Dominik A. Moser

Acute caffeine administration impact on working memory-related brain activation and functional connectivity in the elderly: a BOLD and perfusion MRI study

In young individuals, caffeine-mediated blockade of adenosine receptors and vasoconstriction has direct repercussions on task-related activations, changes in functional connectivity, as well as global vascular effects. To date, no study has explored the effect of caffeine on brain activation patterns during highly demanding cognitive tasks in the elderly. This prospective, placebo-controlled crossover design comprises 24 healthy elderly individuals (mean age 68.8 ± 4.0 years, 17 females) performing a 2-back working memory (WM) task in functional magnetic resonance imaging (fMRI). Analyses include complimentary assessment of task-related activations (general linear model, GLM), functional connectivity (tensorial independent component analysis, TICA), and baseline perfusion (arterial spin labeling). Despite a reduction in whole-brain global perfusion (-22.7%), caffeine-enhanced task-related GLM activation in a local and distributed network is most pronounced in the bilateral striatum and to a lesser degree in the right middle and inferior frontal gyrus, bilateral insula, left superior and inferior parietal lobule as well as in the cerebellum bilaterally. TICA was significantly enhanced (+8.2%) in caffeine versus placebo in a distributed and task-relevant network including the pre-frontal cortex, the supplementary motor area, the ventral premotor cortex and the parietal cortex as well as the occipital cortex (visual stimuli) and basal ganglia. The inverse comparison of placebo versus caffeine had no significant difference. Activation strength of the task-relevant-network component correlated with response accuracy for caffeine yet not for placebo, indicating a selective cognitive effect of caffeine. The present findings suggest that acute caffeine intake enhances WM-related brain activation as well as functional connectivity of blood oxygen level-dependent fMRI in elderly individuals.

Methylation of NR3C1 is related to maternal PTSD, parenting stress and maternal medial prefrontal cortical activity in response to child separation among mothers with histories of violence exposure.

Prior research has shown that mothers with Interpersonal violence-related posttraumatic stress disorder (IPV-PTSD) report greater difficulty in parenting their toddlers. Relative to their frequent early exposure to violence and maltreatment, these mothers display dysregulation of their hypothalamic pituitary adrenal axis (HPA-axis), characterized by hypocortisolism. Considering methylation of the promoter region of the glucocorticoid receptor gene NR3C1 as a marker for HPA-axis functioning, with less methylation likely being associated with less circulating cortisol, the present study tested the hypothesis that the degree of methylation of this gene would be negatively correlated with maternal IPV-PTSD severity and parenting stress, and positively correlated with medial prefrontal cortical (mPFC) activity in response to video-stimuli of stressful versus non-stressful mother–child interactions. Following a mental health assessment, 45 mothers and their children (ages 12–42 months) participated in a behavioral protocol involving free-play and laboratory stressors such as mother–child separation. Maternal DNA was extracted from saliva. Interactive behavior was rated on the CARE-Index. During subsequent fMRI scanning, mothers were shown films of free-play and separation drawn from this protocol. Maternal PTSD severity and parenting stress were negatively correlated with the mean percentage of methylation of NR3C1. Maternal mPFC activity in response to video-stimuli of mother–child separation versus play correlated positively to NR3C1 methylation, and negatively to maternal IPV-PTSD and parenting stress. Among interactive behavior variables, child cooperativeness in play was positively correlated with NR3C1 methylation. Thus, the present study is the first published report to our knowledge, suggesting convergence of behavioral, epigenetic, and neuroimaging data that form a psychobiological signature of parenting-risk in the context of early life stress and PTSD.

BDNF methylation and maternal brain activity in a violence-related sample

It is known that increased circulating glucocorticoids in the wake of excessive, chronic, repetitive stress increases anxiety and impairs Brain-Derived Neurotrophic Factor (BDNF) signaling. Recent studies of BDNF gene methylation in relation to maternal care have linked high BDNF methylation levels in the blood of adults to lower quality of received maternal care measured via self-report. Yet the specific mechanisms by which these phenomena occur remain to be established. The present study examines the link between methylation of the BDNF gene promoter region and patterns of neural activity that are associated with maternal response to stressful versus non-stressful child stimuli within a sample that includes mothers with interpersonal violence-related PTSD (IPV-PTSD). 46 mothers underwent fMRI. The contrast of neural activity when watching children—including their own—was then correlated to BDNF methylation. Consistent with the existing literature, the present study found that maternal BDNF methylation was associated with higher levels of maternal anxiety and greater childhood exposure to domestic violence. fMRI results showed a positive correlation of BDNF methylation with maternal brain activity in the anterior cingulate (ACC), and ventromedial prefrontal cortex (vmPFC), regions generally credited with a regulatory function toward brain areas that are generating emotions. Furthermore we found a negative correlation of BDNF methylation with the activity of the right hippocampus. Since our stimuli focus on stressful parenting conditions, these data suggest that the correlation between vmPFC/ACC activity and BDNF methylation may be linked to mothers who are at a disadvantage with respect to emotion regulation when facing stressful parenting situations. Overall, this study provides evidence that epigenetic signatures of stress-related genes can be linked to functional brain regions regulating parenting stress, thus advancing our understanding of mothers at risk for stress-related psychopathology.

Acute Caffeine Administration Effect on Brain Activation Patterns in Mild Cognitive Impairment

Previous studies showed that acute caffeine administration enhances task-related brain activation in elderly individuals with preserved cognition. To explore the effects of this widely used agent on cognition and brain activation in early phases of cognitive decline, we performed a double-blinded, placebo-controlled functional magnetic resonance imaging (fMRI) study during an n-back working memory task in 17 individuals with mild cognitive impairment (MCI) compared to 17 age-matched healthy controls (HC). All individuals were regular caffeine consumers with an overnight abstinence and given 200 mg caffeine versus placebo tablets 30 minutes before testing. Analyses included assessment of task-related activation (general linear model), functional connectivity (tensorial-independent component analysis, TICA), baseline perfusion (arterial spin labeling, ASL), grey matter density (voxel-based morphometry, VBM), and white matter microstructure (tract-based spatial statistics, TBSS). Acute caffeine administration induced a focal activation of the prefrontal areas in HC with a more diffuse and posteromedial activation pattern in MCI individuals. In MCI, TICA documented a significant caffeine-related enhancement in the prefrontal cortex, supplementary motor area, ventral premotor and parietal cortex as well as the basal ganglia and cerebellum. The absence of significant group differences in baseline ASL perfusion patterns supports a neuronal rather than a purely vascular origin of these differences. The VBM and TBSS analyses excluded potentially confounding differences in grey matter density and white matter microstructure between MCI and HC. The present findings suggest a posterior displacement of working memory-related brain activation patterns after caffeine administration in MCI that may represent a compensatory mechanism to counterbalance a frontal lobe dysfunction.

The association of serotonin receptor 3A methylation with maternal violence exposure, neural activity, and child aggression ☆

Background Methylation of the serotonin 3A receptor gene (HTR3A) has been linked to child maltreatment and adult psychopathology. The present study examined whether HTR3A methylation might be associated with mothers’ lifetime exposure to interpersonal violence (IPV), IPV‐related psychopathology, child disturbance of attachment, and maternal neural activity. Methods Number of maternal lifetime IPV exposures and measures of maternal psychopathology including posttraumatic stress disorder (PTSD), major depression and aggressive behavior (AgB), and a measure of child attachment disturbance known as “secure base distortion” (SBD) were assessed in a sample of 35 mothers and children aged 12–42 months. Brain fMRI activation was assessed in mothers using 30‐s silent film excerpts depicting menacing adult male‐female interactions versus prosocial and neutral interactions. Group and continuous analyses were performed to test for associations between clinical and fMRI variables with DNA methylation. Results Maternal IPV exposure‐frequency was associated with maternal PTSD; and maternal IPV‐PTSD was in turn associated with child SBD. Methylation status of several CpG sites in the HTR3A gene was associated with maternal IPV and IPV‐PTSD severity, AgB and child SBD, in particular, self‐endangering behavior. Methylation status at a specific CpG site (CpG2_III) was associated with decreased medial prefrontal cortical (mPFC) activity in response to film‐stimuli of adult male‐female interactions evocative of violence as compared to prosocial and neutral interactions. Conclusions Methylation status of the HTR3A gene in mothers is linked to maternal IPV‐related psychopathology, trauma‐induced brain activation patterns, and child attachment disturbance in the form of SBD during a sensitive period in the development of self‐regulation. HighlightsMaternal severity of interpersonal violence exposure (IPV) was associated with diagnosis of maternal post‐traumatic stress disorder (PTSD).Maternal IPV‐PTSD was in turn associated with disturbed child attachment.HTR3A gene methylation was linked to maternal IPV exposure and aggressive behavior and disturbed child attachment and self‐endangering behavior.HTR3A methylation at the CpG2_III site was linked to decreased medial prefrontal cortical activity in response to menacing relational stimuli.

Negative and Distorted Attributions Towards Child, Self, and Primary Attachment Figure Among Posttraumatically Stressed Mothers: What Changes with Clinician Assisted Videofeedback Exposure Sessions (CAVES)

Abstract This study found that within a non-referred community pediatrics clinic sample, the severity of mothers’ trauma-related psychopathology, in particular, their interpersonal violence-related (IPV) posttraumatic stress, dissociative, and depressive symptoms predicted the degree of negativity of mothers’ attributions towards their preschool age children, themselves, and their own primary attachment figure. Results also showed that mothers with IPV-related posttraumatic stress disorder (PTSD) as compared to non-PTSD controls showed a significantly greater degree of negativity of their attributions toward their child, themselves and their primary attachment figure during childhood. The study finally found a significant reduction in the degree of negativity of mothers’ attributions only towards their child following a three-session evaluation-protocol that included a form of experimental intervention entitled the “Clinician Assisted Videofeedback Exposure Session(s)” (CAVES), for mothers with IPV-PTSD as compared to control-subjects.

The relation of general socio-emotional processing to parenting specific behavior: a study of mothers with and without posttraumatic stress disorder

Socio-emotional information processing during everyday human interactions has been assumed to translate to social-emotional information processing when parenting a child. Yet, few studies have examined whether this is indeed the case. This study aimed to improve on this by connecting the functional neuroimaging data when seeing socio-emotional interactions that are not parenting specific to observed maternal sensitivity. The current study considered 45 mothers of small children (12–42 months of age). It included healthy controls (HC) and mothers with interpersonal violence-related posttraumatic stress disorder (IPV-PTSD), as well as mothers without PTSD, both with and without IPV exposure. We found that anterior cingulate cortex (ACC) and ventromedial prefrontal cortex (vmPFC) activity correlated negatively with observed maternal sensitivity when mothers watched videos of menacing vs. prosocial adult male–female interactions. This relationship was independent of whether mothers were HC or had IPV-PTSD. We also found dorsolateral prefrontal cortex (dlPFC) activity to be correlated negatively with maternal sensitivity when mothers watched any kind of arousing adult interactions. With regards to ACC and vmPFC activity, we interpret our results to mean that the ease of general emotional information integration translates to parenting-specific behavior. Our dlPFC activity findings support the idea that the efficiency of top-down control of socio-emotional processing in non-parenting specific contexts may be predictive of parenting behavior.

Autonomic functioning in mothers with interpersonal violence-related posttraumatic stress disorder in response to separation-reunion

This study characterizes autonomic nervous system activity reactive to separation-reunion among mothers with Interpersonal Violence-Related Posttraumatic Stress Disorder (IPV-PTSD). Heart-rate (HR) and high frequency heart-rate-variability (HF-HRV) were measured in 17 IPV-PTSD-mothers, 22 sub-threshold-mothers, and 15 non-PTSD mother-controls while interacting with their toddlers (12-48 months). Analyses showed IPV-PTSD-mothers having generally lower HR than other groups. All groups showed negative correlations between changes in HR and HF-HRV from sitting- to standing-baseline. During initial separation, controls no longer showed a negative relationship between HR and HF-HRV. But by the second reunion, the negative relationship reappeared. IPV-PTSD- and sub-threshold-mothers retained negative HR/HF-HRV correlations during the initial separation, but stopped showing them by the second reunion. Results support that mother-controls showed a pattern of autonomic regulation suggestive of hypervigilance during initial separation that resolved by the time of re-exposure. PTSD-mothers showed delayed onset of this pattern only upon re-exposure, and were perhaps exhibiting defensive avoidance or numbing during the initial separation/reunion.

Multivariate Associations Among Behavioral, Clinical, and Multimodal Imaging Phenotypes in Patients With Psychosis

Importance Alterations in multiple neuroimaging phenotypes have been reported in psychotic disorders. However, neuroimaging measures can be influenced by factors that are not directly related to psychosis and may confound the interpretation of case-control differences. Therefore, a detailed characterization of the contribution of these factors to neuroimaging phenotypes in psychosis is warranted. Objective To quantify the association between neuroimaging measures and behavioral, health, and demographic variables in psychosis using an integrated multivariate approach. Design, Setting, and Participants This imaging study was conducted at a university research hospital from June 26, 2014, to March 9, 2017. High-resolution multimodal magnetic resonance imaging data were obtained from 100 patients with schizophrenia, 40 patients with bipolar disorder, and 50 healthy volunteers; computed were cortical thickness, subcortical volumes, white matter fractional anisotropy, task-related brain activation (during working memory and emotional recognition), and resting-state functional connectivity. Ascertained in all participants were nonimaging measures pertaining to clinical features, cognition, substance use, psychological trauma, physical activity, and body mass index. The association between imaging and nonimaging measures was modeled using sparse canonical correlation analysis with robust reliability testing. Main Outcomes and Measures Multivariate patterns of the association between nonimaging and neuroimaging measures in patients with psychosis and healthy volunteers. Results The analyses were performed in 92 patients with schizophrenia (23 female [25.0%]; mean [SD] age, 27.0 [7.6] years), 37 patients with bipolar disorder (12 female [32.4%]; mean [SD] age, 27.5 [8.1] years), and 48 healthy volunteers (20 female [41.7%]; mean [SD] age, 29.8 [8.5] years). The imaging and nonimaging data sets showed significant covariation (r = 0.63, P < .001), which was independent of diagnosis. Among the nonimaging variables examined, age (r = −0.53), IQ (r = 0.36), and body mass index (r = −0.25) were associated with multiple imaging phenotypes; cannabis use (r = 0.23) and other substance use (r = 0.33) were associated with subcortical volumes, and alcohol use was associated with white matter integrity (r = −0.15). Within the multivariate models, positive symptoms retained associations with the global neuroimaging (r = −0.13), the cortical thickness (r = −0.22), and the task-related activation variates (r = −0.18); negative symptoms were mostly associated with measures of subcortical volume (r = 0.23), and depression/anxiety was associated with measures of white matter integrity (r = 0.12). Conclusions and Relevance Multivariate analyses provide a more accurate characterization of the association between brain alterations and psychosis because they enable the modeling of other key factors that influence neuroimaging phenotypes.

Maternal PTSD and corresponding neural activity mediate effects of child exposure to violence on child PTSD symptoms

The aim of this study was to examine the relationship of maternal interpersonal violence-related posttraumatic stress disorder (IPV-PTSD), associated neural activity in response to mother-child relational stimuli, and child psychopathology indicators at child ages 12–42 months and one year later. The study tested the hypothesis that decreased maternal neural activity in regions that subserve emotion regulation would be associated with child symptoms associated with emotional dysregulation at both time points. Functional magnetic resonance imaging of 42 mothers with or without violence-exposure and associated IPV-PTSD were assessed. Their child’s life-events and symptoms/behaviors indicative of high-risk subsequent PTSD diagnosis on a maternal-report questionnaire were measured one year later. Maternal IPV-PTSD severity was significantly associated with decreased ventromedial prefrontal cortex (vmPFC) activation in response to mother-child relational stimuli. Maternal IPV-PTSD severity and decreased vmPFC activation were then significantly associated with a child attachment disturbance at 12–42 months and symptoms/behaviors one year later, that were correlated with emotional dysregulation and risk for child PTSD. Maternal IPV-PTSD and child exposure to IPV were both predictive of child PTSD symptoms with maternal IPV-PTSD likely mediating the effects of child IPV exposure on child PTSD symptoms. These findings suggest that maternal IPV-PTSD severity and associated decreased vmPFC activity in response to mother-child relational stimuli are predictors of child psychopathology by age 12–42 months and one-year later. Significant findings in this paper may well be useful in understanding how maternal top-down cortico-limbic dysregulation promotes intergenerational transmission of IPV and related psychopathology and, thus should be targeted in treatment.