Publications by authors named "Michael M Plichta"

74 Publications

Transdiagnostic neuroimaging of reward system phenotypes in ADHD and comorbid disorders.

Neurosci Biobehav Rev 2021 09 16;128:165-181. Epub 2021 Jun 16.

Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University, Frankfurt, Germany.

ADHD is a disorder characterized by changes in the reward system and which is highly comorbid with other mental disorders, suggesting common neurobiological pathways. Transdiagnostic neuroimaging findings could help to understand whether a dysregulated reward pathway might be the actual link between ADHD and its comorbidities. We here synthesize ADHD neuroimaging findings on the reward system with findings in obesity, depression, and substance use disorder including their comorbid appearance regarding neuroanatomical features (structural MRI) and activation patterns (resting-state and functional MRI). We focus on findings from monetary-incentive-delay (MID) and delay-discounting (DD) tasks and then review data on striatal connectivity and volumetry. Next, for better understanding of comorbidity in adult ADHD, we discuss these neuroimaging features in ADHD, obesity, depression and substance use disorder and ask whether ADHD heterogeneity and comorbidity are reflected by a common dysregulation in the reward system. Finally, we highlight conceptual issues related to heterogeneous paradigms, different phenotyping, longitudinal prediction and highlight some promising future directions for using striatal reward functioning as a clinical biomarker.
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http://dx.doi.org/10.1016/j.neubiorev.2021.06.025DOI Listing
September 2021

Early Maternal Care and Amygdala Habituation to Emotional Stimuli in Adulthood.

Soc Cogn Affect Neurosci 2021 May 8. Epub 2021 May 8.

Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Mannheim, Baden-Württemberg, Germany.

Evidence suggests that maternal care constitutes a protective factor for psychopathology which may be conditional on the level of family adversity. Given that psychopathology is frequently linked with social deficits, and the amygdala with social functioning, we investigated the impact of early maternal care on amygdala function under high versus low familial risk for psychopathology. Amygdala activity and habituation during an emotional face-matching paradigm was analyzed in participants of an epidemiological cohort study followed since birth (N=172, 25 years). Early mother-infant interaction was assessed during a standardized nursing and play setting at the age of 3 months. Information on familial risk during the offspring's childhood and on the participants' lifetime psychopathology was obtained with diagnostic interviews. An interaction between maternal stimulation and familial risk was found on amygdala habituation but not on activation, with higher maternal stimulation predicting stronger amygdala habituation in the familial risk group only. Furthermore, amygdala habituation correlated inversely with ADHD diagnoses. The findings underline the long-term importance of early maternal care on the offspring´s socioemotional neurodevelopment and of interventions targeting maternal sensitivity early in life, particularly by increasing maternal interactive behavior in those with familial risk.
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http://dx.doi.org/10.1093/scan/nsab059DOI Listing
May 2021

Ventral Striatal Activation During Reward Anticipation of Different Reward Probabilities in Adolescents and Adults.

Front Hum Neurosci 2021 20;15:649724. Epub 2021 Apr 20.

Department of Child and Adolescent Psychiatry, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.

Adolescence has been linked to an enhanced tolerance of uncertainty and risky behavior and is possibly connected to an increased response toward rewards. However, previous research has produced inconsistent findings. To investigate whether these findings are due to different reward probabilities used in the experimental design, we extended a monetary incentive delay (MID) task by including three different reward probabilities. Using functional magnetic resonance imaging, 25 healthy adolescents and 22 adults were studied during anticipation of rewards in the VS. Differently colored cue stimuli indicated either a monetary or verbal trial and symbolized different reward probabilities, to which the participants were blinded. Results demonstrated faster reaction times for lower reward probabilities (33%) in both age groups. Adolescents were slower through all conditions and had less activation on a neural level. Imaging results showed a three-way interaction between age group x condition x reward probability with differences in percent signal change between adolescents and adults for the high reward probabilities (66%, 88%) while adolescents demonstrated differences for the lowest (33%). Therefore, previous inconsistent findings could be due to different reward probabilities, which makes examining these crucial for a better understanding of adolescent and adult behavior.
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http://dx.doi.org/10.3389/fnhum.2021.649724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093817PMC
April 2021

Differential impact of COVID-related lockdown on mental health in Germany.

World Psychiatry 2021 Feb;20(1):140-141

Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany.

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http://dx.doi.org/10.1002/wps.20830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801843PMC
February 2021

Transdiagnostic Prediction of Affective, Cognitive, and Social Function Through Brain Reward Anticipation in Schizophrenia, Bipolar Disorder, Major Depression, and Autism Spectrum Diagnoses.

Schizophr Bull 2020 04;46(3):592-602

Systems Neuroscience in Psychiatry, Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.

The relationship between transdiagnostic, dimensional, and categorical approaches to psychiatric nosology is under intense debate. To inform this discussion, we studied neural systems linked to reward anticipation across a range of disorders and behavioral dimensions. We assessed brain responses to reward expectancy in a large sample of 221 participants, including patients with schizophrenia (SZ; n = 27), bipolar disorder (BP; n = 28), major depressive disorder (MD; n = 31), autism spectrum disorder (ASD; n = 25), and healthy controls (n = 110). We also characterized all subjects with an extensive test battery from which a cognitive, affective, and social functioning factor was constructed. These factors were subsequently related to functional responses in the ventral striatum (vST) and neural networks linked to it. We found that blunted vST responses were present in SZ, BP, and ASD but not in MD. Activation within the vST predicted individual differences in affective, cognitive, and social functioning across diagnostic boundaries. Network alterations extended beyond the reward network to include regions implicated in executive control. We further confirmed the robustness of our results in various control analyses. Our findings suggest that altered brain responses during reward anticipation show transdiagnostic alterations that can be mapped onto dimensional measures of functioning. They also highlight the role of executive control of reward and salience signaling in the disorders we study and show the power of systems-level neuroscience to account for clinically relevant behaviors.
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http://dx.doi.org/10.1093/schbul/sbz075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7147576PMC
April 2020

Deficient Amygdala Habituation to Threatening Stimuli in Borderline Personality Disorder Relates to Adverse Childhood Experiences.

Biol Psychiatry 2019 12 19;86(12):930-938. Epub 2019 Jun 19.

Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelburg University, Mannheim, Germany.

Background: Heightened amygdala response to threatening cues has been repeatedly observed in borderline personality disorder (BPD). A previous report linked hyperactivation to deficient amygdala habituation to repeated stimuli, but the biological underpinnings are incompletely understood.

Methods: We examined a sample of 120 patients with BPD and 115 healthy control subjects with a well-established functional magnetic resonance imaging emotional face processing task to replicate the previously reported amygdala habituation deficit in BPD and probed this neural phenotype for associations with symptom severity and early social risk exposure.

Results: Our results confirm a significant reduction in amygdala habituation to repeated negative stimuli in BPD (p = .015, peak-level familywise error [FWE] corrected for region of interest). Post hoc comparison and regression analysis did not suggest a role for BPD clinical state (p > .56) or symptom severity (p > .45) for this phenotype. Furthermore, deficient amygdala habituation was significantly related to increased exposure to adverse childhood experiences (p = .013, region of interest corrected).

Conclusions: Our data replicate a prior report on deficient amygdala habituation in BPD and link this neural phenotype to early adversity, a well-established social environmental risk factor for emotion dysregulation and psychiatric illness.
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http://dx.doi.org/10.1016/j.biopsych.2019.06.008DOI Listing
December 2019

Reliable and efficient recording of the error-related negativity with a speeded Eriksen Flanker Task.

Acta Neuropsychiatr 2019 Jun 18;31(3):135-142. Epub 2018 Dec 18.

Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Heinrich-Hoffmann-Straße 10, 60528 Frankfurt, Germany.

Objective: There is accumulating evidence that the error-related negativity (ERN), an event-related potential elicited after erroneous actions, is altered in different psychiatric disorders and may help to guide treatment options. Thus, the ERN is a promising candidate as a psychiatric biomarker. Basic methodological requirements for a biomarker are that their measurements are standardised and reliable. The aim of the present study was to establish ERN acquisition in a reliable, time-efficient and patient-friendly way for use in clinical practice.

Methods: Healthy subjects performed a speeded Eriksen Flanker Task that increases the number of errors. In a test-retest design (N = 14) with two sessions separated by 28 days we assessed the reliability of the ERN. To ensure external validity, we aimed to replicate previously reported correlation patterns of ERN amplitude with (A) number of errors and (B) negative affect. In order to optimise the clinical use of the task, we determined to which extent the task can be shortened while keeping reliability >0.80.

Results: We found excellent reliability of the ERN (intraclass correlation coefficients = 0.806-0.947) and replicated ERN correlation patterns. The task can be halved to a patient-friendly length of 200 trials (recorded in 8 min) keeping reliability >0.80.

Conclusions: The modified task provides reliable and efficient recording of the ERN, facilitating its use as a psychiatric biomarker.
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http://dx.doi.org/10.1017/neu.2018.36DOI Listing
June 2019

Early maternal care may counteract familial liability for psychopathology in the reward circuitry.

Soc Cogn Affect Neurosci 2018 11;13(11):1191-1201

Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim / Heidelberg University, J5, Mannheim, Germany.

Reward processing is altered in various psychopathologies and has been shown to be susceptible to genetic and environmental influences. Here, we examined whether maternal care may buffer familial risk for psychiatric disorders in terms of reward processing. Functional magnetic resonance imaging during a monetary incentive delay task was acquired in participants of an epidemiological cohort study followed since birth (N = 172, 25 years). Early maternal stimulation was assessed during a standardized nursing/playing setting at the age of 3 months. Parental psychiatric disorders (familial risk) during childhood and the participants' previous psychopathology were assessed by diagnostic interview. With high familial risk, higher maternal stimulation was related to increasing activation in the caudate head, the supplementary motor area, the cingulum and the middle frontal gyrus during reward anticipation, with the opposite pattern found in individuals with no familial risk. In contrast, higher maternal stimulation was associated with decreasing caudate head activity during reward delivery and reduced levels of attention deficit hyperactivity disorder (ADHD) in the high-risk group. Decreased caudate head activity during reward anticipation and increased activity during delivery were linked to ADHD. These findings provide evidence of a long-term association of early maternal stimulation on both adult neurobiological systems of reward underlying externalizing behavior and ADHD during development.
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http://dx.doi.org/10.1093/scan/nsy087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6234324PMC
November 2018

Experimental and methodological factors affecting test-retest reliability of amygdala BOLD responses.

Psychophysiology 2018 12 30;55(12):e13220. Epub 2018 Jul 30.

Department of Clinical Psychology and Neuropsychology, Institute of Psychology, Johannes Gutenberg University, Mainz, Germany.

Previous studies reported poor to fair test-retest reliability of amygdala BOLD responses to emotional stimuli. However, these findings are very heterogeneous across and within studies. The present study sought to systematically examine experimental and methodological factors that contribute to this heterogeneity. Forty-six young subjects were scanned twice with a mean test-retest interval of 7 weeks. We compared amygdala reliability across three tasks: A face-matching task, passive viewing of emotional faces, and passive viewing of emotional scenes. We also explored whether extraction of physiological noise can affect the stability of amygdala responses. We assessed test-retest reliability of amygdala mean amplitudes at the individual level and spatial repeatability (i.e., stability of the spatial distribution of activation) of the amygdala BOLD signal at the group and individual level. All three tasks evoked robust amygdala activation at the group level. At the individual level, amygdala spatial repeatability was poor during passive viewing of scenes and faces and fair or close to fair in the face-matching task. On the other hand, reliability of amygdala mean responses was very poor in the face-matching task while it was significantly higher during passive viewing of faces and scenes. Physiological noise correction changed reliability rates but not uniformly across the three tasks. The current work suggests that the presence of a concurrent task during emotion processing affects amygdala reliability. The dissociation between spatial repeatability and reliability of mean amplitudes highlights the importance of taking into account both measures for a multidimensional assessment of the reliability of BOLD responses.
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http://dx.doi.org/10.1111/psyp.13220DOI Listing
December 2018

Incongruence Between Observers' and Observed Facial Muscle Activation Reduces Recognition of Emotional Facial Expressions From Video Stimuli.

Front Psychol 2018 6;9:864. Epub 2018 Jun 6.

Centre for Applied Autism Research, Department of Psychology, University of Bath, Bath, United Kingdom.

According to embodied cognition accounts, viewing others' facial emotion can elicit the respective emotion representation in observers which entails simulations of sensory, motor, and contextual experiences. In line with that, published research found viewing others' facial emotion to elicit automatic matched facial muscle activation, which was further found to facilitate emotion recognition. Perhaps making congruent facial muscle activity explicit produces an even greater recognition advantage. If there is conflicting sensory information, i.e., incongruent facial muscle activity, this might impede recognition. The effects of actively manipulating facial muscle activity on facial emotion recognition from videos were investigated across three experimental conditions: (a) explicit imitation of viewed facial emotional expressions (stimulus-congruent condition), (b) pen-holding with the lips (stimulus-incongruent condition), and (c) passive viewing (control condition). It was hypothesised that (1) experimental condition (a) and (b) result in greater facial muscle activity than (c), (2) experimental condition (a) increases emotion recognition accuracy from others' faces compared to (c), (3) experimental condition (b) lowers recognition accuracy for expressions with a salient facial feature in the lower, but not the upper face area, compared to (c). Participants (42 males, 42 females) underwent a facial emotion recognition experiment (ADFES-BIV) while electromyography (EMG) was recorded from five facial muscle sites. The experimental conditions' order was counter-balanced. Pen-holding caused stimulus-incongruent facial muscle activity for expressions with facial feature saliency in the lower face region, which reduced recognition of lower face region emotions. Explicit imitation caused stimulus-congruent facial muscle activity without modulating recognition. Methodological implications are discussed.
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http://dx.doi.org/10.3389/fpsyg.2018.00864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5997820PMC
June 2018

Impaired Recognition of Positive Emotions in Individuals with Posttraumatic Stress Disorder, Cumulative Traumatic Exposure, and Dissociation.

Psychother Psychosom 2018 1;87(2):118-120. Epub 2018 Mar 1.

Department of Psychiatry and Psychotherapy, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

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http://dx.doi.org/10.1159/000486342DOI Listing
October 2018

Neural correlates of response inhibition in patients with bipolar disorder during acute versus remitted phase.

World J Biol Psychiatry 2019 10 5;20(8):637-646. Epub 2018 Feb 5.

Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Frankfurt, Frankfurt, Germany.

Elevated behavioural impulsivity has been shown to be a core feature of bipolar disorder. However, no study has so far investigated impulsivity-related brain activation in patients with BD during acute versus remitted phase. To address the question whether elevated behavioural impulsivity and its differential neural pathways is a state or trait marker of BD, we employed a combined stop signal-go/no-go task in 30 controls, and 37 depressed and 15 remitted patients who were retested. Frontal brain activation was recorded using near-infrared spectroscopy. Behaviourally, we found increased impulsivity as indexed by higher stop signal reaction time for patients in their depressed phase while remitted patients did not differ from controls in any measure. In contrast, brain activation measurements revealed an opposite pattern: compared to controls, depressed patients did not show significant differences, while the remitted group displayed significantly decreased activation in bilateral prefrontal cortex during successful inhibition. Analysis of the remaining conditions (go, no-go, unsuccessful inhibition) did not reveal significant differences. Therefore, behavioural impulsivity and prefrontal hypoactivation do not seem to be a trait marker of BD. As only successful inhibition differentiated between groups, a specific dysfunction of this inhibitory process and its neural pathway may be postulated in BD.
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http://dx.doi.org/10.1080/15622975.2018.1428356DOI Listing
October 2019

The impact of enhancing perceived self-efficacy in torture survivors.

Depress Anxiety 2018 01 7;35(1):58-64. Epub 2017 Sep 7.

School of Psychology, University of New South Wales, Sydney, NSW, Australia.

Background: Perceived self-efficacy (SE) is an important factor underlying psychological well-being. Refugees suffer many experiences that can compromise SE. This study tested the impact of enhancing perceived SE on coping with trauma reminders and distress tolerance in tortured refugees.

Methods: Torture survivors (N = 40) were administered a positive SE induction in which they retrieved mastery-related autobiographical memories, or a non-SE (NSE) induction, and then viewed trauma-related images. Participants rated their distress following presentation of each image. Participants then completed a frustration-inducing mirror-tracing task to index distress tolerance.

Results: Participants in the SE condition reported less distress and negative affect, and improved coping in relation to viewing the trauma-related images than those in the NSE condition. The SE induction also led to greater persistence with the mirror-tracing task than the NSE induction.

Conclusions: These findings provide initial evidence that promoting SE in tortured refugees can assist with managing distress from trauma reminders, and promoting greater distress tolerance. Enhancing perceived SE in tortured refugees may increase their capacity to tolerate distress during therapy, and may be a useful means to improve treatment response.
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http://dx.doi.org/10.1002/da.22684DOI Listing
January 2018

Altered reward anticipation: Potential explanation for weight gain in schizophrenia?

Neurosci Biobehav Rev 2017 Apr 29;75:91-103. Epub 2017 Jan 29.

Laboratory for Social and Neural Systems Research, Department of Economics, University of Zurich, Switzerland. Electronic address:

Obesity and weight gain are severe complications of mental illness, especially schizophrenia. They result from changes in lifestyle and nutrition, side effects of medication and other, less well-understood factors. Recent studies suggest that obesity and weight gain are linked to psychopathology. Specifically, severe psychopathology is associated with greater weight dysregulation, typically weight gain. However, our knowledge about the neuroscientific basis of weight gain in schizophrenia is currently limited. We propose that altered reward anticipation, which in turn is related to striatal dopaminergic dysregulation, may explain why obesity is more prevalent in individuals with mental illness. We review evidence that reward anticipation and weight change are linked by a core deficit in dopaminergic striatal circuits. Several lines of evidence, running from animal studies to preclinical and clinical studies, suggest that striatal dopaminergic neurotransmission is a major hub for the regulation of eating behavior and that dopamine links eating behavior to other motivated behavior. From this perspective, the present review outlines a unifying perspective on dopaminergic reward anticipation as a theoretical frame to link weight gain, medication effects and psychopathology. We derive important but open empirical questions and present perspectives for new therapeutic concepts.
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http://dx.doi.org/10.1016/j.neubiorev.2017.01.029DOI Listing
April 2017

Delay discounting and response disinhibition under acute experimental stress in women with borderline personality disorder and adult attention deficit hyperactivity disorder.

Psychol Med 2016 11 30;46(15):3137-3149. Epub 2016 Aug 30.

Department of Psychosomatic Medicine and Psychotherapy,Central Institute of Mental Health,Mannheim,Germany.

Background: Impulsivity is a core feature of borderline personality disorder (BPD) and attention deficit hyperactivity disorder (ADHD). In BPD, impulsive behavior primarily occurs under acute stress; impulse control deficits under non-stress conditions may be partly related to co-morbid ADHD. We aimed to investigate whether acute experimental stress has an impact on self-reported impulsivity, response inhibition (action withholding, action cancelation) and delay discounting in BPD compared to ADHD.

Method: Thirty female BPD patients, 28 female ADHD patients (excluding patients with co-morbid BPD and ADHD), and 30 female healthy controls (HC) completed self-reports and behavioral measures of impulsivity (IMT, assessing action withholding; GoStop, measuring action cancelation, Delay Discounting Task) under baseline conditions and after an experimental stress induction (Mannheim Multicomponent Stress Test).

Results: Both patient groups reported higher impulsivity than HC, ADHD reported higher trait impulsivity than BPD. On the IMT, ADHD showed significant action-withholding deficits under both conditions, while BPD performed significantly worse than HC under stress. In BPD but not ADHD and HC, action-withholding deficits (IMT) were significantly increased under stress compared to baseline, while no group/stress effects were found for action cancelation (GoStop). Delay discounting was significantly more pronounced in BPD than in HC (no stress effect was found).

Conclusions: In BPD, behavioral deficits in action withholding (but not in action cancelation) appear to be influenced by acute experimental stress. Delay discounting seems to be a general feature of BPD, independent of co-morbid ADHD and acute stress, possibly underlying typical expressions of behavioral impulsivity in the disorder.
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http://dx.doi.org/10.1017/S0033291716001677DOI Listing
November 2016

Ventral striatum and amygdala activity as convergence sites for early adversity and conduct disorder.

Soc Cogn Affect Neurosci 2017 02;12(2):261-272

Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, 68159 Mannheim, Germany.

Childhood family adversity (CFA) increases the risk for conduct disorder (CD) and has been associated with alterations in regions of affective processing like ventral striatum (VS) and amygdala. However, no study so far has demonstrated neural converging effects of CFA and CD in the same sample. At age 25 years, functional MRI data during two affective tasks, i.e. a reward (N = 171) and a face-matching paradigm (N = 181) and anatomical scans (N = 181) were acquired in right-handed currently healthy participants of an epidemiological study followed since birth. CFA during childhood was determined using a standardized parent interview. Disruptive behaviors and CD diagnoses during childhood and adolescence were obtained by diagnostic interview (2-19 years), temperamental reward dependence was assessed by questionnaire (15 and 19 years).CFA predicted increased CD and amygdala volume. Both exposure to CFA and CD were associated with a decreased VS response during reward anticipation and blunted amygdala activity during face-matching. CD mediated the effect of CFA on brain activity. Temperamental reward dependence was negatively correlated with CFA and CD and positively with VS activity. These findings underline the detrimental effects of CFA on the offspring's affective processing and support the importance of early postnatal intervention programs aiming to reduce childhood adversity factors.
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http://dx.doi.org/10.1093/scan/nsw120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5390727PMC
February 2017

Cognitive and emotional processing of pleasant and unpleasant experiences in major depression: A matter of vantage point?

J Behav Ther Exp Psychiatry 2017 03 15;54:254-262. Epub 2016 Sep 15.

Department of Psychology, Harvard University, Cambridge, MA, USA.

Background And Objectives: In nonclinical populations, adopting a third-person perspective as opposed to a first-person perspective while analyzing negative emotional experiences fosters understanding of these experiences and reduces negative emotional reactivity. We assessed whether this generalizes to people with major depression (MD). Additionally, we assessed whether the emotion-reducing effects of adopting a third-person perspective also occur when subjects with MD and HC subjects analyze positive experiences.

Methods: Seventy-two MD subjects and 82 HC subjects analyzed a happy and a negative experience from either a first-person or a third-person perspective.

Results: Unexpectedly, we found no emotion-reducing effects of third-person perspective in either group thinking about negative events. However, across groups, third-person perspective was associated with less recounting of negative experiences and with a clearer, more coherent understanding of them. Negative affect decreased and positive affect increased in both groups analyzing happy experiences. In MD subjects, decreases in depressive affect were stronger for the third-person perspective. In both groups, positive affect increased and negative affect decreased more strongly for the third-person perspective.

Limitations: While reflecting on their positive memory, MD subjects adopted their assigned perspective for a shorter amount of time (70%) than HC subjects (78%). However, percentage of time participants adopted their assigned perspective was unrelated to the significant effects we found.

Conclusions: Both people suffering from MD and healthy individuals may benefit from processing pleasant experiences, especially when adopting a self-distant perspective.
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http://dx.doi.org/10.1016/j.jbtep.2016.09.001DOI Listing
March 2017

Interaction between COMT Val(158)Met polymorphism and childhood adversity affects reward processing in adulthood.

Neuroimage 2016 05 12;132:556-570. Epub 2016 Feb 12.

Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany; Department of Psychology, University of Potsdam, Potsdam, Germany. Electronic address:

Background: Accumulating evidence suggests that altered dopamine transmission may increase the risk of mental disorders such as ADHD, schizophrenia or depression, possibly mediated by reward system dysfunction. This study aimed to clarify the impact of the COMT Val(158)Met polymorphism in interaction with environmental variation (G×E) on neuronal activity during reward processing.

Methods: 168 healthy young adults from a prospective study conducted over 25years participated in a monetary incentive delay task measured with simultaneous EEG-fMRI. DNA was genotyped for COMT, and childhood family adversity (CFA) up to age 11 was assessed by a standardized parent interview.

Results: At reward delivery, a G×E revealed that fMRI activation for win vs. no-win trials in reward-related regions increased with the level of CFA in Met homozygotes as compared to Val/Met heterozygotes and Val homozygotes, who showed no significant effect. During the anticipation of monetary vs. verbal rewards, activation decreased with the level of CFA, which was also observed for EEG, in which the CNV declined with the level of CFA.

Conclusions: These results identify convergent genetic and environmental effects on reward processing in a prospective study. Moreover, G×E effects during reward delivery suggest that stress during childhood is associated with higher reward sensitivity and reduced efficiency in processing rewarding stimuli in genetically at-risk individuals. Together with previous evidence, these results begin to define a specific system mediating interacting effects of early environmental and genetic risk factors, which may be targeted by early intervention and prevention.
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http://dx.doi.org/10.1016/j.neuroimage.2016.02.006DOI Listing
May 2016

Positive coping styles and perigenual ACC volume: two related mechanisms for conferring resilience?

Soc Cogn Affect Neurosci 2016 05 7;11(5):813-20. Epub 2016 Jan 7.

Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, J5, 68159 Mannheim, Germany, Department of Psychology, University of Potsdam, Potsdam, Germany.

Stress exposure has been linked to increased rates of depression and anxiety in adults, particularly in females, and has been associated with maladaptive changes in the anterior cingulate cortex (ACC), which is an important brain structure involved in internalizing disorders. Coping styles are important mediators of the stress reaction by establishing homeostasis, and may thus confer resilience to stress-related psychopathology. Anatomical scans were acquired in 181 healthy participants at age 25 years. Positive coping styles were determined using a self-report questionnaire (German Stress Coping Questionnaire, SVF78) at age 22 years. Adult anxiety and depression symptoms were assessed at ages 22, 23 and 25 years with the Young Adult Self-Report. Information on previous internalizing diagnoses was obtained by diagnostic interview (2-19 years). Positive coping styles were associated with increased ACC volume. ACC volume and positive coping styles predicted anxiety and depression in a sex-dependent manner with increased positive coping and ACC volume being related to lower levels of psychopathology in females, but not in males. These results remained significant when controlled for previous internalizing diagnoses. These findings indicate that positive coping styles and ACC volume are two linked mechanisms, which may serve as protective factors against internalizing disorders.
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http://dx.doi.org/10.1093/scan/nsw005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4847701PMC
May 2016

A statistical approach for segregating cognitive task stages from multivariate fMRI BOLD time series.

Front Hum Neurosci 2015 7;9:537. Epub 2015 Oct 7.

Department of Theoretical Neuroscience, Bernstein Center for Computational Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University Mannheim, Germany.

Multivariate pattern analysis can reveal new information from neuroimaging data to illuminate human cognition and its disturbances. Here, we develop a methodological approach, based on multivariate statistical/machine learning and time series analysis, to discern cognitive processing stages from functional magnetic resonance imaging (fMRI) blood oxygenation level dependent (BOLD) time series. We apply this method to data recorded from a group of healthy adults whilst performing a virtual reality version of the delayed win-shift radial arm maze (RAM) task. This task has been frequently used to study working memory and decision making in rodents. Using linear classifiers and multivariate test statistics in conjunction with time series bootstraps, we show that different cognitive stages of the task, as defined by the experimenter, namely, the encoding/retrieval, choice, reward and delay stages, can be statistically discriminated from the BOLD time series in brain areas relevant for decision making and working memory. Discrimination of these task stages was significantly reduced during poor behavioral performance in dorsolateral prefrontal cortex (DLPFC), but not in the primary visual cortex (V1). Experimenter-defined dissection of time series into class labels based on task structure was confirmed by an unsupervised, bottom-up approach based on Hidden Markov Models. Furthermore, we show that different groupings of recorded time points into cognitive event classes can be used to test hypotheses about the specific cognitive role of a given brain region during task execution. We found that whilst the DLPFC strongly differentiated between task stages associated with different memory loads, but not between different visual-spatial aspects, the reverse was true for V1. Our methodology illustrates how different aspects of cognitive information processing during one and the same task can be separated and attributed to specific brain regions based on information contained in multivariate patterns of voxel activity.
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http://dx.doi.org/10.3389/fnhum.2015.00537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4617410PMC
November 2015

Measuring the Neural Basis of Reward Anticipation and Reward Receipt in Attention-Deficit/Hyperactivity Disorder: The Importance of Task Design.

J Am Acad Child Adolesc Psychiatry 2015 Aug;54(8):685-6

Behavioural Science Institute, Radboud University Nijmegen, Nijmegen, the Netherlands.

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http://dx.doi.org/10.1016/j.jaac.2015.05.012DOI Listing
August 2015

Amygdalar and hippocampal volume: A comparison between manual segmentation, Freesurfer and VBM.

J Neurosci Methods 2015 Sep 6;253:254-61. Epub 2015 Jun 6.

Central Institute of Mental Health, Department of Cognitive and Clinical Neuroscience, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.

Automated segmentation of the amygdala and the hippocampus is of interest for research looking at large datasets where manual segmentation of T1-weighted magnetic resonance tomography images is less feasible for morphometric analysis. Manual segmentation still remains the gold standard for subcortical structures like the hippocampus and the amygdala. A direct comparison of VBM8 and Freesurfer is rarely done, because VBM8 results are most often used for voxel-based analysis. We used the same region-of-interest (ROI) for Freesurfer and VBM8 to relate automated and manually derived volumes of the amygdala and the hippocampus. We processed a large manually segmented dataset of n=92 independent samples with an automated segmentation strategy (VBM8 vs. Freesurfer Version 5.0). For statistical analysis, we only calculated Pearsons's correlation coefficients, but used methods developed for comparison such as Lin's concordance coefficient. The correlation between automatic and manual segmentation was high for the hippocampus [0.58-0.76] and lower for the amygdala [0.45-0.59]. However, concordance coefficients point to higher concordance for the amygdala [0.46-0.62] instead of the hippocampus [0.06-0.12]. VBM8 and Freesurfer segmentation performed on a comparable level in comparison to manual segmentation. We conclude (1) that correlation alone does not capture systematic differences (e.g. of hippocampal volumes), (2) calculation of ROI volumes with VBM8 gives measurements comparable to Freesurfer V5.0 when using the same ROI and (3) systematic and proportional differences are caused mainly by different definitions of anatomic boundaries and only to a lesser part by different segmentation strategies. This work underscores the importance of using method comparison techniques and demonstrates that even with high correlation coefficients, there can be still large differences in absolute volume.
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http://dx.doi.org/10.1016/j.jneumeth.2015.05.024DOI Listing
September 2015

Apolipoprotein E-dependent load of white matter hyperintensities in Alzheimer's disease: a voxel-based lesion mapping study.

Alzheimers Res Ther 2015 15;7(1):27. Epub 2015 May 15.

Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, J5, 68159, Mannheim, Germany.

Introduction: White matter (WM) magnetic resonance imaging (MRI) hyperintensities are common in Alzheimer's disease (AD), but their pathophysiological relevance and relationship to genetic factors are unclear. In the present study, we investigated potential apolipoprotein E (APOE)-dependent effects on the extent and cognitive impact of WM hyperintensities in patients with AD.

Methods: WM hyperintensity volume on fluid-attenuated inversion recovery images of 201 patients with AD (128 carriers and 73 non-carriers of the APOE ε4 risk allele) was determined globally as well as regionally with voxel-based lesion mapping. Clinical, neuropsychological and MRI data were collected from prospective multicenter trials conducted by the German Dementia Competence Network.

Results: WM hyperintensity volume was significantly greater in non-carriers of the APOE ε4 allele. Lesion distribution was similar among ε4 carriers and non-carriers. Only ε4 non-carriers showed a correlation between lesion volume and cognitive performance.

Conclusion: The current findings indicate an increased prevalence of WM hyperintensities in non-carriers compared with carriers of the APOE ε4 allele among patients with AD. This is consistent with a possibly more pronounced contribution of heterogeneous vascular risk factors to WM damage and cognitive impairment in patients with AD without APOE ε4-mediated risk.
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http://dx.doi.org/10.1186/s13195-015-0111-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4432954PMC
May 2015

Hippocampal-dorsolateral prefrontal coupling as a species-conserved cognitive mechanism: a human translational imaging study.

Neuropsychopharmacology 2015 Jun 12;40(7):1674-81. Epub 2015 Jan 12.

1] Bernstein Center for Computational Neuroscience Heidelberg-Mannheim, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany [2] Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

Hippocampal-prefrontal cortex (HC-PFC) interactions are implicated in working memory (WM) and altered in psychiatric conditions with cognitive impairment such as schizophrenia. While coupling between both structures is crucial for WM performance in rodents, evidence from human studies is conflicting and translation of findings is complicated by the use of differing paradigms across species. We therefore used functional magnetic resonance imaging together with a spatial WM paradigm adapted from rodent research to examine HC-PFC coupling in humans. A PFC-parietal network was functionally connected to hippocampus (HC) during task stages requiring high levels of executive control but not during a matched control condition. The magnitude of coupling in a network comprising HC, bilateral dorsolateral PFC (DLPFC), and right supramarginal gyrus explained one-fourth of the variability in an independent spatial WM task but was unrelated to visual WM performance. HC-DLPFC coupling may thus represent a systems-level mechanism specific to spatial WM that is conserved across species, suggesting its utility for modeling cognitive dysfunction in translational neuroscience.
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http://dx.doi.org/10.1038/npp.2015.13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4915249PMC
June 2015

Evidence for a Sex-Dependent MAOA× Childhood Stress Interaction in the Neural Circuitry of Aggression.

Cereb Cortex 2016 Mar 19;26(3):904-14. Epub 2014 Oct 19.

Department of Child and Adolescent Psychiatry and Psychotherapy Department of Psychology, University of Potsdam, Potsdam, Germany.

Converging evidence emphasizes the role of an interaction between monoamine oxidase A (MAOA) genotype, environmental adversity, and sex in the pathophysiology of aggression. The present study aimed to clarify the impact of this interaction on neural activity in aggression-related brain systems. Functional magnetic resonance imaging was performed in 125 healthy adults from a high-risk community sample followed since birth. DNA was genotyped for the MAOA-VNTR (variable number of tandem repeats). Exposure to childhood life stress (CLS) between the ages of 4 and 11 years was assessed using a standardized parent interview, aggression by the Youth/Young Adult Self-Report between the ages of 15 and 25 years, and the VIRA-R (Vragenlijst Instrumentele En Reactieve Agressie) at the age of 15 years. Significant interactions were obtained between MAOA genotype, CLS, and sex relating to amygdala, hippocampus, and anterior cingulate cortex (ACC) response, respectively. Activity in the amygdala and hippocampus during emotional face-matching increased with the level of CLS in male MAOA-L, while decreasing in male MAOA-H, with the reverse pattern present in females. Findings in the opposite direction in the ACC during a flanker NoGo task suggested that increased emotional activity coincided with decreased inhibitory control. Moreover, increasing amygdala activity was associated with higher Y(A)SR aggression in male MAOA-L and female MAOA-H carriers. Likewise, a significant association between amygdala activity and reactive aggression was detected in female MAOA-H carriers. The results point to a moderating role of sex in the MAOA× CLS interaction for intermediate phenotypes of emotional and inhibitory processing, suggesting a possible mechanism in conferring susceptibility to violence-related disorders.
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http://dx.doi.org/10.1093/cercor/bhu249DOI Listing
March 2016

The long-term impact of early life poverty on orbitofrontal cortex volume in adulthood: results from a prospective study over 25 years.

Neuropsychopharmacology 2015 Mar 15;40(4):996-1004. Epub 2014 Oct 15.

1] Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany [2] Department of Psychology, University of Potsdam, Potsdam OT Golm, Germany.

Converging evidence has highlighted the association between poverty and conduct disorder (CD) without specifying neurobiological pathways. Neuroimaging research has emphasized structural and functional alterations in the orbitofrontal cortex (OFC) as one key mechanism underlying this disorder. The present study aimed to clarify the long-term influence of early poverty on OFC volume and its association with CD symptoms in healthy participants of an epidemiological cohort study followed since birth. At age 25 years, voxel-based morphometry was applied to study brain volume differences. Poverty (0=non-exposed (N=134), 1=exposed (N=33)) and smoking during pregnancy were determined using a standardized parent interview, and information on maternal responsiveness was derived from videotaped mother-infant interactions at the age of 3 months. CD symptoms were assessed by diagnostic interview from 8 to 19 years of age. Information on life stress was acquired at each assessment and childhood maltreatment was measured using retrospective self-report at the age of 23 years. Analyses were adjusted for sex, parental psychopathology and delinquency, obstetric adversity, parental education, and current poverty. Individuals exposed to early life poverty exhibited a lower OFC volume. Moreover, we replicated previous findings of increased CD symptoms as a consequence of childhood poverty. This effect proved statistically mediated by OFC volume and exposure to life stress and smoking during pregnancy, but not by childhood maltreatment and maternal responsiveness. These findings underline the importance of studying the impact of early life adversity on brain alterations and highlight the need for programs to decrease income-related disparities.
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http://dx.doi.org/10.1038/npp.2014.277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4330514PMC
March 2015

Amygdala habituation: a reliable fMRI phenotype.

Neuroimage 2014 Dec 2;103:383-390. Epub 2014 Oct 2.

Central Institute of Mental Health, Department of Psychiatry and Psychotherapy, University of Heidelberg/Medical Faculty Mannheim, Mannheim, Germany.

Amygdala function is of high interest for cognitive, social and psychiatric neuroscience, emphasizing the need for reliable assessments in humans. Previous work has indicated unsatisfactorily low within-subject reliability of amygdala activation fMRI measures. Based on basic science evidence for strong habituation of amygdala response to repeated stimuli, we investigated whether a quantification of habituation provides additional information beyond the usual estimate of the overall mean activity. We assessed the within-subject reliability of amygdala habituation measures during a facial emotion matching paradigm in 25 healthy subjects. We extracted the amygdala signal decrement across the course of the fMRI run for the two test-retest measurement sessions and compared reliability estimates with previous findings based on mean response amplitude. Retest-reliability of the session-wise amygdala habituation was significantly higher than the evoked amygdala mean amplitude (intraclass correlation coefficients (ICC)=0.53 vs. 0.16). To test the task-specificity of this finding, we compared the retest-reliability of amygdala habituation across two different tasks. Significant amygdala response decrement was also seen in a cognitive task (n-back working memory) that did not per se activate the amygdala, but was totally unreliable in that context (ICC~0.0), arguing for task-specificity. Together the results show that emotion-dependent amygdala habituation is a robust and considerably more reliable index than the mean amplitude, and provides a robust potential endpoint for within-subject designs including pharmaco-fMRI studies.
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http://dx.doi.org/10.1016/j.neuroimage.2014.09.059DOI Listing
December 2014

Impact of early life adversity on reward processing in young adults: EEG-fMRI results from a prospective study over 25 years.

PLoS One 2014 13;9(8):e104185. Epub 2014 Aug 13.

Department of Child and Adolescent Psychiatry and Psychotherapy, CIMH Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany; Department of Psychology, University of Potsdam, Potsdam, Germany.

Several lines of evidence have implicated the mesolimbic dopamine reward pathway in altered brain function resulting from exposure to early adversity. The present study examined the impact of early life adversity on different stages of neuronal reward processing later in life and their association with a related behavioral phenotype, i.e. attention deficit/hyperactivity disorder (ADHD). 162 healthy young adults (mean age = 24.4 years; 58% female) from an epidemiological cohort study followed since birth participated in a simultaneous EEG-fMRI study using a monetary incentive delay task. Early life adversity according to an early family adversity index (EFA) and lifetime ADHD symptoms were assessed using standardized parent interviews conducted at the offspring's age of 3 months and between 2 and 15 years, respectively. fMRI region-of-interest analysis revealed a significant effect of EFA during reward anticipation in reward-related areas (i.e. ventral striatum, putamen, thalamus), indicating decreased activation when EFA increased. EEG analysis demonstrated a similar effect for the contingent negative variation (CNV), with the CNV decreasing with the level of EFA. In contrast, during reward delivery, activation of the bilateral insula, right pallidum and bilateral putamen increased with EFA. There was a significant association of lifetime ADHD symptoms with lower activation in the left ventral striatum during reward anticipation and higher activation in the right insula during reward delivery. The present findings indicate a differential long-term impact of early life adversity on reward processing, implicating hyporesponsiveness during reward anticipation and hyperresponsiveness when receiving a reward. Moreover, a similar activation pattern related to lifetime ADHD suggests that the impact of early life stress on ADHD may possibly be mediated by a dysfunctional reward pathway.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0104185PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4131910PMC
April 2015

Effect of prenatal exposure to tobacco smoke on inhibitory control: neuroimaging results from a 25-year prospective study.

JAMA Psychiatry 2014 Jul;71(7):786-96

Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany6Department of Psychology, University of Potsdam, Potsdam, Germany.

Importance: There is accumulating evidence relating maternal smoking during pregnancy to attention-deficit/hyperactivity disorder (ADHD) without elucidating specific mechanisms. Research investigating the neurobiological underpinnings of this disorder has implicated deficits during response inhibition. Attempts to uncover the effect of prenatal exposure to nicotine on inhibitory control may thus be of high clinical importance.

Objective: To clarify the influence of maternal smoking during pregnancy (hereafter referred to as prenatal smoking) on the neural circuitry of response inhibition and its association with related behavioral phenotypes such as ADHD and novelty seeking in the mother's offspring.

Design, Setting, And Participants: Functional magnetic resonance imaging was performed for the offspring at 25 years of age during a modified Eriksen flanker/NoGo task, and voxel-based morphometry was performed to study brain volume differences of the offspring. Prenatal smoking (1-5 cigarettes per day [14 mothers] or >5 cigarettes per day [24 mothers]) and lifetime ADHD symptoms were determined using standardized parent interviews at the offspring's age of 3 months and over a period of 13 years (from 2 to 15 years of age), respectively. Novelty seeking was assessed at 19 years of age. Analyses were adjusted for sex, parental postnatal smoking, psychosocial and obstetric adversity, maternal prenatal stress, and lifetime substance abuse. A total of 178 young adults (73 males) without current psychopathology from a community sample followed since birth (Mannheim, Germany) participated in the study.

Main Outcomes And Measures: Functional magnetic resonance imaging response, morphometric data, lifetime ADHD symptoms, and novelty seeking.

Results: Participants prenatally exposed to nicotine exhibited a weaker response in the anterior cingulate cortex (t168 = 4.46; peak Montreal Neurological Institute [MNI] coordinates x = -2, y = 20, z = 30; familywise error [FWE]-corrected P = .003), the right inferior frontal gyrus (t168 = 3.65; peak MNI coordinates x = 44, y = 38, z = 12; FWE-corrected P = .04), the left inferior frontal gyrus (t168 = 4.09; peak MNI coordinates x = -38, y = 36, z = 8; FWE-corrected P = .009), and the supramarginal gyrus (t168 = 5.03; peak MNI coordinates x = 64, y = -28, z = 22; FWE-corrected P = .02) during the processing of the NoGo compared to neutral stimuli, while presenting a decreased volume in the right inferior frontal gyrus. These findings were obtained irrespective of the adjustment of confounders, ADHD symptoms, and novelty seeking. There was an inverse relationship between inferior frontal gyrus activity and ADHD symptoms and between anterior cingulate cortex activity and novelty seeking.

Conclusions And Relevance: These findings point to a functional involvement of prenatal exposure to tobacco smoke in neural alterations similar to ADHD, which underlines the importance of smoking prevention treatments.
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http://dx.doi.org/10.1001/jamapsychiatry.2014.343DOI Listing
July 2014

Role of FKBP5 in emotion processing: results on amygdala activity, connectivity and volume.

Brain Struct Funct 2015 23;220(3):1355-68. Epub 2014 Apr 23.

Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, J5, 68159, Mannheim, Germany.

Accumulating evidence suggests a role of FKBP5, a co-chaperone regulating the glucocorticoid receptor sensitivity, in the etiology of depression and anxiety disorders. Based on recent findings of altered amygdala activity following childhood adversity, the present study aimed at clarifying the impact of genetic variation in FKBP5 on threat-related neural activity and coupling as well as morphometric alterations in stress-sensitive brain systems. Functional magnetic resonance imaging during an emotional face-matching task was performed in 153 healthy young adults (66 males) from a high-risk community sample followed since birth. Voxel-based morphometry was applied to study structural alterations and DNA was genotyped for FKBP5 rs1360780. Childhood adversity was measured using retrospective self-report (Childhood Trauma Questionnaire) and by a standardized parent interview assessing childhood family adversity. Depression was assessed by the Beck Depression Inventory. There was a main effect of FKBP5 on the left amygdala, with T homozygotes showing the highest activity, largest volume and increased coupling with the left hippocampus and the orbitofrontal cortex (OFC). Moreover, amygdala-OFC coupling proved to be associated with depression in this genotype. In addition, our results support previous evidence of a gene-environment interaction on right amygdala activity with respect to retrospective assessment of childhood adversity, but clarify that this does not generalize to the prospective assessment. These findings indicated that activity in T homozygotes increased with the level of adversity, whereas the opposite pattern emerged in C homozygotes, with CT individuals being intermediate. The present results point to a functional involvement of FKBP5 in intermediate phenotypes associated with emotional processing, suggesting a possible mechanism for this gene in conferring susceptibility to stress-related disorders.
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http://dx.doi.org/10.1007/s00429-014-0729-5DOI Listing
January 2016
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