Remmelt Schur

Cortisol stress reactivity across psychiatric disorders : A systematic review and meta-analysis

The hypothalamus-pituitary-adrenal (HPA) axis and its end product cortisol are essential for an adequate response to stress. Considering the role of stress as a risk factor for psychiatric disorders, it is not surprising that cortisol stress reactivity has frequently been investigated in patients versus healthy individuals. However, the large heterogeneity in measures of the cortisol stress response has hampered a systematic evaluation of the evidence. We here report of a systematic literature review and meta-analysis on cortisol reactivity to psychosocial stress across psychiatric disorders. Original data from authors were obtained to construct standardized cortisol outcomes (the areas under the curve with respect to increase (AUCi) and ground (AUCg)) and to examine the influence of sex and symptomatic state on cortisol stress reactivity. Fourteen studies on major depressive disorder (MDD) (n=1129), 9 on anxiety disorders (n=732, including social anxiety disorder (SAD), posttraumatic stress disorder, panic disorder and mixed samples of anxiety disorders) and 4 on schizophrenia (n=180) were included that used the Trier Social Stress Test or an equivalent psychosocial stress task. Sex-dependent changes in stress reactivity were apparent in MDD and anxiety disorders. Specifically, women with current MDD or an anxiety disorder exhibited a blunted cortisol stress response, whereas men with current MDD or SAD showed an increased cortisol response to psychosocial stress. In individuals with remitted MDD, altered cortisol stress reactivity was less pronounced in women and absent in men. For schizophrenia, cortisol stress reactivity was blunted in both men and women, but the number of studies was limited and showed evidence for publication bias. These findings illustrate that sharing individual data to disentangle the effects of sex, symptom levels and other factors is essential for further understanding of the alterations in cortisol stress reactivity across psychiatric disorders.

Brain GABA levels across psychiatric disorders: A systematic literature review and meta-analysis of 1H-MRS studies

The inhibitory gamma‐aminobutyric acid (GABA) system is involved in the etiology of most psychiatric disorders, including schizophrenia, autism spectrum disorder (ASD) and major depressive disorder (MDD). It is therefore not surprising that proton magnetic resonance spectroscopy (1H‐MRS) is increasingly used to investigate in vivo brain GABA levels. However, integration of the evidence for altered in vivo GABA levels across psychiatric disorders is lacking. We therefore systematically searched the clinical 1H‐MRS literature and performed a meta‐analysis. A total of 40 studies (N = 1,591) in seven different psychiatric disorders were included in the meta‐analysis: MDD (N = 437), schizophrenia (N = 517), ASD (N = 150), bipolar disorder (N = 129), panic disorder (N = 81), posttraumatic stress disorder (PTSD) (N = 104), and attention deficit/hyperactivity disorder (ADHD) (N = 173). Brain GABA levels were lower in ASD (standardized mean difference [SMD] = −0.74, P = 0.001) and in depressed MDD patients (SMD = −0.52, P = 0.005), but not in remitted MDD patients (SMD = −0.24, P = 0.310) compared with controls. In schizophrenia this finding did not reach statistical significance (SMD = −0.23, P = 0.089). No significant differences in GABA levels were found in bipolar disorder, panic disorder, PTSD, and ADHD compared with controls. In conclusion, this meta‐analysis provided evidence for lower brain GABA levels in ASD and in depressed (but not remitted) MDD patients compared with healthy controls. Findings in schizophrenia were more equivocal. Even though future 1H‐MRS studies could greatly benefit from a longitudinal design and consensus on the preferred analytical approach, it is apparent that 1H‐MRS studies have great potential in advancing our understanding of the role of the GABA system in the pathogenesis of psychiatric disorders. Hum Brain Mapp 37:3337–3352, 2016.

Brain structure–function associations in multi-generational families genetically enriched for bipolar disorder

Recent theories regarding the pathophysiology of bipolar disorder suggest contributions of both neurodevelopmental and neurodegenerative processes. While structural neuroimaging studies indicate disease-associated neuroanatomical alterations, the behavioural correlates of these alterations have not been well characterized. Here, we investigated multi-generational families genetically enriched for bipolar disorder to: (i) characterize neurobehavioural correlates of neuroanatomical measures implicated in the pathophysiology of bipolar disorder; (ii) identify brain-behaviour associations that differ between diagnostic groups; (iii) identify neurocognitive traits that show evidence of accelerated ageing specifically in subjects with bipolar disorder; and (iv) identify brain-behaviour correlations that differ across the age span. Structural neuroimages and multi-dimensional assessments of temperament and neurocognition were acquired from 527 (153 bipolar disorder and 374 non-bipolar disorder) adults aged 18-87 years in 26 families with heavy genetic loading for bipolar disorder. We used linear regression models to identify significant brain-behaviour associations and test whether brain-behaviour relationships differed: (i) between diagnostic groups; and (ii) as a function of age. We found that total cortical and ventricular volume had the greatest number of significant behavioural associations, and included correlations with measures from multiple cognitive domains, particularly declarative and working memory and executive function. Cortical thickness measures, in contrast, showed more specific associations with declarative memory, letter fluency and processing speed tasks. While the majority of brain-behaviour relationships were similar across diagnostic groups, increased cortical thickness in ventrolateral prefrontal and parietal cortical regions was associated with better declarative memory only in bipolar disorder subjects, and not in non-bipolar disorder family members. Additionally, while age had a relatively strong impact on all neurocognitive traits, the effects of age on cognition did not differ between diagnostic groups. Most brain-behaviour associations were also similar across the age range, with the exception of cortical and ventricular volume and lingual gyrus thickness, which showed weak correlations with verbal fluency and inhibitory control at younger ages that increased in magnitude in older subjects, regardless of diagnosis. Findings indicate that neuroanatomical traits potentially impacted by bipolar disorder are significantly associated with multiple neurobehavioural domains. Structure-function relationships are generally preserved across diagnostic groups, with the notable exception of ventrolateral prefrontal and parietal association cortex, volumetric increases in which may be associated with cognitive resilience specifically in individuals with bipolar disorder. Although age impacted all neurobehavioural traits, we did not find any evidence of accelerated cognitive decline specific to bipolar disorder subjects. Regardless of diagnosis, greater global brain volume may represent a protective factor for the effects of ageing on executive functioning.

Longitudinal changes in glucocorticoid receptor exon 1F methylation and psychopathology after military deployment

Several cross-sectional studies have demonstrated the relevance of DNA methylation of the glucocorticoid receptor exon 1F region (GR-1F) for trauma-related psychopathology. We conducted a longitudinal study to examine GR-1F methylation changes over time in relation to trauma exposure and the development of post-deployment psychopathology. GR-1F methylation (52 loci) was quantified using pyrosequencing in whole blood of 92 military men 1 month before and 6 months after a 4-month deployment period to Afghanistan. GR-1F methylation overall (mean methylation and the number of methylated loci) and functional methylation (methylation at loci associated with GR exon 1F expression) measures were examined. We first investigated the effect of exposure to potentially traumatic events during deployment on these measures. Subsequently, changes in GR-1F methylation were related to changes in mental health problems (total Symptom Checklist-90 score) and posttraumatic stress disorder (PTSD) symptoms (Self-Report Inventory for PTSD). Trauma exposure during deployment was associated with an increase in all methylation measures, but development of mental health problems 6 months after deployment was only significantly associated with an increased functional methylation. Emergence of post-deployment PTSD symptoms was not related to increased functional methylation over time. Pre-deployment methylation levels did not predict post-deployment psychopathology. To our knowledge, this is the first study to prospectively demonstrate trauma-related increases in GR-1F methylation, and it shows that only increases at specific functionally relevant sites predispose for post-deployment psychopathology.

Development of psychopathology in deployed armed forces in relation to plasma GABA levels

The GABA system is pivotal for an adequate response to a stressful environment but has remained largely unexplored in this context. The present study investigated the relationship of prospectively measured plasma GABA levels with psychopathology symptoms in military deployed to Afghanistan at risk for developing psychopathology following trauma exposure during deployment, including posttraumatic stress disorder (PTSD) and major depressive disorder (MDD). Plasma GABA levels were measured in military personnel (N=731) one month prior to deployment (T0), and one (T1) and six months (T2) after deployment using ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS). Mental health problems and depressive symptoms were measured with the Dutch revised Symptom Checklist (SCL-90) and PTSD symptoms with the Dutch Self-Rating Inventory for PTSD (SRIP). Six months after deployment increases in GABA concentrations were present in individuals who had developed mental health problems (T2: β=0.06, p=1.6×10-2, T1: β=4.7×10-2, p=0.13), depressive symptoms (T2: β=0.29, p=7.9×10-3, T1: β=0.23, p=0.072) and PTSD symptoms at T2 (T2: β=0.12, p=4.3×10-2, T1: β=0.11, p=0.13). Plasma GABA levels prior to and one month after deployment poorly predicted a high level of psychopathology symptoms either one or six months after deployment. The number of previous deployments, trauma experienced during deployment, childhood trauma, age and sex were not significantly associated with plasma GABA levels over time. Exclusion of subjects who either started or stopped smoking, alcohol or medication use between the three time points rendered the association of increasing GABA levels with the emergence of psychopathology symptoms more pronounced (mental health problems at T2: β=0.09, p=4.2×10-3; depressive symptoms at T2: β=0.35, p=3.5×10-3, PTSD symptoms at T2: β=0.17, p=1.7×10-2). To our knowledge, this is the first study to provide prospective evidence that the development of psychopathology after military deployment is associated with increasing plasma GABA levels. Our finding that plasma GABA rises after the emergence of psychopathology symptoms suggests that GABA increase may constitute a compensatory mechanism and warrants further exploration of the GABA system as a potential target for treatment.

Acute stress effects on GABA and glutamate levels in the prefrontal cortex: A 7T 1H magnetic resonance spectroscopy study

There is ample evidence that the inhibitory GABA and the excitatory glutamate system are essential for an adequate response to stress. Both GABAergic and glutamatergic brain circuits modulate hypothalamus-pituitary-adrenal (HPA)-axis activity, and stress in turn affects glutamate and GABA levels in the rodent brain. However, studies examining stress-induced GABA and glutamate levels in the human brain are scarce. Therefore, we investigated the influence of acute psychosocial stress (using the Trier Social Stress Test) on glutamate and GABA levels in the medial prefrontal cortex of 29 healthy male individuals using 7 Tesla proton magnetic resonance spectroscopy. In vivo GABA and glutamate levels were measured before and 30 min after exposure to either the stress or the control condition. We found no associations between psychosocial stress or cortisol stress reactivity and changes over time in medial prefrontal glutamate and GABA levels. GABA and glutamate levels over time were significantly correlated in the control condition but not in the stress condition, suggesting that very subtle differential effects of stress on GABA and glutamate across individuals may occur. However, overall, acute psychosocial stress does not appear to affect in vivo medial prefrontal GABA and glutamate levels, at least this is not detectable with current practice 1H-MRS.

1H-MRS processing parameters affect metabolite quantification : The urgent need for uniform and transparent standardization

Proton magnetic resonance spectroscopy (1H–MRS) can be used to quantify in vivo metabolite levels, such as lactate, γ‐aminobutyric acid (GABA) and glutamate (Glu). However, there are considerable analysis choices which can alter the accuracy or precision of 1H–MRS metabolite quantification. It is currently unknown to what extent variations in the analysis pipeline used to quantify 1H–MRS data affect outcomes. The purpose of this study was to evaluate whether the quantification of identical 1H–MRS scans across independent and experienced research groups would yield comparable results. We investigated the influence of model parameters and spectral quantification software on fitted metabolite concentration values. Sixty spectra in 30 individuals (repeated measures) were acquired using a 7‐T MRI scanner. Data were processed by four independent research groups with the freedom to choose their own individualized and optimal parameter settings using LCModel software. Data were processed a second time in one group using an independent software package (NMRWizard) for an additional comparison with a different post‐processing platform. Correlations across research groups of the ratio between the highest and, arguably, the most relevant resonances for neurotransmission [N‐acetyl aspartate (NAA), N‐acetyl aspartyl glutamate (NAAG) and Glu] over the total creatine [creatine (Cr) + phosphocreatine (PCr)] concentration, using Pearsons product–moment correlation coefficient (r), were calculated. Mean inter‐group correlations using LCModel software were 0.87, 0.88 and 0.77 for NAA/Cr + PCr, NAA + NAAG/Cr + PCr and Glu/Cr + PCr, respectively. The mean correlations when comparing NMRWizard results with LCModel fitting results at University Medical Center Utrecht (UMCU) were 0.87, 0.89 and 0.71 for NAA/Cr + PCr, NAA + NAAG/Cr + PCr and Glu/Cr + PCr, respectively. Metabolite quantification using identical 1H–MRS data was influenced by processing parameters, basis sets and software choice. Locally preferred processing choices affected metabolite quantification, even when using identical software. Our results reinforce the notion that standard practices should be established to regularize outcomes of 1H–MRS studies, and that basis sets used for processing should be made available to the scientific community.

Glucocorticoid receptor exon 1F methylation and the cortisol stress response in health and disease

Childhood trauma has been proposed to increase vulnerability to develop psychopathology in part through an altered cortisol stress response. Research in rats has suggested that this effect is mediated by methylation in the glucocorticoid receptor 17 region (GR-17 or GR-1F in humans), with higher methylation after poor maternal care leading to an increased cortisol stress response in adulthood. In humans, the associations between childhood trauma and GR-1F methylation or the cortisol stress response are equivocal. Remarkably, evidence for the relation between GR-1F methylation and the cortisol stress response has been conflicting as well. To further explore this, we investigated the associations of peripheral GR-1F methylation (52 CpGs) with the cortisol stress response (Trier Social Stress Test) and with childhood trauma in three independent studies (total N = 241) including healthy controls, patients with schizophrenia and bipolar disorder and unaffected siblings of patients with one of these disorders. We did not find any significant association between GR-1F methylation and the cortisol stress response (areas under the curve) or childhood trauma, nor did we observe any group differences between patients, siblings and healthy controls. Our findings do not support GR-1F methylation as a proxy for the cortisol stress response, nor its link with childhood trauma or psychopathology. These results suggest that multifactorial models for stress-related psychopathology are needed. Alternatively, future longitudinal studies may reveal GR-1F methylation to be a useful parameter at an individual level.

Longitudinal Changes In Glucocorticoid Receptor 1f Methylation And Psychopathology After Military Deployment

Background The glucocorticoid receptor (GR) 1F region is involved in transcription and expression of the GR protein and influences hypothalamic-pituitary-adrenal (HPA)-axis activity. Several studies have investigated GR-1F DNA methylation in the context of traumatic stress and psychiatric disorders, such as major depressive disorder and posttraumatic stress disorder (PTSD). However, longitudinal studies examining GR-1F DNA methylation before and after exposure to traumatic stress are lacking. We therefore aimed to investigate prospective DNA methylation changes in the GR-1F region after military deployment and its relation to the emergence of psychopathology. Methods Whole blood DNA methylation in the entire GR-1F region (52 CpGs) before and six months after deployment was quantified using pyrosequencing (N=92). Methylation levels were linked to post-deployment mental health problems (Revised Symptom Checklist, SCL-90), PTSD symptoms (Self-Rating Inventory for PTSD) and trauma exposure during deployment. Moreover, methylation was related to GR-1F expression, GR binding and genetic variation in the GR. Mean methylation, the number of methylated sites (methylation burden), mean methylation at transcription factor binding sites and at CpGs significantly associated with GR-1F expression (functional methylation) were examined. Results Trauma exposure during deployment and the emergence of mental health problems were significantly related to an increased methylation burden (t=2.23, p=2.8x10-2, =0.45 and t=2.24, p=2.7x10-2 and =0.085, respectively), which was associated with both decreased GR-1F expression (t=-2.92, p=4.7x10-3, =-1.93) and GR binding (t=-2.13, p=3.9x10-2, =-2.9x10-3). Moreover, development of psychopathology symptoms was significantly associated with increased methylation at functionally relevant CpGs (mental health problems: t=3.73, p=3.5x10-4, =1.2x10-2; PTSD symptoms: t=2.10, p=3.8x10-2, =0.59). Change in mean methylation was associated with a change in mental health problems (t=1.99, p=5.0x10-2, =4.1x10-3) and in GR-1F expression (t=-2.35, p=2.2x10-2, =-0.074). Discussion This longitudinal study in a military cohort shows that GR-1F DNA methylation levels are related to trauma exposure during deployment and the development of post-deployment psychopathology symptoms, particularly at functionally relevant sites. Together, our results provide further insight in transcriptional regulation of the glucocorticoid receptor gene, by demonstrating that GR-1F DNA methylation levels can vary over time and are related to stress vulnerability and the emergence of post-deployment psychopathology symptoms.