Dopamine-related deficit in reward learning after catecholamine depletion in unmedicated, remitted subjects with bulimia nervosa

Disturbances in reward processing have been implicated in bulimia nervosa (BN). Abnormalities in processing reward-related stimuli might be linked to dysfunctions of the catecholaminergic neurotransmitter system, but findings have been inconclusive. A powerful way to investigate the relationship between catecholaminergic function and behavior is to examine behavioral changes in response to experimental catecholamine depletion (CD). The purpose of this study was to uncover putative catecholaminergic dysfunction in remitted subjects with BN who performed a reinforcement-learning task after CD. CD was achieved by oral alpha-methyl-para-tyrosine (AMPT) in 19 unmedicated female subjects with remitted BN (rBN) and 28 demographically matched healthy female controls (HC). Sham depletion administered identical capsules containing diphenhydramine. The study design consisted of a randomized, double-blind, placebo-controlled crossover, single-site experimental trial. The main outcome measures were reward learning in a probabilistic reward task analyzed using signal-detection theory. Secondary outcome measures included self-report assessments, including the Eating Disorder Examination-Questionnaire. Relative to healthy controls, rBN subjects were characterized by blunted reward learning in the AMPT-but not in placebo-condition. Highlighting the specificity of these findings, groups did not differ in their ability to perceptually distinguish between stimuli. Increased CD-induced anhedonic (but not eating disorder) symptoms were associated with a reduced response bias toward a more frequently rewarded stimulus. In conclusion, under CD, rBN subjects showed reduced reward learning compared with healthy control subjects. These deficits uncover disturbance of the central reward processing systems in rBN related to altered brain catecholamine levels, which might reflect a trait-like deficit increasing vulnerability to BN.

Bipolar disorder susceptibility region on chromosome 3q29 not confirmed in a case-control association study

We identified a bipolar disorder (BPD) susceptibility region on chromosome 3q29 in a genome-wide linkage scan (Bailer et al. 2002 (Biol Psychiatry 52: 40), NPL-score 4.09) and follow-up linkage analysis (Schosser et al. 2004 (J Psychiatr Res 38(3): 357), NPL-scores >3 with five markers). These findings were supported by further fine-mapping of this region (Schosser et al. 2007 (Eur Neuropsychopharmacol 17(6-7): 501)), finding NPL-scores >3.9 with SNPs (single nucleotide polymorphisms) spanning a region of 3.46 Mbp in BPD families. Since genetic association studies are more powerful than linkage studies for detecting susceptibility genes of small effect size, we aimed to replicate these findings in an independent case-control sample collected in London (UK) and Vienna (Austria).

Reduced neuronal activity in language-related regions after transcranial magnetic stimulation therapy for auditory verbal hallucinations

Transcranial magnetic stimulation (TMS) is a novel therapeutic approach, used in patients with pharmacoresistant auditory verbal hallucinations (AVH). To investigate the neurobiological effects of TMS on AVH, we measured cerebral blood flow with pseudo-continuous magnetic resonance-arterial spin labeling 20 ± 6 hours before and after TMS treatment.

Intra-subject variability in attention-deficit hyperactivity disorder

BACKGROUND: This study is based on a comprehensive survey of the neuropsychological attention-deficit hyperactivity disorder (ADHD) literature and presents the first psychometric analyses of different parameters of intra-subject variability (ISV) in patients with ADHD compared to healthy controls, using the Continuous Performance Test, a Go-NoGo task, a Stop Signal Task, as well as N-back tasks. METHODS: Data of 57 patients with ADHD and 53 age- and gender-matched controls were available for statistical analysis. Different parameters were used to describe central tendency (arithmetic mean, median), dispersion (standard deviation, coefficient of variation, consecutive variance), and shape (skewness, excess) of reaction time distributions, as well as errors (commissions and omissions). RESULTS: Group comparisons revealed by far the strongest effect sizes for measures of dispersion, followed by measures of central tendency, and by commission errors. Statistical control of ISV reduced group differences in the other measures substantially. One (patients) or two (controls) principal components explained up to 67% of the inter-individual differences in intra-individual variability. CONCLUSIONS: Results suggest that, across a variety of neuropsychological tests, measures of ISV contribute best to group discrimination, with limited incremental validity of measures of central tendency and errors. Furthermore, increased ISV might be a unitary construct in ADHD.

Global, regional, and local measures of complexity of multichannel electroencephalography in acute, neuroleptic-naive, first-break schizophrenics

Background: Schizophrenic symptoms commonly are felt to indicate a loosened coordination, i.e. a decreased connectivity of brain processes. Methods: To address this hypothesis directly, global and regional multichannel electroencephalographic (EEG) complexities (omega complexity and dimensional complexity) and single channel EEG dimensional complexities were calculated from 19-channel EEG data from 9 neuroleptic-naive, first-break, acute schizophrenics and 9 age- and sex-matched controls. Twenty artifact-free 2 second EEG epochs during resting with closed eyes were analyzed (2–30 Hz bandpass, average reference for global and regional complexities, local EEG gradient time series for single channels). Results: Anterior regional Omega-Complexity was significantly increased in schizophrenics compared with controls (p < 0.001) and anterior regional Dimensional Complexity showed a trend for increase. Single channel Dimensional Complexity of local gradient waveshapes was prominently increased in the schizophrenics at the right precentral location (p = 0.003). Conclusions: The results indicate a loosened cooperativity or coordination (vice versa: an increased independence) of the active brain processes in the anterior brain regions of the schizophrenics.

Curtailing the voices and the need for predictors

Comment on Transcranial magnetic stimulation of Wernicke's and Right homologous sites to curtail "voices": a randomized trial. [Biol Psychiatry. 2013]

Behavioral responses to catecholamine depletion in unmedicated, remitted subjects with bulimia nervosa and healthy subjects

BACKGROUND: Bulimia nervosa (BN) has been associated with dysregulation of the central catecholaminergic system. An instructive way to investigate the relationship between catecholaminergic function and psychiatric disorder has involved behavioral responses to experimental catecholamine depletion (CD). The purpose of this study was to examine a possible catecholaminergic dysfunction in the pathogenesis of bulimia nervosa. METHODS: CD was achieved by oral administration of alpha-methyl-para-tyrosine (AMPT) in 18 remitted female subjects with BN (rBN) and 31 healthy female control subjects. The study design consisted of a randomized, double blind, placebo-controlled crossover, single-site experimental trial. The main outcome measures were bulimic symptoms assessed by the Eating Disorder Examination-Questionnaire. Measures were assessed before and 26, 30, 54, 78, 102 hours after the first AMPT or placebo administration. RESULTS: In the experimental environment (controlled environment with a low level of food cues) rBN subjects had a greater increase in eating disorder symptoms during CD compared with healthy control subjects (condition × diagnosis interaction, p < .05). In the experimental environment, rBN subjects experienced fewer bulimic symptoms than in the natural environment (uncontrolled environment concerning food cues) 36 hours after the first AMPT intake (environment × diagnosis interaction, p < .05). Serum prolactin levels increased significantly, and to a comparable degree across groups, after AMPT administration. CONCLUSIONS: This study suggests that rBN is associated with vulnerability for developing eating disorder symptoms in response to reduced catecholamine neurotransmission after CD. The findings support the notion of catecholaminergic dysfunction as a possible trait abnormality in BN.

Social support and oxytocin interact to suppress cortisol and subjective responses to psychosocial stress

BACKGROUND The presence of social support has been associated with decreased stress responsiveness. Recent animal studies suggest that the neuropeptide oxytocin is implicated both in prosocial behavior and in the central nervous control of neuroendocrine responses to stress. This study was designed to determine the effects of social support and oxytocin on cortisol, mood, and anxiety responses to psychosocial stress in humans. METHODS In a placebo-controlled, double-blind study, 37 healthy men were exposed to the Trier Social Stress Test. All participants were randomly assigned to receive intranasal oxytocin (24 IU) or placebo 50 min before stress, and either social support from their best friend during the preparation period or no social support. RESULTS Salivary free cortisol levels were suppressed by social support in response to stress. Comparisons of pre- and poststress anxiety levels revealed an anxiolytic effect of oxytocin. More importantly, the combination of oxytocin and social support exhibited the lowest cortisol concentrations as well as increased calmness and decreased anxiety during stress. CONCLUSIONS Oxytocin seems to enhance the buffering effect of social support on stress responsiveness. These results concur with data from animal research suggesting an important role of oxytocin as an underlying biological mechanism for stress-protective effects of positive social interactions.

Dopamine receptor D4 polymorphism predicts the effect of L-DOPA on gambling behavior

BACKGROUND There is ample evidence that a subgroup of Parkinson's disease patients who are treated with dopaminergic drugs develop certain behavioral addictions such as pathological gambling. The fact that only a subgroup of these patients develops pathological gambling suggests an interaction between dopaminergic drug treatment and individual susceptibility factors. These are potentially of genetic origin, since research in healthy subjects suggests that vulnerability for pathological gambling may be linked to variation in the dopamine receptor D4 (DRD4) gene. Using a pharmacogenetic approach, we investigated how variation in this gene modulates the impact of dopaminergic stimulation on gambling behavior in healthy subjects. METHODS We administered 300 mg of L-dihydroxyphenylalanine (L-DOPA) or placebo to 200 healthy male subjects who were all genotyped for their DRD4 polymorphism. Subjects played a gambling task 60 minutes after L-DOPA administration. RESULTS Without considering genetic information, L-DOPA administration did not lead to an increase in gambling propensity compared with placebo. As expected, however, an individual's DRD4 polymorphism accounted for variation in gambling behavior after the administration of L-DOPA. Subjects who carry at least one copy of the 7-repeat allele showed an increased gambling propensity after dopaminergic stimulation. CONCLUSIONS These findings demonstrate that genetic variation in the DRD4 gene determines an individual's gambling behavior in response to a dopaminergic drug challenge. They may have implications for the treatment of Parkinson's disease patients by offering a genotype approach for determining individual susceptibilities for pathological gambling and may also afford insights into the vulnerability mechanisms underlying addictive behavior.