Reappraisal of Interpersonal Criticism in Social Anxiety Disorder: A Brain Network Hierarchy Perspective.

Emotion regulation is thought to involve communication between and within large-scale brain networks that underlie emotion reactivity and cognitive control. Aberrant network interaction might therefore be a key neural feature of mental disorders that involve emotion dysregulation. Here we tested whether connectivity hierarchies within and between emotion reactivity and cognitive reappraisal networks distinguishes social anxiety disorder (SAD) patients (n = 70) from healthy controls (HC) (n = 25). To investigate network organization, we implemented a graph-theory method called Dependency Network Analysis. Participants underwent fMRI while watching or reappraising video clips involving interpersonal verbal criticism. During reappraisal, the reappraisal network exerted less influence on the reactivity network in SAD participants. Specifically, the influence of the right inferior frontal gyrus on both reappraisal and reactivity networks was significantly reduced in SAD compared with HC, and correlated negatively with negative emotion ratings among SAD participants. Surprisingly, the amygdala exhibited reduced influence on the reappraisal network in SAD relative to HC. Yet, during the watch condition, the left amygdala's influence on the reactivity network increased with greater social anxiety symptoms among SAD participants. These findings refine our understanding of network organization that contributes to efficient reappraisal or to disturbances in applying this strategy in SAD.

Sleepless and desynchronized: Impaired inter trial phase coherence of steady-state potentials following sleep deprivation.

Sleep loss has detrimental effects on cognitive and emotional functioning. These impairments have been associated with alterations in EEG measures of power spectrum and event-related potentials, however the impact of sleep loss on inter trial phase coherence (ITPC), a measure of phase consistency over experimental trials, remains mostly unknown. ITPC is thought to reflect the ability of the neural response to temporally synchronize with relevant events, thus optimizing information processing. In the current study we investigated the effects of sleep deprivation on information processing by evaluating the phase consistency of steady-state visual evoked potentials (ssVEPs) as well as amplitude-based measures of ssVEPs, obtained from a group of 18 healthy individuals following 24 h of total sleep deprivation and after a night of habitual sleep. An ssVEP task was utilized, which included the presentation of dots flickering at 7.5 Hz, along with a cognitive-emotional task. Our results show that ITPC is significantly reduced under sleep deprivation relative to habitual sleep. Interestingly, decreased ITPC under sleep deprivation was associated with decreased behavioral performance in the psychomotor vigilance task (PVT), a validated measure of reduced vigilance following a lack of sleep. The results suggest that the capability of the brain to synchronize with rhythmic stimuli is disrupted without sleep. Thus, decreased ITPC may represent an objective and mechanistic measure of sleep loss, allowing future work to study the relation between brain-world synchrony and the specific functional impairments associated with sleep deprivation.

Neural indicators of interpersonal anger as cause and consequence of combat training stress symptoms.

BACKGROUND: Angry 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. METHOD: A 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. RESULTS: Soldiers 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. CONCLUSIONS: Results 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.

Impaired diffusion tensor imaging findings in the corpus callosum and cingulum may underlie impaired learning and memory abilities in systemic lupus erythematosus.

BACKGROUND: Memory impairment is prevalent in systemic lupus erythematosus (SLE); however, its pathogenesis is unknown. In a previous functional magnetic resonance imaging (fMRI) study we demonstrated altered brain activity dynamics and less brain deactivation in patients with SLE as compared with healthy controls, when performing a learning and memory task. Our findings localized this impairment to the default mode network (DMN), and particularly to its anterior medial prefrontal cortex node. In addition, altered networking of the hippocampal subsystem of the DMN was seen in patients with SLE when performing this task, as well as atrophy of the left hippocampus. The present study aimed to search for a structural substrate for the altered recruitment pattern observed in fMRI studies using diffusion tensor imaging (DTI). PATIENTS AND METHODS: Using DTI, we characterized brain diffusivity in 10 patients with SLE and nine healthy controls. Two tracts associated with the DMN were reconstructed: the corpus callosum (CC) and the cingulum bundle. The CC was segmented according to the Witelson segmentation scheme and the cingulum was segmented into superior and descending bundles. RESULTS: A significant increase in mean diffusivity (MD) was seen in patients with SLE without neuropsychiatric SLE (NPSLE) as compared with healthy controls in all five segments of the CC (segment 1: p = 0.043; segment 2: p = 0.005; segment 3: p = 0.003; segment 4: p = 0.012; segment 5: p = 0.023) as well as in the descending portion of the left cingulum bundle (p = 0.026). CONCLUSIONS: Increased MD values in the CC and the left cingulum may indicate impaired organization/reduced integrity of these tracts, which may underlie the abnormal pattern of brain activity recruitment of the DMN observed during a verbal learning and memory task. Taking into account the central role of the left hippocampus in verbal memory, the abnormal integrity of the left cingulum may contribute to the reduced performance of patients with SLE on verbal memory tasks.

A neurobehavioral account for individual differences in resilience to chronic military stress.

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.

I think therefore I am: Rest-related prefrontal cortex neural activity is involved in generating the sense of self.

The sense of self has always been a major focus in the psychophysical debate. It has been argued that this complex ongoing internal sense cannot be explained by any physical measure and therefore substantiates a mind-body differentiation. Recently, however, neuro-imaging studies have associated self-referential spontaneous thought, a core-element of the ongoing sense of self, with synchronous neural activations during rest in the medial prefrontal cortex (PFC), as well as the medial and lateral parietal cortices. By applying deep transcranial magnetic stimulation (TMS) over human PFC before rest, we disrupted activity in this neural circuitry thereby inducing reports of lowered self-awareness and strong feelings of dissociation. This effect was not found with standard or sham TMS, or when stimulation was followed by a task instead of rest. These findings demonstrate for the first time a critical, causal role of intact rest-related PFC activity patterns in enabling integrated, enduring, self-referential mental processing.

Investigating two mobile just-in-time adaptive interventions to foster psychological resilience: research protocol of the DynaM-INT study.

BACKGROUND: Stress-related disorders such as anxiety and depression are highly prevalent and cause a tremendous burden for affected individuals and society. In order to improve prevention strategies, knowledge regarding resilience mechanisms and ways to boost them is highly needed. In the Dynamic Modelling of Resilience - interventional multicenter study (DynaM-INT), we will conduct a large-scale feasibility and preliminary efficacy test for two mobile- and wearable-based just-in-time adaptive interventions (JITAIs), designed to target putative resilience mechanisms. Deep participant phenotyping at baseline serves to identify individual predictors for intervention success in terms of target engagement and stress resilience. METHODS: DynaM-INT aims to recruit N = 250 healthy but vulnerable young adults in the transition phase between adolescence and adulthood (18-27 years) across five research sites (Berlin, Mainz, Nijmegen, Tel Aviv, and Warsaw). Participants are included if they report at least three negative burdensome past life events and show increased levels of internalizing symptoms while not being affected by any major mental disorder. Participants are characterized in a multimodal baseline phase, which includes neuropsychological tests, neuroimaging, bio-samples, sociodemographic and psychological questionnaires, a video-recorded interview, as well as ecological momentary assessments (EMA) and ecological physiological assessments (EPA). Subsequently, participants are randomly assigned to one of two ecological momentary interventions (EMIs), targeting either positive cognitive reappraisal or reward sensitivity. During the following intervention phase, participants' stress responses are tracked using EMA and EPA, and JITAIs are triggered if an individually calibrated stress threshold is crossed. In a three-month-long follow-up phase, parts of the baseline characterization phase are repeated. Throughout the entire study, stressor exposure and mental health are regularly monitored to calculate stressor reactivity as a proxy for outcome resilience. The online monitoring questionnaires and the repetition of the baseline questionnaires also serve to assess target engagement. DISCUSSION: The DynaM-INT study intends to advance the field of resilience research by feasibility-testing two new mechanistically targeted JITAIs that aim at increasing individual stress resilience and identifying predictors for successful intervention response. Determining these predictors is an important step toward future randomized controlled trials to establish the efficacy of these interventions.

Projecting memories: the role of the hippocampus in emotional mentalizing.

Humans have a striking tendency to use past autobiographical events to understand their own behavior. However, it is unknown if we use our own memories to understand others. To assess the role of autobiographical memory in mentalizing we examined the contribution of memory structures, specifically the hippocampus, to emotional judgment of others. Subjects were scanned while making emotional judgments regarding themselves, and protagonists deemed similar to or dissimilar from themselves. Results indicated a significant correlation between rating of the self and the similar protagonists, particularly for the events subjects recalled from their past. Furthermore, we found an interaction between similarity and recollection so that only for events subjects recalled from their past, the hippocampus reacted differently for judgments regarding the self versus dissimilar others, but not for self versus similar others. These results suggest that people actually use their own repertoire of memories and project internal self knowledge while making emotional judgments regarding others. It is speculated that mentalizing is modulated by memories of similar past events and depends on the protagonist we face.

Unsupervised multiparametric classification of dynamic susceptibility contrast imaging: study of the healthy brain.

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.

Impaired memory and learning abilities in patients with systemic lupus erythematosus as measured by the Rey Auditory Verbal Learning Test.

OBJECTIVE: The purpose of this study was to assess and characterise verbal memory impairment in patients with systemic lupus erythematosus (SLE) by the Rey Auditory Verbal Learning Test (Rey AVLT). METHODS: 40 consecutive, unselected patients with SLE were evaluated with the Rey AVLT, a clinical and research tool for the study of multiple learning and memory measures. All patients were assessed for disease activity, damage, presence of antiphospholipid antibodies and depression. Findings were compared with those of 40 healthy controls matched for age, sex and education. RESULTS: The study group included 40 patients with SLE (37 females, 3 males), median age 33 years (range 20-59), median disease duration 8 years (range 0.3-32). The median disease activity measured by the SLE Disease Activity Index (SLEDAI) was 4 (range 0-16). Median damage measured by the SLICC/ACR (Systemic Lupus International Collaborating Clinics/American College of Rheumatology) damage index score was 0 (range 0-4). Depression was detected in 16/40 patients. Several aspects of the memory domain, as measured by the Rey AVLT, were impaired in the SLE group, using analysis of variance with repeated measures. The learning curve of patients with SLE was significantly less steep compared with that of controls, (p = 0.036), the rate of words omitted from trial to trial was higher in the SLE group (p = 0.034) and retrieval was less efficient in SLE compared with controls (p = 0.004). The significance of these findings was maintained after omitting patients with stroke or depression. CONCLUSION: Learning ability was impaired in patients with SLE with a poor and inefficient learning strategy, as reflected by an impaired learning curve, repeated omissions and impaired retrieval. This pattern of memory deficit resembles that seen in patients with frontal lobe damage and warrants further localising brain studies.

An fMRI study of processing novel metaphoric sentences.

Due to inconsistent findings, the role of the two cerebral hemispheres in processing metaphoric language is controversial. The present study examined the possibility that these inconsistent findings may be due, at least partly, to differences in the type (i.e., words vs sentences) or the familiarity of the linguistic material. Previous research has shown that novel two-word metaphoric expressions showed stronger activation in the right homologue of Wernicke's area for the novel metaphors than for both literal expressions and unrelated word pairs. In the present study fMRI was used to identify the left (LH) and the right hemisphere (RH) neural networks associated with processing unfamiliar, novel metaphoric sentences taken from poetry, as compared to those involved in processing familiar literal sentences and unfamiliar nonsensical sentences. Across participants, several left lateralised brain regions showed stronger activation for novel metaphoric sentences than for the nonsensical sentences although both types of sentence represent unfamiliar linguistic expressions. Moreover, the metaphoric sentences elicited more activation in the left dorsolateral prefrontal cortex and the posterior middle temporal gyri than did both the literal sentences and the nonsensical sentences. The increased activation in these brain regions might reflect the enhanced demand on the episodic and semantic memory systems in order to generate de-novo verbal semantic associations. The involvement of the left posterior middle temporal gyri could reflect extra reliance on classical brain structures devoted to sentence comprehension.

Feeling or features: different sensitivity to emotion in high-order visual cortex and amygdala.

Emotionally loaded visual stimuli have shown increased activation in visual and cortex limbic areas. However, differences in visual features of such images could confound these findings. In order to manipulate valence of stimuli while keeping visual features largely unchanged, we took advantage of an "expressional transfiguration" (ET) effect of faces. In addition, we used repetition effects, which enabled us to test more incisively the impact of the ET effect. Using the ET manipulation, we have shown that the activation in lateral occipital complex (LOC) was unaffected by valence attributes, but produced significant modulation of fMR adaptation. Contrary to LOC, amygdala activation was increased by ET manipulation unrelated to the adaptation. A correlation between amygdala and LOC adaptation points to a possible modulatory role of the amygdala upon visual cortex short-term plasticity.

Area-specific amblyopic effects in human occipitotemporal object representations.

The role of early visual experience in the establishment of human high-order visual areas is poorly understood. Here we investigated this issue using human amblyopia--a developmental visual disorder, which manifests a central vision (acuity) deficit. Previous fMRI studies of amblyopes have described abnormal functional activations in early retinotopic areas. Here we report the surprising finding of a selective object-related abnormality in high-order occipitotemporal cortex. Specifically, we found that face-related cortical areas show a severe disconnection from the amblyopic eye, while building-related regions remain essentially normal. The selectivity of the deficit highlights the differential computations performed in the different object-related areas and is compatible with the suggested association of face regions with analysis of fine detail.

Possible remote functional reorganization in left temporal lobe epilepsy.

OBJECTIVE: To provide functional magnetic resonance imaging-based insight into the impact of left temporal lobe epilepsy (TLE) on language-related functional re-organization. MATERIALS AND METHODS: Ten right-handed patients with left TLE were compared with 10 matched healthy controls. Regional brain activation during the language task was measured in the inferior frontal gyrus (IFG) and in the superior temporal gyrus (STG), and the regional inter-hemispheric lateralization index (LI) was calculated. RESULTS: Left language lateralization was documented in all the patients and controls. Reduced lateralization in the IFG was due to decreased activity in the left frontal region rather than to increased activity in the right frontal region. The LI values in the STG correlated with the LI values in the IFG in the controls but not in the patients. CONCLUSIONS: The left IFG was most probably involved in the epileptogenesis and concomitant language-related cortical plasticity in patients with left TLE.

The dynamics of object-selective activation correlate with recognition performance in humans.

To investigate the relationship between perceptual awareness and brain activity, we measured both recognition performance and fMRI signal from object-related areas in human cortex while images were presented briefly using a masking protocol. Our results suggest that recognition performance is correlated with selective activation in object areas. Selective activation was correlated to object naming when exposure duration was varied from 20 to 500 milliseconds. Subjects' recognition during identical visual stimulation could be enhanced by training, which also increased the fMRI signal. Overall, the correlation between recognition performance and fMRI signal was highest in occipitotemporal object areas (the lateral occipital complex).

Visuo-haptic object-related activation in the ventral visual pathway.

The ventral pathway is involved in primate visual object recognition. In humans, a central stage in this pathway is an occipito-temporal region termed the lateral occipital complex (LOC), which is preferentially activated by visual objects compared to scrambled images or textures. However, objects have characteristic attributes (such as three-dimensional shape) that can be perceived both visually and haptically. Therefore, object-related brain areas may hold a representation of objects in both modalities. Using fMRI to map object-related brain regions, we found robust and consistent somatosensory activation in the occipito-temporal cortex. This region showed clear preference for objects compared to textures in both modalities. Most somatosensory object-selective voxels overlapped a part of the visual object-related region LOC. Thus, we suggest that neuronal populations in the occipito-temporal cortex may constitute a multimodal object-related network.

Center-periphery organization of human object areas.

The organizing principles that govern the layout of human object-related areas are largely unknown. Here we propose a new organizing principle in which object representations are arranged according to a central versus peripheral visual field bias. The proposal is based on the finding that building-related regions overlap periphery-biased visual field representations, whereas face-related regions are associated with center-biased representations. Furthermore, the eccentricity maps encompass essentially the entire extent of object-related occipito-temporal cortex, indicating that most object representations are organized with respect to retinal eccentricity. A control experiment ruled out the possibility that the results are due exclusively to unequal feature distribution in these images. We hypothesize that brain regions representing object categories that rely on detailed central scrutiny (such as faces) are more strongly associated with processing of central information, compared to representations of objects that may be recognized by more peripheral information (such as buildings or scenes).

The role of the amygdala in enhanced remembrance of negative episodes and acquired negativity of related neutral cues.

Prior research on the interaction between emotion and episodic memory established that negatively charged events are better remembered compared to neutral events (i.e. enhanced remembrance), as well as that a priori neutral cues that were present in the environment during a negative event can attain aversive meaning by themselves (i.e. acquired negativity). Improved understanding the neural mechanisms that mediate enhanced remembrance of negative episodes and acquired negativity of related neutral cues may carry substantial clinical relevance, particularly in the context of posttraumatic pathophysiology. In order to address this point forty-nine healthy participants completed a novel fMRI task that involve the presentation of neutral pictures before and after a series of short neutral and aversive video-clips from which the neutral pictures were originally extracted, and a subsequent presentation of these pictures as cues for clip recall [termed, Picture-Clip-Picture-Recall (PCPR) task]. Behavioral results indicate that aversive clips were indeed better remembered compared to neutral clips (i.e. enhanced remembrance of negative episode) and that a priori neutral pictures that appeared in aversive clips were rated more negatively after relative to before the exposure to the aversive clips (i.e. acquired negativity of related neutral cues). Whole-brain fMRI analysis revealed that increased amygdala activation in response to pictures when presented as cues for clip recall predicted successful clip remembrance, particularly remembrance of aversive clips. This amygdala activation was also correlated with the magnitude of acquired negativity of the cues following their appearance in aversive clips. Taken together our findings implicate the PCPR as a novel, naturalistic, framework for investigating the neural interface of emotional episodic memory, while highlighting the role of the amygdala in enhanced remembrance of negative episodes and acquired negativity of related neutral cues. Clinical implications are discussed.

An fMRI investigation of the neural correlates underlying the processing of novel metaphoric expressions.

The neural networks associated with processing related pairs of words forming literal, novel, and conventional metaphorical expressions and unrelated pairs of words were studied in a group of 15 normal adults using fMRI. Subjects read the four types of linguistic expressions and decided which relation exists between the two words (metaphoric, literal, or unrelated). According to the Graded Salience Hypothesis (GSH, ), which predicts a selective RH involvement in the processing of novel, nonsalient meanings, it is primarily the degree of meaning salience of a linguistic expression rather than literality or nonliterality, which modulates the degree of left hemisphere (LH) and right hemisphere (RH) processing of metaphors. In the present study, novel metaphorical expressions represented the nonsalient interpretations, whereas conventional metaphors and literal expressions represented the salient interpretations. A direct comparison of the novel metaphors vs. the conventional metaphors revealed significantly stronger activity in right posterior superior temporal sulcus, right inferior frontal gyrus, and left middle frontal gyrus. These results support the GSH and suggest a special role for the RH in processing novel metaphors. Furthermore, the right PSTS may be selectively involved in verbal creativity.

Modulation of fear extinction processes using transcranial electrical stimulation.

Research associates processes of fear conditioning and extinction with treatment of anxiety and stress-related disorders. Manipulation of these processes may therefore be beneficial for such treatment. The current study examines the effects of electrical brain stimulation on fear extinction processes in healthy humans in order to assess its potential relevance for treatment enhancement. Forty-five participants underwent a 3-day fear conditioning and extinction paradigm. Electrical stimulation targeting the medial prefrontal cortex was applied during the extinction-learning phase (Day 2). Participants were randomly assigned to three stimulation conditions: direct-current (DC) stimulation, aimed at enhancing extinction-learning; low-frequency alternating-current (AC) stimulation, aimed at interfering with reconsolidation of the activated fear memory; and sham stimulation. The effect of stimulation on these processes was assessed in the subsequent extinction recall phase (Day 3), using skin conductance response and self-reports. Results indicate that AC stimulation potentiated the expression of fear response, whereas DC stimulation led to overgeneralization of fear response to non-reinforced stimuli. The current study demonstrates the capability of electrical stimulation targeting the medial prefrontal cortex to modulate fear extinction processes. However, the stimulation parameters tested here yielded effects opposite to those anticipated and could be clinically detrimental. These results highlight the potential capacity of stimulation to manipulate processes relevant for treatment of anxiety and stress-related disorders, but also emphasize the need for additional research to identify delivery parameters to enable its translation into clinical practice. Clinical trial identifiers: Modulation of Fear Extinction Processes Using Transcranial Electrical Stimulation; https://clinicaltrials.gov/show/NCT02723188; NCT02723188 NCT02723188.