Multilevel impact of the dopamine system on the emotion-potentiated startle reflex.

RATIONALE/OBJECTIVES: The pathogenetic mechanism of emotion-related disorders such as anxiety disorders is considered to be complex with an interaction of genetic, biochemical, and environmental factors. Particular evidence has accumulated for alterations in the dopaminergic system-partly conferred by catechol-O-methyltransferase (COMT) gene variation-and for distorted emotional processing to constitute risk factors for anxiety and anxiety-related disorders. METHODS: Applying a multilevel approach, we analyzed the main and interactive effects of the functional COMT val158met polymorphism and L-dopa (single-dose 50 mg levodopa and 12.5 mg carbidopa; double-blind, placebo-controlled design) on the emotion-potentiated (unpleasant, neutral, and pleasant IAPS pictures) startle response as an intermediate phenotype of anxiety in a sample of 100 healthy probands (f = 52, m = 48). RESULTS: The COMT 158val allele was associated with an increased startle potentiation by unpleasant stimuli as compared with neutral stimuli irrespective of L-dopa or placebo intervention. COMT 158met/met genotype carriers, while displaying no difference in startle magnitude in response to unpleasant or neutral pictures in the placebo condition, showed startle potentiation by unpleasant pictures under L-dopa administration only. CONCLUSIONS: The present proof-of-concept study provides preliminary support for a complex, multilevel impact of the dopaminergic system on the emotion-potentiated startle reflex suggesting increased phasic dopamine transmission driven by the more active COMT 158val allele and/or a single dose of L-dopa to predispose to maladaptive emotional processing and thereby potentially also to anxiety-related psychopathological states.

Association between reward-related activation in the ventral striatum and trait reward sensitivity is moderated by dopamine transporter genotype.

The impact of individual differences on human reward processing has been a focus of research in recent years, particularly, as they are associated with a variety of neuropsychiatric diseases including addiction and attention-deficit/hyperactivity disorder. Studies exploring the neural basis of individual differences in reward sensitivity have consistently implicated the ventral striatum (VS) as a core component of the human reward system. However, the mechanisms of dopaminergic neurotransmission underlying ventral striatal activation as well as trait reward sensitivity remain speculative. We addressed this issue by investigating the triadic interplay between VS reactivity during reward anticipation using functional magnetic resonance imaging, trait reward sensitivity, and dopamine (DA) transporter genotype (40-bp 3'VNTR of DAT, SLC6A3) affecting synaptic DA neurotransmission. Our results show that DAT variation moderates the association between VS-reactivity and trait reward sensitivity. Specifically, homozygote carriers of the DAT 10-repeat allele exhibit a strong positive correlation between reward sensitivity and reward-related VS activity whereas this relationship is absent in the DAT 9-repeat allele carriers. We discuss the possibility that this moderation of VS-trait relation might arise from DAT-dependent differences in DA availability affecting synaptic plasticity within the VS. Generally, studying the impact of dopaminergic gene variations on the relation between reward-related brain activity and trait reward sensitivity might facilitate the investigation of complex mechanisms underlying disorders linked to dysregulation of DA neurotransmission.

Functional amygdala-hippocampus connectivity during anticipation of aversive events is associated with Gray's trait "sensitivity to punishment".

BACKGROUND: The reinforcement sensitivity theory postulates a behavioral inhibition system that modulates reaction to stimuli indicating aversive events. Gray's dimension of anxiety, reflecting human trait sensitivity to aversive events, determines the extent to which stimuli activate the behavioral inhibition system. Although structural brain imaging has previously identified the amygdala and the hippocampus as two major components related to the behavioral inhibition system, the functional dynamics of the responses in these structures remain unclear. METHODS: In this study, we examined the event-related functional magnetic resonance imaging blood oxygen level-dependent response in the hippocampus and amygdala as well as the functional connectivity of the two regions during anticipation of monetary loss in 45 healthy human subjects. RESULTS: Anticipation of loss elicited activation in the hippocampus as well as in the amygdala. Additionally, substantial functional connectivity between the two areas was observed. Furthermore, this functional connectivity was significantly correlated with individual differences in Gray's trait sensitivity to aversive events. Specifically, higher trait sensitivity to aversive events was associated with increased functional connectivity following cues indicating potential loss. CONCLUSIONS: In summary, we show that individual differences regarding Gray's trait sensitivity to aversive events as defined by the reinforcement sensitivity theory are associated with the neural dynamics of the amygdala-hippocampal circuit during anticipation of aversive events. In particular, evidence is provided for a relationship between functional brain imaging data and a psychometric approach specifically measuring Gray's trait sensitivity to aversive events, thereby potentially identifying the neural substrate of the behavioral inhibition system.

Far field potentials from brain stem after transcutaneous vagus nerve stimulation: optimization of stimulation and recording parameters.

The method of vagus somatosensory evoked potentials (VSEP) was introduced to easily measure the activity of vagus brain stem nuclei. In Alzheimer's disease, this measure was characterized by longer latencies as compared to controls while amplitudes did not show statistical significant differences at frontal and central recording sites. Therefore, the influence of stimulation and recording parameters on amplitudes of VSEP were systematically examined. In 20 healthy participants, VSEP measurement was done by electrical stimulation of the cutaneous representation of the vagus nerve in the external auditory channel and recording of VSEP over the scalp. The optimum stimulation intensity is 8 mA without perception of pain. There is no effect of stimulation side or gender. Maximum VSEP amplitudes are detected at bipolar recordings comprising the electrode T4 without statistically significant differences of latencies, wave shape and polarity. Thus, recordings of future examinations should be performed at 8 mA including this temporal electrode position. The reason for focussing on brain stem evoked potentials is that recent work has accumulated evidence for this area being involved in early phases of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Improved methodological knowledge may facilitate the assessment of this non-invasive and cost-effective method in the early diagnosis of neurodegenerative disorders.

Auricular vagus somatosensory evoked potentials in vascular dementia.

A new method for the assessment of vagus nerve function has recently been introduced into clinical practice. In the present study we could show that, contrary to our results in Alzheimer's disease (AD), in patients with vascular dementia (VaD) vagus sensory evoked potentials (VSEP) did not show statistically significant differences as compared to healthy controls. Thus, we hypothesize that the new method of VSEP could possibly contribute to a differential diagnosis between early cases of AD and VaD.