brain response to negaxve feedback (FRN) and brain-â heart associaxons following negaxve feedback (N300_4). We further show that both of these measures ...
NEUROVISCERAL CONNECTIVITY AND BRAIN ACTIVITY FOLLOWING NEGATIVE FEEDBACK – TWO COMT VAL158MET DEPENDENT INTERMEDIATE PHENOTYPES FOR TRAIT ANXIETY 1 1 1 2 1 Erik M. Mueller , Isabella Mayer , Gerhard Stemmler , Jürgen Hennig , & Jan Wacker 1 Marburg University, Germany 2 Giessen University, Germany Contact: erik.mueller@staff.uni-‐marburg.de
The goal of the present study was to test whether COMT and anxiety are associated with neurovisceral coupling (i.e. N300_4) and feedback processing (i.e. FRN).
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Discussion
COMT Val158Met has previously been linked to neuroWcism and anxiety disorders [1,2]. Here we show that COMT Val158Met independently modulates the brain response to negaWve feedback (FRN) and brain-‐ heart associaWons following negaWve feedback (N300_4). We further show that both of these measures are (independently) correlated with quesWonnaire measures of trait anxiety.
−5 −5
Time in EEG (ms) 4
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COMT modulates N300_4 to neg. Feedback (p < .05)2
VAL/VAL
N300_4 to neg. Feedback predicts anxiety (p < .05)2
VAL/MET 2
MET/MET
-‐0.2 -‐0.15
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0 VAL/VAL VAL/MET MET/MET
0.2 0.1 0 -‐0.1 -‐0.2 -‐0.3 -‐0.4 -‐0.5 -‐0.6 -‐3
-‐1 1 Anxiety-‐Factor score
-3
Replica9on in re-‐analysis of different dataset [6] (p < .05, one-‐tailed)
time rel. feedback (ms)
CECT (Cz, any feedback)
Feedback-‐related Nega9vity predicts anxiety r(175) = .201; p < .01)
Time in HP (ms)
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N300_4
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0.2 0.1 0 -‐0.1 -‐0.2 -‐0.3 -‐0.4 -‐0.5 -‐0.6 1.5
2.5 BIS score
Time in EEG (ms)
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FRN (uV)
How the Val-‐allele could be related to elevated anxiety 0
Intermediate Phenotype
Genotype
Phenotype
VAL>MET Noradrenaline?
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COMT Val158Met
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Anxiety-Factor Score
1 remains significant when controlling for N300_4 (p < .05)
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Neurovisceral ConnecWvity awer negaWve Feedback
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Dopamine?
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NegaWve Feedback Processing 2 remains significant when controlling for FRN (p < .05)
By affecWng DA and NE, the COMTVal158Met Val allele may potenWate central and peripheral responses to negaWve events, respecWvely, and thereby increase the experience of negaWve affect and anxiety across different situaWons.
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FRN
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• N=199 healthy male parWcipants (right handed, 20-‐35 years) performed an adapWve Wme-‐esWmaWon task and received k = 80 Wmes posiWve, negaWve or uninformaWve feedback at the end of each trial [8] • ECG converted to heart period trace (HP) by automated r-‐spike detecWon and conversion tool. • EEG (32/64 channel BioSemi AcWveTwo system) sampled at 128 Hz and band-‐pass filtered (.1 – 40 Hz). Visually inspected for artefacts. Eye movement artefacts removed via ICA. Exclusion of n = 24 parWcipants due to bad EEG or ECG recording. • Individual CECTs computed using Wme-‐lagged correlaWons (correlaWng over trials) of single-‐trial HP (10 lags of 500 ms each, ranging from 0 – 5000 ms relaWve to feedback sWmulus) and EEG magnitude at channel Cz (100 lags of approximately 8 ms each, ranging from -‐300 to 500 ms), separately for all feedback types. • N300_4 was measured as the mean intraindividual correlaWon between EEG magnitude from 300-‐350 ms and HP from 3500-‐4000 ms; FRN was measured as the peak amplitude between 200 and 300 ms relaWve to the feedback sWmulus at channel Fz. • Genotyping by real Wme PCR using fluorescence melWng curve detecWon analysis. Final sample n= 33, 87, 55 for Val/Val, Val/Met and Met/Met, respecWvely. • Phenotyping by factor analysis of ANX scales from several personality quesWonnaires (NEO, ZKPQ, PSWQ, BIS/ BAS). First factor was used for analyses. • Placebo vs. sulpiride (200mg, randomized, double-‐blind) was taken orally 3 hours prior to task. Because sulpiride did not influence N300_4 or FRN this factor will not be further reported here.
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Methods
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COMT modulates Feedback-‐related nega9vity (p < .01)1 Feedback-locked event-related potential (Fz, negative feedback)
N300_4
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t-‐value (df = 174)
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N300_4 (r)
DA has been linked to feedback processing, in parWcular to the feedback-‐related negaWvity (FRN) ERP-‐component [7]. Because the FRN and related components have previously been linked to ANX, the FRN may serve as a further intermediate phenotype linking COMT Val158Met to ANX [8, 9].
No direct associaWon between COMT Val158Met and quesWonnaire measures of anxiety (p > .2)
N300_4 (r)
NE has been linked to neurovisceral (brain-‐body) coupling [3] which plays an important role in the psychophysiology of ANX [4,5]. Cardio-‐electroencephalographic covariance tracing (CECT; 6), which reflects the systemaWc computaWon of intraindividual Wme-‐lagged correlaWons between EEG magnitudes and heart inter-‐beat intervals at varying latencies provides a method to study neurovisceral coupling. The previously idenWfied N300_4 component is an indicator for the magnitude of neurovisceral coupling in the P300 Wme-‐range [6], presumably linked to NE [3], and may therefore serve as an intermediate phenotype linking COMT Val158Met to ANX.
CECT (Cz, any feedback)
Time in HP (ms)
The Catechol-‐O-‐Methyltransferase (COMT) is responsible for the degradaWon of brain norepinephrine (NE) and dopamine (DA). The link between the Val allele of the COMT Val158Met polymorphism (associated with elevated DA and NE metabolism) and neuroWcism/anxiety (ANX) has been heavily studied although the mechanisms of this associaWon are not known [1,2].
Results
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4 N300_4 indicates 9me-‐lagged EEG-‐HP covaria9on 4(p < .05)
N300_4(r)
Voltage (uV)
Background
5
NeuroWcism/ Anxiety
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