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Nathalie Holz

Central Institute of Mental Health, Child and Adolescent Psychiatry and Psychotherpy, Graduate Student

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Address: Mannheim, Baden-Württemberg Region, Germany

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Central Institute of Mental Health

Sarah Baumeister

Central Institute of Mental Health

Case Western Reserve University

Lieke van Domburgh

Jeffrey Spielberg

Stephen V Faraone

SUNY: Upstate Medical University

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Papers by Nathalie Holz

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

Childhood family adversity (CFA) increases the risk for conduct disorder (CD) and has been associ... more 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 ¼ 171) and a face-matching paradigm (N ¼ 181) and anatomical scans (N ¼ 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 Downloaded from 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. < 0.001; ADHD b ¼ 2.21, P < 0.001; impulsivity b ¼ 0.75, P < 0.001; YASR aggression b ¼ 0.56, P ¼ 0.03; CU traits b ¼ 0.53, P ¼ 0.002).

Interaction between COMT Val158Met polymorphism and childhood adversity affects reward processing in adulthood

by Nathalie Holz and Manfred Laucht

NeuroImage, 2016

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

by Nathalie Holz and Manfred Laucht

Social Cognitive and Affective Neuroscience, 2016

Stress exposure has been linked to increased rates of depression and anxiety in adults, particula... more 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.

Frequency-specific coupling between trial-to-trial fluctuations of neural responses and response-time variability

by Nathalie Holz, R. Boecker, and Manfred Laucht

Journal of neural transmission (Vienna, Austria : 1996), Jan 28, 2015

We assessed intra-individual variability of response times (RT) and single-trial P3 amplitudes fo... more We assessed intra-individual variability of response times (RT) and single-trial P3 amplitudes following targets in healthy adults during a Flanker/NO-GO task. RT variability and variability of the neural responses coupled at the faster frequencies examined (0.07-0.17 Hz) at Pz, the target-P3 maxima, despite non-significant associations for overall variability (standard deviation, SD). Frequency-specific patterns of variability in the single-trial P3 may help to understand the neurophysiology of RT variability and its explanatory models of attention allocation deficits beyond intra-individual variability summary indices such as SD.

Abstracts of Presentations at the International Conference

Moderating role of FKBP5 genotype in the impact of childhood adversity on cortisol stress response during adulthood

European Neuropsychopharmacology, 2013

Recent research suggests an important role of FKBP5, a glucocorticoid receptor regulating co-chap... more Recent research suggests an important role of FKBP5, a glucocorticoid receptor regulating co-chaperone, in the development of stress-related diseases such as depression and anxiety disorders. The present study aimed to replicate and extend previous evidence indicating that FKBP5 polymorphisms moderate hypothalamus-pituitary-adrenal (HPA) function by examining whether FKBP5 rs1360780 genotype and different measures of childhood adversity interact to predict stress-induced cortisol secretion. At age 19 years, 195 young adults (90 males, 105 females) participating in an epidemiological cohort study completed the Trier Social Stress Test (TSST) to assess cortisol stress responsiveness and were genotyped for the FKBP5 rs1360780. Childhood adversity was assessed using the Childhood Trauma Questionnaire (CTQ) and by a standardized parent interview yielding an index of family adversity. A significant interaction between genotype and childhood adversity on cortisol response to stress was demonstrated for exposure to childhood maltreatment as assessed by retrospective self-report (CTQ), but not for prospectively ascertained objective family adversity. Severity of childhood maltreatment was significantly associated with attenuated cortisol levels among carriers of the rs1360780 CC genotype, while no such effect emerged in carriers of the T allele. These findings point towards the functional involvement of FKBP5 in long-term alterations of neuroendocrine stress www.elsevier.com/locate/euroneuro http://dx.

C URRENT OPINION Recent advances in understanding the neurobiology of childhood socioeconomic disadvantage

Purpose of review To provide an update of recent research regarding neural mechanisms of socioeco... more Purpose of review To provide an update of recent research regarding neural mechanisms of socioeconomic disadvantage. Recent findings The studies reviewed provide convincing evidence of the detrimental effects of early adversities on brain structure and function. The effects of socioeconomic disadvantage and related environmental risks, such as childhood adversity and smoking during pregnancy, while affecting distributed networks of brain regions, have decreased prefrontal activity and volume as a common feature. Summary Recent work suggests that socioeconomic disadvantage and related risk factors may account for a significant proportion of variance in measures of brain structure and function, which may mediate the increased risk of psychopathology. Impaired prefrontal control may be a convergent mechanism underlying early exposure to socioeconomic risk factors in humans. Environmental imaging, that is, the impact which environmental adversity may have on brain structure and function, has only recently moved into the focus of interest. This is surprising because the link to psychopathology has long since been acknowledged and socioeconomic risk factors are modifiable, meaning that understanding their mechanism may point toward prevention and early intervention mechanisms. In future work, the interplay between different environmental risk factors, their potential epigenetic mechanisms, and their interaction with genetic risk should be studied.

Effect of Prenatal Exposure to Tobacco Smoke on Inhibitory Control Neuroimaging Results From a 25-Year Prospective Study Original Investigation

by Nathalie Holz and Dorothea Blomeyer

IMPORTANCE There is accumulating evidence relating maternal smoking during pregnancy to attention... more 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, psycho-social 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 (t 168 = 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 (t 168 = 3.65; peak MNI coordinates x = 44, y = 38, z = 12; FWE-corrected P = .04), the left inferior frontal gyrus (t 168 = 4.09; peak MNI coordinates x = −38, y = 36, z = 8; FWE-corrected P = .009), and the supramarginal gyrus (t 168 = 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.

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

by Nathalie Holz, Dorothea Blomeyer, and I. Wolf

Converging evidence emphasizes the role of an interaction between monoamine oxidase A (MAOA) geno... more 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.

The Long-Term Impact of Early Life Poverty on Orbitofrontal Cortex Volume in Adulthood: Results from a Prospective Study Over 25 Years

by Nathalie Holz, R. Boecker, Sarah Baumeister, and S. Hohmann

Neuropsychopharmacology, 2014

Converging evidence has highlighted the association between poverty and conduct disorder (CD) wit... more 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.

Impact of Early Life Adversity on Reward Processing in Young Adults: EEG-fMRI Results from a Prospective Study over 25 Years

by R. Boecker, Nathalie Holz, I. Wolf, and Sarah Baumeister

PLoS ONE, 2014

Several lines of evidence have implicated the mesolimbic dopamine reward pathway in altered brain... more 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.

Simultaneous EEG and fMRI Reveals a Causally Connected Subcortical-Cortical Network during Reward Anticipation

by Sarah Baumeister, R. Boecker, Nathalie Holz, and S. Hohmann

Journal of Neuroscience, 2013

along with an excitatory information flow through a THAL3 VS3 SMA route during reward anticipatio... more along with an excitatory information flow through a THAL3 VS3 SMA route during reward anticipation, and (3) the EEG CNV signal is best predicted by a combination of THAL fMRI BOLD response and strength of top-down regulation from SMA to VS and SMA to THAL. Collectively, these findings represent a likely neurobiological mechanism mapping a primarily subcortical process, i.e., reward anticipation, onto a cortical signature.

Effect of Prenatal Exposure to Tobacco Smoke on Inhibitory Control

by Nathalie Holz, R. Boecker, Sarah Baumeister, and S. Hohmann

JAMA Psychiatry, 2014

IMPORTANCE There is accumulating evidence relating maternal smoking during pregnancy to attention... more 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.

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

by Nathalie Holz, R. Boecker, and Sarah Baumeister

Brain Structure and Function, 2014

Accumulating evidence suggests a role of FKBP5, a co-chaperone regulating the glucocorticoid rece... more 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.

Sequential inhibitory control processes assessed through simultaneous EEG-fMRI

by I. Wolf, Sarah Baumeister, R. Boecker, S. Hohmann, Nathalie Holz, and Schwarz, Schwarz

along with an excitatory information flow through a THAL3 VS3 SMA route during reward anticipatio... more along with an excitatory information flow through a THAL3 VS3 SMA route during reward anticipation, and (3) the EEG CNV signal is best predicted by a combination of THAL fMRI BOLD response and strength of top-down regulation from SMA to VS and SMA to THAL. Collectively, these findings represent a likely neurobiological mechanism mapping a primarily subcortical process, i.e., reward anticipation, onto a cortical signature.

Abstracts of Presentations at the International Conference on Basic and Clinical Multimodal Imaging (BaCI), a Joint Conference of the International Society for Neuroimaging in Psychiatry (ISNIP), the International Society for Functional Source Imaging (ISFSI), the International Society for Bioele...

Clinical EEG and neuroscience, Jan 24, 2013

Simultaneous EEG and fMRI Reveals a Causally Connected Subcortical-Cortical Network during Reward Anticipation

by Andreas Meyer-Lindenberg, M. Ruf, Nathalie Holz, and Sarah Baumeister

Journal of Neuroscience, 2013

along with an excitatory information flow through a THAL3 VS3 SMA route during reward anticipatio... more along with an excitatory information flow through a THAL3 VS3 SMA route during reward anticipation, and (3) the EEG CNV signal is best predicted by a combination of THAL fMRI BOLD response and strength of top-down regulation from SMA to VS and SMA to THAL. Collectively, these findings represent a likely neurobiological mechanism mapping a primarily subcortical process, i.e., reward anticipation, onto a cortical signature.

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

by R. Boecker and Nathalie Holz

Converging evidence emphasizes the role of an interaction between monoamine oxidase A (MAOA) geno... more 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.

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

Childhood family adversity (CFA) increases the risk for conduct disorder (CD) and has been associ... more 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 ¼ 171) and a face-matching paradigm (N ¼ 181) and anatomical scans (N ¼ 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 Downloaded from 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. < 0.001; ADHD b ¼ 2.21, P < 0.001; impulsivity b ¼ 0.75, P < 0.001; YASR aggression b ¼ 0.56, P ¼ 0.03; CU traits b ¼ 0.53, P ¼ 0.002).

Interaction between COMT Val158Met polymorphism and childhood adversity affects reward processing in adulthood

by Nathalie Holz and Manfred Laucht

NeuroImage, 2016

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

by Nathalie Holz and Manfred Laucht

Social Cognitive and Affective Neuroscience, 2016

Stress exposure has been linked to increased rates of depression and anxiety in adults, particula... more 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.

Frequency-specific coupling between trial-to-trial fluctuations of neural responses and response-time variability

by Nathalie Holz, R. Boecker, and Manfred Laucht

Journal of neural transmission (Vienna, Austria : 1996), Jan 28, 2015

We assessed intra-individual variability of response times (RT) and single-trial P3 amplitudes fo... more We assessed intra-individual variability of response times (RT) and single-trial P3 amplitudes following targets in healthy adults during a Flanker/NO-GO task. RT variability and variability of the neural responses coupled at the faster frequencies examined (0.07-0.17 Hz) at Pz, the target-P3 maxima, despite non-significant associations for overall variability (standard deviation, SD). Frequency-specific patterns of variability in the single-trial P3 may help to understand the neurophysiology of RT variability and its explanatory models of attention allocation deficits beyond intra-individual variability summary indices such as SD.

Abstracts of Presentations at the International Conference

Moderating role of FKBP5 genotype in the impact of childhood adversity on cortisol stress response during adulthood

European Neuropsychopharmacology, 2013

Recent research suggests an important role of FKBP5, a glucocorticoid receptor regulating co-chap... more Recent research suggests an important role of FKBP5, a glucocorticoid receptor regulating co-chaperone, in the development of stress-related diseases such as depression and anxiety disorders. The present study aimed to replicate and extend previous evidence indicating that FKBP5 polymorphisms moderate hypothalamus-pituitary-adrenal (HPA) function by examining whether FKBP5 rs1360780 genotype and different measures of childhood adversity interact to predict stress-induced cortisol secretion. At age 19 years, 195 young adults (90 males, 105 females) participating in an epidemiological cohort study completed the Trier Social Stress Test (TSST) to assess cortisol stress responsiveness and were genotyped for the FKBP5 rs1360780. Childhood adversity was assessed using the Childhood Trauma Questionnaire (CTQ) and by a standardized parent interview yielding an index of family adversity. A significant interaction between genotype and childhood adversity on cortisol response to stress was demonstrated for exposure to childhood maltreatment as assessed by retrospective self-report (CTQ), but not for prospectively ascertained objective family adversity. Severity of childhood maltreatment was significantly associated with attenuated cortisol levels among carriers of the rs1360780 CC genotype, while no such effect emerged in carriers of the T allele. These findings point towards the functional involvement of FKBP5 in long-term alterations of neuroendocrine stress www.elsevier.com/locate/euroneuro http://dx.

C URRENT OPINION Recent advances in understanding the neurobiology of childhood socioeconomic disadvantage

Purpose of review To provide an update of recent research regarding neural mechanisms of socioeco... more Purpose of review To provide an update of recent research regarding neural mechanisms of socioeconomic disadvantage. Recent findings The studies reviewed provide convincing evidence of the detrimental effects of early adversities on brain structure and function. The effects of socioeconomic disadvantage and related environmental risks, such as childhood adversity and smoking during pregnancy, while affecting distributed networks of brain regions, have decreased prefrontal activity and volume as a common feature. Summary Recent work suggests that socioeconomic disadvantage and related risk factors may account for a significant proportion of variance in measures of brain structure and function, which may mediate the increased risk of psychopathology. Impaired prefrontal control may be a convergent mechanism underlying early exposure to socioeconomic risk factors in humans. Environmental imaging, that is, the impact which environmental adversity may have on brain structure and function, has only recently moved into the focus of interest. This is surprising because the link to psychopathology has long since been acknowledged and socioeconomic risk factors are modifiable, meaning that understanding their mechanism may point toward prevention and early intervention mechanisms. In future work, the interplay between different environmental risk factors, their potential epigenetic mechanisms, and their interaction with genetic risk should be studied.

Effect of Prenatal Exposure to Tobacco Smoke on Inhibitory Control Neuroimaging Results From a 25-Year Prospective Study Original Investigation

by Nathalie Holz and Dorothea Blomeyer

IMPORTANCE There is accumulating evidence relating maternal smoking during pregnancy to attention... more 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, psycho-social 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 (t 168 = 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 (t 168 = 3.65; peak MNI coordinates x = 44, y = 38, z = 12; FWE-corrected P = .04), the left inferior frontal gyrus (t 168 = 4.09; peak MNI coordinates x = −38, y = 36, z = 8; FWE-corrected P = .009), and the supramarginal gyrus (t 168 = 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.

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

by Nathalie Holz, Dorothea Blomeyer, and I. Wolf

Converging evidence emphasizes the role of an interaction between monoamine oxidase A (MAOA) geno... more 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.

The Long-Term Impact of Early Life Poverty on Orbitofrontal Cortex Volume in Adulthood: Results from a Prospective Study Over 25 Years

by Nathalie Holz, R. Boecker, Sarah Baumeister, and S. Hohmann

Neuropsychopharmacology, 2014

Converging evidence has highlighted the association between poverty and conduct disorder (CD) wit... more 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.

Impact of Early Life Adversity on Reward Processing in Young Adults: EEG-fMRI Results from a Prospective Study over 25 Years

by R. Boecker, Nathalie Holz, I. Wolf, and Sarah Baumeister

PLoS ONE, 2014

Several lines of evidence have implicated the mesolimbic dopamine reward pathway in altered brain... more 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.

Simultaneous EEG and fMRI Reveals a Causally Connected Subcortical-Cortical Network during Reward Anticipation

by Sarah Baumeister, R. Boecker, Nathalie Holz, and S. Hohmann

Journal of Neuroscience, 2013

along with an excitatory information flow through a THAL3 VS3 SMA route during reward anticipatio... more along with an excitatory information flow through a THAL3 VS3 SMA route during reward anticipation, and (3) the EEG CNV signal is best predicted by a combination of THAL fMRI BOLD response and strength of top-down regulation from SMA to VS and SMA to THAL. Collectively, these findings represent a likely neurobiological mechanism mapping a primarily subcortical process, i.e., reward anticipation, onto a cortical signature.

Effect of Prenatal Exposure to Tobacco Smoke on Inhibitory Control

by Nathalie Holz, R. Boecker, Sarah Baumeister, and S. Hohmann

JAMA Psychiatry, 2014

IMPORTANCE There is accumulating evidence relating maternal smoking during pregnancy to attention... more 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.

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

by Nathalie Holz, R. Boecker, and Sarah Baumeister

Brain Structure and Function, 2014

Accumulating evidence suggests a role of FKBP5, a co-chaperone regulating the glucocorticoid rece... more 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.

Sequential inhibitory control processes assessed through simultaneous EEG-fMRI

by I. Wolf, Sarah Baumeister, R. Boecker, S. Hohmann, Nathalie Holz, and Schwarz, Schwarz

along with an excitatory information flow through a THAL3 VS3 SMA route during reward anticipatio... more along with an excitatory information flow through a THAL3 VS3 SMA route during reward anticipation, and (3) the EEG CNV signal is best predicted by a combination of THAL fMRI BOLD response and strength of top-down regulation from SMA to VS and SMA to THAL. Collectively, these findings represent a likely neurobiological mechanism mapping a primarily subcortical process, i.e., reward anticipation, onto a cortical signature.

Abstracts of Presentations at the International Conference on Basic and Clinical Multimodal Imaging (BaCI), a Joint Conference of the International Society for Neuroimaging in Psychiatry (ISNIP), the International Society for Functional Source Imaging (ISFSI), the International Society for Bioele...

Clinical EEG and neuroscience, Jan 24, 2013

Simultaneous EEG and fMRI Reveals a Causally Connected Subcortical-Cortical Network during Reward Anticipation

by Andreas Meyer-Lindenberg, M. Ruf, Nathalie Holz, and Sarah Baumeister

Journal of Neuroscience, 2013

along with an excitatory information flow through a THAL3 VS3 SMA route during reward anticipatio... more along with an excitatory information flow through a THAL3 VS3 SMA route during reward anticipation, and (3) the EEG CNV signal is best predicted by a combination of THAL fMRI BOLD response and strength of top-down regulation from SMA to VS and SMA to THAL. Collectively, these findings represent a likely neurobiological mechanism mapping a primarily subcortical process, i.e., reward anticipation, onto a cortical signature.

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

by R. Boecker and Nathalie Holz

Converging evidence emphasizes the role of an interaction between monoamine oxidase A (MAOA) geno... more 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.