Meline Stoy

Reward anticipation and outcomes in adult males with attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) has been suggested to involve deficits in reward processing. We used functional magnetic resonance imaging (fMRI) to compare the neural responses to reward anticipation and outcomes in 10 adults with ADHD and 10 controls as they played a monetary incentive delay task. Adults with ADHD were unmedicated, and groups were matched for age, verbal IQ and smoking habits. Adults with ADHD showed decreased activation in the ventral striatum during the anticipation of gain, but increased activation of the orbitofrontal cortex in response to gain outcomes. Ventral striatal activation in adults with ADHD during gain anticipation was negatively correlated with self-rated symptoms of hyperactivity and impulsivity. These findings suggest that male adults with ADHD show neural signs of abnormal reward processing. Future studies will have to investigate whether these dysfunctional patterns might be normalized by treatment.

Acute exercise ameliorates reduced brain-derived neurotrophic factor in patients with panic disorder.

The neurotrophin brain-derived neurotrophic factor (BDNF) has been implicated in depression and anxiety. Antidepressants and exercise increase BDNF expression, and both have an antidepressant and anxiolytic activity. To further characterize the association of anxiety, BDNF and exercise, we studied panic disorder patients (n=12) and individually matched healthy control subjects (n=12) in a standardized exercise paradigm. Serum samples for BDNF analyses were taken before and after 30min of exercise (70 VO(2max)) or quiet rest. The two conditions were separated by 1 week and the order was randomized. Non-parametric statistical analyses were performed. There was a negative correlation of BDNF concentrations and subjective arousal at baseline (r=-0.42, p=0.006). Compared to healthy control subjects, patients with panic disorder had significantly reduced BDNF concentrations at baseline and 30min of exercise significantly increased BDNF concentrations only in these patients. Our results suggest that acute exercise ameliorates reduced BDNF concentrations in panic disorder patients and raise the question whether this is also found after long-term exercise training and if it is related to the therapeutic outcome.

Delineating self-referential processing from episodic memory retrieval: Common and dissociable networks

Self-referential processing involves a complex set of cognitive functions, posing challenges to delineating its independent neural correlates. While self-referential processing has been considered functionally intertwined with episodic memory, the present study explores their overlap and dissociability. Standard tasks for self-referential processing and episodic memory were combined into a single fMRI experiment. Contrasting the effects of self-relatedness and retrieval success allowed for the two processes to be delineated. Stimuli judged as self-referential specifically activated the posterior cingulate/anterior precuneus, the medial prefrontal cortex, and an inferior division of the inferior parietal lobule. In contrast, episodic memory retrieval specifically involved the posterior precuneus, the right anterior prefrontal cortex, and a superior division of the inferior parietal lobule (extending into superior parietal lobule). Overlapping activations were found in intermediate zones in the precuneus and the inferior parietal lobule, but not in the prefrontal cortex. While our data show common networks for both processes in the medial and lateral parietal cortex, three functional differentiations were also observed: (1) an anterior-posterior differentiation within the medial parietal cortex; (2) a medial-anterolateral differentiation within the prefrontal cortex; and, (3) an inferior-superior differentiation within the lateral parietal cortex for self-referential processing versus episodic memory retrieval.

Altered representation of expected value in the orbitofrontal cortex in mania.

Objective: Increased responsiveness to appetitive and reduced responsiveness to aversive anticipatory cues may be associated with dysfunction of the brain reward system in mania. Here we studied neural correlates of gain and loss expectation in mania using functional magnetic resonance imaging (fMRI). Method: Fifteen manic patients and 26 matched healthy control individuals performed a monetary incentive delay task, during which subjects anticipated to win or lose a varying amount of money. Varying both magnitude and valence (win, loss) of anticipatory cues allowed us to isolate the effects of magnitude, valence and expected value (magnitude‐by‐valence interaction). Results: Response times and total gain amount did not differ significantly between groups. FMRI data indicated that the ventral striatum responded according to cued incentive magnitude in both groups, and this effect did not significantly differ between groups. However, a significant group difference was observed for expected value representation in the left lateral orbitofrontal cortex (OFC; BA 11 and 47). In this region, patients showed increasing BOLD responses during expectation of increasing gain and decreasing responses during expectation of increasing loss, while healthy subjects tended to show the inverse effect. In seven patients retested after remission OFC responses adapted to the response pattern of healthy controls. Conclusions: The observed alterations are consistent with a state‐related affective processing bias during the expectation of gains and losses which may contribute to clinical features of mania, such as the enhanced motivation for seeking rewards and the underestimation of risks and potential punishments. Hum Brain Mapp, 2010.

5-HTT genotype effect on prefrontal–amygdala coupling differs between major depression and controls

RationaleIn major depression, prefrontal regulation of limbic brain areas may be a key mechanism that is impaired during the processing of affective information. This prefrontal–limbic interaction has been shown to be modulated by serotonin (5-HTT) genotype, indicating a higher risk for major depressive disorder (MDD) with increasing number of 5-HTT low-expression alleles.ObjectiveFunctional magnetic resonance imaging was used to assess neural response to uncued unpleasant affective pictures in 21 unmedicated patients with MDD compared to 21 matched healthy controls, taking into account genetic influences of the 5-HTT (SCL6A4) high- and low-expression genotype.ResultsHealthy controls displayed greater prefrontal activation (BA10) to uncued negative pictures compared to patients with MDD. While in healthy controls prefrontal (BA10) activation and BA10–amygdala coupling increased with the number of 5-HTT low-expression risk alleles, this effect was abolished, and even reversed, in patients with MDD. In MDD, connectivity decreased with severity of depressive symptoms (HAMD total score).ConclusionThese findings suggest that increased medial prefrontal (BA10) activation and BA10–amygdala connectivity may counteract the risk for MDD in healthy carriers of 5-HTT low-expression alleles, while this protective factor might be lost in patients who actually suffer from MDD. Prefrontal–limbic regulation in risk populations could be a target of early interventions and should be the focus of further research.

Dimensional psychiatry: reward dysfunction and depressive mood across psychiatric disorders

RationaleA dimensional approach in psychiatry aims to identify core mechanisms of mental disorders across nosological boundaries.ObjectivesWe compared anticipation of reward between major psychiatric disorders, and investigated whether reward anticipation is impaired in several mental disorders and whether there is a common psychopathological correlate (negative mood) of such an impairment.MethodsWe used functional magnetic resonance imaging (fMRI) and a monetary incentive delay (MID) task to study the functional correlates of reward anticipation across major psychiatric disorders in 184 subjects, with the diagnoses of alcohol dependence (n = 26), schizophrenia (n = 44), major depressive disorder (MDD, n = 24), bipolar disorder (acute manic episode, n = 13), attention deficit/hyperactivity disorder (ADHD, n = 23), and healthy controls (n = 54). Subjects’ individual Beck Depression Inventory-and State-Trait Anxiety Inventory-scores were correlated with clusters showing significant activation during reward anticipation.ResultsDuring reward anticipation, we observed significant group differences in ventral striatal (VS) activation: patients with schizophrenia, alcohol dependence, and major depression showed significantly less ventral striatal activation compared to healthy controls. Depressive symptoms correlated with dysfunction in reward anticipation regardless of diagnostic entity. There was no significant correlation between anxiety symptoms and VS functional activation.ConclusionOur findings demonstrate a neurobiological dysfunction related to reward prediction that transcended disorder categories and was related to measures of depressed mood. The findings underline the potential of a dimensional approach in psychiatry and strengthen the hypothesis that neurobiological research in psychiatric disorders can be targeted at core mechanisms that are likely to be implicated in a range of clinical entities.

Reward processing in male adults with childhood ADHD—a comparison between drug-naïve and methylphenidate-treated subjects

RationaleDysfunctional reward processing has been proposed as a main deficit in attention-deficit/hyperactivity disorder (ADHD), which could be modulated by treatment with methylphenidate (MPH).ObjectivesWe examined differences in reward processing in adulthood (independent of actual ADHD) depending on MPH treatment during childhood.MethodsEleven males with childhood ADHD treated with MPH, 12 drug-naïve males with childhood ADHD, and 12 controls matched by age, handedness, and smoking behavior were studied drug-free using functional magnetic resonance imaging. BOLD-responses were compared during a monetary incentive delay task using an ANOVA design focusing on the ventral striatum during anticipation and the orbitofrontal cortex during outcome.ResultsControls, drug-naïve, and treated subjects did not differ significantly in their activations in the ventral striatum and orbitofrontal cortex. Explorative analyses revealed decreased insula activation during outcome of loss avoidance in drug-naïve subjects in comparison to both groups, while treated subjects did not differ from controls. Insula activation correlated significantly positive with harm avoidance in the treated group. Furthermore, comparing subjects with actual ADHD symptoms, remitters and controls we observed decreased putamen activition in ADHD persisters.ConclusionsBasal ganglia reward processing seemed to be unrelated to MPH pretreatment, but was related to remission. On the other hand, the revealed differences between treated and drug-naïve subjects with childhood ADHD, i.e., in the insula, give evidence for more pronounced abnormal activation in reward-associated brain regions in untreated subjects with childhood ADHD and underpin the need of prospective studies on long-term effects of psychostimulant treatment.

A preliminary study of increased amygdala activation to positive affective stimuli in mania

OBJECTIVES The present study in hypomanic and manic patients explored how amygdala responses to affective stimuli depend on the valence of the stimuli presented. METHODS We compared 10 patients with 10 matched healthy control subjects. We measured blood oxygen level-dependent (BOLD) responses in the amygdala while subjects passively viewed photographs taken from the International Affective Picture System. After the fMRI session, subjects saw the pictures again and subjectively rated the emotional valence and intensity of each picture. RESULTS Compared to healthy individuals, hypomanic or manic patients showed higher valence ratings in positive pictures and associated larger BOLD responses in the left amygdala during positive versus neutral picture viewing. This enhanced amygdala activation was correlated with Young Mania Rating Scale scores and with euphoric as opposed to irritable symptom presentation. CONCLUSIONS Increased valence ratings and amygdala responses to positive affective stimuli may reflect a positive processing bias contributing to elevated mood states characteristic for euphoric mania.

Functional neuroanatomy of emotion processing in major depressive disorder is altered after successful antidepressant therapy

Major Depressive Disorder (MDD) is associated with impaired processing and regulation of emotions. A vast body of research has elucidated the altered neural processes that occur in response to emotional stimuli, while little is known about anticipatory processes. Here we used functional magnetic resonance imaging (fMRI) to investigate neural activation during the presentation and anticipation of negative stimuli. Furthermore, we examined the effects of an 8-week antidepressant treatment with escitalopram. We matched 12 unmedicated MDD patients and 12 healthy control participants to perform a task involving affective pictures. The design of our event-related task consisted of presenting positive, negative, and neutral pictures from the International Affective Picture System (IAPS) across two runs and under opposite conditions. For the ‘expected’ condition, the pictures were cued by a word indicating their emotional valence; whereas the ‘unexpected’ condition had a combination of random letters precede the emotion picture. MDD patients displayed greater amygdala activation when anticipating negative pictures and greater prefrontal activation when confronted with them without the anticipatory cues. After antidepressant treatment, both amygdala and prefrontal activation decreased significantly in the treated MDD patients relative to controls. These findings show that the neural mechanisms of emotion anticipation and processing are altered in patients with MDD and that these alterations are able to normalize after treatment with an antidepressant.

Hemispheric Asymmetry for Affective Stimulus Processing in Healthy Subjects–A fMRI Study

Background While hemispheric specialization of language processing is well established, lateralization of emotion processing is still under debate. Several conflicting hypotheses have been proposed, including right hemisphere hypothesis, valence asymmetry hypothesis and region-specific lateralization hypothesis. However, experimental evidence for these hypotheses remains inconclusive, partly because direct comparisons between hemispheres are scarce. Methods The present fMRI study systematically investigated functional lateralization during affective stimulus processing in 36 healthy participants. We normalized our functional data on a symmetrical template to avoid confounding effects of anatomical asymmetries. Direct comparison of BOLD responses between hemispheres was accomplished taking two approaches: a hypothesis-driven region of interest analysis focusing on brain areas most frequently reported in earlier neuroimaging studies of emotion; and an exploratory whole volume analysis contrasting non-flipped with flipped functional data using paired t-test. Results The region of interest analysis revealed lateralization towards the left in the medial prefrontal cortex (BA 10) during positive stimulus processing; while negative stimulus processing was lateralized towards the right in the dorsolateral prefrontal cortex (BA 9 & 46) and towards the left in the amygdala and uncus. The whole brain analysis yielded similar results and, in addition, revealed lateralization towards the right in the premotor cortex (BA 6) and the temporo-occipital junction (BA 19 & 37) during positive stimulus processing; while negative stimulus processing showed lateralization towards the right in the temporo-parietal junction (BA 37,39,42) and towards the left in the middle temporal gyrus (BA 21). Conclusion Our data suggests region-specific functional lateralization of emotion processing. Findings show valence asymmetry for prefrontal cortical areas and left-lateralized negative stimulus processing in subcortical areas, in particular, amygdala and uncus.