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1.  Increased volume and impaired function: the role of the basal ganglia in writer's cramp 
Brain and Behavior  2014;e00301.
The pathophysiology of writer's cramp, a task‐specific dystonia, remains unclear. The objective of this study was to investigate the basal ganglia circuit and the cerebellum during a complex motor sequence learning task carried out with the nonaffected hand in writer's cramp patients.
We applied structural and functional imaging in 22 writer's cramp patients and 28 matched controls using 3T MRI. With the asymptomatic left hand all participants learned a complex, sequential, five‐element sequence‐tapping task as accurately and quickly as possible. Functional imaging was measured during a repeated (15 times), fixed block design with tapping (30 sec) and rest (30 sec). Additionally, gray matter volume of the basal ganglia was analyzed using voxel‐based morphometry (VBM).
While behavior was comparable between groups, after small volume correction the anterior part of the right putamen and the left globus pallidus exhibited reduced blood oxygen level‐dependent (BOLD) activity in patients during the sequential finger‐tapping task. VBM analysis showed larger gray matter volume bilateral in the posterior part of the putamen and globus pallidus. There were no group differences in the cerebellum.
The results indicate an impairment of anterior basal ganglia loops involved in producing complex sequential movements of the unaffected hand. These findings are in line with previous reports of reduced neuronal activity in the globus pallidus internus. Higher gray matter volume of the putamen and globus pallidus may stem from elevated activity of the direct pathway, which could reflect a compensatory phenomenon or a primary predisposition, that is, endophenotypic trait.
PMCID: PMC4309880  PMID: 25642386
Focal hand dystonia; functional magnetic resonance imaging; motor learning; voxel‐based morphometry; writer's cramp
2.  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
3.  Validation of the questionnaire for impulsive-compulsive disorders in Parkinson’s disease (QUIP) and the QUIP-rating scale in a German speaking sample 
Journal of Neurology  2014;261(5):936-942.
Impulsive-compulsive disorders are frequent in patients with Parkinson’s disease (PD). Recently, a screening questionnaire and rating scale were developed for these disorders: the questionnaire for impulsive-compulsive disorders (QUIP) and QUIP-rating scale (QUIP-RS). We assessed the validity of these instruments in the German language in order to reevaluate the benefit and to obtain German screening tools in clinical practice. A convenience sample of 156 patients was assessed in Kiel and Vienna. The patients filled out the QUIP-current, the QUIP-anytime and the QUIP-RS. We validated the questionnaires against a gold standard diagnosis via receiver operating characteristic curves and determined optimal cut-off scores for the instruments. Excluding walkabout, which was not shown to be valid, sensitivities ranged from 60–92 % for the QUIP-current, 68–91 % for the QUIP-anytime, and 73–100 % for the QUIP-RS. Specificities were >71 % for QUIP-current, >69 % for QUIP-anytime and >62 % for QUIP-RS. With its very good sensitivities, the QUIP-RS is a valid instrument to assess impulsive-compulsive disorders and makes an early detection of behavioral disorders in PD possible. The QUIP-anytime was also shown to be a valid screening instrument. Both are expected to prove useful in scientific and clinical practice.
Electronic supplementary material
The online version of this article (doi:10.1007/s00415-014-7299-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4148320  PMID: 24609972
ICD; Addiction; PD; QUIP; QUIP-RS
4.  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
5.  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
6.  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
7.  Impulse control disorders in Parkinson’s disease: seeking a roadmap toward a better understanding 
Brain Structure & Function  2011;216(4):289-299.
The development of an impulse control disorder (ICD) is now recognized as a potential nonmotor adverse effect of dopamine replacement therapy in Parkinson’s disease (PD). Here, recent epidemiological, neurophysiological and genetic advances are summarized to outline potential mechanisms involved. It is safe to say that dopaminergic drugs, particularly dopamine agonists, are able to induce ICDs only in a minority of patients, while the majority are somehow protected from this adverse effect. While it seems clear that men with early-onset PD are more vulnerable, other predisposing factors, such as various current or pre-PD personality traits, are a matter of debate. In terms of neurophysiological advances, one may find striking analogies to the addiction literature suggesting a causal chain beginning with certain predisposing conditions of striatal dopamine synapses, an “unnatural” increase of dopamine stimulation and a characteristic pattern of resulting functional changes in remote networks of appetitive drive and impulse control. Future prospects include potential add-on medications and the possible identification of genetic predispositions at a genome-wide scale. Functional imaging of pharmacogenetic interactions (imaging pharmacogenomics) may be an important tool on that road.
PMCID: PMC3197927  PMID: 21541715
Imaging; Gambling; Addiction; Impulsive; Compulsive; Dopamine agonist
8.  Dopamine Agonists Diminish Value Sensitivity of the Orbitofrontal Cortex: A Trigger for Pathological Gambling in Parkinson’s Disease? 
The neurobehavioral underpinnings of pathological gambling are not well understood. Insight might be gained by understanding pharmacological effects on the reward system in patients with Parkinson’s disease (PD). Treatment with dopamine agonists (DAs) has been associated with pathological gambling in PD patients. However, how DAs are involved in the development of this form of addiction is unknown. We tested the hypothesis that tonic stimulation of dopamine receptors specifically desensitizes the dopaminergic reward system by preventing decreases in dopaminergic transmission that occurs with negative feedback. Using functional magnetic resonance imaging, we studied PD patients during three sessions of a probabilistic reward task in random order: off medication, after levodopa (LD) treatment, and after an equivalent dose of DA (pramipexole). For each trial, a reward prediction error value was computed using outcome, stake, and probability. Pramipexole specifically changed activity of the orbitofrontal cortex (OFC) in two ways that were both associated with increased risk taking in an out-of-magnet task. Outcome-induced activations were generally higher with pramipexole compared with LD or off medication. In addition, only pramipexole greatly diminished trial-by-trial correlation with reward prediction error values. Further analysis yielded that this resulted mainly from impaired deactivation in trials with negative errors in reward prediction. We propose that DAs prevent pauses in dopamine transmission and thereby impair the negative reinforcing effect of losing. Our findings raise the question of whether pathological gambling may in part stem from an impaired capacity of the OFC to guide behavior when facing negative consequences.
PMCID: PMC2972251  PMID: 19741594 CAMSID: cams1534
fMRI; impulse control disorder; dopamine agonist; reward; addiction; reinforcement
9.  Dysfunction of the Default Mode Network in Parkinson Disease 
Archives of neurology  2009;66(7):877-883.
To examine the integrity of the default mode network in patients with Parkinson disease (PD). Previous functional neuroimaging experiments have studied executive deficits in patients with PD with regard to task-related brain activation. However, recent studies suggest that executive performance also relies on the integrity of the default mode network (ie, medial prefrontal cortex, posterior cingulate cortex, precuneus, and lateral parietal and medial temporal cortices), characterized by a deactivation of these cortical areas during the performance of executive tasks.
We used functional magnetic resonance imaging to investigate cortical deactivations during a card-sorting task (retrieval and manipulation of short-term memory contents) compared with a simple sensory-motor matching task. In addition, a functional connectivity analysis was performed.
Tertiary outpatient clinic.
Seven patients with mild to moderate PD (not taking medication) and 7 healthy controls.
Main Outcome Measure
Cortical deactivations.
Both groups showed comparable deactivation of the medial prefrontal cortex but different deactivation in the posterior cingulate cortex and the precuneus. Compared with controls, patients with PD not only showed less deactivation of the posterior cingulate cortex and the precuneus, they even demonstrated a reversed pattern of activation and deactivation. Connectivity analysis yielded that in contrast to healthy individuals, medial prefrontal cortex and the rostral ventromedial caudate nucleus were functionally disconnected in PD.
We describe specific malfunctioning of the default mode network during an executive task in PD. This finding is plausibly linked to dopamine depletion and may critically contribute to the understanding of executive deficits in PD.
PMCID: PMC2972248  PMID: 19597090 CAMSID: cams1533
10.  Stimulation of the Subthalamic Nucleus and Impulsivity 
Annals of neurology  2009;66(6):817-824.
In Parkinson disease (PD) patients, deep brain stimulation (DBS) of the subthalamic nucleus (STN) may contribute to certain impulsive behavior during high-conflict decisions. A neurocomputational model of the basal ganglia has recently been proposed that suggests this behavioral aspect may be related to the role played by the STN in relaying a “hold your horses” signal intended to allow more time to settle on the best option. The aim of the present study was 2-fold: 1) to extend these observations by providing evidence that the STN may influence and prevent the execution of any response even during low-conflict decisions; and 2) to identify the neural correlates of this effect.
We measured regional cerebral blood flow during a Go/NoGo and a control (Go) task to study the motor improvement and response inhibition deficits associated with STN-DBS in patients with PD.
Although it improved Unified Parkinson Disease Rating Scale motor ratings and induced a global decrease in reaction time during task performance, STN-DBS impaired response inhibition, as revealed by an increase in commission errors in NoGo trials. These behavioral effects were accompanied by changes in synaptic activity consisting of a reduced activation in the cortical networks responsible for reactive and proactive response inhibition.
The present results suggest that although it improves motor functions in PD patients, modulation of STN hyperactivity with DBS may tend at the same time to favor the appearance of impulsive behavior by acting on the gating mechanism involved in response initiation.
PMCID: PMC2972250  PMID: 20035509 CAMSID: cams1535
11.  Increased dopamine release in the right anterior cingulate cortex during the performance of a sorting task: A [11C]FLB 457 PET study 
NeuroImage  2009;46(2):516-521.
There is clear evidence that the prefrontal cortex is strongly involved in executive processes and that dopamine can influence performance on working memory tasks. Although, some studies have emphasized the role of striatal dopamine in executive functions, the role played by prefrontal dopamine during executive tasks is unknown. In order to investigate cortical dopamine transmission during executive function, we used D2-dopamine receptor ligand [11C]FLB 457 PET in healthy subjects while performing the Montreal Card Sorting Task (MCST). During the retrieval with shift task of the MCST, the subjects had to match each test card to one of the reference cards based on a classification rule (color, shape or number) determined by comparing the previously viewed cue card and the current test card. A reduction in [11C]FLB 457 binding potential in the right dorsal anterior cingulate cortex (ACC) was observed when subjects performed the active task compared to the control task. These findings may suggest that right dorsal ACC dopamine neurotransmission increases significantly during the performance of certain executive processes, e.g., conflict monitoring, in keeping with previous evidence from fMRI studies showing ACC activation during similar tasks. These results may provide some insights on the origin of cognitive deficits underlying certain neurological disorders associated with dopamine dysfunction, such as Parkinson’s disease and schizophrenia.
PMCID: PMC2972252  PMID: 19264140 CAMSID: cams1532
FLB 457; Positron emission tomography; Executive function; Anterior cingulate cortex; Dopamine; Conflict monitoring

Results 1-11 (11)