Markus Muehlhan

The scanner as a stressor: Evidence from subjective and neuroendocrine stress parameters in the time course of a functional magnetic resonance imaging session

Subjects participating in magnetic resonance imaging (MRI) examinations regularly report anxiety and stress related reactions. This may result in impaired data quality and premature termination of scans. Moreover, cognitive functions and neural substrates can be altered by stress. While prior studies investigated pre-post scan differences in stress reactions only, the present study provides an in-depth analysis of mood changes and hormonal fluctuations during the time course of a typical fMRI session. Thirty-nine subjects participated in the study. Subjective mood, salivary alpha-amylase (sAA) and cortisol were assessed at six time points during the lab visit. Associations between hormonal data and neural correlates of a visual detection task were observed using a region of interest approach applied to the thalamic region. Mood and hormonal levels changed significantly during the experiment. Subjects were most nervous immediately after entering the scanner. SAA was significantly elevated after MRI preparation. A subgroup of n=5 (12.8%) subjects showed pronounced cortisol responses exceeding 2.5 nmol/l. Preliminary fMRI data revealed an association between sAA levels and left thalamic activity during the first half of the experiment that disappeared during the second half. No significant correlation between cortisol and thalamic activity was observed. Results indicate that an fMRI experiment may elicit subjective and neuroendocrine stress reactions that can influence functional activation patterns.

Effects of Acute Psychosocial Stress on Working Memory Related Brain Activity in Men

Acute psychosocial stress in humans triggers the release of glucocorticoids (GCs) and influences performance in declarative and working memory (WM) tasks. These memory systems rely on the hippocampus and prefrontal cortex (PFC), where GC‐binding receptors are present. Previous studies revealed contradictory results regarding effects of acute stress on WM‐related brain activity. We combined functional magnetic resonance imaging with a standardized psychosocial stress protocol to investigate the effects of acute mental stress on brain activity during encoding, maintenance, and retrieval of WM. Participants (41 healthy young men) underwent either a stress or a control procedure before performing a WM task. Stress increased salivary cortisol levels and tended to increase WM accuracy. Neurally, stress‐induced increases in cortical activity were evident in PFC and posterior parietal cortex (PPC) during WM maintenance. Furthermore, hippocampal activity was modulated by stress during encoding and retrieval with increases in the right anterior hippocampus during WM encoding and decreases in the left posterior hippocampus during retrieval. Our study demonstrates that stress increases activity in PFC and PPC specifically during maintenance of items in WM, whereas effects on hippocampal activity are restricted to encoding and retrieval. The finding that psychosocial stress can increase and decrease activity in two different hippocampal areas may be relevant for understanding the often‐reported phase‐dependent opposing behavioral effects of stress on long‐term memory. Hum Brain Mapp, 2010.

How specific is specific phobia? Different neural response patterns in two subtypes of specific phobia

Specific phobia of the animal subtype has been employed as a model disorder exploring the neurocircuitry of anxiety disorders, but evidence is lacking whether the detected neural response pattern accounts for all animal subtypes, nor across other phobia subtypes. The present study aimed at directly comparing two subtypes of specific phobia: snake phobia (SP) representing the animal, and dental phobia (DP) representing the blood-injection-injury subtype. Using functional magnetic resonance imaging (fMRI), brain activation and skin conductance was measured during phobogenic video stimulation in 12 DP, 12 SP, and 17 healthy controls. For SP, the previously described activation of fear circuitry structures encompassing the insula, anterior cingulate cortex and thalamus could be replicated and was furthermore associated with autonomic arousal. In contrast, DP showed circumscribed activation of the prefrontal and orbitofrontal cortex (PFC/OFC) when directly compared to SP, being dissociated from autonomic arousal. Results provide preliminary evidence for the idea that snake and dental phobia are characterized by distinct underlying neural systems during sustained emotional processing with evaluation processes in DP being controlled by orbitofrontal areas, whereas phobogenic reactions in SP are primarily guided by limbic and paralimbic structures. Findings support the current diagnostic classification conventions, separating distinct subtypes in DSM-IV-TR. They highlight that caution might be warranted though for generalizing findings derived from animal phobia to other phobic and anxiety disorders. If replicated, results could contribute to a better understanding of underlying neurobiological mechanisms of specific phobia and their respective classification.

Within and between session changes in subjective and neuroendocrine stress parameters during magnetic resonance imaging: A controlled scanner training study

Accumulating evidence suggests that the magnetic resonance imaging (MRI) scanner can act as a stressor, eliciting subjective and neuroendocrine stress responses. Approaches to familiarize subjects with the scanner could help minimizing unintended effects on neural activation patterns of interest. Controlled studies on the effects of a scanner training are however missing. Using a comparative design, we analyzed within- and between session changes in subjective and neuroendocrine stress parameters in 63 healthy, scanner-naïve adults who participated in a two-day training protocol in an MRI, mock, or lab environment. A habituation task was used to assess within-session changes in subjective and neuroendocrine (cortisol) stress parameters; between-session changes were indicated by differences between days. MRI and mock, but not lab training were successful in reducing subjective distress towards the scanner. In contrast, cortisol reactivity towards the training environment generally increased during day 2, and the percentage of cortisol responders particularly rose in the mock and MRI groups. Within-session habituation of subjective arousal and anxiety was observed during both days and irrespective of training condition. Present findings demonstrate that training in a scanner environment successfully reduces subjective distress, but may also induce sensitization of endocrine stress levels during repeated scanning. Subjective distress can further be stabilized by acclimating subjects to the environment prior to the MRI assessment, including a short habituation phase into the assessment protocol. If replicated, present findings should be considered by researchers employing repeated measurement designs where subjects are exposed to a scanner more than once.

(Don't) panic in the scanner! How panic patients with agoraphobia experience a functional magnetic resonance imaging session

Although functional magnetic resonance imaging (fMRI) has gained increasing importance in investigating neural substrates of anxiety disorders, less is known about the stress eliciting properties of the scanner environment itself. The aim of the study was to investigate feasibility, self-reported distress and anxiety management strategies during an fMRI experiment in a comprehensive sample of patients with panic disorder and agoraphobia (PD/AG). Within the national research network PANIC-NET, n=89 patients and n=90 controls participated in a multicenter fMRI study. Subjects completed a retrospective questionnaire on self-reported distress, including a habituation profile and exploratory questions about helpful strategies. Drop-out rates and fMRI quality parameters were employed as markers of study feasibility. Different anxiety measures were used to identify patients particularly vulnerable to increased scanner anxiety and impaired data quality. Three (3.5%) patients terminated the session prematurely. While drop-out rates were comparable for patients and controls, data quality was moderately impaired in patients. Distress was significantly elevated in patients compared to controls; claustrophobic anxiety was furthermore associated with pronounced distress and lower fMRI data quality in patients. Patients reported helpful strategies, including motivational factors and cognitive coping strategies. The feasibility of large-scale fMRI studies on PD/AG patients could be proved. Study designs should nevertheless acknowledge that the MRI setting may enhance stress reactions. Future studies are needed to investigate the relationship between self-reported distress and fMRI data in patient groups that are subject to neuroimaging research.

Gray and white matter volume abnormalities in generalized anxiety disorder by categorical and dimensional characterization.

Increasing efforts have been made to investigate the underlying pathophysiology of generalized anxiety disorder (GAD), but only limited consistent information is available on gray (GM) and white matter (WM) volume changes in affected adults. Additionally, few studies employed dimensional approaches to GAD pathology. This study compares structural brain imaging data from n=19 GAD subjects and n=24 healthy comparison (HC) subjects, all medication-free and matched on age, sex and education. Separate categorical and dimensional models were employed using voxel-based morphometry for GM and WM. Significantly higher GM volumes were found in GAD subjects mainly in basal ganglia structures and less consistently in the superior temporal pole. For WM, GAD subjects showed significantly lower volumes in the dlPFC. Largely consistent findings in dimensional and categorical models point toward these structural alterations being reliable and of importance for GAD. While lower volume in the dlPFC could reflect impaired emotional processing and control over worry in GAD, basal ganglia alterations may be linked to disturbed gain and loss anticipation as implicated in previous functional GAD studies. As perturbations in anticipation processes are central to GAD, these areas may warrant greater attention in future studies.

Epigenetic variation in the serotonin transporter gene predicts resting state functional connectivity strength within the salience‐network

Genetic variation in the serotonin transporter gene (SLC6A4) has been associated with psychopathology and aberrant brain functioning in a plethora of clinical and imaging studies. In contrast, the neurobiological correlates of epigenetic signatures in SLC6A4, such as DNA methylation profiles, have only recently been explored in human brain imaging research. The present study is the first to apply a resting state functional magnetic resonance imaging approach to identify changes in brain networks related to SLC6A4 promoter methylation (N = 74 healthy individuals). The amygdalae were defined as seed regions given that resting state functional connectivity in this brain area is under serotonergic control and relates to a broad range of psychiatric phenotypes. We further used bisulfite pyrosequencing to analyze quantitative methylation at 83 CpG sites within a promoter‐associated CpG island of SLC6A4 from blood‐derived DNA samples. The major finding of this study indicates a positive relation of SLC6A4 promoter methylation and amygdaloid resting state functional coupling with key nodes of the salience network (SN) including the anterior insulae and the dorsal anterior cingulate cortices. Increased intra‐network connectivity in the SN is thought to facilitate the detection and subsequent processing of potentially negative stimuli and reflects a core feature of psychopathology. As such, epigenetic changes within the SLC6A4 gene predict connectivity patterns in clinically and behaviorally relevant brain networks which may in turn convey increased disease susceptibility. Hum Brain Mapp 36:4361–4371, 2015.

Enhanced Sympathetic Arousal in Response to fMRI Scanning Correlates with Task Induced Activations and Deactivations

It has been repeatedly shown that functional magnetic resonance imaging (fMRI) triggers distress and neuroendocrine response systems. Prior studies have revealed that sympathetic arousal increases, particularly at the beginning of the examination. Against this background it appears likely that those stress reactions during the scanning procedure may influence task performance and neural correlates. However, the question how sympathetic arousal elicited by the scanning procedure itself may act as a potential confounder of fMRI data remains unresolved today. Thirty-seven scanner naive healthy subjects performed a simple cued target detection task. Levels of salivary alpha amylase (sAA), as a biomarker for sympathetic activity, were assessed in samples obtained at several time points during the lab visit. SAA increased two times, immediately prior to scanning and at the end of the scanning procedure. Neural activation related to motor preparation and timing as well as task performance was positively correlated with the first increase. Furthermore, the first sAA increase was associated with task induced deactivation (TID) in frontal and parietal regions. However, these effects were restricted to the first part of the experiment. Consequently, this bias of scanner related sympathetic activation should be considered in future fMRI investigations. It is of particular importance for pharmacological investigations studying adrenergic agents and the comparison of groups with different stress vulnerabilities like patients and controls or adolescents and adults.

The effect of body posture on cognitive performance: a question of sleep quality

Nearly all functional magnetic resonance imaging (fMRI) studies are conducted in the supine body posture, which has been discussed as a potential confounder of such examinations. The literature suggests that cognitive functions, such as problem solving or perception, differ between supine and upright postures. However, the effect of posture on many cognitive functions is still unknown. Therefore, the aim of the present study was to investigate the effects of body posture (supine vs. sitting) on one of the most frequently used paradigms in the cognitive sciences: the N-back working memory paradigm. Twenty-two subjects were investigated in a randomized within-subject design. Subjects performed the N-back task on two consecutive days in either the supine or the upright posture. Subjective sleep quality and chronic stress were recorded as covariates. Furthermore, changes in mood dimensions and heart rate variability (HRV) were assessed during the experiment. Results indicate that the quality of sleep strongly affects reaction times when subjects performed a working memory task in a supine posture. These effects, however, could not be observed in the sitting position. The findings can be explained by HRV parameters that indicated differences in autonomic regulation in the upright vs. the supine posture. The finding is of particular relevance for fMRI group comparisons when group differences in sleep quality cannot be ruled out.

Understanding the role of childhood abuse and neglect as a cause and consequence of substance abuse: the German CANSAS network

ABSTRACT Background: Substance use disorders (SUD) belong to the most frequent behavioural consequences of childhood abuse and neglect (CAN). If parents are concerned, SUD are also an important risk factor for CAN. The relationship between CAN and SUD remains poorly understood. There is a need of adequate treatments for SUD patients suffering from the consequences of CAN, as well as for approaches to prevent CAN by parents with SUD. Objective: To describe the aims and the structure of a German research network on relationships between CAN and SUD (CANSAS network). Method: Descriptive overview of the aims, and the different project clusters of the network. Results: The aims of the CANSAS network are: (1) to examine relationships between SUD and CAN; (2) to examine the effects of an evidence-based treatment for SUD patients with posttraumatic disorders; and (3) to provide SUD services with tools to diagnose CAN, and to assess the risk of maltreatment among parents with SUD. The aims of the network are addressed by six projects in three different project clusters (mediators and risk factors, evidence-based treatment, and improvement of services). Conclusions: It is expected that the CANSAS network will advance the understanding of relationships between early adversity and substance use disorders. It will bring forward the discussion about promising treatments for SUD patients with experiences of CAN. Finally it will provide services with measures to identify patients with CAN, and with tools to break the trans-generational cycle of adversity.