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Identifying vulnerable individuals prone to develop post-traumatic stress symptoms (PTSS) is of paramount importance, especially in populations at high risk for stress exposure such as combat soldiers. While several neural and psychological risk factors are known, no post-traumatic stress disorder (PTSD) biomarker has yet progressed to clinical use. Here we present novel and clinically applicable anger-related neurobehavioral risk markers for military-related PTSS in a large cohort of Israeli soldiers. The psychological, electrophysiological and neural (Simultaneous recording of scalp electroencephalography [EEG] and functional magnetic resonance imaging [fMRI]) reaction to an anger-inducing film were measured prior to advanced military training and PTSS were recorded at 1-year follow-up. Limbic modulation was measured using a novel approach that monitors amygdala modulation using fMRI-inspired EEG, hereafter termed amygdala electrical fingerprint (amyg-EFP). Inter-subject correlation (ISC) analysis on fMRI data indicated that during movie viewing participants’ brain activity was synchronized in limbic regions including the amygdala. Self-reported state-anger and amyg-EFP modulation successfully predicted PTSS levels. State-anger significantly accounted for 20% of the variance in PTSS, and amyg-EFP signal modulation significantly accounted for additional 15% of the variance. Our study was limited by the moderate PTSS levels and lack of systematic baseline symptoms assessment. These results suggest that pre-stress neurobehavioral measures of anger may predict risk for later PTSS, pointing to anger-related vulnerability factors that can be measured efficiently and at a low cost before stress exposure. Possible mechanisms underlying the association between the anger response and risk for PTSS are discussed.

BackgroundAngry outbursts are an important feature of various stress-related disorders, and commonly lead to aggression towards other people. Findings regarding interpersonal anger have linked the ventromedial prefrontal cortex (vmPFC) to anger regulation and the locus coeruleus (LC) to aggression. Both regions were previously associated with traumatic and chronic stress symptoms, yet it is unclear if their functionality represents a consequence of, or possibly also a cause for, stress symptoms. Here we investigated the relationship between the neural trajectory of these indicators of anger and the development and manifestation of stress symptoms.MethodA total of 46 males (29 soldiers, 17 civilians) participated in a prospective functional magnetic resonance imaging experiment in which they played a modified interpersonal anger-provoking Ultimatum Game (UG) at two-points. Soldiers were tested at the beginning and end of combat training, while civilians were tested at the beginning and end of civil service. We assumed that combat training would induce chronic stress and result in increased stress symptoms.ResultsSoldiers showed an increase in stress symptoms following combat training while civilians showed no such change following civil service. All participants were angered by the modified UG irrespective of time point. Higher post-combat training stress symptoms were associated with lower pre-combat training vmPFC activation and with higher activation increase in the LC between pre- and post-combat training.ConclusionsResults suggest that during anger-provoking social interactions, flawed vmPFC functionality may serve as a causal risk factor for the development of stress symptoms, and heightened reactivity of the LC possibly reflects a consequence of stress-inducing combat training. These findings provide potential neural targets for therapeutic intervention and inoculation for stress-related psychopathological manifestations of anger.

Direct cortical stimulation (DCS) is considered the gold-standard for functional cortical mapping during awake surgery for brain tumor resection. DCS is performed by stimulating one local cortical area at a time. We present a feasibility study using an intra-operative technique aimed at improving our ability to map brain functions which rely on activity in distributed cortical regions. Following standard DCS, Multi-Site Stimulation (MSS) was performed in 15 patients by applying simultaneous cortical stimulations at multiple locations. Language functioning was chosen as a case-cognitive domain due to its relatively well-known cortical organization. MSS, performed at sites that did not produce disruption when applied in a single stimulation point, revealed additional language dysfunction in 73% of the patients. Functional regions identified by this technique were presumed to be significant to language circuitry and were spared during surgery. No new neurological deficits were observed in any of the patients following surgery. Though the neuro-electrical effects of MSS need further investigation, this feasibility study may provide a first step towards sophistication of intra-operative cortical mapping.

Contains fulltext : 169963.pdf (Publisher’s version ) (Closed access) The ability to temporarily prioritize rapid and vigilant reactions over slower higher-order cognitive functions is essential for adaptive responding to threat. This reprioritization is believed to reflect shifts in resource allocation between large-scale brain networks that support these cognitive functions, including the salience and executive control networks. However, how changes in communication within and between such networks dynamically unfold as a function of threat-related arousal remains unknown. To address this issue, we collected functional MRI data and continuously assessed the heart rate from 120 healthy human adults as they viewed emotionally arousing and ecologically valid cinematographic material. We then developed an analysis method that tracks dynamic changes in large-scale network cohesion by quantifying the level of within-network and between-network interaction. We found a monotonically increasing relationship between heart rate, a physiological index of arousal, and within-network cohesion in the salience network, indicating that coordination of activity within the salience network dynamically tracks arousal. Strikingly, salience-executive control between-network cohesion peaked at moderate arousal. These findings indicate that at moderate arousal, which has been associated with optimal noradrenergic signaling, the salience network is optimally able to engage the executive control network to coordinate cognitive activity, but is unable to do so at tonically elevated noradrenergic levels associated with acute stress. Our findings extend neurophysiological models of the effects of stress-related neuromodulatory signaling at the cellular level to large-scale neural systems, and thereby explain shifts in cognitive functioning during acute stress, which may play an important role in the development and maintenance of stress-related mental disorders. SIGNIFICANCE STATEMENT: How does brain functioning change in arousing or stressful situations? Extant literature suggests that through global projections, arousal-related neuromodulatory changes can rapidly alter coordination of neural activity across brain-wide neural systems or large-scale networks. Since it is unknown how such processes unfold, we developed a method to dynamically track levels of within-network and between-network interaction. We applied this technique to human neuroimaging data acquired while participants watched realistic and emotionally arousing cinematographic material. Results demonstrate that cohesion within the salience network monotonically increases with arousal, while cohesion of this network with the executive control network peaks at moderate arousal. Our findings explain how cognitive performance shifts as a function of arousal, and provide new insights into vulnerability for stress-related psychopathology. 10 p.

Contains fulltext : 179627.pdf (Publisher’s version ) (Closed access) Consistent failure over the past few decades to reduce the high prevalence of stress-related disorders has motivated a search for alternative research strategies. Resilience refers to the phenomenon of many people maintaining mental health despite exposure to psychological or physical adversity. Instead of aiming to understand the pathophysiology of stress-related disorders, resilience research focuses on protective mechanisms that shield people against the development of such disorders and tries to exploit its insights to improve treatment and, in particular, disease prevention. To fully harness the potential of resilience research, a critical appraisal of the current state of the art - in terms of basic concepts and key methods - is needed. We highlight challenges to resilience research and make concrete conceptual and methodological proposals to improve resilience research. Most importantly, we propose to focus research on the dynamic processes of successful adaptation to stressors in prospective longitudinal studies. 7 p.

The Montreal Cognitive Assessment (MoCA) is a widely used screening test for evaluation of mild cognitive impairment (MCI), with a single cutoff for all ages. We examined whether it is associated with age in a sample of cognitively-intact elderly (CIE). The average MoCA score was negatively correlated with age and was significantly higher for younger than older CIE. Additionally, 42% of the older elderly fell below the proposed MCI cutoff score, although all subjects were CIE. Thus, cognitive abilities captured by the MoCA test decrease with age, even in CIE. Therefore, cutoff scores by age for the MoCA are needed.

Background.Military training is a chronic stressful period that often induces stress-related psychopathology. Stress vulnerability and resilience depend on personality trait anxiety, attentional threat bias and prefrontal–limbic dysfunction. However, how these neurobehavioral elements interact with regard to the development of symptoms following stress remains unclear.Method.Fifty-five healthy combat soldiers undergoing intensive military training completed functional magnetic resonance imaging (fMRI) testing while performing the dot-probe task (DPT) composed of angry (threat) and neutral faces. Participants were then stratified according to their bias tendency to avoidance (n = 25) or vigilance (n = 30) groups, categorized as high or low trait anxiety and assessed for post-stress symptom severity.Results.Avoidance compared to vigilance tendency was associated with fewer post-trauma symptoms and increased hippocampal response to threat among high anxious but not low anxious individuals. Importantly, mediation analysis revealed that only among high anxious individuals did hippocampal activity lead to lower levels of symptoms through avoidance bias tendency. However, in the whole group, avoidance bias was modulated by the interplay between the hippocampus and the dorsal anterior cingulate cortex (dACC).Conclusions.Our results provide a neurobehavioral model to explain the resilience to post-trauma symptoms following chronic exposure. The model points to the importance of considering threat bias tendency in addition to personality traits when investigating the brain response and symptoms of trauma. Such a multi-parametric approach that accounts for individual behavioral sensitivities may also improve brain-driven treatments of anxiety, possibly by targeting the interplay between the hippocampus and the dACC.

Background: Patients with Parkinson’s disease have reduced gray matter volume and fractional anisotropy in both cortical and sub-cortical structures, yet changes in the pre-motor phase of the disease are unknown. Methods: A comprehensive imaging study using voxelbased morphometry and diffusion tensor imaging tract-based spatial statistics analysis was performed on 64 Ashkenazi Jewish asymptomatic first degree relatives of patients with Parkinson’s disease (30 mutation carriers), who carry the G2019S mutation in the leucine-rich repeat kinase 2 (LRRK2) gene. Results: No between-group differences in gray matter volume could be noted in either whole-brain or volume-of-interest analysis. Diffusion tensor imaging analysis did not identify group differences in white matter areas, and volume-of-interest analysis identified no differences in diffusivity parameters in Parkinson’s disease-related structures. Conclusions: G2019S carriers do not manifest changes in gray matter volume or diffusivity parameters in Parkinson’s disease-related structures prior to the appearance of motor symptoms. V C 2014 Interna

The original and corrected figures, and the Editorial Summary, are shown in the accompanying Publisher Correction.An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The original and corrected figures, and the Editorial Summary, are shown in the accompanying Publisher Correction.An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The original and corrected Acknowledgements are shown in the accompanying Author Correction.

BackgroundMemory impairment is prevalent in systemic lupus erythematosus (SLE); however, the pathogenesis is unknown.MethodsWe studied 12 patients with SLE without clinically overt neuropsychiatric manifestations and 11 matched healthy controls, aiming to characterize neural correlates of memory impairment, using structural and functional magnetic resonance imaging (MRI). The paradigm consisted of three encoding and free-recall cycles, allowing characterization of dynamics along consecutive retrieval attempts.ResultsDuring learning, patients with SLE and healthy controls showed brain activity changes in two principal networks, the default mode network (DMN) and the task-positive network (TPN). Patients with SLE demonstrated significantly less deactivation in the DMN and greater activation in the TPN, reflecting greater recruitment of both networks. The anterior medial prefrontal cortex (amPFC) of the DMN emerged as the only region where brain activity dynamics were altered both over the learning process ( p ConclusionsIncreased brain activation in patients with SLE during learning may reflect compensatory mechanisms to overcome memory impairment. Our findings localize this impairment to the amPFC, consistent with the behavioral pattern seen in SLE. Altered networking of the hippocampal subsystem of the DMN is consistent with hippocampal neuronal damage seen in SLE, and may reflect compensatory cortical reorganization to cope with dysfunction in these regions pivotal to mnemonic functions.

To assess differences in gray matter (GM) atrophy between 2 Parkinson disease (PD) subtypes: the tremor dominant (TD) subtype and the postural instability gait difficulty (PIGD) subtype.Patients were classified as belonging to the predominately PIGD (n = 30) or predominately TD (n = 29) subtype. Voxel-based morphometry was used to compare GM in these 2 subtypes and to evaluate correlations between predefined regions of interest and the degree of symptoms. In the regions where GM atrophy was associated with symptoms, the relationship between GM volumes and functional connectivity was examined.GM was reduced in the predominately PIGD group, compared with the predominately TD group, in areas that involve motor, cognitive, limbic, and associative functions (p0.05, false discovery rate corrected). Lower GM volumes in the pre-supplementary motor area (SMA) and in the primary motor area were associated with increased severity of PIGD symptoms (r = -0.42, p0.001; r = -0.38, p0.003, respectively). Higher GM volumes within the pre-SMA were associated with stronger functional connectivity between the pre-SMA and the putamen (r = 0.415, p0.025) in the patients with predominately PIGD.In patients with PD, PIGD symptoms are apparently associated with GM atrophy in motor-related regions and decreased functional connectivity. GM degeneration and a related decrease in spontaneous coactivation between cortical and subcortical motor-planning areas may partially account for the unique clinical characteristics of a subset of patients with PD.

Numerous neuroimaging studies have implicated default mode network (DMN) involvement in both internally driven processes and memory. Nevertheless, it is unclear whether memory operations reflect a particular case of internally driven processing or alternatively involve the DMN in a distinct manner, possibly depending on memory type. This question is critical for refining neurocognitive memory theorem in the context of other endogenic processes and elucidating the functional significance of this key network. We used functional MRI to examine DMN activity and connectivity patterns while participants overtly generated words according to nonmnemonic (phonemic) or mnemonic (semantic or episodic) cues. Overall, mnemonic word fluency was found to elicit greater DMN activity and stronger within-network functional connectivity compared with nonmnemonic fluency. Furthermore, two levels of functional organization of memory retrieval were shown. First, across both mnemonic tasks, activity was greater mainly in the posterior cingulate cortex, implying selective contribution to generic aspects of memory beyond its general involvement in endogenous processes. Second, parts of the DMN showed distinct selectivity for each of the mnemonic conditions; greater recruitment of the anterior prefrontal cortex, retroesplenial cortex, and hippocampi and elevated connectivity between anterior and posterior medial DMN nodes characterized the semantic condition, whereas increased recruitment of posterior DMN components and elevated connectivity between them characterized the episodic condition. This finding emphasizes the involvement of DMN elements in discrete aspects of memory retrieval. Altogether, our results show a specific contribution of the DMN to memory processes, corresponding to the specific type of memory retrieval.

Sleep deprivation (SD) critically affects a range of cognitive and affective functions, typically assessed during task performance. Whether such impairments stem from changes to the brain's intrinsic functional connectivity remain largely unknown. To examine this hypothesis, we applied graph theoretical analysis on resting‐state fMRI data derived from 18 healthy participants, acquired during both sleep‐rested and sleep‐deprived states. We hypothesized that parameters indicative of graph connectivity, such as modularity, will be impaired by sleep deprivation and that these changes will correlate with behavioral outcomes elicited by sleep loss. As expected, our findings point to a profound reduction in network modularity without sleep, evident in the limbic, default‐mode, salience and executive modules. These changes were further associated with behavioral impairments elicited by SD: a decrease in salience module density was associated with worse task performance, an increase in limbic module density was predictive of stronger amygdala activation in a subsequent emotional‐distraction task and a shift in frontal hub lateralization (from left to right) was associated with increased negative mood. Altogether, these results portray a loss of functional segregation within the brain and a shift towards a more random‐like network without sleep, already detected in the spontaneous activity of the sleep‐deprived brain. Hum Brain Mapp 38:3300–3314, 2017. © 2017 Wiley Periodicals, Inc.

Interpersonal space is a nonverbal indicator of affiliation and closeness. In this study we investigated the effects of oxytocin (OT), a neuropeptide known for its social role in humans, on interpersonal space. In a double blind placebo controlled study we measured the effect of intranasal OT on the personal distance preferences of different familiar (friend) and unfamiliar (stranger) protagonists. Behavioral results showed that participants preferred to be closer to a friend than to a stranger. Intranasal OT was associated with an overall distancing effect, but this effect was significant for the stranger and not for the friend. The imaging results showed interactions between treatment (OT, placebo) and protagonist (friend, stranger) in regions that mediate social behavior including the dorsomedial prefrontal cortex (dmPFC), a region associated with the mentalizing system. Specifically, OT increased activity in the dmPFC when a friend approached the participants but not when a stranger approached. The results indicate that the effect of OT on interpersonal space greatly depends on the participant's relationship with the protagonist. This supports the social salience theory, according to which OT increases the salience of social cues depending on the context.

Communication between and within brain regions is essential for information processing within functional networks. The current methods to determine the influence of one region on another are either based on temporal resolution, or require a predefined model for the connectivity direction. However these requirements are not always achieved, especially in fMRI studies, which have poor temporal resolution. We thus propose a new graph theory approach that focuses on the correlation influence between selected brain regions, entitled Dependency Network Analysis (DEPNA). Partial correlations are used to quantify the level of influence of each node during task performance. As a proof of concept, we conducted the DEPNA on simulated datasets and on two empirical motor and working memory fMRI tasks. The simulations revealed that the DEPNA correctly captures the network’s hierarchy of influence. Applying DEPNA to the functional tasks reveals the dynamics between specific nodes as would be expected from prior knowledge. To conclude, we demonstrate that DEPNA can capture the most influencing nodes in the network, as they emerge during specific cognitive processes. This ability opens a new horizon for example in delineating critical nodes for specific clinical interventions.

Generating words according to a given rule relies on retrieval-related search and postretrieval control processes. Using fMRI, we recently characterized neural patterns of word generation in response to episodic, semantic, and phonemic cues by comparing free recall of wordlists, category fluency, and letter fluency [Shapira-Lichter, I., Oren, N., Jacob, Y., Gruberger, M., & Hendler, T. Portraying the unique contribution of the default mode network to internally driven mnemonic processes. Proceedings of the National Academy of Sciences, U.S.A., 110, 4950–4955, 2013]. Distinct selectivity for each condition was evident, representing discrete aspects of word generation-related memory retrieval. For example, the precuneus, implicated in processing spatiotemporal information, emerged as a key contributor to the episodic condition, which uniquely requires this information. Gamma band is known to play a central role in memory, and increased gamma power has been observed before word generation. Yet, gamma modulation in response to task demands has not been investigated. To capture the task-specific modulation of gamma power, we analyzed the EEG data recorded simultaneously with the aforementioned fMRI, focusing on the activity locked to and immediately preceding word articulation. Transient increases in gamma power were identified in a parietal electrode immediately before episodic and semantic word generation, however, within a different time frame relative to articulation. Gamma increases were followed by an alpha-theta decrease in the episodic condition, a gamma decrease in the semantic condition. This pattern indicates a task-specific modulation of the gamma signal corresponding to the specific demands of each word generation task. The gamma power and fMRI signal from the precuneus were correlated during the episodic condition, implying the existence of a common cognitive construct uniquely required for this task, possibly the reactivation or processing of spatiotemporal information.

Recent evidence suggests that learned self-regulation of localized brain activity in deep limbic areas such as the amygdala, may alleviate symptoms of affective disturbances. Thus far self-regulation of amygdala activity could be obtained only via fMRI guided neurofeedback, an expensive and immobile procedure. EEG on the other hand is relatively inexpensive and can be easily implemented in any location. However the clinical utility of EEG neurofeedback for affective disturbances remains limited due to low spatial resolution, which hampers the targeting of deep limbic areas such as the amygdala. We introduce an EEG prediction model of amygdala activity from a single electrode. The gold standard used for training is the fMRI-BOLD signal in the amygdala during simultaneous EEG/fMRI recording. The suggested model is based on a time/frequency representation of the EEG data with varying time-delay. Previous work has shown a strong inhomogeneity among subjects as is reflected by the models created to predict the amygdala BOLD response from EEG data. In that work, different models were constructed for different subjects. In this work, we carefully analyzed the inhomogeneity among subjects and were able to construct a single model for the majority of the subjects. We introduce a method for inhomogeneity assessment. This enables us to demonstrate a choice of subjects for which a single model could be derived. We further demonstrate the ability to modulate brain-activity in a neurofeedback setting using feedback generated by the model. We tested the effect of the neurofeedback training by showing that new subjects can learn to down-regulate the signal amplitude compared to a sham group, which received a feedback obtained by a different participant. This EEG based model can overcome substantial limitations of fMRI-NF. It can enable investigation of NF training using multiple sessions and large samples in various locations.

Trauma causes variable risk of posttraumatic stress symptoms (PTSS) owing to yet-unknown genome–neuronal interactions. Here, we report co-intensified amygdala and ventromedial prefrontal cortex (vmPFC) emotional responses that may overcome PTSS in individuals with the single-nucleotide polymorphism (SNP) rs17228616 in the acetylcholinesterase (AChE) gene. We have recently shown that in individuals with the minor rs17228616 allele, this SNP interrupts AChE suppression by microRNA (miRNA)-608, leading to cortical elevation of brain AChE and reduced cortisol and the miRNA-608 target GABAergic modulator CDC42, all stress-associated. To examine whether this SNP has effects on PTSS and threat-related brain circuits, we exposed 76 healthy Israel Defense Forces soldiers who experienced chronic military stress to a functional magnetic resonance imaging task of emotional and neutral visual stimuli. Minor allele individuals predictably reacted to emotional stimuli by hyperactivated amygdala, a hallmark of PTSS and a predisposing factor of posttraumatic stress disorder (PTSD). Despite this, minor allele individuals showed no difference in PTSS levels. Mediation analyses indicated that the potentiated amygdala reactivity in minor allele soldiers promoted enhanced vmPFC recruitment that was associated with their limited PTSS. Furthermore, we found interrelated expression levels of several miRNA-608 targets including CD44, CDC42 and interleukin 6 in human amygdala samples (N=7). Our findings suggest that miRNA-608/AChE interaction is involved in the threat circuitry and PTSS and support a model where greater vmPFC regulatory activity compensates for amygdala hyperactivation in minor allele individuals to neutralize their PTSS susceptibility.

Contains fulltext : 167889.pdf (Publisher’s version ) (Closed access) Cognitive impairments are prevalent in patients with Parkinson's disease. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common cause of genetic Parkinsonism. Non-manifesting carriers of the G2019S mutation in the LRRK2 gene were found to have lower executive functions as measured by the Stroop task. This exploratory study aimed to assess whether the cognitive impairment in non-manifesting carriers is specific for executive functions or includes other cognitive domains such as working memory. We recruited 77 non-manifesting first-degree relatives of Parkinson's disease patients (38 carriers). A block-design fMRI N-back task, with 0-back, 2-back and 3-back conditions, was used in order to assess working memory. Participants were well matched on the Montreal Cognitive Assessment, University of Pennsylvania Smell Identification Test, Unified Parkinson's Disease Rating Scale part III, digit span, age, gender and Beck Depression Inventory. The task achieved the overall expected effect in both groups with longer reaction times and lower accuracy rates with increasing task demands. However, no whole-brain or region-of-interest between-groups differences were found on any of the task conditions. These results indicate that non-manifesting carriers of the G2019S mutation in the LRRK2 gene have a specific cognitive profile with executive functions, as assessed by the Stroop task, demonstrating significant impairment but with working memory, as assessed with the N-back task, remaining relatively intact. These finding shed light on the pre-motor cognitive changes in this unique 'at risk' population and should enable more focused cognitive assessments of these cohorts.

article i nfo Keywords: Language fMRI DMN Schizophrenia Reduced functional connectivity (FC) in schizophrenia has been demonstrated either in task related or 'de- fault network' areas, but not between these networks, which interact meaningfully. We examined the role of FC between the inferior frontal gyrus (IFG) and medial prefrontal cortex (mPFC) in determining language-lateralization during a language task, and its association with structural integrity of the corpus-callosum. Only schizophrenia patients presented increased mPFC-IFG FC during task, which addition- ally corresponded to decreased white-matter organization of the corpus-callosum. These findings suggest that inability to suppress irrelevant internally-generated information while processing external stimuli might be the basis of functional psychopathology in schizophrenia.

Previous studies have shown that people who develop psychopathology such as posttrau- matic 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 con- nectivity 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 pro- spectively 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 follow- ing 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-expo- sure 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

Dynamic functional integration of distinct neural systems plays a pivotal role in emotional experience. We introduce a novel approach for studying emotion-related changes in the interactions within and between networks using fMRI. It is based on continuous computation of a network cohesion index (NCI), which is sensitive to both strength and variability of signal correlations between pre-defined regions. The regions encompass three clusters (namely limbic, medial prefrontal cortex (mPFC) and cognitive), each previously was shown to be involved in emotional processing. Two sadness-inducing film excerpts were viewed passively, and comparisons between viewer's rated sadness, parasympathetic, and inter-NCI and intra-NCI were obtained. Limbic intra-NCI was associated with reported sadness in both movies. However, the correlation between the parasympathetic-index, the rated sadness and the limbic-NCI occurred in only one movie, possibly related to a "deactivated" pattern of sadness. In this film, rated sadness intensity also correlated with the mPFC intra-NCI, possibly reflecting temporal correspondence between sadness and sympathy. Further, only for this movie, we found an association between sadness rating and the mPFC-limbic inter-NCI time courses. To the contrary, in the other film in which sadness was reported to commingle with horror and anger, dramatic events coincided with disintegration of these networks. Together, this may point to a difference between the cinematic experiences with regard to inter-network dynamics related to emotional regulation. These findings demonstrate the advantage of a multi-layered dynamic analysis for elucidating the uniqueness of emotional experiences with regard to an unguided processing of continuous and complex stimulation.

r r Abstract: 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 fail- ure of these mechanisms in PTSD. Hum Brain Mapp 00:000-000, 2012. V C 2012 Wiley Periodicals, Inc.

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.

An extensive body of research has demonstrated that anxious individuals abnormally process threat-related content. Yet, the manner in which clinical anxiety affects the selection of threatening signals and their maintenance within consciousness is yet to be explored. The present study used an emotional binocular rivalry (e-BR) procedure, in which pictures of faces depicting either fearful or neutral expressions competed with pictures of a house for conscious perception. We assumed that first- or cumulative-preferred perception of faces with fearful over neutral expression (i.e., initial or sustained threat bias, respectively) stand for preferential selection or maintenance of fear content in awareness, correspondingly. Unmedicated patients with social anxiety disorder (SAD) and panic disorder (PAD) were compared to healthy controls for threat-related perceptual biases in the e-BR. At first perception of face, both SAD and PAD patients showed a greater initial threat bias than healthy controls. In contrast, at cumulative dwell-time of face, patient groups demonstrated a diminished sustained threat bias relative to healthy controls, yet in a different manner. SAD patients showed a sustained threat bias, though it was smaller than in healthy controls. Furthermore, increased levels of reported anxiety among SAD patients were associated with enhanced sustained perception of neutral faces. PAD patients, on the other hand, showed no sustained threat bias and a diminished cumulative perception of fearful faces with increased levels of anxiety traits. These findings indicate that anxiety disorders commonly involve an initially enhanced selection of threat signals into awareness, followed by disorder-specific manifestation of diminished preferred maintenance of threat in awareness.

Anger may be caused by a wide variety of triggers, and though it has negative consequences on health and well-being, it is also crucial in motivating to take action and approach rather than avoid a confrontation. While anger is considered a survival response inherent in all living creatures, humans are endowed with the mental flexibility that enables them to control and regulate their anger, and adapt it to socially accepted norms. Indeed, a profound interpersonal nature is apparent in most events which evoke anger among humans. Since anger consists of physiological, cognitive, subjective, and behavioral components, it is a contextualized multidimensional construct that poses theoretical and operational difficulties in defining it as a single psychobiological phenomenon. Although most neuroimaging studies have neglected the multidimensionality of anger and thus resulted in brain activations dispersed across the entire brain, there seems to be several reoccurring neural circuits subserving the subjective experience of human anger. Nevertheless, to capture the large variety in the forms and fashions in which anger is experienced, expressed, and regulated, and thus to better portray the related underlying neural substrates, neurobehavioral investigations of human anger should aim to further embed realistic social interactions within their anger induction paradigms.

The neural bases of empathy have been examined mainly in the context of reacting to others' distress, while almost no attention has been paid to the mechanisms by which we share others' joy. Using functional magnetic resonance imaging, we demonstrated that the same neural network mediates judgment of the emotional state of the other in response to both negative and positive events through empathy-related structures, such as the medial prefrontal cortex (MPFC), the insula, the superior temporal sulcus (STS) and the inferior frontal gyrus (IFG). However, the responses of the MPFC, bilateral insula and the right IFG to negative experiences occurring to the other (but not to the self) were found to be much more intense than the responses to positive experiences, indicating that humans have a remarkable ability to share the distress of others, but may react less to the joy of others.

One of the greatest challenges involved in studying the brain mechanisms of fear is capturing the individual's unique instantaneous experience. Brain imaging studies to date commonly sacrifice valuable information regarding the individual real-time conscious experience, especially when focusing on elucidating the amygdala's activity. Here, we assumed that by using a minimally intrusive cue along with applying a robust clustering approach to probe the amygdala, it would be possible to rate fear in real time and to derive the related network of activation. During functional magnetic resonance imaging scanning, healthy volunteers viewed two excerpts from horror movies and were periodically auditory cued to rate their instantaneous experience of "I'm scared." Using graph theory and community mathematical concepts, data-driven clustering of the fear-related functional cliques in the amygdala was performed guided by the individually marked periods of heightened fear. Individually tailored functions derived from these amygdala activation cliques were subsequently applied as general linear model predictors to a whole-brain analysis to reveal the correlated networks. Our results suggest that by using a localized robust clustering approach, it is possible to probe activation in the right dorsal amygdala that is directly related to individual real-time emotional experience. Moreover, this fear-evoked amygdala revealed two opposing networks of co-activation and co-deactivation, which correspond to vigilance and rest-related circuits, respectively.

Background Recent studies have demonstrated that even survivors of mild stroke experience residual damage, which persists and in fact increases in subsequent years. About 45% of stroke victims remain with different levels of disability. Identifying factors associated with poststroke cognitive and neurological decline could potentially yield more effective therapeutic opportunities. Aims and hypothesis We hypothesize that data based on biochemical, neuroimaging, genetic and psychological measures can, in aggregate, serve as better predictors for subsequent disability, cognitive and neurological deterioration, and suggest possible interventions. Design The Tel-Aviv Brain Acute Stroke Cohort (TABASCO) study is an ongoing, prospective cohort study that will recruit approximately 1125 consecutive first-ever mild–moderate stroke patients. It is designed to evaluate the association between predefined demographic, psychological, inflammatory, biochemical, neuroimaging and genetic markers, measured during the acute phase, and long-term outcome: subsequent cognitive deterioration, vascular events (including recurrent strokes), falls, affect changes, functional everyday difficulties and mortality. Discussion This study is an attempt to comprehensively investigate the long-term outcome of mild–moderate strokes. Its prospective design will provide quantitative data on stroke recurrence, the incidence of other vascular events and the evaluation of cognitive, affective and functional decline. Identifying the factors associated with poststroke cognitive and functional decline could potentially yield more effective therapeutic approaches.

The mother-infant bond provides the foundation for the infant's future mental health and adaptation and depends on the provision of species-typical maternal behaviors that are supported by neuroendocrine and motivation-affective neural systems. Animal research has demonstrated that natural variations in patterns of maternal care chart discrete profiles of maternal brain-behavior relationships that uniquely shape the infant's lifetime capacities for stress regulation and social affiliation. Such patterns of maternal care are mediated by the neuropeptide Oxytocin and by stress- and reward-related neural systems. Human studies have similarly shown that maternal synchrony--the coordination of maternal behavior with infant signals--and intrusiveness--the excessive expression of maternal behavior--describe distinct and stable maternal styles that bear long-term consequences for infant well-being. To integrate brain, hormones, and behavior in the study of maternal-infant bonding, we examined the fMRI responses of synchronous vs intrusive mothers to dynamic, ecologically valid infant videos and their correlations with plasma Oxytocin. In all, 23 mothers were videotaped at home interacting with their infants and plasma OT assayed. Sessions were micro-coded for synchrony and intrusiveness. Mothers were scanned while observing several own and standard infant-related vignettes. Synchronous mothers showed greater activations in the left nucleus accumbens (NAcc) and intrusive mothers exhibited higher activations in the right amygdala. Functional connectivity analysis revealed that among synchronous mothers, left NAcc and right amygdala were functionally correlated with emotion modulation, theory-of-mind, and empathy networks. Among intrusive mothers, left NAcc and right amygdala were functionally correlated with pro-action areas. Sorting points into neighborhood (SPIN) analysis demonstrated that in the synchronous group, left NAcc and right amygdala activations showed clearer organization across time, whereas among intrusive mothers, activations of these nuclei exhibited greater cross-time disorganization. Correlations between Oxytocin with left NAcc and right amygdala activations were found only in the synchronous group. Well-adapted parenting appears to be underlay by reward-related motivational mechanisms, temporal organization, and affiliation hormones, whereas anxious parenting is likely mediated by stress-related mechanisms and greater neural disorganization. Assessing the integration of motivation and social networks into unified neural activity that reflects variations in patterns of parental care may prove useful for the study of optimal vs high-risk parenting.

Characterization and quantification of magnetic resonance perfusion images is important for clinical interpretation, though this calls for a reproducible and accurate method of analysis and a robust healthy reference. The few studies which have examined the perfusion of the healthy brain using dynamic susceptibility contrast (DSC) imaging were largely limited to manual definition of the regions of interest (ROI) and results were dependent on the location of the ROI. The current study aimed to develop a methodology for DSC data analysis and to obtain reference values of healthy subjects. Twenty three healthy volunteers underwent DSC. An unsupervised multiparametric clustering method was applied to four perfusion parameters. Three clusters were defined and identified as: dura-blood-vessels, gray matter and white matter and their vascular characteristics were obtained. Additionally, regional perfusion differences were studied and revealed a prolonged mean transient time and a trend for higher vascularity in the posterior compared with the anterior and middle cerebral vascular territories. While additional studies are required to confirm our findings, this result may have important clinical implications. The proposed unsupervised multiparametric method enabled accurate tissue differentiation, is easy replicable and has a wide range of applications in both pathological and healthy brains.

Functional connectivity analysis of resting-state functional magnetic resonance imaging data (fcrs-fMRI) has been shown to be a robust non-invasive method for localization of functional networks (without using specific tasks) and to be promising for presurgical planning. However, in order to transfer the approach to everyday clinical practice, fcrs-fMRI needs to be further validated and made easily accessible to neurosurgeons. This paper addresses the latter by presenting a software tool designed for neurosurgeons for analyzing and visualizing fcrs-fMRI data. A prototypical interactive visualization tool was developed to enable neurosurgeons to explore functional connectivity data and evaluate its usability. The implementation builds upon LIPSIA, an established software package for the assessment of functional neuroimaging data, and integrates the selection of a region-of-interest with the computation and visualization of functionally connected areas. The tool was used to explore data from a healthy participant and eight brain lesion patients. The usability of the software was evaluated with four neurosurgeons previously unacquainted with the methodology, who were asked to identify prominent, large-scale cortical networks. With this novel tool, previously published findings, such as tumor displacement of the sensorimotor cortex and other disturbances of functional networks, were reproduced. The neurosurgeons were able to consistently obtain results similar to the results of an expert, with the exception of the language network. Immediate feedback helped to pinpoint functional networks quickly and intuitively, with even inexperienced users requiring less than 3 min per network. Although fcrs-fMRI is a nascent method still undergoing evaluation with respect to established standards, the interactive software is nonetheless a promising tool for non-invasive exploration of individual functional connectivity networks in neurosurgical practice, both for well-known networks and for those less typically addressed.

Object Preserving motor function is a major challenge in surgery for intraaxial brain tumors. Navigation systems are unreliable in predicting the location of the corticospinal tracts (CSTs) because of brain shift and the inability of current intraoperative systems to produce reliable diffusion tensor imaging data. The authors describe their experience with elaborate neurophysiological assessment and tractography-based navigation, corrected in real time by 3D intraoperative ultrasonography (IOUS) to identify motor pathways during subcortical tumor resection. Methods A retrospective analysis was conducted in 55 patients undergoing resection of tumors located within or in proximity to the CSTs at the authors' institution between November 2007 and June 2009. Corticospinal tract tractography was coregistered to surgical navigation-derived images in 42 patients. Direct cortical-stimulated motor evoked potentials (dcMEPs) and subcortical-stimulated MEPs (scrtMEPs) were recorded intraoperatively to assess function and estimate the distance from the CSTs. Intraoperative ultrasonography updated the navigation imaging and estimated resection proximity to the CSTs. Preoperative clinical motor function was compared with postoperative outcome at several time points and correlated with incidences of intraoperative dcMEP alarm and low scrtMEP values. Results The threshold level needed to elicit scrtMEPs was plotted against the distance to the CSTs based on diffusion tensor imaging tractography after brain shift compensation with 3D IOUS, generating a trend line that demonstrated a linear order between these variables, and a relationship of 0.97 mA for every 1 mm of brain tissue distance from the CSTs. Clinically, 39 (71%) of 55 patients had no postoperative deficits, and 9 of the remaining 16 improved to baseline function within 1 month. Seven patients had varying degrees of permanent motor deficits. Subcortical stimulation was applied in 45 of the procedures. The status of 32 patients did not deteriorate postoperatively (stable or improved motor status): 27 of them (84%) displayed minimum scrtMEP thresholds > 7 mA. Six patients who experienced postoperative deterioration quickly recovered (within 5 days) and displayed minimum scrtMEP thresholds > 6.8 mA. Five of the 7 patients who had late (> 5 days postoperatively) or no recovery had minimal scrtMEP thresholds < 3 mA. An scrtMEP threshold of 3 mA was found to be the cutoff point below which irreversible disruption of CST integrity may be anticipated (sensitivity 83%, specificity 95%). Conclusions Combining elaborate neurophysiological assessment, tractography-based neuronavigation, and updated IOUS images provided accurate localization of the CSTs and enabled the safe resection of tumors approximating these tracts. This is the first attempt to evaluate the distance from the CSTs using the threshold of subcortical monopolar stimulation with real-time IOUS for the correction of brain shift. The linear correlation between the distance to the CSTs and the threshold of subcortical stimulation producing a motor response provides an intraoperative technique to better preserve motor function.

A leftward bias is well known in humans and animals, and commonly related to the right hemisphere dominance for spatial attention. Our previous fMRI study suggested that this bias is mediated by faster conduction from the right to left parietal cortices, than the reverse (Siman-Tov et al., 2007). However, the limited temporal resolution of fMRI and evidence on the critical involvement of sub-cortical regions in orienting of spatial attention suggested further investigation of the leftward bias using multi-scale measurement. In this simultaneous EEG-fMRI study, healthy participants were presented with face pictures in either the right or left visual fields while performing a central fixation task. Temporo-occipital event related potentials, time-locked to the stimulus onset, showed an association between faster conduction from the right to the left hemisphere and higher fMRI activation in the left pulvinar nucleus following left visual field stimulation. This combined-modal finding provides original evidence of the involvement of sub-cortical central attention-related regions in the leftward bias. This assertion was further strengthened by a DCM analysis designated at cortical (i.e., inferior parietal sulcus; IPS) and sub-cortical (pulvinar nucleus) attention-related nodes that revealed: 1. Stronger inter-hemispheric connections from the right to left than vice versa, already at the pulvinar level. 2. Stronger connections within the right than the left hemisphere, from the pulvinar to the IPS. This multi-level neural superiority can guide future efforts in alleviating attention deficits by focusing on improving network connectivity.

Characterizing and mapping the relationship between neuronal reorganization and functional recovery are essential to the understanding of cerebral plasticity and the dynamic processes which occur following brain damage. The neuronal mechanisms underlying linguistic recovery following left hemisphere (LH) lesions are still unknown. Using functional magnetic resonance imaging (fMRI), we investigated whether the extent of brain lateralization of linguistic functioning in specific regions of interest (ROIs) is correlated with the level of linguistic performance following recovery from acquired childhood aphasia. The study focused on a rare group of children in whom lesions occurred after normal language acquisition, but prior to complete maturation of the brain. During fMRI scanning, rhyming, comprehension and verb generation activation tasks were monitored. The imaging data were evaluated with reference to linguistic performance measured behaviorally during imaging, as well as outside the scanner. Compared with normal controls, we found greater right hemisphere (RH) lateralization in patients. However, correlations with linguistic performance showed that increased proficiency in linguistic tasks was associated with greater lateralization to the LH. These results were replicated in a longitudinal case study of a patient scanned twice, 3 years apart. Additional improvement in linguistic performance of the patient was accompanied by increasing lateralization to the LH in the anterior language region. This, however, was the result of a decreased involvement of the RH. These findings suggest that recovery is a dynamic, ongoing process, which may last for years after onset. The role of each hemisphere in the recovery process may continuously change within the chronic stage.

Object Resection of lesions involving the supplementary motor area (SMA) may result in immediate postoperative motor and speech deficits that are reversible in most cases. In the present study the authors aimed to determine the critical involvement of SMA in the lesioned and healthy hemispheres in this functional recovery. They hypothesized that compensatory mechanisms take place following surgery in the SMA, and that these mechanisms can involve either the lesioned or the non-lesioned hemisphere. In addition, they hypothesized that a correlation will be present between the functional MR imaging (fMR) imaging–related activation in the SMA and the occurrence of a functional deficit during intraoperative cortical stimulation. Methods Twenty-six patients scheduled for resection of space-occupying lesions involving, or in the vicinity of, the SMA were recruited. Patients underwent an fMR imaging examination that included finger-tapping and verb-generation tests to assess for motor and language functions. Intraoperatively direct cortical stimulation (DCS) of the SMA region was performed while patients were monitored for language and motor functions using tests similar to those used for the fMR imaging. Task dysfunction during DCS assessed the critical involvement of the SMA in the tested functions. Neurological evaluations were performed prior to surgery and at 3 time points within a month following surgery. A region of interest–based approach was used to evaluate fMR imaging blood oxygen level–dependent activation level and asymmetry in the SMA. These measurements were later compared with the intraoperative DCS and neurological findings. Results Functional MR imaging showed greater activation and dominance of the SMA in the lesioned hemisphere in patients who exhibited no motor or language dysfunction during DCS. In addition, patients with the highest activation of the SMA in the lesioned hemisphere for language and motor tests showed stronger coupling of this region with ipsilateral motor and language networks. In contrast, activation in the nonlesioned hemisphere did not correspond with DCS results. Conclusions The authors' findings demonstrate the necessity of activation in the vicinity of the lesioned SMA for functional compensation in motor and language tasks. It is possible that more effective functional coupling of the SMA with motor and language areas in the same hemisphere prevents dysfunctions following surgical intervention. Importantly, fMR imaging activation in the unaffected SMA was not sufficient for development of functional compensation and, if anything, indicated decompensation.

This article proposes the establishment of a United States–Israel Longitudinal Database for Healthy Aging and Preclinical Dementia as a prototype model for the eventual creation of an international database. It is envisioned that such a comprehensive international database, as a shared research resource, will provide the foundation for a systems approach to solve the dual public health problems of: (1) Early detection of individuals at an elevated risk of developing Alzheimer's disease, and (2) Developing interventions to delay onset of, or prevent, chronic brain disorders later in life.

Data acquired by functional brain imaging are of a multivariate and complex nature. Selecting relevant topographically specific information for system-level analysis is a highly non-trivial task. This challenge has traditionally been addressed by hypothesis-driven approaches. Recently, data-driven methods making no a priori assumptions about the signal were developed. Here, we present a hybrid approach, selecting data-driven voxels in paradigm-driven measurements in order to identify functional connectivity motifs in the voxel correlations. Our tool is the functional holography (FH) method, originally developed for analyzing electrophysiological recordings and based on analyzing the voxel-voxel correlation matrices. The algorithm selects the relevant voxels using a dendrogram clustering method combined with a unique standard deviation (STD) filter, identifying the voxels with high STD correlations. Functional connectivity motifs are revealed through a dimension-reduction procedure by principal component analysis (PCA) allowing for a reduced three-dimensional holographic presentation space. Information loss due to PCA is retrieved by connecting voxels in the reduced space with lines that are color-coded according to the correlations. Our results show that the FH analysis performed for a single trial reveals interesting motifs, even in a simple motor task: unilateral hand movements yielded two clusters, one in the contralateral M1 region showing neuronal activation and one in the ipsilateral homologues region showing deactivation. Thus, according to a single trial level analysis, of 12-time points alone, we can determine which hand the subject moved. Moreover, using cluster quantification based on eigenvalue entropy calculation, we obtained good separation between right- and left-handed subjects.

An identical sensory stimulus may or may not be incorporated into perceptual experience, depending on the behavioral and cognitive state of the organism. What determines whether a sensory stimulus will be perceived? While different behavioral and cognitive states may share a similar profile of electrophysiology, metabolism, and early sensory responses, neuromodulation is often different and therefore may constitute a key mechanism enabling perceptual awareness. Specifically, noradrenaline improves sensory responses, correlates with orienting toward behaviorally relevant stimuli, and is markedly reduced during sleep, while experience is largely "disconnected" from external events. Despite correlative evidence hinting at a relationship between noradrenaline and perception, causal evidence remains absent. Here, we pharmacologically down- and upregulated noradrenaline signaling in healthy volunteers using clonidine and reboxetine in double-blind placebo-controlled experiments, testing the effects on perceptual abilities and visually evoked electroencephalography (EEG) and fMRI responses. We found that detection sensitivity, discrimination accuracy, and subjective visibility change in accordance with noradrenaline (NE) levels, whereas decision bias (criterion) is not affected. Similarly, noradrenaline increases the consistency of EEG visually evoked potentials, while lower noradrenaline levels delay response components around 200 ms. Furthermore, blood-oxygen-level-dependent (BOLD) fMRI activations in high-order visual cortex selectively vary along with noradrenaline signaling. Taken together, these results point to noradrenaline as a key factor causally linking visual awareness to external world events. VIDEO ABSTRACT.