Alain Dagher

Anatomically distinct dopamine release during anticipation and experience of peak emotion to music

Music, an abstract stimulus, can arouse feelings of euphoria and craving, similar to tangible rewards that involve the striatal dopaminergic system. Using the neurochemical specificity of [11C]raclopride positron emission tomography scanning, combined with psychophysiological measures of autonomic nervous system activity, we found endogenous dopamine release in the striatum at peak emotional arousal during music listening. To examine the time course of dopamine release, we used functional magnetic resonance imaging with the same stimuli and listeners, and found a functional dissociation: the caudate was more involved during the anticipation and the nucleus accumbens was more involved during the experience of peak emotional responses to music. These results indicate that intense pleasure in response to music can lead to dopamine release in the striatal system. Notably, the anticipation of an abstract reward can result in dopamine release in an anatomical pathway distinct from that associated with the peak pleasure itself. Our results help to explain why music is of such high value across all human societies.

Repetitive Transcranial Magnetic Stimulation of the Human Prefrontal Cortex Induces Dopamine Release in the Caudate Nucleus

Dopamine is implicated in movement, learning, and motivation, and in illnesses such as Parkinsons disease, schizophrenia, and drug addiction. Little is known about the control of dopamine release in humans, but research in experimental animals suggests that the prefrontal cortex plays an important role in regulating the release of dopamine in subcortical structures. Here we used [(11)C]raclopride and positron emission tomography to measure changes in extracellular dopamine concentration in vivo after repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex in healthy human subjects. Repetitive TMS of the left dorsolateral prefrontal cortex caused a reduction in [(11)C]raclopride binding in the left dorsal caudate nucleus compared with rTMS of the left occipital cortex. There were no changes in binding in the putamen, nucleus accumbens, or right caudate. This shows that rTMS of the prefrontal cortex induces the release of endogenous dopamine in the ipsilateral caudate nucleus. This finding has implications for the therapeutic and research use of rTMS in neurological and psychiatric disorders.

Dopamine Release in Response to a Psychological Stress in Humans and Its Relationship to Early Life Maternal Care: A Positron Emission Tomography Study Using [11C]Raclopride

Mesolimbic dopamine is thought to play a role in the processing of rewards. However, animal studies also demonstrate dopamine release in response to aversive stressful stimuli. Also, in animal studies, disruptions of the mother–infant relationship have been shown to have long-lasting effects on the mesolimbic dopamine system and the hypothalamic-pituitary adrenal axis. We therefore investigated dopamine release in response to stress in human subjects, considering the relationship to early life parental care. We screened 120 healthy young college students for parental care in early life using a combination of telephone interviews and questionnaires. Five students from the top end and five students from the bottom end of the parental care distribution were then invited for a positron emission tomography study using [11C]raclopride and a psychosocial stress task. The psychosocial stressor caused a significant release of dopamine in the ventral striatum as indicated by a reduction in [11C]raclopride binding potential in the stress versus resting condition in subjects reporting low parental care. Moreover, the magnitude of the salivary cortisol response to stress was significantly correlated with the reduction in [11C]raclopride binding in the ventral striatum (r = 0.78), consistent with a facilitating effect of cortisol on dopamine neuron firing. These data suggest that aversive stressful events can be associated with mesolimbic dopamine release in humans, and that the method presented here may be useful to study the effects of early life events on neurobiological stress systems.

Ghrelin Modulates Brain Activity in Areas that Control Appetitive Behavior

Feeding behavior is often separated into homeostatic and hedonic components. Hedonic feeding, which can be triggered by visual or olfactory food cues, involves brain regions that play a role in reward and motivation, while homeostatic feeding is thought to be under the control of circulating hormones acting primarily on the hypothalamus. Ghrelin is a peptide hormone secreted by the gut that causes hunger and food consumption. Here, we show that ghrelin administered intravenously to healthy volunteers during functional magnetic resonance imaging increased the neural response to food pictures in regions of the brain, including the amygdala, orbitofrontal cortex, anterior insula, and striatum, implicated in encoding the incentive value of food cues. The effects of ghrelin on the amygdala and OFC response were correlated with self-rated hunger ratings. This demonstrates that metabolic signals such as ghrelin may favor food consumption by enhancing the hedonic and incentive responses to food-related cues.

Feeding-induced dopamine release in dorsal striatum correlates with meal pleasantness ratings in healthy human volunteers

Seven healthy subjects underwent two [(11)C]raclopride positron emission tomography (PET) scans, one following a 16-h fast and the other after consumption of a favorite meal (following a 16-h fast) in counterbalanced fashion. Before and after each scan subjects gave ratings of hunger/fullness and desire to eat. In addition, meal pleasantness ratings were collected immediately after consumption of the favorite meal. PET data were analyzed using brain parametric maps to generate regions of statistically significant change, as well as regions of interest manually drawn on each individuals coregistered anatomical image. [(11)C]Raclopride binding potential was compared across the two states (hungry and full). A significant reduction in binding potential was observed in the full compared to the hungry state in the dorsal putamen and caudate nucleus, indicative of dopamine release. There were no changes elsewhere in the striatum. A correlation was observed between the reduction in [(11)C]raclopride binding and meal pleasantness ratings, but not with desire to eat (hunger) or satiety after eating. These results suggest that feeding is associated with dopamine release in the dorsal, but not the ventral striatum, and that the amount of dopamine released correlates with the degree of experienced pleasure.

Deactivation of the Limbic System During Acute Psychosocial Stress: Evidence from Positron Emission Tomography and Functional Magnetic Resonance Imaging Studies

BACKGROUND Stress-induced metabolic changes can have detrimental health effects. Newly developed paradigms to investigate stress in neuroimaging environments allow the assessment of brain activation changes in association with the perception of and the metabolic response to stress. METHODS We exposed human subjects to a psychosocial stressor in one positron emission tomography (n = 10) and one functional magnetic resonance imaging (fMRI; n = 40) experiment. RESULTS We observed a profound deactivation of limbic system components including hippocampus, hypothalamus, medio-orbitofrontal cortex and anterior cingulate cortex in subjects who reacted to the stressor with a significant increase of the endocrine stress marker cortisol. Further, in the fMRI study, the degree of deactivation in the hippocampus was correlated with the release of cortisol in response to the stress task. CONCLUSIONS The observed deactivation of limbic system structures suggests elevated activation at rest and during nonstressful situations. A model is proposed where the observed reduction in limbic system activity is essential for the initiation of the stress response.

Dopamine neurons implanted into people with Parkinson's disease survive without pathology for 14 years

Postmortem analysis of five subjects with Parkinsons disease 9–14 years after transplantation of fetal midbrain cell suspensions revealed surviving grafts that included dopamine and serotonin neurons without pathology. These findings are important for the understanding of the etiopathogenesis of midbrain dopamine neuron degeneration and future use of cell replacement therapies.

Amphetamine-induced increases in extracellular dopamine, drug wanting, and novelty seeking: A PET/[11C]raclopride study in healthy men

Eight healthy men underwent two positron emission tomography (PET) [11C]raclopride scans, one following placebo, the second following d-amphetamine (0.30 mg/kg, p.o.). PET data were analyzed using: (1) brain parametric maps to statistically generate regions of significant change; and (2) a priori identified regions of interest (ROI) manually drawn on each individuals co-registered magnetic resonance (MR) images. Compared with placebo, d-amphetamine decreased [11C]raclopride binding potential (BP) with significant effects in ventral but not dorsal striatum. Change in BP in the statistically generated cluster correlated with self-reported drug-induced ‘drug wanting’ (r = 0.83, p = .01) and the personality trait of Novelty Seeking-Exploratory Excitability (r = 0.79, p = .02). The same associations were seen in the manually drawn ROI in ventral striatum but not in dorsal putamen or caudate. Changes in extracellular dopamine (DA) did not correlate with mood. Mesolimbic DA might mediate interest in obtaining reward rather than reward, per se. Individual differences in amphetamine-induced DA release might be related to predispositions to drug and novelty seeking.

Neural Bases of Set-Shifting Deficits in Parkinson's Disease

Patients with Parkinsons disease (PD) exhibit impairments in several cognitive functions similar to those observed in patients with prefrontal cortex (PFC) lesions. The physiological origins of these cognitive deficits are not well documented. Two mechanisms have been proposed: disruptions in corticostriatal circuits or a deficiency in frontal dopamine. We previously used functional magnetic resonance imaging (fMRI) in young healthy subjects to separate patterns of PFC and striatum activity during distinct phases of performance of the Wisconsin Card Sorting Task, a set-shifting task that reveals deficits in patients with PD. Here, the same fMRI protocol was used in PD patients and matched controls. Decreased activation was observed in the PD group compared with the matched control group in the ventrolateral PFC when receiving negative feedback and the posterior PFC when matching after negative feedback. In controls, these prefrontal regions specifically coactivated with the striatum during those stages of task performance. In contrast, greater activation was found in the PD group compared with the matched control group in prefrontal regions, such as the posterior and the dorsolateral PFC when receiving positive or negative feedback, that were not coactivated with the striatum in controls. These results suggest that both nigrostriatal dopamine depletion and intracortical dopamine deficiency may play a role in cognitive deficits in PD, depending on the involvement of the striatum in the task at hand.

Fibromyalgia patients show an abnormal dopamine response to pain

Fibromyalgia is characterized by chronic widespread pain and bodily tenderness and is often accompanied by affective disturbances. Accumulating evidence indicates that fibromyalgia may involve a dysfunction of modulatory systems in the brain. While brain dopamine is best known for its role in pleasure, motivation and motor control, recent evidence suggests that it is also involved in pain modulation. Because dopamine is implicated in both pain modulation and affective processing, we hypothesized that fibromyalgia may involve a disturbance of dopaminergic neurotransmission. Fibromyalgia patients and matched healthy control subjects were subjected to deep muscle pain produced by injection of hypertonic saline into the anterior tibialis muscle. In order to determine the endogenous release of dopamine in response to painful stimulation, we used positron emission tomography to examine binding of [11C]‐raclopride (D2/D3 ligand) in the brain during injection of painful hypertonic saline and nonpainful normal saline. Fibromyalgia patients experienced the hypertonic saline as more painful than healthy control subjects. Control subjects released dopamine in the basal ganglia during the painful stimulation, whereas fibromyalgia patients did not. In control subjects, the amount of dopamine release correlated with the amount of perceived pain but in fibromyalgia patients no such correlation was observed. These findings provide the first direct evidence that fibromyalgia patients have an abnormal dopamine response to pain. The disrupted dopaminergic reactivity in fibromyalgia patients could be a critical factor underlying the widespread pain and discomfort in fibromyalgia and suggests that the therapeutic effects of dopaminergic treatments for this intractable disorder should be explored.