Differences in neural recovery from acute stress between cortisol responders and non-responders

Adaptive recovery from a stressor fosters resilience. So far, however, few studies have examined brain functional connectivity in the aftermath of stress, with inconsistent results reported. Focusing on the immediate recovery from psychosocial stress, the current study compared amygdala resting-state functional connectivity (RSFC) before and immediately after psychosocial stress between cortisol responders and non-responders. Differences between groups were expected for amygdala RSFC with regions involved in down-regulation of the physiological stress response, emotion regulation, and memory consolidation. Eighty-six healthy participants (36 males/50 females) underwent a social stress paradigm inside the MRI scanner. Before and immediately after stress, resting-state (RS) fMRI scans were acquired to determine amygdala RSFC. Next, changes in connectivity from pre- to post-stress were compared between cortisol responders and non-responders. Responders demonstrated a cortisol increase, higher negative affect, and decreased heart rate variability (HRV) in response to stress compared to non-responders. A significant Sex-by-Responder-by-Time interaction was found between the bilateral amygdala and posterior cingulate cortex (PCC) and precuneus (p < 0.05, corrected). As males were also more likely to show a cortisol increase to the stress task than females, follow-up analyses were conducted for both sexes separately. Whereas no difference was observed between female responders and non-responders, male non-responders showed an increase in FC after stress between the bilateral amygdala and the PCC and precuneus (p < 0.05, corrected). The increased coupling of the amygdala with the PCC/precuneus, a core component of the default mode network (DMN), might indicate an increased engagement of the amygdala within the DMN directly after stress in non-responders. Although this study was carried out in healthy participants, and the results likely reflect normal variations in the neural response to stress, understanding the mechanisms that underlie these variations could prove beneficial in revealing neural markers that promote resilience to stress-related disorders

Childhood maltreatment and amygdala connectivity in methamphetamine dependence: a pilot study.

IntroductionChildhood maltreatment, a well-known risk factor for the development of substance abuse disorders, is associated with functional and structural abnormalities in the adult brain, particularly in the limbic system. However, almost no research has examined the relationship between childhood maltreatment and brain function in individuals with drug abuse disorders.MethodsWe conducted a pilot study of the relationship between childhood maltreatment (evaluated with the Childhood Trauma Questionnaire; Bernstein and Fink 1998) and resting-state functional connectivity of the amygdala (bilateral region of interest) with functional magnetic resonance imaging in 15 abstinent, methamphetamine-dependent research participants. Within regions that showed connectivity with the amygdala as a function of maltreatment, we also evaluated whether amygdala connectivity was associated positively with negative affect and negatively with healthy emotional processing.ResultsThe results indicated that childhood maltreatment was positively associated with resting-state connectivity between the amygdala and right hippocampus, right parahippocampal gyrus, right inferior temporal gyrus, right orbitofrontal cortex, cerebellum, and brainstem. Furthermore, connectivity between the amygdala and hippocampus was positively related to measures of depression, trait anxiety, and emotion dysregulation, and negatively related to self-compassion and dispositional mindfulness.ConclusionsThese findings suggest that childhood maltreatment may contribute to increased limbic connectivity and maladaptive emotional processing in methamphetamine-dependent adults, and that healthy emotion regulation strategies may serve as a therapeutic target to ameliorate the associated behavioral phenotype. Childhood maltreatment warrants further investigation as a potentially important etiological factor in the neurobiology and treatment of substance use disorders

The association of sleep and stress with psychological well-being and neuronal functional connectivity

Sufficient sleep and an adequate stress response are two important components when it comes to coping with adverse events. Previous studies have shown that both are related to the occurrence of psychological and physical disorders, emphasizing the necessity to explore both concepts within the scope of this PhD thesis individually as well as their association among each other. In Study 1, we investigated the association of sleep-related variables with psychological well-being based on an online survey. We found evidence that the association of psychological well-being towards chronotype follows a U-shaped function, which means that being an early or late chronotype is related to impaired well-being. Additionally, reduced sleep durations, especially when occurring on work days, was associated with depressive symptomatology and sleep quality. For Study 2 and 3 we deployed neuroimaging data, as both sleep deprivation and psychosocial stress have been proven to change neuronal activity and connectivity patterns in the aftermath of stress. Study 2 focused on replicating results concerning the previously reported increased connectivity of the amygdala with regions involved in the down-regulation of the physiological stress response, in emotion regulation, and in memory consolidation. Analyzing resting state connectivity after stress compared to the pre-stress condition, we found an increase in bilateral amygdala resting-state functional connectivity (RSFC) with the posterior cingulate cortex (PCC) and the adjacent precuneus only in male cortisol non-responders, but not in responders. We did not detect changes in amygdala RSFC between female cortisol responders and non-responders. This finding shows the influence of sex and cortisol reactivity, when exploring neural signatures of stress reactivity and recovery. In Study 3 we focused on male participants only, now expanding the results from Study 2 by exploring the impact of sleep loss on neural signatures of stress recovery. We found a negative association of sleep loss, as reported in a seven-day sleep diary, with the stress-induced change of left amygdala RSFC to several cortical brain regions, including the medial prefrontal cortex, dorsolateral prefrontal cortex, dorsal anterior cingulate cortex, anterior insula, and PCC. That is, the higher the sleep loss, the more decrease in left amygdala RSFC was found with these regions after stress. Taken together, the results of this PhD thesis contribute to a better understanding of associations between sleep, stress, and psychological well-being on a behavioral as well as neuronal level.Ausreichend Schlaf und eine angemessene Stressantwort stellen zwei wichtige Faktoren im Umgang mit belastenden Ereignissen dar. Frühere Studien berichteten von einem Zusammenhang mit dem Auftreten von psychologischen und physischen Erkrankungen. Dies belegt die Notwendigkeit, deren Wirkung im Rahmen der vorliegenden Doktorarbeit sowohl als einzelne Konstrukte als auch in Verbindung zueinander zu explorieren. Im Rahmen der ersten Studie untersuchten wir den Zusammenhang von schlafbezogenen Variablen zu psychologischem Wohlbefinden mithilfe einer Online Umfrage. Die Ergebnisse zeigten, dass der Zusammenhang zwischen psychologischem Wohlbefinden und Chronotyp einer u-förmigen Funktion folgt. Damit haben vor allem sehr frühe und späte Chronotypen ein erhöhtes Risiko für vermindertes Wohlbefinden. Zusätzlich fanden wir, dass eine reduzierte Schlafdauer, vor allem an Arbeitstagen, mit vermehrten depressiven Symptomen und geringerer Schlafqualität assoziiert war. Für die anderen beiden Studien setzten wir bildgebende Verfahren (funktionelle Magnetresonanztomografie) ein, da sowohl Schlafmangel als auch psychosozialer Stress nachweislich einen Einfluss auf die neuronale Aktivität und funktionelle Konnektivität während der Erholung von Stress haben. In Studie 2 konzentrierten wir uns auf die Replikation von früheren Studienergebnissen, die eine stressbedingte Steigerung der Konnektivität zwischen der Amygdala und Gehirnregionen fanden, die in die Herabregulation der physiologischen Stressantwort, in die emotionale Antwort, und die Gedächtniskonsolidierung involviert sind. In der Phase nach einem Stressor fanden wir im Vergleich zu vor dem Stressor eine gesteigerte bilaterale Konnektivität der Amygdala zum posterioren cingulären Cortex (PCC) und dem angrenzenden Precuneus nur in männlichen Teilnehmern ohne Cortisolreaktion im Vergleich zu männlichen Teilnehmern mit einer Cortisolreaktion. Bei weiblichen Teilnehmerinnen fanden sich keine Unterschiede in funktioneller Konnektivität. Die Ergebnisse unterstreichen die Relevanz von Geschlecht und Cortisolraktion beim Betrachten der Erholungsphase nach Stress. Studie 3 erweitert die Ergebnisse aus Studie 2, indem nur bei männlichen Teilnehmern zusätzlich den Einfluss von Schlafmangel auf die neuronale Erholung von Stress untersuchten. Die Auswertung zeigte eine negative Assoziation zwischen Schlafmangel, der in einem siebentägigen Tagebuch festgehalten wurde, und der stressbedingten funktionelle Konnektivtät der linke Amygdala zu mehreren Gehirnregionen, u.a. dem medialen Präfrontalcortex, dem dorsolateralen Präfrontalcortex, dem dorsalen anterioren cingulären Cortex, der anterioren Insula, und dem PCC. Das bedeutet, je mehr Schlafmangel berichtet wurde, desto schwächer war die funktionelle Konnektivität der linken Amygdala zu den genannten Regionen. Zusammengefasst tragen die Ergebnisse der Doktorarbeit zu einem besseren Verständnis des Zusammenhangs von Schlaf, Stress und psychologischem Wohlbefinden auf sowohl Verhaltens. als auch neuronaler Ebene bei

Neural traces of stress: cortisol related sustained enhancement of amygdala-hippocampal functional connectivity

Stressful experiences modulate neuro-circuitry function, and the temporal trajectory of these alterations, elapsing from early disturbances to late recovery, heavily influences resilience and vulnerability to stress. Such effects of stress may depend on processes that are engaged during resting-state, through active recollection of past experiences and anticipation of future events, all known to involve the default mode network (DMN). By inducing social stress and acquiring resting-state functional magnetic resonance imaging (fMRI) before stress, immediately following it, and 2 h later, we expanded the time-window for examining the trajectory of the stress response. Throughout the study repeated cortisol samplings and self-reports of stress levels were obtained from 51 healthy young males. Post-stress alterations were investigated by whole brain resting-state functional connectivity (rsFC) of two central hubs of the DMN: the posterior cingulate cortex (PCC) and hippocampus. Results indicate a ’recovery’ pattern of DMN connectivity, in which all alterations, ascribed to the intervening stress, returned to pre-stress levels. The only exception to this pattern was a stress-induced rise in amygdala-hippocampal connectivity, which was sustained for as long as 2 h following stress induction. Furthermore, this sustained enhancement of limbic connectivity was inversely correlated to individual stress-induced cortisol responsiveness (AUCi) and characterized only the group lacking such increased cortisol (i.e., non-responders). Our observations provide evidence of a prolonged post-stress response profile, characterized by both the comprehensive balance of most DMN functional connections and the distinct time and cortisol dependent ascent of intra-limbic connectivity. These novel insights into neuro-endocrine relations are another milestone in the ongoing search for individual markers in stress-related psychopathologies

Habitual physical activity mediates the acute exercise-induced modulation of anxiety-related amygdala functional connectivity

Aerobic exercise, in relation to physical activity, has been shown to have beneficial effects on anxiety. However, the underlyig neural mechanism remains elusive. Using a within-subject crossover design, this fMRI study examined how exercise (12-min treadmill running versus walking) mediated amygdala reactivity to explicit and implicit (backward masked) perception of emotional faces in young adults (N?=?40). Results showed that acute exercise-induced differences of state anxiety (STAI-S) varied as a function of individual’s habitual physical activity (IPAQ). Subjects with high IPAQ levels showed significant STAI-S reduction (P?&lt;?0.05). Path analyses indicated that IPAQ explained 14.67% of the variance in acute exercise-induced STAI-S differences. Running elicited stronger amygdala reactivity to implicit happiness than fear, whereas walking did the opposite. The exercise-induced amygdala reactivity to explicit fear was associated with the IPAQ scores and STAI-S differences. Moreover, after running, the amygdala exhibited a positive functional connectivity with the orbitofrontal cortex and insula to implicit happiness, but a negative connectivity with the parahippocampus and subgenual cingulate to implicit fear. The findings suggest that habitual physical activity could mediate acute exercise-induced anxiolytic effects in regards to amygdala reactivity, and help establish exercise training as a form of anxiolytic therapy towards clinical applications

Structural covariance of the ventral visual stream predicts posttraumatic intrusion and nightmare symptoms: a multivariate data fusion analysis

Visual components of trauma memories are often vividly re-experienced by survivors with deleterious consequences for normal function. Neuroimaging research on trauma has primarily focused on threat-processing circuitry as core to trauma-related dysfunction. Conversely, limited attention has been given to visual circuitry which may be particularly relevant to posttraumatic stress disorder (PTSD). Prior work suggests that the ventral visual stream is directly related to the cognitive and affective disturbances observed in PTSD and may be predictive of later symptom expression. The present study used multimodal magnetic resonance imaging data (n = 278) collected two weeks after trauma exposure from the AURORA study, a longitudinal, multisite investigation of adverse posttraumatic neuropsychiatric sequelae. Indices of gray and white matter were combined using data fusion to identify a structural covariance network (SCN) of the ventral visual stream 2 weeks after trauma. Participant\u27s loadings on the SCN were positively associated with both intrusion symptoms and intensity of nightmares. Further, SCN loadings moderated connectivity between a previously observed amygdala-hippocampal functional covariance network and the inferior temporal gyrus. Follow-up MRI data at 6 months showed an inverse relationship between SCN loadings and negative alterations in cognition in mood. Further, individuals who showed decreased strength of the SCN between 2 weeks and 6 months had generally higher PTSD symptom severity over time. The present findings highlight a role for structural integrity of the ventral visual stream in the development of PTSD. The ventral visual stream may be particularly important for the consolidation or retrieval of trauma memories and may contribute to efficient reactivation of visual components of the trauma memory, thereby exacerbating PTSD symptoms. Potentially chronic engagement of the network may lead to reduced structural integrity which becomes a risk factor for lasting PTSD symptoms

Structural covariance of the ventral visual stream predicts posttraumatic intrusion and nightmare symptoms: A multivariate data fusion analysis

Visual components of trauma memories are often vividly re-experienced by survivors with deleterious consequences for normal function. Neuroimaging research on trauma has primarily focused on threat-processing circuitry as core to trauma-related dysfunction. Conversely, limited attention has been given to visual circuitry which may be particularly relevant to posttraumatic stress disorder (PTSD). Prior work suggests that the ventral visual stream is directly related to the cognitive and affective disturbances observed in PTSD and may be predictive of later symptom expression. The present study used multimodal magnetic resonance imaging data (n = 278) collected two weeks after trauma exposure from the AURORA study, a longitudinal, multisite investigation of adverse posttraumatic neuropsychiatric sequelae. Indices of gray and white matter were combined using data fusion to identify a structural covariance network (SCN) of the ventral visual stream 2 weeks after trauma. Participant\u27s loadings on the SCN were positively associated with both intrusion symptoms and intensity of nightmares. Further, SCN loadings moderated connectivity between a previously observed amygdala-hippocampal functional covariance network and the inferior temporal gyrus. Follow-up MRI data at 6 months showed an inverse relationship between SCN loadings and negative alterations in cognition in mood. Further, individuals who showed decreased strength of the SCN between 2 weeks and 6 months had generally higher PTSD symptom severity over time. The present findings highlight a role for structural integrity of the ventral visual stream in the development of PTSD. The ventral visual stream may be particularly important for the consolidation or retrieval of trauma memories and may contribute to efficient reactivation of visual components of the trauma memory, thereby exacerbating PTSD symptoms. Potentially chronic engagement of the network may lead to reduced structural integrity which becomes a risk factor for lasting PTSD symptoms

DACC Resting State Functional Connectivity as a Predictor of Pain Symptoms Following Motor Vehicle Crash: A Preliminary Investigation

There is significant heterogeneity in pain outcomes following motor vehicle crashes (MVCs), such that a sizeable portion of individuals develop symptoms of chronic pain months after injury while others recover. Despite variable outcomes, the pathogenesis of chronic pain is currently unclear. Previous neuroimaging work implicates the dorsal anterior cingulate cortex (dACC) in adaptive control of pain, while prior resting state functional magnetic resonance imaging studies find increased functional connectivity (FC) between the dACC and regions involved in pain processing in those with chronic pain. Hyper-connectivity of the dACC to regions that mediate pain response may therefore relate to pain severity. The present study completed rsfMRI scans on N=22 survivors of MVCs collected within two weeks of the incident to test whole-brain dACC-FC as a predictor of pain severity six months later. At two weeks, pain symptoms were predicted by positive connectivity between the dACC and the premotor cortex. Controlling for pain symptoms at two weeks, pain symptoms at six months were predicted by negative connectivity between the dACC and the precuneus. Previous research implicates the precuneus in the individual subjective awareness of pain. Given a relatively small sample size, approximately half of which did not experience chronic pain at six months, findings warrant replication. Nevertheless, this study provides preliminary evidence of enhanced dACC connectivity with motor regions and decreased connectivity with pain processing regions as immediate and prospective predictors of pain following MVC. Perspective: This article presents evidence of distinct neural vulnerabilities that predict chronic pain in motor vehicle crash survivors based on whole-brain connectivity with the dorsal anterior cingulate cortex

EEG revealed improved vigilance regulation after stress exposure under Nx4: A randomized, placebo-controlled, double-blind, cross-over trial

ObjectivesVigilance is characterized by alertness and sustained attention. The hyper-vigilance states are indicators of stress experience in the resting brain. Neurexan (Nx4) has been shown to modulate the neuroendocrine stress response. Here, we hypothesized that the intake of Nx4 would alter brain vigilance states at rest.MethodIn this post-hoc analysis of the NEURIM study, EEG recordings of three, 12 min resting-state conditions in 39 healthy male volunteers were examined in a randomized, placebo-controlled, double-blind, cross-over clinical trial. EEG was recorded at three resting-state sessions: at baseline (RS0), after single-dose treatment with Nx4 or placebo (RS1), and subsequently after a psychosocial stress task (RS2). During each resting-state session, each 2-s segment of the consecutive EEG epochs was classified into one of seven different brain states along a wake-sleep continuum using the VIGALL 2.1 algorithm.ResultsIn the post-stress resting-state, subjects exhibited a hyper-stable vigilance regulation characterized by an increase in the mean vigilance level and by more rigidity in the higher vigilance states for a longer period of time. Importantly, Nx4-treated participants exhibited significantly lower mean vigilance level compared to placebo-treated ones. Also, Nx4- compared to placebo-treated participants spent comparably less time in higher vigilance states and more time in lower vigilance states in the post-stress resting-state.ConclusionStudy participants showed a significantly lower mean vigilance level in the post-stress resting-state condition and tended to stay longer in lower vigilance states after treatment with Nx4. These findings support the known stress attenuation effect of Nx4