of discounting delayed reward. Healthy right-handed volunteers underwent three stimulation sessions, intermittent TBS (iTBS), continuous TBS (cTBS), and sham. The steepness of the discount function (k-value), reaction time for choice and consistency were measured for each subjects. cTBS of the DLPFC reduced by 36.88 % the k-value of the DD task compared to sham condition. In contrast, iTBS did not affect impulsivity level. There were no changes neither in reaction time for choice nor consistency after either the iTBS or cTBS compared with the sham stimulation. These results demonstrate that cTBS-induced modulation of cortical excitability of the right DLPFC may affect and reduce impulsive decision making. These observations may provide some insights into the role of the right DLPFC in modulating impulsivity level and calculating reward value at different time scales under less ambiguous circumstances.
PMCID: PMC3707839  PMID: 20633446 CAMSID: cams3169
rTMS; theta burst stimulation; dorsolateral prefrontal cortex; decision making; impulsivity; delay discounting task
4.  Prefrontal D2-Receptor Stimulation Mediates Flexible Adaptation of Economic Preference Hierarchies 
Human brain mapping  2011;34(1):226-232.
Advantageous economic decision making requires flexible adaptation of gain-based and loss-based preference hierarchies. However, where the neuronal blueprints for economic preference hierarchies are kept and how they may be adapted remains largely unclear. Phasic cortical dopamine release likely mediates flexible adaptation of neuronal representations. In this PET study, cortical-binding potential (BP) for the D2-dopamine receptor ligand [11C]FLB 457 was examined in healthy participants during multiple sessions of a probabilistic four-choice financial decision-making task with two behavioral variants. In the changing-gains/constant-losses variant, the implicit gain-based preference hierarchy was unceasingly changing, whereas the implicit loss-based preference hierarchy was constant. In the constant-gains/changing-losses variant, it was the other way around. These variants served as paradigms, respectively, contrasting flexible adaptation versus maintenance of loss-based and gain-based preference hierarchies. We observed that in comparison with the constant-gains/changing-losses variant, the changing-gains/constant-losses variant was associated with a decreased D2-dopamine receptor-BP in the right lateral frontopolar cortex. In other words, lateral frontopolar D2-dopamine receptor stimulation was specifically increased during continuous adaptation of mental representations of gain-based preference hierarchies. This finding provides direct evidence for the existence of a neuronal blueprint of gain-based decision-making in the lateral frontopolar cortex and a crucial role of local dopamine in the flexible adaptation of mental concepts of future behavior.
PMCID: PMC3521779  PMID: 22020993 CAMSID: cams2371
dopamine; feedback-learning; frontopolar; FLB; imaging; gambling
5.  Increased striatal dopamine release in Parkinsonian patients with pathological gambling: a [11C] raclopride PET study 
Brain : a journal of neurology  2009;132(Pt 5):1376-1385.
Pathological gambling is an impulse control disorder reported in association with dopamine agonists used to treat Parkinson’s 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 Parkinson’s disease patients with impulse control disorders. We describe results of a [11C] raclopride positron emission tomography (PET) study comparing dopaminergic function during gambling in Parkinson’s 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 Parkinson’s disease patients may provide a model into the pathophysiology of this disorder.
PMCID: PMC3479148  PMID: 19346328 CAMSID: cams2369
Parkinson’s disease; dopamine; impulse control disorders; pathological gambling; PET; functional imaging
6.  Heterozygous carriers of a Parkin or PINK1 mutation share a common functional endophenotype 
Neurology  2009;72(12):1041-1047.
To use a combined neurogenetic-neuroimaging approach to examine the functional consequences of preclinical dopaminergic nigrostriatal dysfunction in the human motor system. Specifically, we examined how a single heterozygous mutation in different genes associated with recessively inherited Parkinson disease alters the cortical control of sequential finger movements.
Nonmanifesting individuals carrying a single heterozygous Parkin (n = 13) or PINK1 (n = 9) mutation and 23 healthy controls without these mutations were studied with functional MRI (fMRI). During fMRI, participants performed simple sequences of three thumb-to-finger opposition movements with their right dominant hand. Since heterozygous Parkin and PINK1 mutations cause a latent dopaminergic nigrostriatal dysfunction, we predicted a compensatory recruitment of those rostral premotor areas that are normally implicated in the control of complex motor sequences. We expected this overactivity to be independent of the underlying genotype.
Task performance was comparable for all groups. The performance of a simple motor sequence task consistently activated the rostral supplementary motor area and right rostral dorsal premotor cortex in mutation carriers but not in controls. Task-related activation of these premotor areas was similar in carriers of a Parkin or PINK1 mutation.
Mutations in different genes linked to recessively inherited Parkinson disease are associated with an additional recruitment of rostral supplementary motor area and rostral dorsal premotor cortex during a simple motor sequence task. These premotor areas were recruited independently of the underlying genotype. The observed activation most likely reflects a “generic” compensatory mechanism to maintain motor function in the context of a mild dopaminergic deficit.
= blood oxygen level–dependent;
= cingulate motor area;
= false discovery rate;
= functional MRI;
= hemodynamic response function;
= intraparietal sulcus;
= primary motor hand area;
= Parkinson disease;
= dorsal premotor cortex;
= supplementary motor area;
= statistical parametric mapping;
= small volume correction;
= echo time;
= transcranial magnetic stimulation;
= repetition time;
= volumes of interest.
PMCID: PMC2821837  PMID: 19038850

Results 1-6 (6)