Bénédicte Ballanger

Stimulation of the subthalamic nucleus and impulsivity: release your horses.

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.

Dysfunction of the Default Mode Network in Parkinson Disease: A Functional Magnetic Resonance Imaging Study

OBJECTIVE 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. DESIGN 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. SETTING Tertiary outpatient clinic. PARTICIPANTS Seven patients with mild to moderate PD (not taking medication) and 7 healthy controls. MAIN OUTCOME MEASURE Cortical deactivations. RESULTS 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. CONCLUSIONS 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.

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.

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 Parkinsons 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.

Cerebral blood flow changes induced by pedunculopontine nucleus stimulation in patients with advanced Parkinson's disease: A [15O] H2O PET study

Patients with advanced Parkinsons disease (PD) develop disabling axial symptoms, including gait disturbances, freezing and postural instability poorly responsive to levodopa replacement therapy. The pedunculopontine nucleus (PPN) is involved in locomotion, control of posture, and behavioral states [i.e. wakefulness, rapid eye movement sleep]. Recent reports suggested that PPN modulation with deep brain stimulation (DBS) may be beneficial in the treatment of axial symptoms. However, the mechanisms underlying these effects are still unknown. We used [15O] H2O PET to investigate regional cerebral blood flow in three patients with advanced PD who underwent a new experimental surgical procedure with implantation of unilateral PPN‐DBS. Patients were studied Off‐medication with stimulator Off and On, both at rest and during a self‐paced alternating motor task of the lower limbs. We used SPM2 for imaging data analysis, threshold P < 0.05 corrected at the cluster level. Stimulation induced significant regional cerebral blood flow increment in subcortical regions such as the thalamus (P < 0.006), cerebellum (P < 0.001), and midbrain region (P < 0.001) as well as different cortical areas involving medial sensorimotor cortex extending into caudal supplementary motor area (BA 4/6; P < 0.001). PPN‐DBS in advanced PD resulted in blood flow and presumably neuronal activity changes in subcortical and cortical areas involved in balance and motor control, including the mesencephalic locomotor region (e.g. PPN) and closely interconnected structures within the cerebello‐(rubro)‐thalamo‐cortical circuit. Whether these findings are associated with the DBS‐PPN clinical effect remains to be proven. However, they suggest that PPN modulation may induce functional changes in neural networks associated with the control of lower limb movements. Hum Brain Mapp, 2009.

Role of serotonergic 1A receptor dysfunction in depression associated with Parkinson's disease.

Depression is frequent in Parkinsons disease, but its pathophysiology remains unclear. Two recent studies have investigated the role of serotonergic system at the presynaptic level. The objective of the present study was to use positron emission tomography and [18F]MPPF to investigate the role of postsynaptic serotonergic system dysfunction in the pathophysiology of depression in Parkinsons disease. Four parkinsonian patients with depression and 8 parkinsonian patients without depression were enrolled. Each patient underwent a scan using [18F]MPPF, a selective serotonin 1A receptor antagonist. Voxel‐by‐voxel statistical comparison of [18F]MPPF uptake of the 2 groups of parkinsonian patients and with 7 matched normal subjects was made using statistical parametric mapping (P uncorrected < .001). Compared with nondepressed parkinsonian patients, depressed patients exhibited reduced tracer uptake in the left hippocampus, the right insula, the left superior temporal cortex, and the orbitofrontal cortex. Compared with controls, nondepressed parkinsonian patients presented reduced [18F]MPPF uptake bilaterally in the inferior frontal cortex as well as in the right ventral striatum and insula. Compared with controls, [18F]MPPF uptake was decreased in depressed parkinsonian patients in the left dorsal anterior cingulate and orbitofrontal cortices, in the right hippocampic region, and in the temporal cortex. The present imaging study suggests that abnormalities in serotonin 1A receptor neurotransmission in the limbic system may be involved in the neural mechanisms underlying depression in patients with Parkinsons disease.

rCBF Changes Associated with PPN Stimulation in a Patient with Parkinson's disease : A PET Study

Gait disturbances and akinesia are disabling symptoms in advanced Parkinsons disease (PD). The pedunculopontine nucleus (PPN) is involved in locomotion, control of posture, and behavioral states [i.e. wakefulness, rapid eye movement (REM) sleep]. Some reports have suggested that modulation of the activity of the PPN with deep brain stimulation (DBS) may be beneficial in the treatment of gait dysfunction and akinesia. To gain some insights on effects of PPN‐DBS in the human brain, we used [15O] H2O positron emission tomography (PET) to measure changes in regional cerebral blood flow (rCBF) at rest during Off and On stimulation in an advanced PD patient with unilateral PPN‐DBS. PPN‐DBS increased rCBF in different subcortical areas most notably the thalamus, bilaterally. Double‐blinded clinical evaluation revealed an improvement in motor function by ∼20%. The PET changes provide for the first time evidence in the human brain that PPN‐DBS may be able to influence and modify rCBF of closely connected subcortical structures. Given the importance of the PPN in locomotion, control of posture, and behavioral states, DBS may have significant implication for more complicated forms of movement disorders where deterioration of gait, postural instability, and REM sleep behavior disorders are very disabling.

Increased dopamine release in the right anterior cingulate cortex during the performance of a sorting task: A [11C]FLB 457 PET study

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 D(2)-dopamine receptor ligand [(11)C]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 [(11)C]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 Parkinsons disease and schizophrenia.

“Paradoxical Kinesis” is not a Hallmark of Parkinson's disease but a general property of the motor system

Although slowness of movement is a typical feature of Parkinsons disease (PD), it has been suggested that severely disabled patients remained able to produce normal motor responses in the context of urgent or externally driven situations. To investigate this phenomenon (often designated “paradoxical kinesis”), we required PD patients and healthy subjects to press a large switch under three main conditions: Self Generated, produce the fastest possible movement; External Cue, same as Self Generated but in response to an acoustic cue; Urgent External Cue, same as External Cue with the switch controlling an electromagnet that prevented a ball falling at the bottom of a tilted ramp. Task difficulty was equalized for the two experimental groups. Results showed that external cues and urgent conditions decreased movement duration (Urgent External Cue < External Cue < Self Generated) and reaction time (Urgent External Cue < External Cue). The amount of reduction was identical in PD patients and healthy subjects. These observations show that paradoxical kineses are not a hallmark of PD or a byproduct of basal ganglia dysfunctions, but a general property of the motor system.