Longitudinal volumetric evaluation of hippocampus and amygdala subregions in recent trauma survivors.

The hippocampus and the amygdala play a central role in post-traumatic stress disorder (PTSD) pathogenesis. While alternations in volumes of both regions have been consistently observed in individuals with PTSD, it remains unknown whether these reflect pre-trauma vulnerability traits or acquired post-trauma consequences of the disorder. Here, we conducted a longitudinal panel study of adult civilian trauma survivors admitted to a general hospital emergency department (ED). One hundred eligible participants (mean age = 32.97 ± 10.97, n = 56 females) completed both clinical interviews and structural MRI scans at 1-, 6-, and 14-months after ED admission (alias T1, T2, and T3). While all participants met PTSD diagnosis at T1, only n = 29 still met PTSD diagnosis at T3 (a "non-Remission" Group), while n = 71 did not (a "Remission" Group). Bayesian multilevel modeling analysis showed robust evidence for smaller right hippocampus volume (P+ of ~0.014) and moderate evidence for larger left amygdala volume (P+ of ~0.870) at T1 in the "non-Remission" group, compared to the "Remission" group. Subregion analysis further demonstrated robust evidence for smaller volume in the subiculum and right CA1 hippocampal subregions (P+ of ~0.021-0.046) in the "non-Remission" group. No time-dependent volumetric changes (T1 to T2 to T3) were observed across all participants or between groups. Results support the "vulnerability trait" hypothesis, suggesting that lower initial volumes of specific hippocampus subregions are associated with non-remitting PTSD. The stable volume of all hippocampal and amygdala subregions does not support the idea of consequential, progressive, stress-related atrophy during the first critical year following trauma exposure.

Graph analysis uncovers an opposing impact of methylphenidate on connectivity patterns within default mode network sub-divisions.

BACKGROUND: The Default Mode Network (DMN) is a central neural network, with recent evidence indicating that it is composed of functionally distinct sub-networks. Methylphenidate (MPH) administration has been shown before to modulate impulsive behavior, though it is not yet clear whether these effects relate to MPH-induced changes in DMN connectivity. To address this gap, we assessed the impact of MPH administration on functional connectivity patterns within and between distinct DMN sub-networks and tested putative relations to variability in sub-scales of impulsivity. METHODS: Fifty-five right-handed healthy adults underwent two resting-state functional MRI (rs-fMRI) scans, following acute administration of either MPH (20 mg) or placebo, via a randomized double-blind placebo-controlled design. Graph modularity analysis was implemented to fractionate the DMN into distinct sub-networks based on the impact of MPH (vs. placebo) on DMN connectivity patterns with other neural networks. RESULTS: MPH administration led to an overall decreased DMN connectivity, particularly with the auditory, cinguloopercular, and somatomotor networks, and increased connectivity with the parietomedial network. Graph analysis revealed that the DMN could be fractionated into two distinct sub-networks, with one exhibiting MPH-induced increased connectivity and the other decreased connectivity. Decreased connectivity of the DMN sub-network with the cinguloopercular network following MPH administration was associated with elevated impulsivity and non-planning impulsiveness. CONCLUSION: Current findings highlight the intricate effects of MPH administration on DMN rs-fMRI connectivity, uncovering its opposing impact on distinct DMN sub-divisions. MPH-induced dynamics in DMN connectivity patterns with other neural networks may account for some of the effects of MPH administration on impulsive behavior.

Reduced anhedonia following internet-based cognitive-behavioral therapy for depression is mediated by enhanced reward circuit activation.

BACKGROUND: Major depressive disorder (MDD) is a highly prevalent psychiatric condition, yet many patients do not receive adequate treatment. Novel and highly scalable interventions such as internet-based cognitive-behavioral-therapy (iCBT) may help to address this treatment gap. Anhedonia, a hallmark symptom of MDD that refers to diminished interest and ability to experience pleasure, has been associated with reduced reactivity in a neural reward circuit that includes medial prefrontal and striatal brain regions. Whether iCBT can reduce anhedonia severity in MDD patients, and whether these therapeutic effects are accompanied by enhanced reward circuit reactivity has yet to be examined. METHODS: Fifty-two MDD patients were randomly assigned to either 10-week iCBT (n = 26) or monitored attention control (MAC, n = 26) programs. All patients completed pre- and post-treatment assessments of anhedonia (Snaith-Hamilton Pleasure Scale; SHAPS) and reward circuit reactivity [monetary incentive delay (MID) task during functional magnetic resonance imaging (fMRI)]. Healthy control participants (n = 42) also underwent two fMRI scans while completing the MID task 10 weeks apart. RESULTS: Both iCBT and MAC groups exhibited a reduction in anhedonia severity post-treatment. Nevertheless, only the iCBT group exhibited enhanced nucleus accumbens (Nacc) and subgenual anterior cingulate cortex (sgACC) activation and functional connectivity from pre- to post-treatment in response to reward feedback. Enhanced Nacc and sgACC activations were associated with reduced anhedonia severity following iCBT treatment, with enhanced Nacc activation also mediating the reduction in anhedonia severity post-treatment. CONCLUSIONS: These findings suggest that increased reward circuit reactivity may contribute to a reduction in anhedonia severity following iCBT treatment for depression.

Assessment of early neurocognitive functioning increases the accuracy of predicting chronic PTSD risk.

Post-traumatic stress disorder (PTSD) is a protracted and debilitating consequence of traumatic events. Identifying early predictors of PTSD can inform the disorder's risk stratification and prevention. We used advanced computational models to evaluate the contribution of early neurocognitive performance measures to the accuracy of predicting chronic PTSD from demographics and early clinical features. We consecutively enrolled adult trauma survivors seen in a general hospital emergency department (ED) to a 14-month long prospective panel study. Extreme Gradient Boosting algorithm evaluated the incremental contribution to 14 months PTSD risk of demographic variables, 1-month clinical variables, and concurrent neurocognitive performance. The main outcome variable was PTSD diagnosis, 14 months after ED admission, obtained by trained clinicians using the Clinician-Administered PTSD Scale (CAPS). N = 138 trauma survivors (mean age = 34.25 ± 11.73, range = 18-64; n = 73 [53%] women) were evaluated 1 month after ED admission and followed for 14 months, at which time n = 33 (24%) met PTSD diagnosis. Demographics and clinical variables yielded a discriminatory accuracy of AUC = 0.68 in classifying PTSD diagnostic status. Adding neurocognitive functioning improved the discriminatory accuracy (AUC = 0.88); the largest contribution emanating from poorer cognitive flexibility, processing speed, motor coordination, controlled and sustained attention, emotional bias, and higher response inhibition, and recall memory. Impaired cognitive functioning 1-month after trauma exposure is a significant and independent risk factor for PTSD. Evaluating cognitive performance could improve early screening and prevention.

Deep learning model of fMRI connectivity predicts PTSD symptom trajectories in recent trauma survivors.

Early intervention following exposure to a traumatic life event could change the clinical path from the development of post traumatic stress disorder (PTSD) to recovery, hence the interest in early detection and underlying biological mechanisms involved in the development of post traumatic sequelae. We introduce a novel end-to-end neural network that employs resting-state and task-based functional MRI (fMRI) datasets, obtained one month after trauma exposure, to predict PTSD symptoms at one-, six- and fourteen-months after the exposure. FMRI data, as well as PTSD status and symptoms, were collected from adults at risk for PTSD development, after admission to emergency room following a traumatic event. Our computational method utilized a per-region encoder to extract brain regions embedding, which were subsequently updated by applying the algorithmic technique of pairwise attention. The affinities obtained between each pair of regions were combined to create a pairwise co-activation map used to perform multi-label classification. The results demonstrate that the novel method's performance in predicting PTSD symptoms, in a prospective manner, outperforms previous analytical techniques reported in the fMRI literature, all trained on the same dataset. We further show a high predictive ability for predicting PTSD symptom clusters and PTSD persistence. To the best of our knowledge, this is the first deep learning method applied on fMRI data with respect to prospective clinical outcomes, to predict PTSD status, severity and symptom clusters. Future work could further delineate the mechanisms that underlie such a prediction, and potentially improve single patient characterization.

Striatal hypofunction as a neural correlate of mood alterations in chronic pain patients.

BACKGROUND: Chronic pain and mood disorders share common neuroanatomical substrates involving disruption of the reward system. Although increase in negative affect (NA) and decrease in positive affect (PA) are well-known factors complicating the clinical presentation of chronic pain patients, our understanding of the mechanisms underlying the interaction between pain and PA/NA remains limited. Here, we used a validated task probing behavioral and neural responses to monetary rewards and losses in conjunction with functional magnetic resonance imaging (fMRI) to test the hypothesis that dysfunction of the striatum, a key mesolimbic structure involved in the encoding of motivational salience, relates to mood alterations comorbid with chronic pain. METHODS: Twenty-eight chronic musculoskeletal pain patients (chronic low back pain, n=15; fibromyalgia, n=13) and 18 healthy controls underwent fMRI while performing the Monetary Incentive Delay (MID) task. Behavioral and neural responses were compared across groups and correlated against measures of depression (Beck Depression Inventory) and hedonic capacity (Snaith-Hamilton Pleasure Scale). RESULTS: Compared to controls, patients demonstrated higher anhedonia and depression scores, and a dampening of striatal activation and incentive-related behavioral facilitation (reduction in reaction times) during reward and loss trials of the MID task (ps â€‹< â€‹0.05). In all participants, lower activation of the right striatum during reward trials was correlated with lower incentive-related behavioral facilitation and higher anhedonia scores (ps â€‹< â€‹0.05). Finally, among patients, lower bilateral striatal activation during loss trials was correlated with higher depression scores (ps â€‹< â€‹0.05). CONCLUSIONS: In chronic pain, PA reduction and NA increase are accompanied by striatal hypofunction as measured by the MID task.

Inflammation and depressive phenotypes: evidence from medical records from over 12 000 patients and brain morphology.

BACKGROUND: Preclinical and human studies suggest an association between chronic inflammation and the development of depressive behaviors. This is proposed to occur through downstream effects of inflammatory cytokines on neuroplasticity, neurogenesis and neurotransmitter function, although the neural correlates remain poorly understood in humans. METHODS: In Study 1, structural magnetic resonance imaging and serum inflammatory cytokine data were analyzed from 53 psychiatrically healthy female participants. Correlational analyses were conducted between interleukin-6 (IL-6) and volume in a priori regions implicated in the pathophysiology of major depressive disorder (MDD). In Study 2, medical data [including serum inflammatory acute phase reactants (C-reactive protein)] were analyzed for 12 589 participants. Participants were classified as having (n = 2541) v. not having (n = 10 048) probable lifetime MDD using phenotypes derived using machine-learning approaches. Non-parametric analyses compared inflammation between groups, whereas regression analyses probed whether inflammation predicted probable MDD classification while accounting for other variables. RESULTS: In Study 1, significant negative correlations emerged between IL-6 and hippocampal, caudate, putamen and amygdalar volume. In Study 2, the MDD group showed a higher probability of elevated inflammation than the non-MDD group. Moreover, elevated inflammation was a significant predictor of probable MDD classification. CONCLUSIONS: Findings indicate that inflammation is cross-sectionally related to reduced volume in brain regions implicated in MDD phenotypes among a sample of psychiatrically healthy women, and is associated with the presence of probable MDD in a large clinical dataset. Future investigations may identify specific inflammatory markers predicting first MDD onset.

Anhedonia modulates the effects of positive mood induction on reward-related brain activation.

Blunted activation in the reward circuitry has been associated with anhedonia, the inability to experience pleasure in previously rewarding activities. In healthy individuals, reward-related activation has been found to be modulated by acute contextual factors such as induced positive mood. Accordingly, blunted reward response in anhedonia might involve a failure to appropriately modulate reward-related activation as a function of context. To test this hypothesis, 29 participants (19 females, mean age of 24.14 ±â€¯4.61, age range 18-34), with a wide range of anhedonic symptoms, underwent functional MRI while anticipating and receiving monetary rewards, before and after a positive mood induction. Change in neural activation from before to after mood induction was quantified, and effects of anhedonia were investigated through whole-brain, ROI, and functional connectivity analyses. Contrary to hypotheses, results indicated that during reward anticipation (but not receipt), nucleus accumbens activation decreased while its connectivity with the dorsolateral prefrontal cortex increased, following positive mood induction. Critically, anhedonia modulated both effects. The unexpected finding of decreased activation to reward cues following positive mood induction is compelling as it aligns with a prominent behavioral model of the effect of positive mood on exploration of rewarding and neutral stimuli. Furthermore, the modulation of this effect by anhedonia suggests that it may be a key process altered in anhedonia.

Distinct Trajectories of Cortisol Response to Prolonged Acute Stress Are Linked to Affective Responses and Hippocampal Gray Matter Volume in Healthy Females.

The development of robust laboratory procedures for acute stress induction over the last decades has greatly advanced our understanding of stress responses in humans and their underlying neurobiological mechanisms. Nevertheless, attempts to uncover linear relationships among endocrine, neural, and affective responses to stress have generally yielded inconsistent results. Here, 79 healthy females completed a well established laboratory procedure of acute stress induction that was modified to prolong its effect. Endocrinological and subjective affect assessments revealed stress-induced increases in cortisol release and negative affect that persisted 65 and 100 min after stress onset, respectively, confirming a relatively prolonged acute stress induction. Applying latent class linear mixed modeling on individuals' patterns of cortisol responses identified three distinct trajectories of cortisol response: the hyper-response (n = 10), moderate-response (n = 21), and mild-response (n = 48) groups. Notably, whereas all three groups exhibited a significant stress-induced increase in cortisol release and negative affect, the hyper-response and mild-response groups both reported more negative affect relative to the moderate-response group. Structural MRI revealed no group differences in hippocampal and amygdala volumes, yet a continuous measure of cortisol response (area under the curve) showed that high and low levels of stress-induced cortisol release were associated with less hippocampal gray matter volume compared with moderate cortisol release. Together, these results suggest that distinct trajectories of cortisol response to prolonged acute stress among healthy females may not be captured by conventional linear analyses; instead, quadratic relations may better describe links between cortisol response to stress and affective responses, as well as hippocampal structural variability.SIGNIFICANCE STATEMENT Despite substantial research, it is unclear whether and how individual neuroendocrine stress response patterns are linked to affective responses to stress and structural variability in neuroendocrine regulatory brain regions. By applying latent class linear mixed modeling on individuals' patterns of cortisol responses to a prolonged acute stressor, we identified three distinct trajectories of cortisol response. Relative to the group showing a moderate cortisol response, groups characterized by hyper and mild cortisol response were both associated with more negative affect. Moreover, a continuous measure of cortisol response showed that high and low levels of stress-induced cortisol release correlated with reduced hippocampal gray matter volume. Given that neuroendocrine stress responses are conceptualized as biomarkers of stress susceptibility, these insights may have clinical implications.

Robust inter-subject audiovisual decoding in functional magnetic resonance imaging using high-dimensional regression.

Major methodological advancements have been recently made in the field of neural decoding, which is concerned with the reconstruction of mental content from neuroimaging measures. However, in the absence of a large-scale examination of the validity of the decoding models across subjects and content, the extent to which these models can be generalized is not clear. This study addresses the challenge of producing generalizable decoding models, which allow the reconstruction of perceived audiovisual features from human magnetic resonance imaging (fMRI) data without prior training of the algorithm on the decoded content. We applied an adapted version of kernel ridge regression combined with temporal optimization on data acquired during film viewing (234 runs) to generate standardized brain models for sound loudness, speech presence, perceived motion, face-to-frame ratio, lightness, and color brightness. The prediction accuracies were tested on data collected from different subjects watching other movies mainly in another scanner. Substantial and significant (QFDR<0.05) correlations between the reconstructed and the original descriptors were found for the first three features (loudness, speech, and motion) in all of the 9 test movies (R¯=0.62, R¯ = 0.60, R¯ = 0.60, respectively) with high reproducibility of the predictors across subjects. The face ratio model produced significant correlations in 7 out of 8 movies (R¯=0.56). The lightness and brightness models did not show robustness (R¯=0.23, R¯ = 0). Further analysis of additional data (95 runs) indicated that loudness reconstruction veridicality can consistently reveal relevant group differences in musical experience. The findings point to the validity and generalizability of our loudness, speech, motion, and face ratio models for complex cinematic stimuli (as well as for music in the case of loudness). While future research should further validate these models using controlled stimuli and explore the feasibility of extracting more complex models via this method, the reliability of our results indicates the potential usefulness of the approach and the resulting models in basic scientific and diagnostic contexts.

Brain activity and connectivity in response to negative affective stimuli: Impact of dysphoric mood and sex across diagnoses.

Negative affective stimuli elicit behavioral and neural responses which vary on a continuum from adaptive to maladaptive, yet are typically investigated in a dichotomous manner (healthy controls vs. psychiatric diagnoses). This practice may limit our ability to fully capture variance from acute responses to negative affective stimuli to psychopathology at the extreme end. To address this, we conducted a functional magnetic resonance imaging study to examine the neural responses to negative valence/high arousal and neutral valence/low arousal images as a function of dysphoric mood and sex across individuals (n = 99) who represented traditional categories of healthy controls, major depressive disorder, bipolar psychosis, and schizophrenia. Observation of negative (vs. neutral) stimuli elicited blood oxygen-level dependent responses in the following circuitry: periaqueductal gray, hypothalamus (HYPO), amygdala (AMYG), hippocampus (HIPP), orbitofrontal cortex (OFC), medial prefrontal cortex (mPFC), and greater connectivity between AMYG and mPFC. Across all subjects, severity of dysphoric mood was associated with hyperactivity of HYPO, and, among females, right (R) AMYG. Females also demonstrated inverse relationships between severity of dysphoric mood and connectivity between HYPO - R OFC, R AMYG - R OFC, and R AMYG - R HIPP. Overall, our findings demonstrated sex-dependent deficits in response to negative affective stimuli increasing as a function of dysphoric mood state. Females demonstrated greater inability to regulate arousal as mood became more dysphoric. These findings contribute to elucidating biosignatures associated with response to negative stimuli across disorders and suggest the importance of a sex-dependent lens in determining these biosignatures. Hum Brain Mapp 37:3733-3744, 2016. © 2016 Wiley Periodicals, Inc.

Functional connectivity dynamics during film viewing reveal common networks for different emotional experiences.

Recent theoretical and empirical work has highlighted the role of domain-general, large-scale brain networks in generating emotional experiences. These networks are hypothesized to process aspects of emotional experiences that are not unique to a specific emotional category (e.g., "sadness," "happiness"), but rather that generalize across categories. In this article, we examined the dynamic interactions (i.e., changing cohesiveness) between specific domain-general networks across time while participants experienced various instances of sadness, fear, and anger. We used a novel method for probing the network connectivity dynamics between two salience networks and three amygdala-based networks. We hypothesized, and found, that the functional connectivity between these networks covaried with the intensity of different emotional experiences. Stronger connectivity between the dorsal salience network and the medial amygdala network was associated with more intense ratings of emotional experience across six different instances of the three emotion categories examined. Also, stronger connectivity between the dorsal salience network and the ventrolateral amygdala network was associated with more intense ratings of emotional experience across five out of the six different instances. Our findings demonstrate that a variety of emotional experiences are associated with dynamic interactions of domain-general neural systems.

Imbalanced neural responsivity to risk and reward indicates stress vulnerability in humans.

Trauma-related psychopathology has been associated with an intense emotional reaction to stressful event. Emotional responses have evolved to signal the presence of risks to be avoided or of rewards to be approached in the environment. Thus, individuals' sensitivity to signals of risk and reward may affect the level of stress vulnerability. Stress, however, can modify these sensitivities as well. In the current functional magnetic resonance imaging (fMRI) study, we prospectively probed the neural correlates of such sensitivities in 24 healthy soldiers by using an interactive game that encompasses risky and rewarding intervals both pre-exposure and post-exposure to stressful military service. As expected, risky and rewarding intervals elicited selective responses in the amygdala and nucleus accumbens (Nacc), respectively. Furthermore, increased post-traumatic stress disorder symptoms post-exposure (i.e., stress vulnerability) corresponded to greater amygdala's response to risk both pre-exposure and post-exposure and to decreased NAcc response to reward only post-exposure. By combining these regional responsivities post-exposure, we accurately identified all the most vulnerable soldiers. Imbalanced neural responsivity to risk and reward following exposure to stress may therefore constitute a marker for stress vulnerability. Such identification of vulnerability biomarkers can aid future diagnostic and therapeutic efforts by allowing early detection of vulnerability as well as follow up on patient's treatment progression.

Cortisol interdependence during psychotherapy in major depressive disorder.

The current study explored cortisol interdependence between patients and therapists during psychotherapy, the possible moderating effect of patient alliance ratings on this interdependence, and the associations between cortisol interdependence and treatment outcome. While cortisol interdependence was explored in other interpersonal contexts, its presence in psychotherapy has remained unexplored. We hypothesized that (a) patients' and therapists' cortisol levels at pre-session will predict their own and their partner's subsequent cortisol levels at post-session, (b) patient ratings of their relationship with their therapists will moderate these partner effects, and (c) cortisol interdependence will be associated with better treatment outcome. Fifty dyads undergoing 16 weeks of psychodynamic treatment for major depressive disorder participated in this study. Patient-therapist salivary cortisol samples were collected at eight time points, alongside a post-session patient-rated alliance questionnaire and a symptom severity interview. For analyses we employed the actor-partner interdependence model. Results revealed that (a) patients' and therapists' cortisol levels before sessions predicted their own post-session cortisol changes. However, significant cortisol interdependence was observed in patients' pre-session cortisol levels predicting therapists' post-session cortisol levels. Furthermore, (b) poorer alliance ratings associated with more pronounced cortisol interdependence, and (c) in dyads where patient pre-session cortisol predicted therapist's post-session cortisol, a better treatment outcome was found. This study found novel evidence of cortisol interdependence in psychotherapy and is partially in line with other studies inspecting cortisol interdependence in adjacent research fields. These findings emphasize the intricate psychophysiological interactions within therapeutic relationships and their associations with treatment outcome.

How do people use reappraisal? An investigation of selection frequency and affective outcomes of reappraisal tactics.

Although the effects of different emotion regulation strategies are well-documented, most studies to date have focused on the selection and implementation of broad strategies, while overlooking the selection and implementation of specific tactics to enact those strategies. The present research investigated the strategy of cognitive reappraisal and the differences in selection frequency and affective outcomes that are associated with the implementation of different reappraisal tactics to enact that strategy. Participants completed a laboratory task in which they were instructed to reappraise or not to reappraise negative images and reported on their use of specific reappraisal tactics for every trial. Using established reappraisal tactic coding, we assessed how people selected from among common tactics for each image (Study 1) and all tactics (Study 2) and implemented those tactics to reappraise negative images. We compared reappraisal tactic selection and implementation when used during instructed reappraisal versus during spontaneous reappraisal, in the nonreappraise condition. Results of both studies indicate that tactics were used more often when instructed to reappraise versus when spontaneously reappraising. Participants used some tactics (e.g., reality challenge) more frequently compared to the rest of the tactics in both conditions. Negative affect was lower following instructed versus spontaneous reappraisal. Some tactics (e.g., change current circumstances) were more effective at decreasing negative affect in both conditions. Knowing which reappraisal tactics are most frequently selected, and their affective outcomes when used when prompted or spontaneously, may help us better understand how to improve people's ability to use reappraisal to achieve their emotional goals. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Aberrant positive affect dynamics in individuals with subthreshold depression: Evidence from laboratory and real-world assessments.

Background/Objective: Reduced positive affect (PA) is a core feature of major depressive disorder (MDD). However, the precursor of MDD, subthreshold depression (StD), has received less attention in this regard. Therefore, we examined PA dynamics in StD, integrating laboratory-based and ecological momentary assessment (EMA) approaches. Method: Participants were college students recruited from Chinese universities (31 with StD, and 39 healthy controls (HC)). Positive mood was induced in the laboratory by an eight-minute comedy clip used to assess PA reactivity and maintenance. To extend findings to the real world and explore mechanisms of PA maintenance, 53 participants with StD and 64 HC reported their emotional states 14 times daily for one week via EMA. Multilevel models were used to test for predictors of PA inertia. Results: In the laboratory, participants with StD achieved the same PA reactivity as HC when facing positive stimuli, yet the curve-fitting revealed difficulties for the StD group in maintaining PA over time. Such reduced capacity was further observed in real-world settings, manifesting in significantly greater PA inertia. Conclusions: High PA inertia in daily life may reflect resistance to mood change in StD, explaining anhedonia and difficulties with emotional maintenance, and highlighting the need for early identification.

From animal model to human brain networking: dynamic causal modeling of motivational systems.

An organism's behavior is sensitive to different reinforcements in the environment. Based on extensive animal literature, the reinforcement sensitivity theory (RST) proposes three separate neurobehavioral systems to account for such context-sensitive behavior, affecting the tendency to react to punishment, reward, or goal-conflict stimuli. The translation of animal findings to complex human behavior, however, is far from obvious. To examine whether the neural networks underlying humans' motivational processes are similar to those proposed by the RST model, we conducted a functional MRI study, in which 24 healthy subjects performed an interactive game that engaged the different motivational systems using distinct time periods (states) of punishment, reward, and conflict. Crucially, we found that the different motivational states elicited activations in brain regions that corresponded exactly to the brain systems underlying RST. Moreover, dynamic causal modeling of each motivational system confirmed that the coupling strengths between the key brain regions of each system were enabled selectively by the appropriate motivational state. These results may shed light on the impairments that underlie psychopathologies associated with dysfunctional motivational processes and provide a translational validity for the RST.

Stress-induced reduction in hippocampal volume and connectivity with the ventromedial prefrontal cortex are related to maladaptive responses to stressful military service.

Previous studies have shown that people who develop psychopathology such as posttraumatic stress disorder (PTSD) following stress exposure are characterized by reduced hippocampal (HC) volume and impaired HC functional connectivity with the ventromedial prefrontal cortex (vmPFC). Nevertheless, the exact interrelationship between reduced HC volume and HC-vmPFC connectivity deficits in the context of stress has yet to be established. Furthermore, it is still not clear whether such neural abnormalities are stress induced or precursors for vulnerability. In this study, we combined measurements of MRI, functional MRI (fMRI), and diffusion tensor imaging (DTI) to prospectively study 33 a priori healthy Israeli soldiers both pre- and post-exposure to stress during their military service. Thus, we were able to assess the contributions of structural and functional features of the HC and its connectivity to the onset and progression of maladaptive response to stress (i.e., increased PTSD symptoms post-exposure). We found that soldiers with decreased HC volume following military service (i.e., post-exposure) displayed more PTSD-related symptoms post-exposure as well as reduced HC-vmPFC functional and structural connectivity post-exposure, compared to soldiers with increased HC volume following military service. In contrast, initial smaller HC volume pre-exposure did not have an effect on any of these factors. Our results therefore suggest that reduction in HC volume and connectivity with the vmPFC together mark a maladaptive response to stressful military service. As stress-induced HC volume reductions were previously shown to be reversible, these localized biological markers may carry valuable therapeutic potential.

Emotional brain rhythms and their impairment in post-traumatic patients.

Patients with post-traumatic stress disorder (PTSD) suffer from a failure of cognitive control over emotional distracters. The physiological substrates of cognitive-emotional interactions and their breakdown in disease are, however, unknown. Here, we studied brain activity in PTSD patients and healthy controls in response to emotion-provoking pictures using electroencephalography and functional magnetic resonance imaging (fMRI). We demonstrate that in healthy individuals, emotion-induced frontal theta rhythm modulates activity in the beta rhythm mainly in sensory-motor regions. In contrast, in PTSD patients, beta activity is elevated irrespective of emotion, and is not modulated by frontal theta activity in response to negative emotion. EEG source localization and fMRI findings suggest that theta activity is localized to the prefrontal and anterior cingulate cortices while beta activity is localized to sensory-motor regions. We further found that beta activity in sensory-motor regions is related to the emotion-induced slowing of the motor response in healthy controls while the excess frontal theta activity in PTSD is related to the intensity of negative emotional experience. These findings reveal for the first time the importance of brain electrical oscillations and coherence in emotional top-down modulation and point to specific failure of these mechanisms in PTSD.

From childhood adversity to latent stress vulnerability in adulthood: the mediating roles of sleep disturbances and HPA axis dysfunction.

Childhood adversity is a prominent predisposing risk factor for latent stress vulnerability, expressed as an elevated likelihood of developing stress-related psychopathology upon subsequent exposure to trauma in adulthood. Sleep disturbances have emerged as one of the most pronounced maladaptive behavioral outcomes of childhood adversity and are also a highly prevalent core feature of stress-related psychopathology, including post-traumatic stress disorder (PTSD). After reviewing the extensive literature supporting these claims, the current review addresses the notion that childhood adversity-induced sleep disturbances may play a causal role in elevating individuals' stress vulnerability in adulthood. Corroborating this, sleep disturbances that predate adult trauma exposure have been associated with an increased likelihood of developing stress-related psychopathology post-exposure. Furthermore, novel empirical evidence suggests that sleep disturbances, including irregularity of the sleep-wake cycle, mediate the link between childhood adversity and stress vulnerability in adulthood. We also discuss cognitive and behavioral mechanisms through which such a cascade may evolve, highlighting the putative role of impaired memory consolidation and fear extinction. Next, we present evidence to support the contribution of the hypothalamic-pituitary-adrenal (HPA) axis to these associations, stemming from its critical role in stress and sleep regulatory pathways. Childhood adversity may yield bi-directional effects within the HPA stress and sleep axes in which sleep disturbances and HPA axis dysfunction reinforce each other, leading to elevated stress vulnerability. To conclude, we postulate a conceptual path model from childhood adversity to latent stress vulnerability in adulthood and discuss the potential clinical implications of these notions, while highlighting directions for future research.