title: Representational similarity analysis offers a preview of the noradrenergic modulation of long-term fear memory at the time of encoding.
abstract: Neuroimaging research on emotional memory has greatly advanced our understanding of the pathogenesis of anxiety disorders. While the behavioral expression of fear at the time of encoding does not predict whether an aversive experience will evolve into long-term fear memory, the application of multi-voxel pattern analysis (MVPA) for the analysis of BOLD-MRI data has recently provided a unique marker for memory formation. Here, we aimed to further investigate the utility of this marker by modulating the strength of fear memory with an α2-adrenoceptor antagonist (yohimbine HCl). Fifty-two healthy participants were randomly assigned to two conditions - either receiving 20mg yohimbine or a placebo pill (double-blind) - prior to differential fear conditioning and MRI-scanning. We examined the strength of fear associations during acquisition and retention of fear (48 h later) by assessing the similarity of BOLD-MRI patterns and pupil dilation responses. Additionally, participants returned for a follow-up test outside the scanner (2-4 weeks), during which we assessed fear-potentiated startle responses. Replicating our previous findings, neural pattern similarity reflected the development of fear associations over time, and unlike average activation or pupil dilation, predicted the later expression of fear memory (pupil dilation 48 h later). While no effect of yohimbine was observed on markers of autonomic arousal, including salivary α-amylase (sAA), we obtained indirect evidence for the noradrenergic enhancement of fear memory consolidation: sAA levels showed a strong increase prior to fMRI scanning, irrespective of whether participants had received yohimbine, and this increase correlated with the subsequent expression of fear (48 h later). Remarkably, this noradrenergic enhancement of fear was associated with changes in neural response patterns at the time of learning. These findings provide further evidence that representational similarity analysis is a sensitive tool for studying (enhanced) memory formation.
authors.affiliation: Department of Psychology, University of Amsterdam, 1018 XA Amsterdam, The Netherlands; Amsterdam Brain and Cognition (ABC), University of Amsterdam, 1018 VZ Amsterdam, The Netherlands.
authors.forename: Renée M
authors.initials: RM
authors.lastname: Visser
authors.affiliation: Department of Psychology, University of Amsterdam, 1018 XA Amsterdam, The Netherlands; Amsterdam Brain and Cognition (ABC), University of Amsterdam, 1018 VZ Amsterdam, The Netherlands.
authors.forename: Anna E
authors.initials: AE
authors.lastname: Kunze
authors.affiliation: Department of Psychology, University of Amsterdam, 1018 XA Amsterdam, The Netherlands.
authors.forename: Bianca
authors.initials: B
authors.lastname: Westhoff
authors.affiliation: Department of Psychology, University of Amsterdam, 1018 XA Amsterdam, The Netherlands; Amsterdam Brain and Cognition (ABC), University of Amsterdam, 1018 VZ Amsterdam, The Netherlands.
authors.forename: H Steven
authors.initials: HS
authors.lastname: Scholte
authors.affiliation: Department of Psychology, University of Amsterdam, 1018 XA Amsterdam, The Netherlands; Amsterdam Brain and Cognition (ABC), University of Amsterdam, 1018 VZ Amsterdam, The Netherlands. Electronic address: M.Kindt@uva.nl.
authors.forename: Merel
authors.initials: M
authors.lastname: Kindt
mesh_terms: D000293:Adolescent; D058669:Adrenergic alpha-2 Receptor Antagonists / Q000494:pharmacology; D000679:Amygdala / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000502:physiology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D004311:Double-Blind Method; D005239:Fear / Q000187:drug effects / Q000502:physiology*; D005260:Female; D059907:Functional Neuroimaging; D006179:Gyrus Cinguli / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D057567:Memory, Long-Term / Q000187:drug effects / Q000502:physiology*; D009638:Norepinephrine / Q000502:physiology*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000502:physiology; D011680:Pupil / Q000187:drug effects / Q000502:physiology; D011897:Random Allocation; D021641:Recognition, Psychology; D013216:Reflex, Startle / Q000187:drug effects / Q000502:physiology; D012463:Saliva / Q000737:chemistry; D055291:Salivary alpha-Amylases / Q000032:analysis / Q000187:drug effects; D015016:Yohimbine / Q000494:pharmacology; D055815:Young Adult
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D015016:Yohimbine; D055291:Salivary alpha-Amylases; D009638:Norepinephrine
keywords: Fear conditioning; Multi-voxel pattern analysis; Noradrenergic activation; Representational similarity analysis; Salivary α-amylase; fMRI