Heiko Graf

Neural Correlates of Error Monitoring Modulated by Atomoxetine in Healthy Volunteers

BACKGROUND Atomoxetine is a selective norepinephrine reuptake inhibitor clinically used for treatment of attention-deficit/hyperactivity disorder. In healthy control subjects, doses of 40 mg or 60 mg improved inhibitory control in combination with modulation of prefrontal cortex functioning. We investigated the effects of atomoxetine (80 mg) on error monitoring as a second key component of cognitive control. METHODS Twelve healthy, male volunteers were included in a randomized double-blind, placebo-controlled, within-subjects design to examine the effects of a single dose of atomoxetine on neural activities during a combined Eriksen flanker-Go/NoGo task as measured by functional magnetic resonance imaging. RESULTS Behaviorally, atomoxetine led to a significant increase in failed inhibition. Functionally, interaction analysis revealed a significant increase of the error signal (incorrect minus correct NoGo trials) under atomoxetine in bilateral inferior frontal cortex and presupplementary motor area. Drug-dependent increases in error signaling did not correlate with increased error rates. Analysis of neuropsychological data indexed a significant increase in phasic alertness. CONCLUSIONS Results support that atomoxetine increases neural sensitivity for errors in healthy control subjects, possibly due to an accentuated representation of the task set. However, this gain was accompanied by deterioration in inhibitory control, possibly reflecting a shift beyond the optimal working range of the norepinephrine system.

Antidepressant-related sexual dysfunction — Perspectives from neuroimaging

Sexual dysfunction is not only a common symptom in major depression but also a frequent side-effect of antidepressant medication, mainly of the selective serotonin reuptake-inhibitors (SSRI) that are often prescribed as a first line treatment option. Despite of the increasing incidence and prescription rates, neuronal mechanisms underlying SSRI-related sexual dysfunction are poorly understood and investigations on this topic are scarce. Neuroimaging techniques, mainly functional magnetic resonance imaging (fMRI), provide a feasible approach to investigate these mechanisms since SSRI-related sexual dysfunction is most likely related to central nervous processes. This review summarizes the recent literature regarding the basic clinical findings and imaging correlates of antidepressant-related sexual dysfunction linking brain regions and networks potentially involved to phases and subcomponents of sexual processing and antidepressant action. In particular, fMRI studies on SSRI antidepressants including paroxetine and SNRIs including bupropion are highlighted.

Local and Global Resting State Activity in the Noradrenergic and Dopaminergic Pathway Modulated by Reboxetine and Amisulpride in Healthy Subjects

Background: Various psychiatric populations are currently investigated with resting state fMRI, with the aim of individualizing diagnostics and treatment options and improving treatment outcomes. Many of these studies are conducted in large naturalistic samples, providing rich insights regarding disease-related neural alterations, but with the common psychopharmacological medication limiting interpretations of the results. We therefore investigated the effects of common noradrenergic and anti-dopaminergic medications on local and global resting state activity (rs-activity) in healthy volunteers to further the understanding of the respective effects independent from disease-related alterations. Methods: Within a randomized, double-blind, placebo-controlled crossover design, we investigated 19 healthy male subjects by resting state fMRI after the intake of reboxetine (4mg/d), amisulpride (200mg/d), and placebo for 7 days each. Treatment-related differences in local and global rs-activity were measured by the fractional amplitude of low frequency fluctuations (fALFF) and resting state functional connectivity (rs-FC). Results: fALFF revealed alterations of local rs-activity within regions of the core noradrenergic pathway, including the locus coeruleus under reboxetine, correlated with its plasma levels. Moreover, reboxetine led to increased rs-FC between regions within this pathway, i.e. the locus coeruleus, tectum, thalamus, and amygdala. Amisulpride modulated local rs-activity of regions within the dopaminergic pathway, with the altered signal in the putamen correlating with amisulpride plasma levels. Correspondingly, amisulpride increased rs-FC between regions of the dopaminergic pathway comprising the substantia nigra and putamen. Conclusion: Our data provide evidence of how psychopharmacological agents alter local and global rs-activity within the respective neuroanatomical pathways in healthy subjects, which may help with interpreting data in psychiatric populations.

Effects of amisulpride on human resting cerebral perfusion.

RationaleQuantitative neuroimaging studies show that different neuroleptics have similar effects on resting metabolism/perfusion in the basal ganglia, but vary in their effect on the cortex, especially in the prefrontal and temporal lobes. These differences may represent signatures of the action of medication on distinctive receptor combinations.ObjectivesThis study seeks to determine the effect on cerebral perfusion at rest of low-dose amisulpride, a neuroleptic with a receptor profile relatively selective to dopaminergic D2-receptors and both antidepressant and antipsychotic efficacy.MethodsContinuous arterial spin labelling in a placebo-controlled, double blind, crossover study at steady state of N = 20 healthy male adults.ResultsRelative to placebo, amisulpride was associated with extensive and significant cortical decrements in resting perfusion levels, particularly in the prefrontal lobes (p = 0.01, corrected). Decrements spared the basal ganglia, where perfusion was slightly increased.ConclusionsIn contrast to earlier reports on other neuroleptics, amisulpride was associated with intense cortical perfusion decrements at rest. These results are consistent with an existing model in which dopaminergic blockade is associated not only with metabolism/perfusion increases in the basal ganglia, but also with decreases in the cerebral cortex that in most neuroleptics are compensated by action on other receptor systems. The selective receptor profile of amisulpride may explain the extensive cortical decrements.

Serotonergic antidepressants decrease hedonic signals but leave learning signals in the nucleus accumbens unaffected.

Investigating the effects of serotonergic antidepressants on neural correlates of visual erotic stimulation revealed decreased reactivity within the dopaminergic reward network along with decreased subjective sexual functioning compared with placebo. However, a global dampening of the reward system under serotonergic drugs is not intuitive considering clinical observations of their beneficial effects in the treatment of depression. Particularly, learning signals as coded in prediction error processing within the dopaminergic reward system can be assumed to be rather enhanced as antidepressant drugs have been demonstrated to facilitate the efficacy of psychotherapeutic interventions relying on learning processes. Within the same study sample, we now explored the effects of serotonergic and dopaminergic/noradrenergic antidepressants on prediction error signals compared with placebo by functional MRI. A total of 17 healthy male participants (mean age: 25.4 years) were investigated under the administration of paroxetine, bupropion and placebo for 7 days each within a randomized, double-blind, within-subject cross-over design. During functional MRI, we used an established monetary incentive task to explore neural prediction error signals within the bilateral nucleus accumbens as region of interest within the dopaminergic reward system. In contrast to diminished neural activations and subjective sexual functioning under the serotonergic agent paroxetine under visual erotic stimulation, we revealed unaffected or even enhanced neural prediction error processing within the nucleus accumbens under this antidepressant along with unaffected behavioural processing. Our study provides evidence that serotonergic antidepressants facilitate prediction error signalling and may support suggestions of beneficial effects of these agents on reinforced learning as an essential element in behavioural psychotherapy.

Erotic Stimulus Processing under Amisulpride and Reboxetine: A Placebo-Controlled fMRI Study in Healthy Subjects

Background: Impaired sexual function is increasingly recognized as a side effect of psychopharmacological treatment. However, underlying mechanisms of action of the different drugs on sexual processing are still to be explored. Using functional magnetic resonance imaging, we previously investigated effects of serotonergic (paroxetine) and dopaminergic (bupropion) antidepressants on sexual functioning (Abler et al., 2011). Here, we studied the impact of noradrenergic and antidopaminergic medication on neural correlates of visual sexual stimulation in a new sample of subjects. Methods: Nineteen healthy heterosexual males (mean age 24 years, SD 3.1) under subchronic intake (7 days) of the noradrenergic agent reboxetine (4mg/d), the antidopaminergic agent amisulpride (200mg/d), and placebo were included and studied with functional magnetic resonance imaging within a randomized, double-blind, placebo-controlled, within-subjects design during an established erotic video-clip task. Subjective sexual functioning was assessed using the Massachusetts General Hospital-Sexual Functioning Questionnaire. Results: Relative to placebo, subjective sexual functioning was attenuated under reboxetine along with diminished neural activations within the caudate nucleus. Altered neural activations correlated with decreased sexual interest. Under amisulpride, neural activations and subjective sexual functioning remained unchanged. Conclusions: In line with previous interpretations of the role of the caudate nucleus in the context of primary reward processing, attenuated caudate activation may reflect detrimental effects on motivational aspects of erotic stimulus processing under noradrenergic agents.

Noradrenergic modulation of neural erotic stimulus perception

We recently investigated neuromodulatory effects of the noradrenergic agent reboxetine and the dopamine receptor affine amisulpride in healthy subjects on dynamic erotic stimulus processing. Whereas amisulpride left sexual functions and neural activations unimpaired, we observed detrimental activations under reboxetine within the caudate nucleus corresponding to motivational components of sexual behavior. However, broadly impaired subjective sexual functioning under reboxetine suggested effects on further neural components. We now investigated the same sample under these two agents with static erotic picture stimulation as alternative stimulus presentation mode to potentially observe further neural treatment effects of reboxetine. 19 healthy males were investigated under reboxetine, amisulpride and placebo for 7 days each within a double-blind cross-over design. During fMRI static erotic picture were presented with preceding anticipation periods. Subjective sexual functions were assessed by a self-reported questionnaire. Neural activations were attenuated within the caudate nucleus, putamen, ventral striatum, the pregenual and anterior midcingulate cortex and in the orbitofrontal cortex under reboxetine. Subjective diminished sexual arousal under reboxetine was correlated with attenuated neural reactivity within the posterior insula. Again, amisulpride left neural activations along with subjective sexual functioning unimpaired. Neither reboxetine nor amisulpride altered differential neural activations during anticipation of erotic stimuli. Our results verified detrimental effects of noradrenergic agents on neural motivational but also emotional and autonomic components of sexual behavior. Considering the overlap of neural network alterations with those evoked by serotonergic agents, our results suggest similar neuromodulatory effects of serotonergic and noradrenergic agents on common neural pathways relevant for sexual behavior.

Development, Implementation, and Evaluation of a Movie-Based Curriculum to Teach Psychopathology

Background: Because medical students’ attitudes toward psychiatry are often fostered by media, we provided an elective movie-based seminar to teach psychopathology. Description: We assessed attitudes toward psychiatry by using the Attitudes towards Psychiatry (ATP 35) scale in a pre–post design. Furthermore we evaluated the knowledge of diagnostic criteria in a pre–post design within one sample. Evaluation: Of the 75 students who attended the seminar during 3 consecutive semesters, 54 (60.8% female) participated in the pre–post assessment. We observed a significant positive change in attitudes toward psychiatry and a significant gain of knowledge. Conclusions: Using movies is a feasible and effective method to teach psychiatry.

Somatosensory Stimulus Intensity Encoding in Borderline Personality Disorder

Borderline Personality Disorder (BPD) is clinically characterized by emotional instability, interpersonal disturbances and dysfunctional behavior such as non-suicidal self-injury (NSSI). During NSSI, patients with BPD typically report analgesic or hypoalgesic phenomena, and pain perception and pain processing in BPD have been repeatedly investigated. Most of the studies so far focused on affective-motivational and cognitive-evaluative neural components of pain within categorial study designs. By contrast, rather basic somatosensory aspects such as neural intensity-encoding of somatosensory stimuli were not examined in further details. Thus, we investigated patients with BPD and healthy controls (HC) by functional magnetic resonance imaging (fMRI) during an unpleasant sensory stimulation task with parametrically increasing stimulus intensities. 15 females diagnosed with BPD and 15 HCs were investigated with fMRI during four individually adjusted levels of electrical stimulus intensities. Ratings of stimulus intensity were assessed by button presses during fMRI. fMRI-data were analyzed by analyses of variances (ANOVA) at a statistical threshold of p < 0.05 FWE-corrected on cluster level. Subjective ratings of stimulus intensities were alike between BPD and HC, and intensity levels identified with equal accuracy. Significant intensity-encoding neural activations were observed within the primary and secondary somtasensory cortex, the posterior insula, the posterior midcingulate cortex (pMCC) and the supplementary motor area (SMA) in both, HC and BPD. Notably, there were no significant between-groups differences in intensity-encoding neural activations, even at lowered significance thresholds. Present results suggest a similar neural somatosensory stimulus intensity encoding in BPD as previously observed on a behavioral level. The alterations in neural affective-motivational or cognitive-evaluative components reported so far may be restricted to pain rather than unpleasant stimulus processing and were absent in our study.

Differential Noradrenergic Modulation of Monetary Reward and Visual Erotic Stimulus Processing

We recently investigated the effects of the noradrenergic antidepressant reboxetine and the antipsychotic amisulpride compared to placebo on neural correlates of primary reinforcers by visual erotic stimulation in healthy subjects. Whereas, amisulpride left subjective sexual functions and corresponding neural activations unimpaired, attenuated neural activations were observed under reboxetine within the nucleus accumbens (Nacc) along with diminished behavioral sexual functioning. However, a global dampening of the reward system under reboxetine seemed not intuitive considering the complementary role of the noradrenergic to the dopamine system in reward-related learning mediated by prediction error processing. We therefore investigated the sample of 17 healthy males in a mean age of 23.8 years again by functional magnetic resonance imaging (fMRI), to explore the noradrenergic effects on neural reward prediction error signaling. Participants took reboxetine (4 mg/d), amisulpride (200 mg/d), and placebo each for 7 days within a randomized, double-blind, within-subject cross-over design. During fMRI, we used an established monetary incentive task to assess neural reward expectation and prediction error signals within the bilateral Nacc using an independent anatomical mask for a region of interest (ROI) analysis. Activations within the same ROI were also assessed for the erotic picture paradigm. We confirmed our previous results from the whole brain analysis for the selected ROI by significant (p < 0.05 FWE-corrected) attenuated activations within the Nacc during visual sexual stimulation under reboxetine compared to placebo. However, activations in the Nacc concerning prediction error processing and monetary reward expectation were unimpaired under reboxetine compared to placebo, along with unimpaired reaction times in the reward task. For both tasks, neural activations and behavioral processing were not altered by amisulpride compared to placebo. The observed attenuated neural activations within the Nacc during visual erotic stimulation along with unimpaired neural prediction error and monetary reward expectation processing provide evidence for a differential modulation of the neural reward system by the noradrenergic agent reboxetine depending on the presence of primary reinforcers such as erotic stimuli in contrast to secondary such as monetary rewards.