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

Background: Aerobic training has been shown to promote structural and functional neurocognitive plasticity in cognitively intact older adults. However, little is known about the neuroplastic potential of aerobic exercise in individuals at risk of Alzheimer’s disease (AD) and dementia. Objective: We aimed to explore the effect of aerobic exercise intervention and cardiorespiratory fitness improvement on brain and cognitive functions in older adults with amnestic mild cognitive impairment (aMCI). Methods: 27 participants with aMCI were randomized to either aerobic training (n = 13) or balance and toning (BAT) control group (n = 14) for a 16-week intervention. Pre- and post-assessments included functional MRI experiments of brain activation during associative memory encoding and neural synchronization during complex information processing, cognitive evaluation using neuropsychological tests, and cardiorespiratory fitness assessment. Results: The aerobic group demonstrated increased frontal activity during memory encoding and increased neural synchronization in higher-order cognitive regions such as the frontal cortex and temporo-parietal junction (TPJ) following the intervention. In contrast, the BAT control group demonstrated decreased brain activity during memory encoding, primarily in occipital, temporal, and parietal areas. Increases in cardiorespiratory fitness were associated with increases in brain activation in both the left inferior frontal and precentral gyri. Furthermore, changes in cardiorespiratory fitness were also correlated with changes in performance on several neuropsychological tests. Conclusion: Aerobic exercise training may result in functional plasticity of high-order cognitive areas, especially, frontal regions, among older adults at risk of AD and dementia. Furthermore, cardiorespiratory fitness may be an important mediating factor of the observed changes in neurocognitive functions.

Resolving approach-avoidance conflicts relies on encoding motivation outcomes and learning from past experiences. Accumulating evidence points to the role of the Medial Temporal Lobe (MTL) and Medial Prefrontal Cortex (mPFC) in these processes, but their differential contributions have not been convincingly deciphered in humans. We detect 310 neurons from mPFC and MTL from patients with epilepsy undergoing intracranial recordings and participating in a goal-conflict task where rewards and punishments could be controlled or not. mPFC neurons are more selective to punishments than rewards when controlled. However, only MTL firing following punishment is linked to a lower probability for subsequent approach behavior. mPFC response to punishment precedes a similar MTL response and affects subsequent behavior via an interaction with MTL firing. We thus propose a model where approach-avoidance conflict resolution in humans depends on outcome value tagging in mPFC neurons influencing encoding of such value in MTL to affect subsequent choice., Optimizing approach-avoidance behavior calls for neural encoding of related motivation outcomes. Here, the authors show that behavioral choice under conflict relies on differential neuronal firing patterns after punishment, in which mPFC neurons decode the outcome’s value and MTL neurons follow by reducing subsequent approach.

BACKGROUND: Low hippocampal volume could serve as an early risk factor for Post-traumatic Stress Disorder (PTSD) in interaction with other brain anomalies of developmental origin. One such anomaly may well be a presence of large Cavum Septum Pellucidum (CSP), which has been loosely associated with PTSD. Here, we performed a longitudinal prospective study of recent trauma survivors. We hypothesized that at one-month after trauma exposure, the relation between hippocampal volume and PTSD symptom severity will be moderated by CSP volume, and that this early interaction will account for persistent PTSD symptoms at subsequent time-points. METHODS: 171 adults (87 females, average age=34.22, range=18–65) admitted to a general hospital’s emergency department following a traumatic event, underwent clinical assessment and structural MRI within one-month after trauma. Follow-up clinical evaluations were conducted at six (n=97) and fourteen (n=78) months after trauma. Hippocampus and CSP volumes were measured automatically by FreeSurfer software and verified manually by a neuroradiologist. RESULTS: At one-month following trauma, CSP volume significantly moderated the relation between hippocampal volume and PTSD severity (p=0.026), and this interaction further predicted symptom severity at fourteen months post-trauma (p=0.018). Specifically, individuals with smaller hippocampus and larger CSP at one-month post-trauma, showed more severe symptoms at one- and fourteen months following trauma exposure. CONCLUSIONS: Our study provides evidence for an early neuroanatomical risk factors for PTSD, which could also predict the progression of the disorder in the year following trauma exposure. Such a simple-to-acquire neuroanatomical signature for PTSD could guide early management, as well as long-term monitoring. TRIAL REGISTRATION: Neurobehavioral Moderators of Post-traumatic Disease Trajectories. ClinicalTrials.gov registration: NCT03756545. https://clinicaltrials.gov/ct2/show/NCT03756545

Highlights • We propose a novel end-to-end neural network that employs resting-state and task-based functional MRI (fMRI) datasets, obtained one month after trauma exposure, to predict PTSD one, six and 14-months after the exposure. • The method utilizes connectivity maps extracted from pairs of brain regions which are subsequently updated by applying the algorithmic technique of pairwise attention. • The proposed deep learning method predicts PTSD status, PTSD symptom clusters and survival analysis within the prospective design. We demonstrate a significant improvement in performance on all the datasets and experiments in comparison to other relevant analytical techniques. • Pairwise association analysis reveals several significant functional connectivity patterns, in line with previous PTSD neuroimaging literature., Early intervention following exposure to a traumatic life event could change the clinical path from the development of post traumatic stress disorder (PTSD) to recovery, hence the interest in early detection and underlying biological mechanisms involved in the development of post traumatic sequelae. We introduce a novel end-to-end neural network that employs resting-state and task-based functional MRI (fMRI) datasets, obtained one month after trauma exposure, to predict PTSD symptoms at one-, six- and fourteen-months after the exposure. FMRI data, as well as PTSD status and symptoms, were collected from adults at risk for PTSD development, after admission to emergency room following a traumatic event. Our computational method utilized a per-region encoder to extract brain regions embedding, which were subsequently updated by applying the algorithmic technique of pairwise attention. The affinities obtained between each pair of regions were combined to create a pairwise co-activation map used to perform multi-label classification. The results demonstrate that the novel method’s performance in predicting PTSD symptoms, in a prospective manner, outperforms previous analytical techniques reported in the fMRI literature, all trained on the same dataset. We further show a high predictive ability for predicting PTSD symptom clusters and PTSD persistence. To the best of our knowledge, this is the first deep learning method applied on fMRI data with respect to prospective clinical outcomes, to predict PTSD status, severity and symptom clusters. Future work could further delineate the mechanisms that underlie such a prediction, and potentially improve single patient characterization.

With approximately 75% of smokers resuming cigarette smoking after using the Gold Standard Programme for smoking cessation, investigation into novel therapeutic approaches is warranted. Typically, smoking cue reactivity is crucial for smoking behaviour. Here we developed a novel closed-loop, smoking cue reactivity patterns EEG-based neurofeedback protocol and evaluated its therapeutic efficacy on nicotine addiction. During an evoked smoking cue reactivity task participants' brain activity patterns corresponding to smoking cues were obtained with multivariate pattern analysis of all EEG channels data, then during neurofeedback the EEG activity patterns of smoking cue reactivity were continuously deactivated with adaptive closed-loop training. In a double-blind, placebo-controlled, randomized clinical trial, 60 nicotine-dependent participants were assigned to receive two neurofeedback training sessions (∼1 h/session) either from their own brain (n = 30, real-feedback group) or from the brain activity pattern of a matched participant (n = 30, yoked-feedback group). Cigarette craving and craving-related P300 were assessed at pre-neurofeedback and post-neurofeedback. The number of cigarettes smoked per day was assessed at baseline, 1 week, 1 month, and 4 months following the final neurofeedback visit. In the real-feedback group, participants successfully deactivated EEG activity patterns of smoking cue reactivity. The real-feedback group showed significant decrease in cigarette craving and craving-related P300 amplitudes compared with the yoked-feedback group. The rates of cigarettes smoked per day at 1 week, 1 month and 4 months follow-up decreased 30.6%, 38.2%, and 27.4% relative to baseline in the real-feedback group, compared to decreases of 14.0%, 13.7%, and 5.9% in the yoked-feedback group. The neurofeedback effects on craving change and smoking amount at the 4-month follow-up were further predicted by neural markers at pre-neurofeedback. This novel neurofeedback training approach produced significant short-term and long-term effects on cigarette craving and smoking behaviour, suggesting the neurofeedback protocol described herein is a promising brain-based tool for treating addiction.

How can music—merely a stream of sounds—be enjoyable for so many people? Recent accounts of this phenomenon are inspired by predictive coding models, hypothesizing that both confirmation and violations of musical expectations associate with the hedonic response to music via recruitment of the mesolimbic system and its connections with the auditory cortex. Here we provide support for this model, by revealing associations of music-induced pleasantness with musical surprises in the activity and connectivity patterns of the nucleus accumbens (NAcc)—a central component of the mesolimbic system. We examined neurobehavioral responses to surprises in three naturalistic musical pieces using fMRI and subjective ratings of valence and arousal. Surprises were associated with changes in reported valence and arousal, as well as with enhanced activations in the auditory cortex, insula and ventral striatum, relative to unsurprising events. Importantly, we found that surprise-related activation in the NAcc was more pronounced among individuals who experienced greater music-induced pleasantness. These participants also exhibited stronger surprise-related NAcc–auditory cortex connectivity during the most pleasant piece, relative to participants who found the music less pleasant. These findings provide a novel demonstration of a direct link between musical surprises, NAcc activation and music-induced pleasantness.

Interoception, the perception and interpretation of one's own bodily signals, is a key aspect of human caregiving that impacts infant health and well-being across life. Interoception relies on limbic structures, mainly the amygdala, and the agranular visceromotor cortex, particularly the anterior insula (AI), that integrate with the oxytocin (OT) system to support interoceptive sensitivity. Here, we used functional magnetic resonance imaging (fMRI) to examine whether interoception sensitivity in the parent's brain during the first months of parenting combines with sensitive parenting and OT-system functionality to predict children's somatic symptoms six years later. We followed 45 primary-caregiving first-time mothers and fathers and their infants across the first six years of parenting. In infancy (Time 1), parents' brain response to infant stimuli was imaged, salivary OT measured, and parent-infant interactions coded for parent sensitivity. In preschool (Time 2), parent and child's OT and parent sensitivity were measured again. At six years (Time 3), parents reported on children's somatic symptoms. Greater activation of the parent's AI bilaterally when his/her child was an infant predicted lower child somatic problems at six years. Parent sensitivity partially mediated the links between parental AI activation and child somatic symptoms. In addition, greater parental bilateral amygdala activity predicted higher child OT levels at 3 years and parental OT moderated the relations between preschoolers' OT and later somatic symptoms. Our findings chart two independent cross-generational pathways from interoception sensitivity in the parent's brain and child somatization. The first defines an evolutionary-ancient path including the amygdala and the OT system that support mammalian attention to arousal modulations in response to social cues; the second, via the AI, implicates higher-order interoceptive representations of bodily responses and affective states that underpins human embodiment.

Angry outbursts during interpersonal provocations may lead to violence and prevails in numerous pathological conditions. In the anger-infused Ultimatum Game (aiUG), unfair monetary offers accompanied by written provocations induce anger. Rejection of such offers relates to aggression, whereas acceptance to anger regulation. We previously demonstrated the involvement of the ventro-medial prefrontal cortex (vmPFC) in accepting unfair offers and attenuating anger during an aiUG, suggestive of its role in anger regulation. Here, we aimed to enhance anger regulation by facilitating vmPFC activity during anger induction, using anodal transcranial direct current stimulation (tDCS) and simultaneously with functional Magnetic Resonance Imaging to validate modulation of vmPFC activity. In a cross-over, sham-controlled, double-blind study, participants (N = 25) were each scanned twice, counterbalancing sham and active tDCS applied during administration of the aiUG. Outcome measures included the effect of active versus sham stimulation on vmPFC activity, unfair offers' acceptance rates, self-reported anger, and aggressive behavior in a subsequent reactive aggression paradigm. Results indicate that active stimulation led to increased vmPFC activity during the processing of unfair offers, increased acceptance rates of these offers, and mitigated the increase in self-reported anger following the aiUG. We also noted a decrease in subsequent aggressive behavior following active stimulation, but only when active stimulation was conducted in the first experimental session. Finally, an exploratory finding indicated that participants with a stronger habitual tendency to use suppression as an emotion regulation strategy, reported less anger following the aiUG in the active compared to sham stimulation conditions. Findings support a potential causal link between vmPFC functionality and the experience and expression of anger, supporting vmPFC's role in anger regulation, and providing a promising avenue for reducing angry and aggressive outbursts during interpersonal provocations in various psychiatric and medical conditions.

Aging is associated with compromised neurocognition. While aerobic exercise has been linked with cognitive resilience, findings regarding its relationship with brain morphology are inconsistent. Furthermore, the biological underpinnings of the relationship between aerobic activity and memory in the aging human brain are unclear. To investigate these issues, we examined hippocampal and non-hippocampal structural correlates of aerobically active lifestyle and cardiorespiratory fitness in older adults. We then examined structural pathways which may potentially mediate the association between active lifestyle and memory. Fifty participants (aged 65-80) underwent structural and diffusion MRI, memory evaluation, were examined for active lifestyle and cardiorespiratory fitness. Morphological features of the hippocampus and fornix, white matter lesions, and brain atrophy were assessed. Active lifestyle and cardiorespiratory fitness correlated with all neurocognitive measures. An exploratory mediation analysis revealed hippocampal and white matter lesions pathways linking active lifestyle and cardiorespiratory fitness with memory. Our results support a neuroprotective role of aerobic exercise on the aging brain and suggest plausible morphological pathways that may underlie the relationship between aerobic exercise and memory.

Objective Presurgical memory functional MRI (fMRI) mapping for temporal lobe epilepsy surgery is important because of the excision of structures in the temporal lobe (e.g., hippocampus) that are relevant for intact memory. Although the American Academy of Neurology recommends the use of fMRI for presurgical mapping of epilepsy of verbal and nonverbal memory to predict memory outcome, there are still no specific recommendations about which tests to use. In the current study, we evaluate the potential for clinical utility of two established neuropsychological tests of memory adapted into the fMRI setting. Method We used the Verbal Paired Associates (VPA) for assessment of verbal memory and the Object Learning and Location (OLL) task for assessment of visuospatial memory. To confirm that these tasks engage the hippocampus, we examined their neural underpinning and patterns of laterality in 20 healthy volunteers (mean age = 26.35). Results During fMRI of the VPA task of verbal memory, we found a strong left-lateralized posterior hippocampal activation. Remembering the location of objects in the OLL task of visuospatial memory elicited right-lateralized hippocampal activation. Conclusions These findings demonstrate the utility of the VPA and OLL tests to delineate domain-specific activity and laterality and, as such, may provide supportive evidence to strengthen links between presurgical neuropsychological assessment and memory fMRI mapping for epilepsy surgery. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Neurofeedback is going through a renaissance. Advances in brain imaging and computing have renewed efforts to modify brain activity and behaviour using this technique. Here, over 80 neurofeedback researchers present a consensus-derived checklist – CRED-nf – for reporting and experimental design standards in the field., Neurofeedback has begun to attract the attention and scrutiny of the scientific and medical mainstream. Here, neurofeedback researchers present a consensus-derived checklist that aims to improve the reporting and experimental design standards in the field.

ObjectiveTo characterize the functional brain changes involved in δ-9-tetrahydrocannabinol (THC) modulation of chronic neuropathic pain.MethodsFifteen patients with chronic radicular neuropathic pain participated in a randomized, double-blind, placebo-controlled trial employing a counterbalanced, within-subjects design. Pain assessments and functional resting state brain scans were performed at baseline and after sublingual THC administration. We examined functional connectivity of the anterior cingulate cortex (ACC) and pain-related network dynamics using graph theory measures.ResultsTHC significantly reduced patients' pain compared to placebo. THC-induced analgesia was correlated with a reduction in functional connectivity between the anterior cingulate cortex (ACC) and the sensorimotor cortex. Moreover, the degree of reduction was predictive of the response to THC. Graph theory analyses of local measures demonstrated reduction in network connectivity in areas involved in pain processing, and specifically in the dorsolateral prefrontal cortex (DLPFC), which were correlated with individual pain reduction.ConclusionThese results suggest that the ACC and DLPFC, 2 major cognitive-emotional modulation areas, and their connections to somatosensory areas, are functionally involved in the analgesic effect of THC in chronic pain. This effect may therefore be mediated through induction of functional disconnection between regulatory high-order affective regions and the sensorimotor cortex. Moreover, baseline functional connectivity between these brain areas may serve as a predictor for the extent of pain relief induced by THC.

Aging is marked by memory decline that is exacerbated with attentional loading. Portraying older adults' neural functions when encoding information in conditions of high and low attentional load is a necessary step toward understanding this phenomenon. Furthermore, the information gained may be used to devise strategies aimed to prevent age-related decline in memory. To address this issue, a group of older adults underwent fMRI scanning while encoding short movies under two levels of attentional loading. High attentional load was associated with increased inter-subject correlation (inter-SC) in only a subset of prefrontal regions that were previously identified in younger adults. It was also associated with lower inter-SC in task-relevant visual regions, suggesting that as load increased, visual processing became less synchronized across participants. Critically, while we have shown that inter-SC in the dorsal posterior cingulate cortex (dPCC) was increased for younger adults at high load, older adults did not generally show this effect. However, those older adults who did display this pattern also displayed a 'younger-like' memory profile. These results point to a pivotal role of the dPCC in the interplay between attention and memory across the lifespan.

Impairments in social cognition and interactions are core psychopathologies in schizophrenia, often manifesting as an inability to appropriately relate to the intentions and feelings of others. Neuroimaging has helped to demarcate the dynamics of two distinct functional connectivity circuits underlying the social-affective processes related to mentalization (known as Theory of Mind, ToM) and somatic-affiliation (known as Embodied Simulation, ES). While evidence points to abnormal activation patterns within these networks among those suffering from schizophrenia, it is yet unclear however, if these patients exhibit this abnormal functional connectivity in the context of social-affective experiences. The current fMRI study, investigated functional connectivity dynamics within ToM and ES networks as subjects experienced evolving cinematic portrayals of fear. During scanning, schizophrenia patients and healthy controls passively watched a cinematic scene in which a mother and her son face various threatening events. Participants then provided a continuous and retrospective report of their fear intensity during a second viewing outside the scanner. Using network cohesion index (NCI) analysis, we examined modulations of ES-related and ToM-related functional connectivity dynamics and their relation to symptom severity and the continuous emotional ratings of the induced cinematic fear. Compared to patients, healthy controls showed higher ES-NCI and marginally lower ToM-NCI during emotional peaks. Cross-correlation analysis revealed an intriguing dynamic between NCI and the inter-group difference of reported fear. Schizophrenia patients rated their fear as lower relative to healthy controls, shortly after exhibiting lower ES connectivity. This increased difference in rating was also followed by higher ToM connectivity among schizophrenia patients. The clinical relevance of these findings is further highlighted by the following two results: (a) ToM-NCI was found to have a strong correlation with the severity of general symptoms during one of the two main emotional peaks (Spearman R = 0.77); and (b) k-mean clustering demonstrated that the networks’ NCI dynamic during the social-affective context reliably differentiated between patients and controls. Together, these findings point to a possible neural marker for abnormal social-affective processing in schizophrenia, manifested as the disturbed balance between two functional networks involved in social-affective affiliation. This in turn suggests that exaggerated mentalization over somatic-affiliative processing, in response to another’s’ distress may underlie social-affective deficits in schizophrenia.

Previous research indicates abnormal comprehension of verbal information in patients with schizophrenia. Yet the neural mechanism underlying the breakdown of verbal information processing in schizophrenia is poorly understood. Imaging studies in healthy populations have shown a network of brain areas involved in hierarchical processing of verbal information over time. Here, we identified critical aspects of this hierarchy, examining patients with schizophrenia. Using functional magnetic resonance imaging, we examined various levels of information comprehension elicited by naturally presented verbal stimuli; from a set of randomly shuffled words to an intact story. Specifically, patients with first episode schizophrenia (N = 15), their non-manifesting siblings (N = 14) and healthy controls (N = 15) listened to a narrated story and randomly scrambled versions of it. To quantify the degree of dissimilarity between the groups, we adopted an inter-subject correlation (inter-SC) approach, which estimates differences in synchronization of neural responses within and between groups. The temporal topography found in healthy and siblings groups were consistent with our previous findings – high synchronization in responses from early sensory toward high order perceptual and cognitive areas. In patients with schizophrenia, stimuli with short and intermediate temporal scales evoked a typical pattern of reliable responses, whereas story condition (long temporal scale) revealed robust and widespread disruption of the inter-SCs. In addition, the more similar the neural activity of patients with schizophrenia was to the average response in the healthy group, the less severe the positive symptoms of the patients. Our findings suggest that system-level neural indication of abnormal verbal information processing in schizophrenia reflects disease manifestations., Highlights • Critical aspects in semantic information processing in patients with schizophrenia, their non-manifesting siblings and healthy controls • High synchronization in responses in early sensory areas in all groups • Robust disruption of the responses in high order perceptual and cognitive areas in patients with schizophrenia

Emotional experiences are frequently shaped by the emotional responses of co-present others. Research has shown that people constantly monitor and adapt to the incoming social–emotional signals, even without face-to-face interaction. And yet, the neural processes underlying such emotional transmissions have not been directly studied. Here, we investigated how the human brain processes emotional cues which arrive from another, co-attending individual. We presented continuous emotional feedback to participants who viewed a movie in the scanner. Participants in the social group (but not in the control group) believed that the feedback was coming from another person who was co-viewing the same movie. We found that social–emotional feedback significantly affected the neural dynamics both in the core affect and in the medial pre-frontal regions. Specifically, the response time-courses in those regions exhibited increased similarity across recipients and increased neural alignment with the timeline of the feedback in the social compared with control group. Taken in conjunction with previous research, this study suggests that emotional cues from others shape the neural dynamics across the whole neural continuum of emotional processing in the brain. Moreover, it demonstrates that interpersonal neural alignment can serve as a neural mechanism through which affective information is conveyed between individuals.

Working memory (WM) declines with age. Older adults, however, perform similar to younger adults in WM tasks with negative distractors at low WM load. To clarify the neural basis of this phenomenon, older (n = 28) and younger (n = 24) adults performed an emotional n-back task during an fMRI scan, and activity in task-related regions was examined. Comparing negative with neutral distraction at low WM load, older adults demonstrated shorter reaction times (RT) and reduced activation in frontoparietal regions: bilateral middle frontal gyrus (MFG) and left parietal cortex. They also had greater coherence within the frontoparietal network, as well as greater deactivation of the ventromedial prefrontal cortex and the amygdala. These patterns probably contributed to the older adults' diminished distractibility by negative task-irrelevant stimuli. Since recruitment of control mechanisms was less required, the frontoparietal network was less activated and performance was improved. Faster RT during the negative condition was related to lesser activation of the MFG in both age groups, corroborating the functional significance of this region to WM across the lifespan.

Alloparental care, the cooperative care of offspring by group members other than the biological mother, has been widely practiced since early hominin evolution to increase infant survival and thriving. The coparental bond-a relationship of solidarity and commitment between two adults who join their effort to care for children-is a central contributor to children's well-being and sociality; yet, the neural basis of coparenting has not been studied in humans. Here, we followed 84 first-time co-parents (42 couples) across the first 6 years of family formation, including opposite-sex and same-sex couples, measured brain response to coparental stimuli, observed collaborative and undermining coparental behaviors in infancy and preschool, assayed oxytocin (OT) and vasopressin (AVP), and measured coparenting and child behavior problems at 6 years. Across family types, coparental stimuli activated the striatum, specifically the ventral striatum and caudate, striatal nodes implicated in motivational goal-directed social behavior. Psychophysiological interaction analysis indicated that both nodes were functionally coupled with the vmPFC in support of the human coparental bond and this connectivity was stronger as collaborative coparental behavior increased. Furthermore, caudate functional connectivity patterns differentiated distinct corticostriatal pathways associated with two stable coparental behavioral styles; stronger caudate-vmPFC connectivity was associated with more collaborative coparenting and was linked to OT, whereas a stronger caudate-dACC connectivity was associated with increase in undermining coparenting and was related to AVP. Finally, dyadic path-analysis model indicated that the parental caudate-vmPFC connectivity in infancy predicted lower child externalizing symptoms at 6 years as mediated by collaborative coparenting in preschool. Findings indicate that the coparental bond is underpinned by striatal activations and corticostriatal connectivity similar to other human affiliative bonds; highlight specific corticostriatal pathways as defining distinct coparental orientations that underpin family life; chart brain-hormone-behavior constellations for the mature, child-orientated coparental bond; and demonstrate the flexibility of this bond across family constellations and its unique contribution to child well-being.

Music is a powerful means for communicating emotions among individuals. Here we reveal that this continuous stream of affective information is commonly represented in the brains of different listeners and that particular musical attributes mediate this link. We examined participants' brain responses to two naturalistic musical pieces using functional Magnetic Resonance imaging (fMRI). Following scanning, as participants listened to the musical pieces for a second time, they continuously indicated their emotional experience on scales of valence and arousal. These continuous reports were used along with a detailed annotation of the musical features, to predict a novel index of Dynamic Common Activation (DCA) derived from ten large-scale data-driven functional networks. We found an association between the unfolding music-induced emotionality and the DCA modulation within a vast network of limbic regions. The limbic-DCA modulation further corresponded with continuous changes in two temporal musical features: beat-strength and tempo. Remarkably, this "collective limbic sensitivity" to temporal features was found to mediate the link between limbic-DCA and the reported emotionality. An additional association with the emotional experience was found in a left fronto-parietal network, but only among a sub-group of participants with a high level of musical experience (>5years). These findings may indicate two processing-levels underlying the unfolding of common music emotionality; (1) a widely shared core-affective process that is confined to a limbic network and mediated by temporal regularities in music and (2) an experience based process that is rooted in a left fronto-parietal network that may involve functioning of the 'mirror-neuron system'.

Objective: Although simultaneous recording of EEG and MRI has gained increasing popularity in recent years, the extent of its clinical use remains limited by various technical challenges. Motion interference is one of the major challenges in EEG-fMRI. Here we present an approach which reduces its impact with the aid of an MR compatible dual-array EEG (daEEG) in which the EEG itself is used both as a brain signal recorder and a motion sensor. Methods: We implemented two arrays of EEG electrodes organized into two sets of nearly orthogonally intersecting wire bundles. The EEG was recorded using referential amplifiers inside a 3 T MR-scanner. Virtual bipolar measurements were taken both along bundles (creating a small wire loop and therefore minimizing artifact) and across bundles (creating a large wire loop and therefore maximizing artifact). Independent component analysis (ICA) was applied. The resulting ICA components were classified into brain signal and noise using three criteria: 1) degree of two-dimensional spatial correlation between ICA coefficients along bundles and across bundles; 2) amplitude along bundles vs. across bundles; 3) correlation with ECG. The components which passed the criteria set were transformed back to the channel space. Motion artifact suppression and the ability to detect interictal epileptic spikes following daEEG and Optimal Basis Set (OBS) procedures were compared in 10 patients with epilepsy. Results: The SNR achieved by daEEG was 11.05 +/- 3.10 and by OBS was 8.25 +/- 1.01 (p

Activity-dependent neuroprotective protein (ADNP), discovered and first characterized in our laboratory (IG), is vital for mammalian brain formation and presents one of the leading genes mutated de novo causing an autistic syndrome, namely the ADNP syndrome. Furthermore, a unique mouse model of Adnp-haploinsufficiency was developed in the laboratory (IG), with mice exhibiting cognitive and social deficiencies. ADNP is regulated by vasoactive intestinal peptide (VIP), and pituitary adenylate cyclase-activating peptide (PACAP). In this respect, PACAP was independently identified as a sexual divergent master regulator of the stress response. Here, we sought to determine the impact of the Adnp genotype and the efficacy of PACAP pre-treatment when subjecting Adnp+/− mice to stressful conditions. Significant sex differences were observed with Adnp+/− males being more susceptible to stress in the object and social recognition tests, and the females more susceptible in the open field and elevated plus maze tests. Splenic Adnp expression and plasma cortisol levels in mice were correlated with cognition (male mice) and anxiety-related behavior. These findings were further translated to humans, with observed correlations between ADNP expression and stress/cortisol content in a young men cohort. Altogether, our current results may establish ADNP as a marker of stress response.

Non‐manifesting carriers (NMC) of the G2019S mutation in the LRRK2 gene represent an “at risk” group for future development of Parkinson's disease (PD) and have demonstrated task related fMRI changes. However, resting‐state networks have received less research focus, thus this study aimed to assess the integrity of the motor, default mode (DMN), salience (SAL), and dorsal attention (DAN) networks among this unique population by using two different connectivity measures: interregional functional connectivity analysis and Dependency network analysis (D(EP)NA). Machine learning classification methods were used to distinguish connectivity between the two groups of participants. Forty‐four NMC and 41 non‐manifesting non‐carriers (NMNC) participated in this study; while no behavioral differences on standard questionnaires could be detected, NMC demonstrated lower connectivity measures in the DMN, SAL, and DAN compared to NMNC but not in the motor network. Significant correlations between NMC connectivity measures in the SAL and attention were identified. Machine learning classification separated NMC from NMNC with an accuracy rate above 0.8. Reduced integrity of non‐motor networks was detected among NMC of the G2019S mutation in the LRRK2 gene prior to identifiable changes in connectivity of the motor network, indicating significant non‐motor cerebral changes among populations “at risk” for future development of PD.

OBJECTIVE Providing a reliable assessment of language lateralization is an important task to be performed prior to neurosurgery in patients with epilepsy. Over the last decade, functional MRI (fMRI) has emerged as a useful noninvasive tool for language lateralization, supplementing or replacing traditional invasive methods. In standard practice, fMRI-based language lateralization is assessed qualitatively by visual inspection of fMRI maps at a specific chosen activation threshold. The purpose of this study was to develop and evaluate a new computational technique for providing the probability of each patient to be left, right, or bilateral dominant in language processing. METHODS In 76 patients with epilepsy, a language lateralization index was calculated using the verb-generation fMRI task over a wide range of activation thresholds (from a permissive threshold, analyzing all brain regions, to a harsh threshold, analyzing only the strongest activations). The data were classified using a probabilistic logistic regression method. RESULTS Concordant results between fMRI and Wada lateralization were observed in 89% of patients. Bilateral and right-dominant groups showed similar fMRI lateralization patterns differentiating them from the left-dominant group but still allowing classification in 82% of patients. CONCLUSIONS These findings present the utility of a semi-supervised probabilistic learning approach for presurgical language-dominance mapping, which may be extended to other cognitive domains such as memory and attention.

The ability to store, integrate, and manipulate information declines with aging. These changes occur earlier, faster, and to a greater degree as a result of neurodegeneration. One of the most common and early characteristics of cognitive decline is difficulty with comprehension of information. The neural mechanisms underlying this breakdown of information processing are poorly understood. Using functional MRI and natural stimuli (e.g., stories), we mapped the neural mechanisms by which the human brain accumulates and processes information with increasing duration and complexity in participants with amnestic mild cognitive impairment (aMCI) and healthy older adults. To explore the mechanisms of information processing, we measured the reliability of brain responses elicited by listening to different versions of a narrated story created by segmenting the story into words, sentences, and paragraphs and then scrambling the segments. Comparing healthy older adults and participants with aMCI revealed that in both groups, all types of stimuli similarly recruited primary auditory areas. However, prominent differences between groups were found at the level of processing long and complex stimuli. In healthy older adults, parietal and frontal regions demonstrated highly synchronized responses in both the paragraph and full story conditions, as has been previously reported in young adults. Participants with aMCI, however, exhibited a robust functional shift of long time scale processing to the pre- and post-central sulci. Our results suggest that participants with aMCI experienced a functional shift of higher order auditory information processing, possibly reflecting a functional response to concurrent or impending neuronal or synaptic loss. This observation might assist in understanding mechanisms of cognitive decline in aMCI.

The cross-generational transmission of mammalian sociality, initiated by the parent's postpartum brain plasticity and species-typical behavior that buttress offspring's socialization, has not been studied in humans. In this longitudinal study, we measured brain response of 45 primary-caregiving parents to their infant's stimuli, observed parent-infant interactions, and assayed parental oxytocin (OT). Intra- and inter-network connectivity were computed in three main networks of the human parental brain: core limbic, embodied simulation and mentalizing. During preschool, two key child social competencies were observed: emotion regulation and socialization. Parent's network integrity in infancy predicted preschoolers' social outcomes, with subcortical and cortical network integrity foreshadowing simple evolutionary-based regulatory tactics vs complex self-regulatory strategies and advanced socialization. Parent-infant synchrony mediated the links between connectivity of the parent's embodied simulation network and preschoolers' ability to use cognitive/executive emotion regulation strategies, highlighting the inherently dyadic nature of this network and its long-term effects on tuning young to social life. Parent's inter-network core limbic-embodied simulation connectivity predicted children's OT as moderated by parental OT. Findings challenge solipsistic neuroscience perspectives by demonstrating how the parent-offspring interface enables the brain of one human to profoundly impact long-term adaptation of another.

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

Goal conflict situations, involving the simultaneous presence of reward and punishment, occur commonly in real life, and reflect well-known individual differences in the behavioral tendency to approach or avoid. However, despite accumulating neural depiction of motivational processing, the investigation of naturalistic approach behavior and its interplay with individual tendencies is remarkably lacking. We developed a novel ecological interactive scenario which triggers motivational behavior under high or low goal conflict conditions. Fifty-five healthy subjects played the game during a functional magnetic resonance imaging scan. A machine-learning approach was applied to classify approach/avoidance behaviors during the game. To achieve an independent measure of individual tendencies, an integrative profile was composed from three established theoretical models. Results demonstrated that approach under high relative to low conflict involved increased activity in the ventral tegmental area (VTA), peri-aquaductal gray, ventral striatum (VS) and precuneus. Notably, only VS and VTA activations during high conflict discriminated between approach/avoidance personality profiles, suggesting that the relationship between individual personality and naturalistic motivational tendencies is uniquely associated with the mesostriatal pathway. VTA–VS further demonstrated stronger coupling during high vs low conflict. These findings are the first to unravel the multilevel relationship among personality profile, approach tendencies in naturalistic set-up and their underlying neural manifestation, thus enabling new avenues for investigating approach-related psychopathologies.

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.

1.AbstractSleep 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 ssVEP, obtained from a group of 18 healthy individuals following 24 hours 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 validate measure of reduced vigilance following 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.

Film theorists and practitioners suggest that motion can be manipulated in movie scenes to elicit emotional responses in viewers. However, our understanding of the role of motion in emotion perception remains limited. On the one hand, movies continuously depict local motion- movements of objects and humans, which are crucial for generating emotional responses. Movie scenes also frequently portray global motion, mainly induced by large camera movements, global motion being yet another source of information used by the brain during natural vision. Here we used functional MRI to elucidate the contributions of local and global motion to emotion perception during movie viewing. Subjects observed long (1 min) movie segments depicting emotional or neutral content. Brain activity in areas that showed preferential responses to emotional content was strongly linked over time with frame-wide variations in global motion, and to a lesser extent with local motion information. Similarly, stronger responses to emotional content were recorded within regions of interest whose activity was attuned to global and local motion over time. Since global motion fields are experienced during self-motion, we suggest that camera movements may induce illusory self-motion cues in viewers that interact with the movie’s narrative and with other emotional cues in generating affective responses.

Disturbances in reward processing occur in Parkinson’s disease (PD) however it is unclear whether these are solely drug-related. We applied an event-related fMRI gambling task to a group of non-manifesting carriers (NMC) of the G2019S mutation in the LRRK2 gene, in order to assess the reward network in an “at risk” population for future development of PD. Sixty-eight non-manifesting participants, 32 of which were non-manifesting non-carriers (NMNC), performed a gambling task which included defined intervals of anticipation and response to both reward and punishment in an fMRI setup. Behavior and cerebral activations were measured using both hypothesis driven and whole brain analysis. NMC demonstrated higher trait anxiety scores (p = 0.04) compared to NMNC. Lower activations were detected among NMC during risky anticipation in the left nucleus accumbens (NAcc) (p = 0.05) and during response to punishment in the right insula (p = 0.02), with higher activations among NMC during safe anticipation in the right insula (p = 0.02). Psycho-Physiological Interaction (PPI) analysis from the NAcc and insula revealed differential connectivity patterns. Whole brain analysis demonstrated divergent between-group activations in distributed cortical regions, bilateral caudate, left midbrain, when participants were required to press the response button upon making their next chosen move. Abnormal neural activity in both the reward and motor networks were detected in NMC indicating involvement of the ventral striatum regardless of medication use in “at risk” individuals for future development of PD.

Volitional neural modulation using neurofeedback has been indicated as a potential treatment for chronic conditions that involve peripheral and central neural dysregulation. Here we utilized neurofeedback in patients suffering from Fibromyalgia - a chronic pain syndrome that involves sleep disturbance and emotion dysregulation. These ancillary symptoms, which have an amplification effect on pain, are known to be mediated by heightened limbic activity. In order to reliably probe limbic activity in a scalable manner fit for EEG-neurofeedback training, we utilized an Electrical Finger Print (EFP) model of amygdala-BOLD signal (termed Amyg-EFP), that has been successfully validated in our lab in the context of volitional neuromodulation. We anticipated that Amyg-EFP-neurofeedback training aimed at limbic down modulation should improve chronic pain in patients suffering from Fibromyalgia, by balancing disturbed indices for sleep and affect. We further expected that improved clinical status would correspond to successful training as indicated by improved down modulation of the Amygdala-EFP signal. Thirty-Four Fibromyalgia patients (31F; age 35.6 ± 11.82) participated in a randomized placebo-controlled trial with biweekly Amyg-EFP-neurofeedback sessions and placebo of sham neurofeedback (n = 9) for a total duration of five consecutive weeks. Following training, participants in the Real-neurofeedback group were divided into good (n = 13) or poor (n = 12) modulators according to their success in the neurofeedback training. Before and after treatment, self-reports on pain, depression, anxiety, fatigue and sleep quality were obtained, as well as objective sleep Indices. Long-term clinical follow-up was made available, within up to three years of the neurofeedback training completion. REM latency and objective sleep quality index were robustly improved following the treatment course only in the Real-neurofeedback group (both time × group p < 0.05) and to a greater extent among good modulators (both time*sub-group p < 0.05). In contrast, self-report measures did not reveal a treatment-specific response at the end of the treatment. However, the follow-up assessment revealed a delayed improvement in chronic pain and subjective sleep experience, evident only in the Real-neurofeedback group (both time × group p < 0.05). Moderation analysis showed that the enduring clinical effects on pain evident in the follow-up assessment were predicted by the immediate improvements following training in objective sleep and subjective affect measures. Our findings suggest that Amyg-EFP- neurofeedback that specifically targets limbic activity down modulation offers a successful principled approach for volitional EEG based neuromodulation training in Fibromyalgia patients. Importantly, it seems that via its immediate sleep improving effect, the neurofeedback training induced a delayed reduction in the target subjective symptom of chronic pain, far and beyond the immediate placebo effect. This indirect approach to chronic pain management reflects the necessary link between somatic and affective dysregulation that can be successfully targeted using neurofeedback.

EEG-fMRI allows the localization of the hemodynamic correlates of neural activity and has been shown to be useful as a diagnostic tool in pre-surgical evaluation of refractory epilepsy. However, EEG recordings may be highly contaminated by artifacts induced by movements inside the magnetic field thus rendering the scan difficult for interpretation. Existing methods for motion correction require additional equipment or hardware modification. We introduce a simple method for motion artifact detection, the conductive gel bridge sensor (CGBS), easily applicable using the standard setup. We report examples of CGBS use in two patients with epilepsy and demonstrate the method's ability to successfully differentiate between epochs of brain activity and those of movement.

OBJECTIVES: Implicit regulation of emotions involves medial-prefrontal cortex (mPFC) regions exerting regulatory control over limbic structures. Diminished regulation relates to aberrant mPFC functionality and psychopathology. Establishing means of modulating mPFC functionality could benefit research on emotion and its dysregulation. Here, we tested the capacity of transcranial direct-current stimulation (tDCS) targeting mPFC to modulate subjective emotional states by facilitating implicit emotion regulation. MATERIALS AND METHODS: Stimulation was applied concurrently with functional magnetic resonance imaging to validate the neurobehavioral effect of stimulation. Sixteen participants were each scanned twice, counterbalancing active and sham tDCS application, while undergoing negative mood induction (clips featuring negative vs neutral contents). Effects of stimulation on emotional experience were assessed using subjective and neural measures. RESULTS: Subjectively, active stimulation led to significant reduction in reported intensity of experienced emotions to negatively-valenced (p=0.005) clips but not to neutral clips (p>0.99). Active stimulation further mitigated a rise in stress levels from pre- to post-induction (sham: p=0.004; active: p=0.15). Neurally, stimulation increased activation in mPFC regions associated with implicit emotion regulation (ventromedial-prefrontal cortex; subgenual anterior-cingulate cortex, sgACC), and in ventral striatum, a core limbic structure (ps0.64, ps

The Ultimatum Game (UG) is a canonical social decision-making task whereby a proposer divides a sum of money between himself and a responder who accepts or rejects the offer. Studies consistently demonstrate that unfair offers induce anger, and that rejecting such offers relates to aggression. Nevertheless, the UG is limited in interpersonal provocations common to real-life experiences of anger. Moreover, the psychometric properties of the UG as an anger-induction paradigm have yet to be evaluated. Here, to induce a more intense and genuine anger experience, we implemented a modified UG whereby short written provocations congruent with unfairness levels accompanied each offer. We aimed to test whether this anger-infused UG led to more anger and aggressive responses relative to the standard UG and to establish the reliability and validity of both versions. Participants performed either the anger-infused UG or a standard version, repeated twice, a week apart. They also performed the Taylor Aggression Paradigm, a reactive aggression paradigm, and completed emotion ratings and a trait anger inventory. Results indicate similar decreases in acceptance rates with increase in offer unfairness, and increases in reported anger, across both UG versions. Both versions demonstrated strong test-retest reliability. However, the anger-infused UG led to significantly stronger relations with reactive aggression and trait anger compared to the standard UG, providing evidence for better validity. The development of the anger-infused UG as a reliable and valid paradigm is pivotal for the induction and assessment of interpersonal anger and its aggressive expression in basic and clinical research settings. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Real-time functional magnetic resonance imaging (rt-fMRI) has revived the translational perspective of neurofeedback (NF)1. Particularly for stress management, targeting deeply located limbic areas involved in stress processing2 has paved new paths for brain-guided interventions. However, the high cost and immobility of fMRI constitute a challenging drawback for the scalability (accessibility and cost-effectiveness) of the approach, particularly for clinical purposes3. The current study aimed to overcome the limited applicability of rt-fMRI by using an electroencephalography (EEG) model endowed with improved spatial resolution, derived from simultaneous EEG–fMRI, to target amygdala activity (termed amygdala electrical fingerprint (Amyg-EFP))4–6. Healthy individuals (n = 180) undergoing a stressful military training programme were randomly assigned to six Amyg-EFP-NF sessions or one of two controls (control-EEG-NF or NoNF), taking place at the military training base. The results demonstrated specificity of NF learning to the targeted Amyg-EFP signal, which led to reduced alexithymia and faster emotional Stroop, indicating better stress coping following Amyg-EFP-NF relative to controls. Neural target engagement was demonstrated in a follow-up fMRI-NF, showing greater amygdala blood-oxygen-level-dependent downregulation and amygdala–ventromedial prefrontal cortex functional connectivity following Amyg-EFP-NF relative to NoNF. Together, these results demonstrate limbic specificity and efficacy of Amyg-EFP-NF during a stressful period, pointing to a scalable non-pharmacological yet neuroscience-based training to prevent stress-induced psychopathology. A new study by Keynan and colleagues provides evidence that training in amygdala self-regulation via EEG neurofeedback (‘electrical fingerprint’) results in neurobehavioural markers of stress resilience in a cohort of individuals undergoing military training.

In managing our way through interpersonal conflict, anger might be crucial in determining whether the dispute escalates to aggressive behaviors or resolves cooperatively. The Ultimatum Game (UG) is a social decision-making paradigm that provides a framework for studying interpersonal conflict over division of monetary resources. Unfair monetary UG-offers elicit anger and while accepting them engages regulatory processes, rejecting them is regarded as an aggressive retribution. Ventro-medial prefrontal-cortex (vmPFC) activity has been shown to relate to idiosyncratic tendencies in accepting unfair offers possibly through its role in emotion regulation. Nevertheless, standard UG paradigms lack fundamental aspects of real-life social interactions in which one reacts to other people in a response contingent fashion. To uncover the neural substrates underlying the tendency to accept anger-infused ultimatum offers during dynamic social interactions, we incorporated on-line verbal negotiations with an obnoxious partner in a repeated-UG during fMRI scanning. We hypothesized that vmPFC activity will differentiate between individuals with high or low monetary gains accumulated throughout the game and reflect a divergence in the associated emotional experience. We found that as individuals gained more money, they reported less anger but also more positive feelings and had slower sympathetic response. In addition, high-gain individuals had increased vmPFC activity, but also decreased brainstem activity, which possibly reflected the locus coeruleus. During the more angering unfair offers, these individuals had increased dorsal-posterior Insula (dpI) activity which functionally coupled to the medial-thalamus (mT). Finally, both vmPFC activity and dpI-mT connectivity contributed to increased gain, possibly by modulating the ongoing subjective emotional experience. These ecologically valid findings point towards a neural mechanism that might nurture pro-social interactions by modulating an individual's dynamic emotional experience.

Sleep deprivation has been shown recently to alter emotional processing possibly associated with reduced frontal regulation. Such impairments can ultimately fail adaptive attempts to regulate emotional processing (also known as cognitive control of emotion), although this hypothesis has not been examined directly. Therefore, we explored the influence of sleep deprivation on the human brain using two different cognitive–emotional tasks, recorded using fMRI and EEG. Both tasks involved irrelevant emotional and neutral distractors presented during a competing cognitive challenge, thus creating a continuous demand for regulating emotional processing. Results reveal that, although participants showed enhanced limbic and electrophysiological reactions to emotional distractors regardless of their sleep state, they were specifically unable to ignore neutral distracting information after sleep deprivation. As a consequence, sleep deprivation resulted in similar processing of neutral and negative distractors, thus disabling accurate emotional discrimination. As expected, these findings were further associated with a decrease in prefrontal connectivity patterns in both EEG and fMRI signals, reflecting a profound decline in cognitive control of emotion. Notably, such a decline was associated with lower REM sleep amounts, supporting a role for REM sleep in overnight emotional processing. Altogether, our findings suggest that losing sleep alters emotional reactivity by lowering the threshold for emotional activation, leading to a maladaptive loss of emotional neutrality.SIGNIFICANCE STATEMENTSleep loss is known as a robust modulator of emotional reactivity, leading to increased anxiety and stress elicited by seemingly minor triggers. In this work, we aimed to portray the neural basis of these emotional impairments and their possible association with frontal regulation of emotional processing, also known as cognitive control of emotion. Using specifically suited EEG and fMRI tasks, we were able to show that sleep deprivation alters emotional reactivity by triggering enhanced processing of stimuli regarded previously as neutral. These changes were further accompanied by diminished frontal connectivity, reduced REM sleep, and poorer performance. Therefore, we suggest that sleep loss alters emotional reactivity by lowering the threshold for emotional activation, leading to a maladaptive loss of emotional neutrality.

Motivation: Detecting modules of co-ordinated activity is fundamental in the analysis of large biological studies. For two-dimensional data (e.g. genes × patients), this is often done via clustering or biclustering. More recently, studies monitoring patients over time have added another dimension. Analysis is much more challenging in this case, especially when time measurements are not synchronized. New methods that can analyze three-way data are thus needed. Results: We present a new algorithm for finding coherent and flexible modules in three-way data. Our method can identify both core modules that appear in multiple patients and patient-specific augmentations of these core modules that contain additional genes. Our algorithm is based on a hierarchical Bayesian data model and Gibbs sampling. The algorithm outperforms extant methods on simulated and on real data. The method successfully dissected key components of septic shock response from time series measurements of gene expression. Detected patient-specific module augmentations were informative for disease outcome. In analyzing brain functional magnetic resonance imaging time series of subjects at rest, it detected the pertinent brain regions involved. Availability and implementation: R code and data are available at http://acgt.cs.tau.ac.il/twigs/. Contact: rshamir@tau.ac.il Supplementary information : Supplementary data are available at Bioinformatics online.

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.

Verbal fluency tasks are typically used in neuropsychological practice for assessment of language function in a variety of neurological disorders. Recently, it has been shown that the hippocampus, a region thought to be exclusive to the domain of memory, is also involved in tests of semantic fluency. The present study further explores hippocampal contribution to verbal fluency using functional Magnetic Resonance Imaging (fMRI) and examining mean activity and inter-regional functional connectivity with known task-related brain regions. Given the clear lateralization of brain areas involved in language, lateralization of hippocampal involvement in semantic and phonemic word fluency was also investigated. Different hippocampal recruitment during semantic and phonemic fluency was found: greater change in activity was seen during semantic fluency, as compared with phonemic fluency. This pattern was obtained in the right and the left hippocampus, with no lateralization effects. Functional connectivity analyses corroborate the notion of selective contribution of the hippocampus to semantic fluency. During the semantic fluency task, connectivity levels between the hippocampi and components of the semantic network did not differ from connectivity levels within the semantic network. In contrast, during the phonemic fluency task, the hippocampi were less correlated with components of the phonemic network, as compared to the within phonemic network connectivity. Importantly, hippocampal connectivity with the semantic network was task-dependent and restricted to periods of semantic fluency performance. Altogether, results suggest that the right and the left hippocampus are integral components of the brain network that selectively supports verbal semantic fluency, but not phonemic fluency.

Background The search for a validated neuroimaging-based brain marker in psychiatry has thus far been fraught with both clinical and methodological difficulties. The present study aimed to apply a novel data-driven machine-learning approach to functional Magnetic Resonance Imaging (fMRI) data obtained during a cognitive task in order to delineate the neural mechanisms involved in two schizophrenia subgroups: schizophrenia patients with and without Obsessive–Compulsive Disorder (OCD). Methods 16 schizophrenia patients with OCD (“schizo-obsessive”), 17 pure schizophrenia patients, and 20 healthy controls underwent fMRI while performing a working memory task. A whole brain search for activation clusters of cognitive load was performed using a recently developed data-driven multi-voxel pattern analysis (MVPA) approach, termed Searchlight Based Feature Extraction (SBFE), and which yields a robust fMRI-based classifier. Results The SBFE successfully classified the two schizophrenia groups with 91% accuracy based on activations in the right intraparietal sulcus (r-IPS), which further correlated with reduced symptom severity among schizo-obsessive patients. Conclusions The results indicate that this novel SBFE approach can successfully delineate between symptom dimensions in the context of complex psychiatric morbidity.

Our emotions tend to be directed towards someone or something. Such emotional intentionality calls for the integration between two streams of information; abstract hedonic value and its associated concrete content. In a previous functional magnetic resonance imaging (fMRI) study we found that the combination of these two streams, as modeled by short emotional music excerpts and neutral film clips, was associated with synergistic activation in both temporal-limbic (TL) and ventral-lateral PFC (vLPFC) regions. This additive effect implies the integration of domain-specific 'affective' and 'cognitive' processes. Yet, the low temporal resolution of the fMRI limits the characterization of such cross-domain integration. To this end, we complemented the fMRI data with intracranial electroencephalogram (iEEG) recordings from twelve patients with intractable epilepsy. As expected, the additive fMRI activation in the amygdala and vLPFC was associated with distinct spatio-temporal iEEG patterns among electrodes situated within the vicinity of the fMRI activation foci. On the one hand, TL channels exhibited a transient (0-500 msec) increase in gamma power (61-69 Hz), possibly reflecting initial relevance detection or hedonic value tagging. On the other hand, vLPFC channels showed sustained (1-12 sec) suppression of low frequency power (2.3-24 Hz), possibly mediating changes in gating, enabling an on-going readiness for content-based processing of emotionally tagged signals. Moreover, an additive effect in delta-gamma phase-amplitude coupling (PAC) was found among the TL channels, possibly reflecting the integration between distinct domain specific processes. Together, this study provides a multi-faceted neurophysiological signature for computations that possibly underlie emotional intentionality in humans.

Life requires monitoring and adjusting behavior in the face of conflicts. The conflict monitoring theory implicates the anterior cingulate cortex (ACC) in these processes; its ventral aspect (vACC) specializes in emotional conflict. To elucidate the underpinning neural mechanism, we recorded vACC extracellular activity from 12 patients with mood disorders or epilepsy who performed the face-emotional Stroop task. Behaviorally, both conflict detection and adaptation to conflict were evident. The firing rate of neurons in the vACC represented current conflict, i.e., current-congruency. The late onset of the effect is compatible with a role in monitoring. Additionally, early responses of some neurons represented the immediate history of conflicts, i.e., previous-trial-congruency. Finally, in some neurons the response to the current-trial was modulated by previous-trial-congruency, laying the ground for adjusting-to-conflicts. Our results uncover a single neuron level mechanism in the vACC that encodes and integrates past and present emotional conflicts, allowing humans to accommodate their responses accordingly.

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.

Research on creativity shows that creative thinking entails both executive (controlled) and associative (spontaneous) processes. Yet standard creativity tasks cannot reliably isolate these two types of cognitive processes, making it difficult to understand the relation between the two and the roles of their corresponding brain networks in creative cognition. In this study we used a behavioral and neuroimaging approach in an effort to establish chain free association (FA) tasks as a relevant method for directly investigating spontaneous associative thinking and its role in creative cognition. We further examined the relation between performance on such tasks and intelligence. Participants completed common creativity tasks and then underwent fMRI scanning while producing FA chains. Instructions to participants that emphasized the spontaneous nature of the task, coupled with proper control conditions that were balanced for difficulty, enabled us to uncover spontaneous (as opposed to controlled) processes. To examine whether behavioral measures that can be derived from FA chains (associative fluency, associative flexibility and semantic remoteness between associations) are indicative of unconstrained spontaneous associative processing and are related to different aspects of verbal creativity and intelligence, scores on these measures were correlated with scores on creativity tasks and on an intelligence task, and with brain activity. We found that: (1) the Default Mode Network (DMN), a network involved in self-generated and internally-directed thought, was more involved in chain FA than in other tasks expected to reflect more controlled forms of internally-directed thought, suggesting that the DMN involvement might be related to the unconstrained spontaneous nature of chain FA. Higher involvement of the left IFG, SFG, MFG under chain FA was also revealed; (2) higher scores on different behavioral measures from FA chains were related to higher activation of the DMN and to reduced activation of the left IFG, a major node in the executive function network; (3) behavioral measures from FA chains were correlated with different aspects of creative performance but not with intelligence. Taken together, these findings lend support to the hypothesis that chain FA involves associative spontaneous thinking. They further suggest that behavioral measures derived from chain FA could indicate patterns of unconstrained associative thinking, related to reduced cognitive control, that are relevant for creative ideation, and might be able to serve as a measure of these patterns.

Prior knowledge can either assist or hinder the ability to learn new information. These contradicting behavioral outcomes, referred to as schema benefit and proactive interference respectively, have been studied separately. Here we examined whether the known neural correlates of each process coexist, and how they are influenced by attentional loading and aging. To this end we used an fMRI task that affected both processes simultaneously by presenting pairs of related short movies in succession. The first movie of each pair provided context for the second movie, which could evoke schema benefit and/or proactive interference. Inclusion of an easy or hard secondary task performed during encoding of the movies, as well as testing both younger (22-35y) and older (65-79y) adults, allowed examining the effect of attentional load and older age on the neural patterns associated with context. Analyses focused on three predefined regions and examined how their inter-subject correlation (inter-SC) and functional connectivity (FC) with the hippocampi changed between the first and second movie. The results in the medial prefrontal cortex (mPFC) and posterior cingulate cortex (PCC) matched and expanded previous findings: higher inter-SC and lower FC were observed during the second compared to the first movie; yet the differentiation between the first and second movies in these regions was attenuated under high attentional load, pointing to dependency on attentional resources. Instead, at high load there was a significant context effect in the FC of the left ventrolateral prefrontal cortex (vlPFC), and greater FC in the second movie was related to greater proactive interference. Further, older adults showed context effect in the PCC and vlPFC. Intriguingly, older adults with inter-SC mPFC patterns similar to younger adults exhibited schema benefit in our task, while those with inter-SC PCC patterns similar to younger adults showed proactive interference in an independent task. The brain-behavior relationships corroborate the functional significance of these regions and indicate that the mPFC mainly contributes to schema benefit, while the left vlPFC and PCC contribute to proactive interference. Importantly, our findings show that the functions of the regions are retained throughout the lifespan and may predict the predominant behavioral outcome.

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.