Erik M. Mueller

Acute tryptophan depletion attenuates brain-heart coupling following external feedback

External and internal performance feedback triggers neural and visceral modulations such as reactions in the medial prefrontal cortex and insulae or changes of heart period (HP). The functional coupling of neural and cardiac responses following feedback (cortico-cardiac connectivity) is not well understood. While linear time-lagged within-subjects correlations of single-trial EEG and HP (cardio-electroencephalographic covariance tracing, CECT) indicate a robust negative coupling of EEG magnitude 300 ms after presentation of an external feedback stimulus with subsequent alterations of heart period (the so-called N300H phenomenon), the neurotransmitter systems underlying feedback-evoked cortico-cardiac connectivity are largely unknown. Because it has been shown that acute tryptophan depletion (ATD), attenuating brain serotonin (5-HT), decreases cardiac but not neural correlates of feedback processing, we hypothesized that 5-HT may be involved in feedback-evoked cortico-cardiac connectivity. In a placebo-controlled double-blind cross-over design, 12 healthy male participants received a tryptophan-free amino-acid drink at one session (TRP−) and a balanced amino-acid control-drink (TRP+) on another and twice performed a time-estimation task with feedback presented after each trial. N300H magnitude and plasma tryptophan levels were assessed. Results indicated a robust N300H after TRP+, which was significantly attenuated following TRP−. Moreover, plasma tryptophan levels during TRP+ were correlated with N300H amplitude such that individuals with lower tryptophan levels showed reduced N300H. Together, these findings indicate that 5-HT is important for feedback-induced covariation of cortical and cardiac activity. Because individual differences in anxiety have previously been linked to 5-HT, cortico-cardiac coupling and feedback processing, the present findings may be particularly relevant for futures studies on the relationship between 5-HT and anxiety.

Electrophysiological Correlates of Spatial Orienting Towards Angry Faces: A Source Localization Study

The goal of this study was to examine behavioral and electrophysiological correlates of involuntary orienting toward rapidly presented angry faces in non-anxious, healthy adults using a dot-probe task in conjunction with high-density event-related potentials and a distributed source localization technique. Consistent with previous studies, participants showed hypervigilance toward angry faces, as indexed by facilitated response time for validly cued probes following angry faces and an enhanced P1 component. An opposite pattern was found for happy faces suggesting that attention was directed toward the relatively more threatening stimuli within the visual field (neutral faces). Source localization of the P1 effect for angry faces indicated increased activity within the anterior cingulate cortex, possibly reflecting conflict experienced during invalidly cued trials. No modulation of the early C1 component was found for affect or spatial attention. Furthermore, the face-sensitive N170 was not modulated by emotional expression. Results suggest that the earliest modulation of spatial attention by face stimuli is manifested in the P1 component, and provide insights about mechanisms underlying attentional orienting toward cues of threat and social disapproval.

Dopamine Effects on Human Error Processing Depend on Catechol-O-Methyltransferase VAL158MET Genotype

Brain dopamine (DA) has been linked to error processing. Because high and low (vs medium) prefrontal cortex (PFC) DA levels may facilitate D2-receptor-related modulations of PFC neural activation patterns, we hypothesized that high and low DA predicts increased error-specific transitions of PFC activity. Male human participants (n = 169) were genotyped for the catechol-O-methyltransferase (COMT) Val158Met polymorphism, associated with low (Val) and medium (Met) PFC DA levels. In addition, DRD2TaqIa and 5-HTTLPR, associated with striatal D2 receptor density and serotonin uptake, respectively, were assessed. Participants received placebo or a selective DA–D2 receptor blocker (sulpiride, 200 mg) and performed a Flanker task. EEG was recorded and decomposed into independent brain components (ICs) using independent component analysis. After errors, participants displayed (1) a negative deflection in ICs source-localized to the proximity of the anterior midcingulate cortex [IC-error-related negativity (IC-ERN)], (2) increased midcingulate cortex IC power in the delta/theta frequency range, and (3) slowing in the subsequent trial [posterror slowing (PES)]. Importantly, all, IC-ERN, delta/theta power, and PES were modulated by COMT × Substance interactions such that the Val allele predicted elevated IC-ERN, delta/theta power, and PES after placebo; this association was reversed under sulpiride. Because low doses of sulpiride presumably increase PFC DA levels, the COMT × Substance interaction supports the hypothesis that low (Val, placebo) and high (Met, sulpiride) versus medium (Val, sulpiride; Met, placebo) DA levels elevate reactivity to errors. Consistent with an influence of serotonin on PFC DA, the COMT × Substance interaction was modulated by 5-HTTLPR.

Dopamine-D2-Receptor Blockade Reverses the Association Between Trait Approach Motivation and Frontal Asymmetry in an Approach-Motivation Context

Individual differences in the behavioral approach system (BAS)—referred to as trait approach motivation or trait BAS)—have been linked to both frontal electroencephalogram (EEG) alpha asymmetry between left and right hemispheres (frontal alpha asymmetry) and brain dopamine. However, evidence directly linking frontal alpha asymmetry and dopamine is scarce. In the present study, female experimenters recorded EEG data in 181 male participants after double-blind administration of either a placebo or a dopamine D2 blocker. As expected, trait BAS was associated with greater left- than right-frontal cortical activity (i.e., greater right- than left-frontal EEG alpha) in the placebo group, but a reversed association emerged in the dopamine-blocker group. Furthermore, frontal alpha asymmetry was associated with a genetic variant known to modulate prefrontal dopamine levels (the catechol-O-methyltransferase Val158Met polymorphism). Finally, each of these effects was significant only in the subgroup of male participants interacting with female experimenters rated as most attractive; this finding suggests that associations between frontal alpha asymmetry and both dopamine and trait BAS are detectable only in approach-motivation contexts.

Prefrontal Oscillations during Recall of Conditioned and Extinguished Fear in Humans

Human neuroimaging studies indicate that the anterior midcingulate cortex (AMC) and the ventromedial prefrontal cortex (vmPFC) play important roles in the expression and extinction of fear, respectively. Electrophysiological rodent studies further indicate that oscillatory neuronal activity in homolog regions (i.e., prelimbic and infralimbic cortices) changes during fear expression and fear extinction recall. Whether similar processes occur in humans remains largely unexplored. By assessing scalp surface EEG in conjunction with LORETA source estimation of CS-related theta and gamma activity, we tested whether a priori defined ROIs in the human AMC and vmPFC similarly modulate their oscillatory activity during fear expression and extinction recall, respectively. To this end, 42 healthy individuals underwent a differential conditioning/differential extinction protocol with a Recall Test on the next day. In the Recall Test, nonextinguished versus extinguished stimuli evoked an increased differential (CS+ vs CS−) response with regard to skin conductance and AMC-localized theta power. Conversely, extinguished versus nonextinguished stimuli evoked an increased differential response with regard to vmPFC-localized gamma power. Finally, individuals who failed to show a suppressed skin conductance response to the extinguished versus nonextinguished CS+ also failed to show the otherwise observed alterations in vmPFC gamma power to extinguished CS+. These results indicate that fear expression is associated with AMC theta activity, whereas successful fear extinction recall relates to changes in vmPFC gamma activity. The present work thereby bridges findings from prior rodent electrophysiological research and human neuroimaging studies and indicates that EEG is a valuable tool for future fear extinction research.

POTENTIATED PROCESSING OF NEGATIVE FEEDBACK IN DEPRESSION IS ATTENUATED BY ANHEDONIA

Although cognitive theories of depression have postulated enhanced processing of negatively valenced information, previous EEG studies have shown both increased and reduced sensitivity for negative performance feedback in MDD. To reconcile these paradoxical findings, it has been speculated that sensitivity for negative feedback is potentiated in moderate MDD, but reduced in highly anhedonic subjects. The goal of this study was to test this hypothesis by analyzing the feedback‐related negativity (FRN), frontomedial theta power (FMT), and source‐localized anterior midcingulate cortex (aMCC) activity after negative feedback.

The COMT Val158Met polymorphism regulates the effect of a dopamine antagonist on the feedback-related negativity

Consistent with dopamine accounts of internal and external feedback processing, prior work showed that the dopamine D2 receptor antagonist sulpiride modulates the relationship between the dopaminergic COMT Val158Met polymorphism and the error-related negativity (ERN). Here, we tested in an independent sample whether this Gene × Substance interaction generalizes to the feedback-related negativity (FRN), which presumably shares underlying dopaminergic mechanisms with the ERN. N = 83 female participants genotyped for COMT Val158Met received 200 mg sulpiride versus placebo and performed a virtual ball-catching task. The FRN to positive versus negative feedback was modulated by a significant COMT × Substance interaction. Mirroring prior work on the ERN, the tendency of the FRN to be more pronounced for VAL+ versus MET/MET carriers after placebo was reversed by sulpiride. The findings thus provide new evidence for dopaminergic models of feedback processing.

5-HTTLPR and anxiety modulate brain-heart covariation.

To date, little is known about genes affecting the interplay of brain and heart activity. Because serotonin (5-HT) is involved in corticovagal neurotransmission, we tested whether the 5-HT transporter polymorphism 5-HTTLPR affects brain-heart covariation. Further, associations with neuroticism/anxiety (NANX) were tested, as anxiety is related to 5-HT and neurogenic changes of heart period (HP). N = 168 participants performed a time-estimation task while EEG and HP were recorded. Brain-heart covariation was measured using time-lagged within-subject correlations of centromedial feedback-evoked single-trial EEG at 300 ms and subsequent changes of HP. EEG-HP correlations were higher in 5-HTTLPR long allele carriers. Moreover, after negative feedback, EEG-HP correlations and feedback-related negativity amplitudes independently correlated with NANX. The results indicate that individual differences in brain-heart covariation relate to 5-HT and NANX.

The type IV phosphodiesterase inhibitor rolipram disturbs expression and extinction of conditioned fear in mice

Recent studies suggest that intracellular signaling pathways involving cyclic adenosine monophosphate (cAMP) may be related to fear processing and long-term memory formation. The type IV phosphodiesterase (PDE4) inhibitor rolipram prevents breakdown of cAMP, enhances long-term memory and may reduce anxiety. In the present study we investigated the role of rolipram in the expression (0, 0.2, or 1 mg/kg), acquisition (0, 0.03, 0.2 or 1 mg/kg), and extinction (0, 0.03, 0.2, 1 mg/kg) of fear using a fear-potentiated startle paradigm in mice. It was shown that rolipram reduced the expression (Experiment 1), did not influence acquisition (Experiment 2) and disturbed between-session extinction (Experiments 3 and 4) of fear responses to conditioned tones. Because within-session extinction was not impaired by rolipram and because low (i.e. 0.03 and 0.2 mg/kg) doses strongly affected extinction but not expression of fear, these findings suggest that the effect of rolipram on extinction is not directly dependent on its effect on fear expression. Taken together, these experiments indicate that preventing breakdown of cAMP interferes with the expression and extinction consolidation of conditioned fear.

Conditioned and extinguished fear modulate functional corticocardiac coupling in humans.

Although the conditioned cardiac fear response is an important index of psychophysiological fear processing, underlying neural mechanisms remain unclear. N = 22 participants underwent differential fear conditioning and extinction with face pictures as conditioned stimuli (CS) and loud noise bursts as aversive unconditioned stimulus (US) on Day 1 and a recall test 1 day later. We assessed ERPs, evoked heart period (HP), and time-lagged within-subject correlations of single-trial EEG amplitude and HP as index for corticocardiac coupling in response to the CS. Fear-conditioned stimuli (CS+) triggered cardiac deceleration during fear acquisition and recall. Meanwhile, only during Day 1 acquisition, CS+ evoked larger late positivities in the ERP than CS-. Most importantly, during Day 2 recall, stimulus-evoked single-trial EEG responses in the time window between 250 and 500 ms predicted the magnitude of cardiac fear responses 2 to 5 s later. This marker of corticocardiac coupling selectively emerged in response to not previously extinguished CS+ but was absent in response to CS- or previously extinguished CS+. The present results provide first evidence that fear conditioning and extinction modulate functional corticocardiac coupling in humans. Underlying mechanisms may involve subcortical structures enhancing corticocardiac transmission to facilitate processing of consolidated conditioned fear.