- Email: [email protected]
Early-life stress and stratified approaches in mental health
Abstracts / Psychoneuroendocrinology 71S (2016) 1–77
Symposium 2: Child Maltreatment Time: Thursday, 08/Sep/2016: 3:00pm – 4:30pm Session Chair: Christine M. Heim Brain structural alterations in newborns of mothers exposed to childhood trauma Claudia Buss 1,2,∗ , Nora K. Moog 1 , Sonja Entringer 1,2 , Jerod Rasmussen 2 , Martin A. Styner 3 , John H. Gilmore 3 , Christine M. Heim 1 , Pathik D. Wadhwa 2 1
Charité Universitätsmedizin Berlin, Germany University of California Irvine, USA 3 University of North Carolina, USA E-mail address: [email protected] (C. Buss). 2
Exposure to childhood trauma (CT) has long-term consequences and growing evidence suggests some of the effects may be transmitted across generations. Children of mothers exposed to CT have an increased risk of developing neuropsychiatric and neurodevelopmental disease. We sought to elucidate whether changes in infant brain structure were already visible shortly after birth to address the hypothesis that the window of transmission commences during the period of intrauterine development. The study was conducted in a population-based sample of 113 mother-child dyads. Maternal CT exposure was assessed using the Childhood Trauma Questionnaire. Multi-modal magnetic resonance imaging (MRI) was employed to characterize newborn brain structure near the time of birth (mean: 26 days ± 13). Maternal CT exposure was associated with lower intracranial volume in their newborns (F1,67 = 4.52, p = .037). Specifically, gray matter volume was reduced globally (F1,67 = 6.50, p = .013), whereas white matter volume and cerebrospinal fluid volume were not associated with maternal CT (ps > .10). The effect was independent of age at birth and age at scan, obstetric risk, socio-economic status, maternal depression and infant sex. Diffusion tensor imaging revealed an association between maternal CT and altered integrity of major white matter fiber tracts (corrected ps < .05). These findings represent the first report to date linking maternal CT exposure with structural alterations in their newborns’ brains. These alterations have likely implications for the development of psychopathology and suggest that the effects of CT can be transmitted across generations as early as during intrauterine life. http://dx.doi.org/10.1016/j.psyneuen.2016.07.015 Early-life adversity is associated with differential gene expression response to acute psychological stress Idan Shalev ∗ , Waylon Hastings, Susan Siegel Penn State University, USA E-mail address: [email protected] (I. Shalev). Background: Early-life adversity can ‘get under the skin’ and program biological systems, which in turn increases risk for laterlife physical and mental-health problems. This early programming of stress-responsive systems can lead to dysregulation of physiological resources in response to common stressors. However, little is known how early-life adversity translates to dynamic cellular responses when facing acute stressors. In this pilot study, we tested how young adults’ exposure to stressful events in early-life influence dynamic cellular processes in response to acute psychological stress, compared with controls.
3
Methods: 12 young men (mean age = 21.25, SD = 2.3) participated in this pilot study. Using a validated screening instrument, we invited 6 participants who endorsed at least 3 early-life adverse events (‘risk group’), and 6 who confirmed zero (‘controls’). In a randomized within-subjects design, we induced acute stress in the lab (Trier Social Stress Test), and included a no-stress control condition one week apart. During these sessions, we obtained repeated measurements of physiological reactivity (salivary cortisol, blood-pressure, heart rate), and gene expression of peripheral blood mononuclear cells, over a 4-hour window post-test. As a preliminary prototype, we focused specifically on the glucocorticoid receptor (NR3C1) gene. Results: The risk group showed a trend of reporting higher levels of anxiety (F = 2.54, p = .142) and depressive symptoms (F = 2.73, p = .129), compared with controls. In the entire sample, a significant within-subjects effect was observed for salivary cortisol in response to the TSST, compared with a no-stress condition (F = 4.28, p = .003), as well as for mean arterial pressure (F = 7.00, p < .001). The risk group had a significantly higher mean arterial pressure response (F = 8.59, p<.001), and a trend towards a higher cortisol response to the TSST (F = 3.16, p = .106). With NR3C1 gene expression analysis, a significant within-subjects effect was observed in the whole sample in response to the TSST vs. the no-stress condition (F = 4.85, p = .006). Closer examination revealed this was true in the control group (F = 5.10, p = .013), but not in the risk group, which had a blunted response to the TSST vs. the no-stress (F = 1.00, p = .406), and a trend toward a lower response to the TSST compared with controls (F = 4.01, p = .073). Notably, no differences were observed in the no-stress condition between risk and control groups. Conclusions: These preliminary findings suggest that early-life adversity may program biological systems as evidenced by dysregulated transcriptional responses to acute psychological stress. Although these response patterns could be adaptive over the short-term, documenting stress-induced transcriptional changes, via programming of biological systems, can provide critical temporal insights into specific cellular pathways that, when repeated, may lead to increased disease risk. http://dx.doi.org/10.1016/j.psyneuen.2016.07.016 Early-life stress and stratified approaches in mental health Andrea Danese Institute of Psychiatry, King’s College London, United Kingdom E-mail address: [email protected]. Objective: Psychiatric diagnoses identify heterogeneous groups of individuals with different clinical presentations, course of illness, and response to treatment. Childhood maltreatment is associated with biological abnormalities associated with unfavourable course of illness and treatment response across psychiatric diagnoses, such as abnormal HPA axis functioning and high inflammation levels. Methods: We tested whether information on childhood maltreatment could be used for early identification of psychiatric patients with poor prognosis. Results: Childhood maltreatment predicts unfavourable course of illness and poor treatment response in individuals with major depression. Childhood maltreatment also predicts negative clinical features and course of illness in individuals with bipolar disorder. Conclusions: Within heterogeneous groups of psychiatric patients, information on childhood maltreatment can help identify individuals with greater risk and needs. Better understanding
4
Abstracts / Psychoneuroendocrinology 71S (2016) 1–77
of the stratified, trans-diagnostic, biological effects of childhood maltreatment may inform innovative treatment strategies. http://dx.doi.org/10.1016/j.psyneuen.2016.07.017 Telomere biology as a mechanism in developmental programming of health and disease risk Sonja Entringer 1,5,∗ , Elissa Epel 2 , Jue Lin 2 , Claudia Buss 1,5 , Elizabeth Blackburn 2 , Hyagriv Simhan 3 , Katri Räikkonen 4 , Pathik Wadhwa 5
Symposium 3: How Important is Sex/Gender in Personalized Medicine for Mental Health? Time: Thursday, 08/Sep/2016: 3:00pm – 4:30pm Session Chair: Mallory Elva Bowers Session Chair: Sonia Lupien A neural basis for sex-dependent fear expression Rebecca Shansky Northeastern University, USA E-mail address: [email protected].
1
Charité Universitätsmedizin Berlin, Germany University of California, San Francisco, United States 3 University of Pittsburgh, United States 4 University of Helsinki, United States 5 University of California, Irvine, United States E-mail address: [email protected] (S. Entringer). 2
Background: The long-term consequences of exposure to excess stress on the initiation and progression of many age-related diseases are well established. The effects of stress are particularly salient if exposure occurs during sensitive developmental windows such as intrauterine life and the early postnatal period. The elucidation of mechanisms underlying such effects is an area of intense interest and investigation. We propose that the integrity of the telomere system represents a candidate system of particular interest in this context, potentially underlying the observed effects of a disparate set of suboptimal early life exposures on various health and disease risk phenotypes of interest. Methods: Data will be presented from several different longitudinal birth cohorts in which intrauterine conditions (including obstetric risk conditions, maternal stress- and nutrition-related processes) were assessed, and telomere length (TL) was subsequently measured in newborns and infants. In one of the cohorts, data from child follow-up assessments regarding temperament, developmental milestones and behavior problems are available. Results: Obstetric risk conditions, maternal pre-pregnancy obesity, suboptimal maternal nutrition and maternal stress during pregnancy are each independently associated with offspring TL. Furthermore, newborn TL is associated with child behavioral problems related to attention deficit hyperactivity disorder (ADHD) at 3.5 years age. Conclusions: Taken together, our findings provide evidence in humans that suboptimal conditions during pregnancy may exert a programming effect on the newborn and infant telomere biology system, and that newborn telomere length may be a predictor of later child behavioral problems. Telomere biology represents a potential molecular mechanism whereby different exposures in this critical developmental period before birth could impact subsequent health and disease susceptibility-related outcomes over the life span. http://dx.doi.org/10.1016/j.psyneuen.2016.07.018
An individual faced with a threatening stimulus may respond in many different ways. The selection of either an active or passive response can predict long-term outcomes in clinical populations, but what leads to the selection of one over the other is unknown. Using a classic rodent model of Pavlovian cued fear conditioning, we found that female rats were four times as likely as males to exhibit an active, escape-like “darting” response to the conditioned stimulus, even though escape was not possible. We have now begun to investigate the neural substrates of darting by examining c-fos activity in the medial prefrontal cortex (mPFC) and periaqueductal gray (PAG) after fear conditioning in darting and freezing subpopulations. Darters exhibited greater activity in the dorsolateral PAG, which is consistent with active response strategies. Freezers exhibited greater rostral mPFC activity compared to the ventral mPFC, and the rostral:ventral ratio was tightly correlated to freezing in both Freezers and Darters. These data suggest that darting may be mediated by a shift in the balance of mPFC activity, resulting in enhanced dlPAG activation. http://dx.doi.org/10.1016/j.psyneuen.2016.07.019 Association between estradiol and posttraumatic stress disorder in men and women military veterans Mallory E. Bowers 1,2,∗ , Janine D. Flory 1,2 , Duna Abu-Amara 3 , Charles D. Marmar 3 , Rachel Yehuda 1,2 1
Icahn School of Medicine at Mount Sinai, USA James J. Peters Bronx Veterans Affairs Medical Center, USA 3 NYU Langone School of Medicine, USA E-mail address: [email protected] (M.E. Bowers). 2
Posttraumatic stress disorder (PTSD) manifests after a traumatic, typically life-threatening event and is characterized by four core clusters of symptoms – hyperarousal, intrusions (“flashbacks”, e.g. nightmares), avoidance of trauma cues, and negative cognitions and mood. PTSD is twice as prevalent among women compared to men, even when normalizing for amount and type of trauma. Discordant prevalence of PTSD across genders could stem from biological factor(s) that are differentially expressed in women compared to men. Accordingly, the estrogen system is an appealing target for investigation. Using immunoassay, we observed a main effect of PTSD diagnosis on plasma estradiol levels in men and women military veterans with trauma in a combat zone. Specifically, PTSD+ veterans had lower levels of estradiol compared to PTSD-, trauma-control veterans. In men, an association between estradiol and PTSD diagnosis could be mediated by hyperarousal symptoms, as we found a significant negative correlation between
Symposium 2: Child Maltreatment Time: Thursday, 08/Sep/2016: 3:00pm – 4:30pm Session Chair: Christine M. Heim Brain structural alterations in newborns of mothers exposed to childhood trauma Claudia Buss 1,2,∗ , Nora K. Moog 1 , Sonja Entringer 1,2 , Jerod Rasmussen 2 , Martin A. Styner 3 , John H. Gilmore 3 , Christine M. Heim 1 , Pathik D. Wadhwa 2 1
Charité Universitätsmedizin Berlin, Germany University of California Irvine, USA 3 University of North Carolina, USA E-mail address: [email protected] (C. Buss). 2
Exposure to childhood trauma (CT) has long-term consequences and growing evidence suggests some of the effects may be transmitted across generations. Children of mothers exposed to CT have an increased risk of developing neuropsychiatric and neurodevelopmental disease. We sought to elucidate whether changes in infant brain structure were already visible shortly after birth to address the hypothesis that the window of transmission commences during the period of intrauterine development. The study was conducted in a population-based sample of 113 mother-child dyads. Maternal CT exposure was assessed using the Childhood Trauma Questionnaire. Multi-modal magnetic resonance imaging (MRI) was employed to characterize newborn brain structure near the time of birth (mean: 26 days ± 13). Maternal CT exposure was associated with lower intracranial volume in their newborns (F1,67 = 4.52, p = .037). Specifically, gray matter volume was reduced globally (F1,67 = 6.50, p = .013), whereas white matter volume and cerebrospinal fluid volume were not associated with maternal CT (ps > .10). The effect was independent of age at birth and age at scan, obstetric risk, socio-economic status, maternal depression and infant sex. Diffusion tensor imaging revealed an association between maternal CT and altered integrity of major white matter fiber tracts (corrected ps < .05). These findings represent the first report to date linking maternal CT exposure with structural alterations in their newborns’ brains. These alterations have likely implications for the development of psychopathology and suggest that the effects of CT can be transmitted across generations as early as during intrauterine life. http://dx.doi.org/10.1016/j.psyneuen.2016.07.015 Early-life adversity is associated with differential gene expression response to acute psychological stress Idan Shalev ∗ , Waylon Hastings, Susan Siegel Penn State University, USA E-mail address: [email protected] (I. Shalev). Background: Early-life adversity can ‘get under the skin’ and program biological systems, which in turn increases risk for laterlife physical and mental-health problems. This early programming of stress-responsive systems can lead to dysregulation of physiological resources in response to common stressors. However, little is known how early-life adversity translates to dynamic cellular responses when facing acute stressors. In this pilot study, we tested how young adults’ exposure to stressful events in early-life influence dynamic cellular processes in response to acute psychological stress, compared with controls.
3
Methods: 12 young men (mean age = 21.25, SD = 2.3) participated in this pilot study. Using a validated screening instrument, we invited 6 participants who endorsed at least 3 early-life adverse events (‘risk group’), and 6 who confirmed zero (‘controls’). In a randomized within-subjects design, we induced acute stress in the lab (Trier Social Stress Test), and included a no-stress control condition one week apart. During these sessions, we obtained repeated measurements of physiological reactivity (salivary cortisol, blood-pressure, heart rate), and gene expression of peripheral blood mononuclear cells, over a 4-hour window post-test. As a preliminary prototype, we focused specifically on the glucocorticoid receptor (NR3C1) gene. Results: The risk group showed a trend of reporting higher levels of anxiety (F = 2.54, p = .142) and depressive symptoms (F = 2.73, p = .129), compared with controls. In the entire sample, a significant within-subjects effect was observed for salivary cortisol in response to the TSST, compared with a no-stress condition (F = 4.28, p = .003), as well as for mean arterial pressure (F = 7.00, p < .001). The risk group had a significantly higher mean arterial pressure response (F = 8.59, p<.001), and a trend towards a higher cortisol response to the TSST (F = 3.16, p = .106). With NR3C1 gene expression analysis, a significant within-subjects effect was observed in the whole sample in response to the TSST vs. the no-stress condition (F = 4.85, p = .006). Closer examination revealed this was true in the control group (F = 5.10, p = .013), but not in the risk group, which had a blunted response to the TSST vs. the no-stress (F = 1.00, p = .406), and a trend toward a lower response to the TSST compared with controls (F = 4.01, p = .073). Notably, no differences were observed in the no-stress condition between risk and control groups. Conclusions: These preliminary findings suggest that early-life adversity may program biological systems as evidenced by dysregulated transcriptional responses to acute psychological stress. Although these response patterns could be adaptive over the short-term, documenting stress-induced transcriptional changes, via programming of biological systems, can provide critical temporal insights into specific cellular pathways that, when repeated, may lead to increased disease risk. http://dx.doi.org/10.1016/j.psyneuen.2016.07.016 Early-life stress and stratified approaches in mental health Andrea Danese Institute of Psychiatry, King’s College London, United Kingdom E-mail address: [email protected]. Objective: Psychiatric diagnoses identify heterogeneous groups of individuals with different clinical presentations, course of illness, and response to treatment. Childhood maltreatment is associated with biological abnormalities associated with unfavourable course of illness and treatment response across psychiatric diagnoses, such as abnormal HPA axis functioning and high inflammation levels. Methods: We tested whether information on childhood maltreatment could be used for early identification of psychiatric patients with poor prognosis. Results: Childhood maltreatment predicts unfavourable course of illness and poor treatment response in individuals with major depression. Childhood maltreatment also predicts negative clinical features and course of illness in individuals with bipolar disorder. Conclusions: Within heterogeneous groups of psychiatric patients, information on childhood maltreatment can help identify individuals with greater risk and needs. Better understanding
4
Abstracts / Psychoneuroendocrinology 71S (2016) 1–77
of the stratified, trans-diagnostic, biological effects of childhood maltreatment may inform innovative treatment strategies. http://dx.doi.org/10.1016/j.psyneuen.2016.07.017 Telomere biology as a mechanism in developmental programming of health and disease risk Sonja Entringer 1,5,∗ , Elissa Epel 2 , Jue Lin 2 , Claudia Buss 1,5 , Elizabeth Blackburn 2 , Hyagriv Simhan 3 , Katri Räikkonen 4 , Pathik Wadhwa 5
Symposium 3: How Important is Sex/Gender in Personalized Medicine for Mental Health? Time: Thursday, 08/Sep/2016: 3:00pm – 4:30pm Session Chair: Mallory Elva Bowers Session Chair: Sonia Lupien A neural basis for sex-dependent fear expression Rebecca Shansky Northeastern University, USA E-mail address: [email protected].
1
Charité Universitätsmedizin Berlin, Germany University of California, San Francisco, United States 3 University of Pittsburgh, United States 4 University of Helsinki, United States 5 University of California, Irvine, United States E-mail address: [email protected] (S. Entringer). 2
Background: The long-term consequences of exposure to excess stress on the initiation and progression of many age-related diseases are well established. The effects of stress are particularly salient if exposure occurs during sensitive developmental windows such as intrauterine life and the early postnatal period. The elucidation of mechanisms underlying such effects is an area of intense interest and investigation. We propose that the integrity of the telomere system represents a candidate system of particular interest in this context, potentially underlying the observed effects of a disparate set of suboptimal early life exposures on various health and disease risk phenotypes of interest. Methods: Data will be presented from several different longitudinal birth cohorts in which intrauterine conditions (including obstetric risk conditions, maternal stress- and nutrition-related processes) were assessed, and telomere length (TL) was subsequently measured in newborns and infants. In one of the cohorts, data from child follow-up assessments regarding temperament, developmental milestones and behavior problems are available. Results: Obstetric risk conditions, maternal pre-pregnancy obesity, suboptimal maternal nutrition and maternal stress during pregnancy are each independently associated with offspring TL. Furthermore, newborn TL is associated with child behavioral problems related to attention deficit hyperactivity disorder (ADHD) at 3.5 years age. Conclusions: Taken together, our findings provide evidence in humans that suboptimal conditions during pregnancy may exert a programming effect on the newborn and infant telomere biology system, and that newborn telomere length may be a predictor of later child behavioral problems. Telomere biology represents a potential molecular mechanism whereby different exposures in this critical developmental period before birth could impact subsequent health and disease susceptibility-related outcomes over the life span. http://dx.doi.org/10.1016/j.psyneuen.2016.07.018
An individual faced with a threatening stimulus may respond in many different ways. The selection of either an active or passive response can predict long-term outcomes in clinical populations, but what leads to the selection of one over the other is unknown. Using a classic rodent model of Pavlovian cued fear conditioning, we found that female rats were four times as likely as males to exhibit an active, escape-like “darting” response to the conditioned stimulus, even though escape was not possible. We have now begun to investigate the neural substrates of darting by examining c-fos activity in the medial prefrontal cortex (mPFC) and periaqueductal gray (PAG) after fear conditioning in darting and freezing subpopulations. Darters exhibited greater activity in the dorsolateral PAG, which is consistent with active response strategies. Freezers exhibited greater rostral mPFC activity compared to the ventral mPFC, and the rostral:ventral ratio was tightly correlated to freezing in both Freezers and Darters. These data suggest that darting may be mediated by a shift in the balance of mPFC activity, resulting in enhanced dlPAG activation. http://dx.doi.org/10.1016/j.psyneuen.2016.07.019 Association between estradiol and posttraumatic stress disorder in men and women military veterans Mallory E. Bowers 1,2,∗ , Janine D. Flory 1,2 , Duna Abu-Amara 3 , Charles D. Marmar 3 , Rachel Yehuda 1,2 1
Icahn School of Medicine at Mount Sinai, USA James J. Peters Bronx Veterans Affairs Medical Center, USA 3 NYU Langone School of Medicine, USA E-mail address: [email protected] (M.E. Bowers). 2
Posttraumatic stress disorder (PTSD) manifests after a traumatic, typically life-threatening event and is characterized by four core clusters of symptoms – hyperarousal, intrusions (“flashbacks”, e.g. nightmares), avoidance of trauma cues, and negative cognitions and mood. PTSD is twice as prevalent among women compared to men, even when normalizing for amount and type of trauma. Discordant prevalence of PTSD across genders could stem from biological factor(s) that are differentially expressed in women compared to men. Accordingly, the estrogen system is an appealing target for investigation. Using immunoassay, we observed a main effect of PTSD diagnosis on plasma estradiol levels in men and women military veterans with trauma in a combat zone. Specifically, PTSD+ veterans had lower levels of estradiol compared to PTSD-, trauma-control veterans. In men, an association between estradiol and PTSD diagnosis could be mediated by hyperarousal symptoms, as we found a significant negative correlation between