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Background Empathy refers to the cognitive and emotional reactions of an individual to the experiences of another. Women with premenstrual dysphoric disorder (PMDD) report severe social difficulties during the luteal phase of their menstrual cycle. Aims This clinical and functional magnetic resonance imaging study aimed to explore affective and cognitive empathy in women with PMDD, during the highly symptomatic luteal phase. Method Overall, 32 women with PMDD and 20 healthy controls participated in the study. The neuroimaging data were collected using a highly empathy-engaging movie. First, we characterised the synchrony of neural responses within PMDD and healthy groups, using the inter-individual correlation approach. Next, using network cohesion analysis, we compared connectivity within and between brain networks associated with affective and cognitive empathy between groups, and assessed the association of these network patterns with empathic measures. Results A consistent, although complex, picture of empathy abnormalities was found. Patients with PMDD showed decreased neural synchrony in parietal and frontal key nodes of cognitive empathy processing (theory-of-mind network), but higher neural synchrony in the anterior insula and anterior cingulate cortex, a part of the salience network, implicated in affective empathy. Positive correlations between cognitive perspective-taking scores and neural synchrony were found within the theory-of-mind network. Interestingly, during highly emotional moments, the PMDD group showed increased functional connectivity within this network. Conclusions Similar to major depression, individuals with PMDD show enhanced affective empathy and reduced cognitive empathy. These findings echo clinical observations reported when women with PMDD have a dysregulated emotional response to negative stimuli.

ABSTRACTTreatment Rationale: Exposure to repeated sexual trauma, particularly during childhood, often leads to protracted mental health problems. Childhood adversity is specifically associated with complex posttraumatic stress disorder (PTSD) presentation, which is particularly tenacious and treatment refractory, and features severe emotion dysregulation. Augmentation approaches have been suggested to enhance treatment efficacy in PTSD thus integrating first-line psychotherapy with mechanistically informed self-neuromodulation procedures (i.e. neurofeedback) may pave the way to enhanced clinical outcomes. A central neural mechanism of PTSD and emotion dysregulation involves amygdala hyperactivity that can be volitionally regulated by neurofeedback. We outline a treatment rationale that includes a detailed justification for the potential of combining psychotherapy and NF and delineate mechanisms of change. We illustrate key processes of reciprocal interactions between neurofeedback engagement and therapeutic goals.Case Study: We describe a clinical case of a woman with complex PTSD due to early and repetitive childhood sexual abuse using adjunctive neurofeedback as an augmentation to an ongoing, stable, traditional treatment plan. The woman participated in (a) ten sessions of neurofeedback by the use of an fMRI-inspired EEG model of limbic related activity (Amygdala Electrical-Finger-Print; AmygEFP-NF), (b) traditional weekly individual psychotherapy, (c) skills group. Before and after NF training period patient was blindly assessed for PTSD symptoms, followed by a 1, 3- and 6-months self-report follow-up. We demonstrate mechanisms of change as well as the clinical effectiveness of adjunctive treatment as indicated by reduced PTSD symptoms and improved daily functioning within this single case.Conclusions: We outline an integrative neuropsychological framework for understanding the unique mechanisms of change conferring value to conjoining NF applications with trauma-focused psychotherapy in complex PTSD.

Background: Guilt and Shame, two core self-related emotions, often emerge following trauma and play an important role in the development and maintenance of post-traumatic stress disorder (PTSD). Importantly, Guilt and Shame exhibit specific focal and non-specific global impacts of trauma on self-perception, respectively. Objective and Methods: Integrating psychological theories with neuroscientific knowledge, we suggest a scheme of two diverging clinical phenotypes of PTSD, associated with distinct self-related processes and differential functionality of relevant neural networks. Proposal: The Guilt-driven phenotype is characterized by preoccupation with negative self-attributes of one's actions in the traumatic event. It involves altered functionality of both the salience network (SN) and the default-mode network (DMN), associated with heightened interoceptive signalling and ruminative introspection which may lead to hyperarousal and intrusive symptoms, respectively. On the contrary, the Shame-driven phenotype is characterized by global, identity-related negative self-attributions. It involves altered functionality of both the SN and the DMN, associated with blunted interoceptive signalling and diminished introspection which may result in withdrawal and anhedonia symptoms together with dissociative experiences, respectively. Conclusion: The proposed PTSD phenotypes may inform neuropsychological therapeutic interventions (e.g. self-focused psychotherapy and neuromodulation) aiming to restore the function of large-scale self-related neural processing.

Visual areas activated during perception can retain specific information held in memory without the presence of physical stimuli via distributed activity patterns. Neuroimaging studies have shown that the delay-period representation of information in visual areas is modulated by factors such as memory load and task demands, raising the possibility of serial position as another potential modulator. Specifically, enhanced representation of first items during the post-encoding delay period may serve as a mechanism underlying the well-established but not well-understood primacy effect – the mnemonic advantage of first items. To test this hypothesis, 13 males and 16 females performed a human fMRI task, wherein each trial consisted of the sequential encoding of two stimuli (a famous face and landscape, order counterbalanced), followed by a distracting task, a delay period, and then a cued recall of one of the items. Participants exhibited the expected behavioral primacy effect, manifested as faster recall of the first items. In order to elucidate the still debated neural underpinnings of this effect, using multivariate decoding, a classifier was trained on data collected during encoding to differentiate stimulus categories (i.e., faces vs. landscapes) and tested on data collected during the post-encoding period. Greater reactivation of first versus second items was observed in the ventral occipito-temporal cortex during the entire post-encoding period but not during encoding. Moreover, trial-level analyses revealed that the degree of first-item neural advantage during the post-encoding delay predicted the behavioral primacy effect. These findings highlight the role of item reinstatement in ventral occipito-temporal cortex in the primacy effect and are discussed in the context of the uniqueness of the very first item and event boundaries, illuminating putative neural mechanisms underlying the effect.

Reward processing is essential for our mental-health and well-being. In the current study, we developed and validated a scalable, fMRI-informed EEG model for monitoring reward processing related to activation in the ventral-striatum (VS), a significant node in the brain's reward system. To develop this EEG-based model of VS-related activation, we collected simultaneous EEG/fMRI data from 17 healthy individuals while listening to individually-tailored pleasurable music – a highly rewarding stimulus known to engage the VS. Using these cross-modal data, we constructed a generic regression model for predicting the concurrently acquired Blood-Oxygen-Level-Dependent (BOLD) signal from the VS using spectro-temporal features from the EEG signal (termed hereby VS-related-Electrical Finger Print; VS-EFP). The performance of the extracted model was examined using a series of tests that were applied on the original dataset and, importantly, an external validation dataset collected from a different group of 14 healthy individuals who underwent the same EEG/FMRI procedure. Our results showed that the VS-EFP model, as measured by simultaneous EEG, predicted BOLD activation in the VS and additional functionally relevant regions to a greater extent than an EFP model derived from a different anatomical region. The developed VS-EFP was also modulated by musical pleasure and predictive of the VS-BOLD during a monetary reward task, further indicating its functional relevance. These findings provide compelling evidence for the feasibility of using EEG alone to model neural activation related to the VS, paving the way for future use of this scalable neural probing approach in neural monitoring and self-guided neuromodulation.

Functional magnetic resonance imaging data acquired during passive listening to music suggest that pre-motor area 55b acts as a core hub of music processing in humans.

BackgroundStress-related mental disorders are highly prevalent and pose a substantial burden on individuals and society. Improving strategies for the prevention and treatment of mental disorders requires a better understanding of their risk and resilience factors. This multicenter study aims to contribute to this endeavor by investigating psychological resilience in healthy but susceptible young adults over 9 months. Resilience is conceptualized in this study as the maintenance of mental health or quick recovery from mental health perturbations upon exposure to stressors, assessed longitudinally via frequent monitoring of stressors and mental health. ObjectiveThis study aims to investigate the factors predicting mental resilience and adaptive processes and mechanisms contributing to mental resilience and to provide a methodological and evidence-based framework for later intervention studies. MethodsIn a multicenter setting, across 5 research sites, a sample with a total target size of 250 young male and female adults was assessed longitudinally over 9 months. Participants were included if they reported at least 3 past stressful life events and an elevated level of (internalizing) mental health problems but were not presently affected by any mental disorder other than mild depression. At baseline, sociodemographic, psychological, neuropsychological, structural, and functional brain imaging; salivary cortisol and α-amylase levels; and cardiovascular data were acquired. In a 6-month longitudinal phase 1, stressor exposure, mental health problems, and perceived positive appraisal were monitored biweekly in a web-based environment, while ecological momentary assessments and ecological physiological assessments took place once per month for 1 week, using mobile phones and wristbands. In a subsequent 3-month longitudinal phase 2, web-based monitoring was reduced to once a month, and psychological resilience and risk factors were assessed again at the end of the 9-month period. In addition, samples for genetic, epigenetic, and microbiome analyses were collected at baseline and at months 3 and 6. As an approximation of resilience, an individual stressor reactivity score will be calculated. Using regularized regression methods, network modeling, ordinary differential equations, landmarking methods, and neural net–based methods for imputation and dimension reduction, we will identify the predictors and mechanisms of stressor reactivity and thus be able to identify resilience factors and mechanisms that facilitate adaptation to stressors. ResultsParticipant inclusion began in October 2020, and data acquisition was completed in June 2022. A total of 249 participants were assessed at baseline, 209 finished longitudinal phase 1, and 153 finished longitudinal phase 2. ConclusionsThe Dynamic Modelling of Resilience–Observational Study provides a methodological framework and data set to identify predictors and mechanisms of mental resilience, which are intended to serve as an empirical foundation for future intervention studies. International Registered Report Identifier (IRRID)DERR1-10.2196/39817

Summary: Linking scalp electroencephalography (EEG) signals and spontaneous firing activity from deep nuclei in humans is not trivial. To examine this, we analyzed simultaneous recordings of scalp EEG and unit activity in deeply located sites recorded overnight from patients undergoing pre-surgical invasive monitoring. We focused on modeling the within-subject average unit activity of two medial temporal lobe areas: amygdala and hippocampus. Linear regression model correlates the units’ average firing activity to spectral features extracted from the EEG during wakefulness or non-REM sleep. We show that changes in mean firing activity in both areas and states can be estimated from EEG (Pearson r > 0.2, p≪0.001). Region specificity was shown with respect to other areas. Both short- and long-term fluctuations in firing rates contributed to the model accuracy. This demonstrates that scalp EEG frequency modulations can predict changes in neuronal firing rates, opening a new horizon for non-invasive neurological and psychiatric interventions.

IntroductionEpisodes of eating great quantities of extremely sweet and often aversive tasting food are a hallmark of bulimia nervosa. This unique eating pattern led researchers to seek and find differences in taste perception between patients and healthy control subjects. However, it is currently not known if these originate from central or peripheral impairment in the taste perception system. In this cross sectional study, we compare brain response to sweet and sour stimuli in 5 bulimic and 8 healthy women using functional magnetic resonance imaging (fMRI).Materials and methodsSweet, sour and neutral (colorless and odorless) taste solutions were presented to subjects while undergoing fMRI scanning. Data were analyzed using a block design paradigm.ResultsBetween-group differences in brain activation in response to both sweet and sour tastes were found in 11 brain regions, including operculum, anterior cingulate cortex, midbrain, and cerebellum. These are all considered central to perception and processing of taste.ConclusionOur data propose that sweet and sour tastes may have reward or aversion eliciting attributes in patients suffering from bulimia nervosa not found in healthy subjects, suggesting that alteration in taste processing may be a core dysfunction in bulimia nervosa (BN).

The right inferior frontal gyrus (rIFG) is a region involved in the neural underpinning of cognitive control across several domains such as inhibitory control and attentional allocation process. Therefore, it constitutes a desirable neural target for brain-guided interventions such as neurofeedback (NF). To date, rIFG-NF has shown beneficial ability to rehabilitate or enhance cognitive functions using functional Magnetic Resonance Imaging (fMRI-NF). However, the utilization of fMRI-NF for clinical purposes is severely limited, due to its poor scalability. The present study aimed to overcome the limited applicability of fMRI-NF by developing and validating an EEG model of fMRI-defined rIFG activity (hereby termed ''Electrical FingerPrint of rIFG''; rIFG-EFP). To validate the computational model, we employed two experiments in healthy individuals. The first study (n = 14) aimed to test the target engagement of the model by employing rIFG-EFP-NF training while simultaneously acquiring fMRI. The second study (n = 41) aimed to test the functional outcome of two sessions of rIFG-EFP-NF using a risk preference task (known to depict cognitive control processes), employed before and after the training. Results from the first study demonstrated neural target engagement as expected, showing associated rIFG-BOLD signal changing during simultaneous rIFG-EFP-NF training. Target anatomical specificity was verified by showing a more precise prediction of the rIFG-BOLD by the rIFG-EFP model compared to other EFP models. Results of the second study suggested that successful learning to up-regulate the rIFG-EFP signal through NF can reduce one's tendency for risk taking, indicating improved cognitive control after two sessions of rIFG-EFP-NF. Overall, our results confirm the validity of a scalable NF method for targeting rIFG activity by using an EEG probe.

Music is a complex phenomenon that elicits a range of emotional responses, influenced by numerous variables, such as rhythm, melody and harmony. One interesting aspect of music is listeners’ ability to predict its continuation as it unfolds – an inherent attribute hypothesized to contribute to our emotional response to music. In this study, we investigated this link by examining the relationship between temporal predictability – the ability to predict the timing of the next event – and the ongoing changes in music-induced pleasantness. Temporal predictability was operationalized as the degree to which taps of 20 musically trained participants, who tapped to the beat along three naturalistic and highly contrastive musical pieces, were aligned. We then examined the degree to which this measure could explain the ongoing emotional experience, as reflected in continuous measures of arousal and valence, in a separate group of 40 participants that listened to these pieces. Our findings reveal a positive correlation between fluctuations in reported valence and temporal predictability, even when controlling for a set of other musical features, in four out of five musical sections. The only exception being a lyrical slow section. These findings were further supported by a large online database of annotated musical emotions (n = 1780 songs), where a consistent and robust correlation between valence ratings and an automatically extracted feature of pulse clarity was demonstrated. Overall, our findings shed light on the significance of temporal predictability as a contributing factor to the hedonic experience of music, especially within the tempo range of salient beat perception.

The functional neural mechanisms underlying the cognitive benefits of aerobic exercise have been a subject of ongoing research in recent years. However, while most neuroimaging studies to date which examined functional neural correlates of aerobic exercise have used simple stimuli in highly controlled and artificial experimental conditions, our everyday life experiences require a much more complex and dynamic neurocognitive processing. Therefore, we have used a naturalistic complex information processing fMRI paradigm of story comprehension to investigate the role of an aerobically active lifestyle in the processing of real-life cognitive-demanding situations. By employing the inter-subject correlation (inter-SC) approach, we have identified differences in reliable stimulus-induced neural responses between groups of aerobically active (n = 27) and non-active (n = 22) cognitively intact older adults (age 65–80). Since cardiorespiratory fitness has previously been suggested to play a key role in the neuroprotective potential of aerobic exercise, we have investigated its dose-response relationship with regional inter-subject neural responses. We found that aerobically active lifestyle and cardiorespiratory fitness were associated with more synchronized inter-subject neural responses during story comprehension in higher order cognitive and linguistic brain regions in the prefrontal and temporo-parietal cortices. In addition, while higher regional inter-SC values were associated with higher performance on a post-listening memory task, this was not translated to a significant between-group difference in task performance. We, therefore, suggest that the modulatory potential of aerobic exercise and cardiorespiratory fitness on cognitive processing may extend beyond simple and highly controlled stimuli to situations in which the brain faces continuous real-life complex information. Additional studies incorporating other aspects of real-life situations such as naturalistic visual stimuli, everyday life decision making, and motor responses in these situations are desired to further validate the observed relationship between aerobic exercise, cardiorespiratory fitness, and complex naturalistic information processing.

BackgroundChronic pain disorders are often associated with cognitive-emotional dysregulation. However, the relations between such dysregulation, underlying brain processes, and clinical symptom constellations, remain unclear. Here, we aimed to characterize the abnormalities in cognitive-emotional processing involved in fibromyalgia syndrome (FMS) and their relation to disease severity.MethodsFifty-eight participants, 39 FMS patients (35F), and 19 healthy control subjects (16F) performed an EEG-based paradigm assessing attention allocation by extracting steady-state visually evoked potentials (ssVEP) in response to affective distractors presented during a cognitive task. Patients were also evaluated for pain severity, sleep quality, depression, and anxiety.ResultsEEG ssVEP measurement indicated that, compared to healthy controls, FMS patients displayed impaired affective discrimination, and sustained attention to negative distractors. Moreover, patients displayed decreased task-related fronto-occipital EEG connectivity. Lack of adaptive attentional discrimination, measured via EEG, was predictive of pain severity, while impairments in fronto-occipital connectivity were predictive of impaired sleep.ConclusionsFMS patients display maladaptive affective attention modulation, which predicts disease symptoms. These findings support the centrality of cognitive-emotional dysregulation in the pathophysiology of chronic pain.

Abstract The SARS-CoV-2 pandemic is not only a threat to physical health but is also having severe impacts on mental health. Although increases in stress-related symptomatology and other adverse psycho-social outcomes, as well as their most important risk factors have been described, hardly anything is known about potential protective factors. Resilience refers to the maintenance of mental health despite adversity. To gain mechanistic insights about the relationship between described psycho-social resilience factors and resilience specifically in the current crisis, we assessed resilience factors, exposure to Corona crisis-specific and general stressors, as well as internalizing symptoms in a cross-sectional online survey conducted in 24 languages during the most intense phase of the lockdown in Europe (22 March to 19 April) in a convenience sample of N = 15,970 adults. Resilience, as an outcome, was conceptualized as good mental health despite stressor exposure and measured as the inverse residual between actual and predicted symptom total score. Preregistered hypotheses (osf.io/r6btn) were tested with multiple regression models and mediation analyses. Results confirmed our primary hypothesis that positive appraisal style (PAS) is positively associated with resilience (p

“Do what you do best” conveys an intuition about the association between ability and preference. In the field of emotion regulation, ability and preference are manifested in two central stages, namely, implementation and selection of regulatory strategies, which to date have been mainly studied separately. Accordingly, the present proof-of-concept study wished to provide preliminary evidence for an association between neural indices of implementation ability and behavioral selection preferences. In this pilot study, participants performed a classic neuroimaging regulatory implementation task that examined their ability (neurally reflected in the degree of amygdala modulation) to execute two central regulatory strategies, namely, attentional distraction and cognitive reappraisal while viewing negative images. Then participants performed a separate, classic behavioral selection task that examined their choice preferences for using distraction and reappraisal while viewing negative images. Confirming our conceptual framework, we found that exclusively for distraction, which has been associated with robust amygdala modulation, a decrease in amygdala activity during implementation (i.e., enhanced ability) was associated with enhanced preference to behaviorally select distraction [r(15) = −0.69, p = 0.004]. These preliminary findings link between two central emotion regulatory stages, suggesting a clue of the adaptive association between neural ability and behavioral preference for particular regulatory strategies.

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.

The personality trait of neuroticism is considered a risk factor for stress vulnerability, putatively via its association with elevated limbic reactivity. Nevertheless, majority of evidence to date that relates neuroticism, neural reactivity and stress vulnerability stems from cross-sectional studies conducted in a “stress-free” environment. Here, using a unique prospective longitudinal design, we assessed personality, stress-related symptoms and neural reactivity at three time points over the course of four and a half years; accounting for prior to, during, and long-time following a stressful military service that included active combat. Results revealed that despite exposure to multiple potentiality traumatic events, majority of soldiers exhibited none-to-mild levels of posttraumatic and depressive symptoms during and following their military service. In contrast, a quadratic pattern of change in personality emerged overtime, with neuroticism being the only personality trait to increase during stressful military service and subsequently decrease following discharge. Elevated neuroticism during military service was associated with reduced amygdala and hippocampus activation in response to stress-related content, and this association was also reversed following discharge. A similar pattern was found between neuroticism and hippocampus-anterior cingulate cortex (ACC) functional connectivity in response to stress-related content. Taken together these findings suggest that stressful military service at young adulthood may yield a temporary increase in neuroticism mediated by a temporary decrease in limbic reactivity, with both effects being reversed long-time following discharge. Considering that participants exhibited low levels of stress-related symptoms throughout the study period, these dynamic patterns may depict behavioral and neural mechanisms that facilitate stress resilience.

Alterations in hippocampal function have been shown in older adults, which are expressed as changes in hippocampal activity and connectivity. While hippocampal activation during memory demands has been demonstrated to decrease with age, some older individuals present increased activity, or hyperactivity, of the hippocampus which is associated with increased neuropathology and poor memory function. In addition, lower functional coherence between the hippocampus and core hubs of the default mode network (DMN), namely, the posteromedial and medial prefrontal cortices, as well as increased local intrahippocampal connectivity, were also demonstrated in cognitively intact older adults. Aerobic exercise has been shown to elicit neuroprotective effects on hippocampal structure and vasculature in aging, and improvements in cardiorespiratory fitness have been suggested to mediate these exercise-related effects. However, how these lifestyle factors relate to hippocampal function is not clear. Fifty-two cognitively intact older adults (aged 65–80 years) have been recruited and divided into physically active (n = 29) or non-active (n = 23) groups based on their aerobic activity lifestyle habits. Participants underwent resting-state and task-based fMRI experiments which included an associative memory encoding paradigm followed by a post-scan memory recognition test. In addition, 44 participants also performed cardiopulmonary exercise tests to evaluate cardiorespiratory fitness by measuring peak oxygen consumption (Vo2peak). While both groups demonstrated increased anterior hippocampal activation during memory encoding, a physically active lifestyle was associated with significantly lower activity level and higher memory performance in the recognition task. In addition, the physically active group also demonstrated higher functional connectivity of the anterior and posterior hippocampi with the core hubs of the DMN and lower local intra-hippocampal connectivity within and between hemispheres. Vo2peak was negatively associated with the hippocampal activation level and demonstrated a positive correlation with hippocampal-DMN connectivity. According to these findings, an aerobically active lifestyle may be associated with attenuation of hippocampal dysfunction in cognitively intact older adults.

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.

Real-time fMRI neurofeedback is an increasingly popular neuroimaging technique that allows an individual to gain control over his/her own brain signals, which can lead to improvements in behavior in healthy participants as well as to improvements of clinical symptoms in patient populations. However, a considerably large ratio of participants undergoing neurofeedback training do not learn to control their own brain signals and, consequently, do not benefit from neurofeedback interventions, which limits clinical efficacy of neurofeedback interventions. As neurofeedback success varies between studies and participants, it is important to identify factors that might influence neurofeedback success. Here, for the first time, we employed a big data machine learning approach to investigate the influence of 20 different design-specific (e.g. activity vs. connectivity feedback), region of interest-specific (e.g. cortical vs. subcortical) and subject-specific factors (e.g. age) on neurofeedback performance and improvement in 608 participants from 28 independent experiments.With a classification accuracy of 60% (considerably different from chance level), we identified two factors that significantly influenced neurofeedback performance: Both the inclusion of a pre-training no-feedback run before neurofeedback training and neurofeedback training of patients as compared to healthy participants were associated with better neurofeedback performance. The positive effect of pre-training no-feedback runs on neurofeedback performance might be due to the familiarization of participants with the neurofeedback setup and the mental imagery task before neurofeedback training runs. Better performance of patients as compared to healthy participants might be driven by higher motivation of patients, higher ranges for the regulation of dysfunctional brain signals, or a more extensive piloting of clinical experimental paradigms. Due to the large heterogeneity of our dataset, these findings likely generalize across neurofeedback studies, thus providing guidance for designing more efficient neurofeedback studies specifically for improving clinical neurofeedback-based interventions. To facilitate the development of data-driven recommendations for specific design details and subpopulations the field would benefit from stronger engagement in open science research practices and data sharing.

Polymicrogyria (PMG) is a common malformation of cortical development associated with a higher susceptibility to epileptic seizures. Seizures secondary to PMG are characterized by difficult-to-localize cerebral sources due to the complex and widespread lesion structure. Tracing the dynamics of interictal epileptiform discharges (IEDs) in patients with epilepsy has been shown to reveal the location of epileptic activity sources, crucial for successful treatment in cases of focal drug-resistant epilepsy. In this case series IED dynamics were evaluated with simultaneous EEG-fMRI recordings in four patients with unilateral peri-sylvian polymicrogyria (PSPMG) by tracking BOLD activations over time: before, during and following IED appearance on scalp EEG. In all cases, focal BOLD activations within the lesion itself preceded the activity associated with the time of IED appearance on EEG, which showed stronger and more widespread activations. We therefore propose that early hemodynamic activity corresponding to IEDs may hold important localizing information potentially leading to the cerebral sources of epileptic activity. IEDs are suggested to develop within a small area in the PSPMG lesion with structural properties obscuring the appearance of their electric field on the scalp and only later engage widespread structures which allow the production of large currents which are recognized as IEDs on EEG.

Background: Amygdala activity dysregulation plays a central role in post-traumatic stress disorder (PTSD). Hence learning to self-regulate one's amygdala activity may facilitate recovery. PTSD is further characterized by abnormal contextual processing related to the traumatic memory. Therefore, provoking the personal traumatic narrative while training amygdala down-regulation could enhance clinical efficacy. We report the results of a randomized controlled trial (NCT02544971) of a novel self-neuromodulation procedure (i.e. NeuroFeedback) for PTSD, aimed at down-regulating limbic activity while receiving feedback from an auditory script of a personal traumatic narrative. To scale-up applicability, neural activity was probed by an fMRI-informed EEG model of amygdala activity, termed Amygdala Electrical Finger-Print (AmygEFP). Methods: Fifty-nine adults meeting DSM-5 criteria for PTSD were randomized between three groups: Trauma-script feedback interface (Trauma-NF) or Neutral feedback interface (Neutral-NF), and a control group of No-NF (to control for spontaneous recovery). Before and immediately after 15 NF training sessions patients were blindly assessed for PTSD symptoms and underwent one session of amygdala fMRI-NF for transferability testing. Follow-up clinical assessment was performed at 3- and 6-months following NF treatment. Results: Patients in both NF groups learned to volitionally down-regulate AmygEFP signal and demonstrated a greater reduction in PTSD symptoms and improved down-regulation of the amygdala during fMRI-NF, compared to the No-NF group. The Trauma-NF group presented the largest immediate clinical improvement. Conclusions: This proof-of-concept study indicates the feasibility of the AmygEFP-NF process-driven as a scalable intervention for PTSD and illustrates its clinical potential. Further investigation is warranted to elucidate the contribution of AmygEFP-NF beyond exposure and placebo effects.

Neuropharmacotherapy is substantially hindered by poor drug targeting, resulting in low specificity and efficacy. It is known that different behavioral tasks increase functional activity and cerebral blood flow (CBF), two key parameters controlling drug delivery and efficacy. Here, we tested a novel, non-invasive drug targeting approach (termed functional-pharmacological coupling), which couples drug administration with a task that is known to specifically activate the drug’s sites-of-action in the brain. In two studies we administered Methylphenidate (MPH) to neurotypical adults and to subjects with attention deficit hyperactivity disorder (ADHD). In study 1 we employed a within-subject factorial design and found that only following MPH administration, subjects that performed better in the cognitive induction task showed greater improvements in N-back performance. Moreover, only under MPH-Cognitive induction condition, this improvement correlated with concurrent N-Back rDLPFC activation. In Study 2, subjects with ADHD performed better on sustained attention when MPH administration was followed by a cognitive challenge rather than a control task. Again, those who were more attentive to the cognitive challenge scored higher. Our results provide preliminary support for the feasibility of functional-pharmacological coupling concept, hence opening a new horizon for patient-tailored, context-driven drug therapy.

BackgroundRuminative responding involves repetitive and passive thinking about one’s negative affect. This tendency interferes with initiation of goal-directed rewarding strategies, which could alleviate depressive states. Such reward-directed response selection has been shown to be mediated by ventral striatum/nucleus accumbens (VS/NAcc) function. However, to date, no study has examined whether trait rumination relates to VS/NAcc functionality. Here, we tested whether rumination moderates VS/NAcc function both in response to reward and during a ruminative state.MethodsTrait rumination was considered dimensionally using Rumination Response Scale (RRS) scores. Our sample (N = 80) consisted of individuals from a community sample and from patients diagnosed with major depressive disorder, providing a broad range of RRS scores. Participants underwent fMRI to assess two modes of VS/NAcc functionality: 1) in response to reward, and 2) during resting-state, as a proxy for ruminative state. We then tested for associations between RRS scores and VS/NAcc functional profiles, statistically controlling for overall depressive symptom severity.ResultsRRS scores correlated positively with VS/NAcc response to reward. Furthermore, we noted that higher RRS scores were associated with increased ruminative-dependent resting-state functional connectivity of the VS/NAcc with the left orbitofrontal cortex.ConclusionsThese findings suggest that ruminative tendencies manifest in VS/NAcc reward- and rumination-related functions, providing support for a theoretical-clinical perspective of rumination as a habitual impairment in selection of rewarding, adaptive coping strategies.

Background: Post-traumatic stress disorder (PTSD) is triggered by distinct events and is therefore amenable to studies of its early pathogenesis. Longitudinal studies during the year that follows trauma exposure revealed typical symptom trajectories leading to either recovery or protracted PTSD. Thezneurobehavioral correlates of early PTSD symptoms’ trajectories have not been longitudinally explored. Objective: To present the rationale and design of a longitudinal study exploring the relationship between evolving PTSD symptoms and co-occurring cognitive functioning and structural and functional brain imaging parameters. Method: Adult civilians consecutively admitted to a general hospital emergency room (ER) for traumatic injury will be screened for early PTSD symptoms suggestive of chronic PTSD risk, and consecutively evaluated 1, 6 and 14 months following the traumatic event. Consecutive assessments will include structured clinical interviews for PTSD and comorbid disorders, self-reported depression and anxiety symptoms, a web-based assessment of cognitive domains previously linked with PTSD (e.g., memory, executive functions, cognitive flexibility), high-resolution structural MRI of both grey and white matter, functional resting-state connectivity, and fMRI tasks examining emotional reactivity and regulation, as well as motivation processing and sensitivity to risk and reward. Data analyses will explore putative cognitive predictors of non-remitting PTSD, and brain structural and functional correlates of PTSD persistence or recovery. Conclusion: This work will longitudinally document patterns of brain structures, connectivity, and functioning, predictive of (or associated with) emerging PTSD during the critical first year of after the traumatic event. It will thereby inform our understanding of the disorder’s pathogenesis and underlying neuropathology. Challenges to longitudinal MRI studies of recent survivors, and methodological choices used to optimize the study’s design are discussed.

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. Keywords: Information processing, Schizophrenia, Siblings, Narrated story, fMRI

Objective: A pilot study to preliminarily examine the effects of Prism EFP NeuroFeedback (NF) in adult ADHD. Method: Prism EFP NF is a form of NF specifically designed to target emotional dysregulation (ED) through down regulation of amygdala activity. Prism EFP NF has been shown to improve other disorders with significant ED. Nine participants with adult ADHD received an open trial of Prism EFP NF consisting of fifteen sessions over 8 weeks; all completed at least 5 weeks of treatment with seven completing all 8 weeks. Outcomes were assessed by change in ADHD symptoms from baseline to End of Treatment. Results: About two-third reduction was seen in total DSM ADHD symptom scores (primary outcome measure) with improvement observed in all other clinical measures. No significant adverse events were seen. Conclusion: This preliminary trial found substantial effects of Prism EFP NF on ADHD/ED symptoms and global impairment.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Introduction: Post-Traumatic Stress Disorder (PTSD) is a prevalent, severe and tenacious psychopathological consequence of traumatic events. Neurobehavioral mechanisms underlying PTSD pathogenesis have been identified, and may serve as risk-resilience factors during the early aftermath of trauma exposure. Longitudinally documenting the neurobehavioral dimensions of early responses to trauma may help characterize survivors at risk and inform mechanism-based interventions. We present two independent longitudinal studies that repeatedly probed clinical symptoms and neurocognitive domains in recent trauma survivors. We hypothesized that better neurocognitive functioning shortly after trauma will be associated with less severe PTSD symptoms a year later, and that an early neurocognitive intervention will improve cognitive functioning and reduce PTSD symptoms.Methods: Participants in both studies were adult survivors of traumatic events admitted to two general hospitals’ emergency departments (EDs) in Israel. The studies used identical clinical and neurocognitive tools, which included assessment of PTSD symptoms and diagnosis, and a battery of neurocognitive tests. The first study evaluated 181 trauma-exposed individuals one-, six-, and 14 months following trauma exposure. The second study evaluated 97 trauma survivors 1 month after trauma exposure, randomly allocated to 30 days of web-based neurocognitive intervention (n = 50) or control tasks (n = 47), and re-evaluated all subjects three- and 6 months after trauma exposure.Results: In the first study, individuals with better cognitive flexibility at 1 month post-trauma showed significantly less severe PTSD symptoms after 13 months (p = 0.002). In the second study, the neurocognitive training group showed more improvement in cognitive flexibility post-intervention (p = 0.019), and lower PTSD symptoms 6 months post-trauma (p = 0.017), compared with controls. Intervention- induced improvement in cognitive flexibility positively correlated with clinical improvement (p = 0.002).Discussion: Cognitive flexibility, shortly after trauma exposure, emerged as a significant predictor of PTSD symptom severity. It was also ameliorated by a neurocognitive intervention and associated with a better treatment outcome. These findings support further research into the implementation of mechanism-driven neurocognitive preventive interventions for PTSD.

Emotion regulation is hypothesized to be mediated by the interactions between emotional reactivity and regulation networks during the dynamic unfolding of the emotional episode. Yet, it remains unclear how to delineate the effective relationships between these networks. In this study, we examined the aforementioned networks’ information flow hierarchy during viewing of an anger provoking movie excerpt. Anger regulation is particularly essential for averting individuals from aggression and violence, thus improving prosocial behavior. Using subjective ratings of anger intensity we differentiated between low and high anger periods of the film. We then applied the Dependency Network Analysis (DEPNA), a newly developed graph theory method to quantify networks’ node importance during the two anger periods. The DEPNA analysis revealed that the impact of the ventromedial prefrontal cortex (vmPFC) was higher in the high anger condition, particularly within the regulation network and on the connections between the reactivity and regulation networks. We further showed that higher levels of vmPFC impact on the regulation network were associated with lower subjective anger intensity during the high-anger cinematic period, and lower trait anger levels. Supporting and replicating previous findings, these results emphasize the previously acknowledged central role of vmPFC in modulating negative affect. We further show that the impact of the vmPFC relies on its correlational influence on the connectivity between reactivity and regulation networks. More importantly, the hierarchy network analysis revealed a link between connectivity patterns of the vmPFC and individual differences in anger reactivity and trait, suggesting its potential therapeutic role.

Uncontrolled anger may lead to aggression and is common in various clinical conditions, including post traumatic stress disorder. Emotion regulation strategies may vary with some more adaptive and efficient than others in reducing angry feelings. However, such feelings tend to linger after anger provocation, extending the challenge of coping with anger beyond provocation. Task-independent resting-state (rs) fMRI may be a particularly useful paradigm to reveal neural processes of spontaneous recovery from a preceding negative emotional experience. We aimed to trace the carryover effects of anger on endogenous neural dynamics by applying a data-driven examination of changes in functional connectivity (FC) during rs-fMRI between before and after an interpersonal anger induction (N = 44 men). Anger was induced based on unfair monetary offers in a previously validated decision-making task. We calculated a common measure of global FC (gFC) which captures the level of FC between each region and all other regions in the brain, and examined which brain regions manifested changes in this measure following anger. We next examined the changes in all functional connections of each individuated brain region with all other brain regions to reveal which connections underlie the differences found in the gFC analysis of the previous step. We subsequently examined the relation of the identified neural modulations in the aftermath of anger with state- and trait- like measures associated with anger, including brain structure, and in a subsample of designated infantry soldiers (N = 21), with levels of traumatic stress symptoms (TSS) measured 1 year later following combat-training. The analysis pipeline revealed an increase in right amygdala gFC in the aftermath of anger and specifically with the right inferior frontal gyrus (IFG).We found that the increase in FC between the right amygdala and right IFG following anger was positively associated with smaller right IFG volume, higher trait-anger level and among soldiers with more TSS. Moreover, higher levels of right amygdala gFC at baseline predicted less reported anger during the subsequent anger provocation. The results suggest that increased amygdala-IFG connectivity following anger is associated with maladaptive recovery, and relates to long-term development of stress symptomatology in a subsample of soldiers.

Identification of early changes in Dopamine-Transporter (DaT) SPECT imaging expected in the prodromal phase of Parkinson's disease (PD), are usually overlooked. Carriers of the G2019S LRRK2 mutation are known to be at high risk for developing PD, compared to non-carriers. In this work we aimed to study early changes in Dopamine uptake in non-manifesting PD carriers (NMC) of the G2019S LRRK2 mutation using quantitative DaT-SPECT analysis and to examine the potential for early prediction of PD. Eighty Ashkenazi-Jewish subjects were included in this study: eighteen patients with PD; thirty-one NMC and thirty-one non-manifesting non-carriers (NMNC). All subjects underwent a through clinical assessment including evaluation of motor, olfactory, affective and non-motor symptoms and DaT-SPECT imaging. A population based DaT-SPECT template was created based on the NMNC cohort, and data driven volumes-of-interest (VOIs) were defined. Comparisons between groups were performed based on VOIs and voxel-wise analysis. The striatum area of all three cohorts was segmented into four VOIs, corresponding to the right/left dorsal and ventral striatum. Significant differences in clinical measures were found between patients with PD and non-manifesting subjects with no differences between NMC and NMNC. Significantly lower uptake (p

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.

When encoding a real-life, continuous stimulus, the same neural circuits support processing and integration of prior as well as new incoming information. This ongoing interplay is modulated by attention, which is evident in the prefrontal cortex sections of the task positive network (TPN), and in the posterior cingulate cortex (PCC), a hub of the default mode network (DMN). Yet the exact nature of such modulation is still unclear. To investigate this issue, we utilized an fMRI task that employed movies as the encoded stimuli and manipulated attentional load via an easy or hard secondary task that was performed simultaneously with encoding. Results showed increased intersubject correlation (inter-SC) levels when encoding movies in a condition of high, as compared to low attentional load. This was evident in bilateral ventrolateral and dorsomedial prefrontal cortices and the dorsal PCC (dPCC). These regions became more attuned to the combination of the movie and the secondary task as the attentional demand of the task increased. Activation analyses revealed that at higher load the frontal TPN regions were more activated, whereas the dPCC was more deactivated. Attentional load also influenced connectivity within and between the networks. At high load the dPCC was anti-correlated to the frontal regions, which were more functionally coherent amongst themselves. Finally and critically, greater inter-SC in the dPCC at high load during encoding predicted lower memory strength when that information was retrieved. This association between inter-SC levels and memory strength suggest that as attentional demands increased, the dPCC was more attuned to the secondary task at the expense of the encoded stimulus, thus weakening memory for the encoded stimulus. Together, our findings show that attentional load modulated the function of core TPN and DMN regions. Furthermore, the observed correlation between memory strength and the modulation of the dPCC points to this region as a key area involved in the manipulation of attentional load on memory function.

In the past decade neurofeedback has become the focus of a growing body of research. With real-time fMRI enabling on-line monitoring of emotion related areas such as the amygdala, many have begun testing its therapeutic benefits. However most existing neurofeedback procedures still use monotonic uni-modal interfaces, thus possibly limiting user engagement and weakening learning efficiency. The current study tested a novel multi-sensory neurofeedback animated scenario aimed at enhancing user experience and improving learning. We examined whether relative to a simple uni-modal 2D interface, learning via an interface of complex multi-modal 3D scenario will result in improved neurofeedback learning. As a neural-probe, we used the recently developed fMRI-inspired EEG model of amygdala activity (amygdala-EEG finger print; amygdala-EFP), enabling low-cost and mobile limbic neurofeedback training. Amygdala-EFP was reflected in the animated scenario by the unrest level of a hospital waiting-room in which virtual characters become impatient, approach the admission-desk and complain loudly. Successful down-regulation was reflected as an ease in the room unrest-level. We tested whether relative to a standard uni-modal 2D graphic thermometer interface, this animated scenario could facilitate more effective learning and improve the training experience. Thirty participants underwent two separated neurofeedback sessions (one-week apart) practicing down-regulation of the amygdala-EFP signal. In the first session, half trained via the animated scenario and half via a thermometer interface. Learning efficiency was tested by three parameters: (a) effect-size of the change in amygdala-EFP following training, (b) sustainability of the learned down-regulation in the absence of online feedback, and (c) transferability to an unfamiliar context. Comparing amygdala-EFP signal amplitude between the last and the first neurofeedback trials revealed that the animated scenario produced a higher effect size. In addition, neurofeedback via the animated scenario showed better sustainability, as indicated by a no-feedback trial conducted in session 2 and better transferability to a new unfamiliar interface. Lastly, participants reported that the animated scenario was more engaging and more motivating than the thermometer. Together, these results demonstrate the promising potential of integrating realistic virtual environments in neurofeedback to enhance learning and improve user's experience.

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

As the use of large-scale data-driven analysis becomes increasingly common, the need for robust methods for interpreting a large number of results increases. To date, neuroimaging attempts to interpret large-scale activity or connectivity results often turn to existing neural mapping based on previous literature. In case of a large number of results, manual selection or percent of overlap with existing maps is frequently used to facilitate interpretation, often without a clear statistical justification. Such methodology holds the risk of reporting false positive results and overlooking additional results. Here, we propose using enrichment analysis for improving the interpretation of large-scale neuroimaging results. We focus on two possible cases: position group analysis, where the identified results are a set of neural positions; and connection group analysis, where the identified results are a set of neural position-pairs (i.e. neural connections). We explore different models for detecting significant overrepresentation of known functional brain annotations using simulated and real data. We implemented our methods in a tool called RichMind, which provides both statistical significance reports and brain visualization. We demonstrate the abilities of RichMind by revisiting two previous fMRI studies. In both studies RichMind automatically highlighted most of the findings that were reported in the original studies as well as several additional findings that were overlooked. Hence, RichMind is a valuable new tool for rigorous inference from neuroimaging results.

Stress research has progressively become more integrative in nature, seeking to unfold crucial relations between the different phenotypic levels of stress manifestations. This study sought to unravel stress-induced variations in expression of human microRNAs sampled in peripheral blood mononuclear cells and further assess their relationship with neuronal and psychological indices. We obtained blood samples from 49 healthy male participants before and three hours after performing a social stress task, while undergoing functional magnetic resonance imaging (fMRI). A seed-based functional connectivity (FC) analysis was conducted for the ventro-medial prefrontal cortex (vmPFC), a key area of stress regulation. Out of hundreds of microRNAs, a specific increase was identified in microRNA-29c (miR-29c) expression, corresponding with both the experience of sustained stress via self-reports, and alterations in vmPFC functional connectivity. Explicitly, miR-29c expression levels corresponded with both increased connectivity of the vmPFC with the anterior insula (aIns), and decreased connectivity of the vmPFC with the left dorso-lateral prefrontal cortex (dlPFC). Our findings further revealed that miR-29c mediates an indirect path linking enhanced vmPFC-aIns connectivity during stress with subsequent experiences of sustained stress. The correlative patterns of miR-29c expression and vmPFC FC, along with the mediating effects on subjective stress sustainment and the presumed localization of miR-29c in astrocytes, together point to an intriguing assumption; miR-29c may serve as a biomarker in the blood for stress-induced functional neural alterations reflecting regulatory processes. Such a multi-level model may hold the key for future personalized intervention in stress psychopathology.

BACKGROUND: The Vegetative State (VS) is a severe disorder of consciousness in which patients are awake but display no signs of awareness. Yet, recent functional magnetic resonance imaging (fMRI) studies have demonstrated evidence for covert awareness in VS patients by recording specific brain activations during a cognitive task. However, the possible existence of incommunicable subjective emotional experiences in VS patients remains largely unexplored. This study aimed to probe the question of whether VS patients retain a brain ability to selectively process external stimuli according to their emotional value and look for evidence of covert emotional awareness in patients. METHODS AND FINDINGS: In order to explore these questions we employed the emotive impact of observing personally familiar faces, known to provoke specific perceptual as well as emotional brain activations. Four VS patients and thirteen healthy controls first underwent an fMRI scan while viewing pictures of non-familiar faces, personally familiar faces and pictures of themselves. In a subsequent imagery task participants were asked to actively imagine one of their parent's faces. Analyses focused on face and familiarity selective regional brain activations and inter-regional functional connectivity. Similar to controls, all patients displayed face selective brain responses with further limbic and cortical activations elicited by familiar faces. In patients as well as controls, Connectivity was observed between emotional, visual and face specific areas, suggesting aware emotional perception. This connectivity was strongest in the two patients who later recovered. Notably, these two patients also displayed selective amygdala activation during familiar face imagery, with one further exhibiting face selective activations, indistinguishable from healthy controls. CONCLUSIONS: Taken together, these results show that selective emotional processing can be elicited in VS patients both by external emotionally salient stimuli and by internal cognitive processes, suggesting the ability for covert emotional awareness of self and the environment in VS patients.

The perceived emotional value of stimuli and, as a consequence the subjective emotional experience with them, can be affected by context-dependent styles of processing. Therefore, the investigation of the neural correlates of emotional experience requires accounting for such a variable, a matter of an experimental challenge. Closing the eyes affects the style of attending to auditory stimuli by modifying the perceptual relationship with the environment without changing the stimulus itself. In the current study, we used fMRI to characterize the neural mediators of such modification on the experience of emotionality in music. We assumed that closed eyes position will reveal interplay between different levels of neural processing of emotions. More specifically, we focused on the amygdala as a central node of the limbic system and on its co-activation with the Locus Ceruleus (LC) and Ventral Prefrontal Cortex (VPFC); regions involved in processing of, respectively, 'low', visceral-, and 'high', cognitive-related, values of emotional stimuli. Fifteen healthy subjects listened to negative and neutral music excerpts with eyes closed or open. As expected, behavioral results showed that closing the eyes while listening to emotional music resulted in enhanced rating of emotionality, specifically of negative music. In correspondence, fMRI results showed greater activation in the amygdala when subjects listened to the emotional music with eyes closed relative to eyes open. More so, by using voxel-based correlation and a dynamic causal model analyses we demonstrated that increased amygdala activation to negative music with eyes closed led to increased activations in the LC and VPFC. This finding supports a system-based model of perceived emotionality in which the amygdala has a central role in mediating the effect of context-based processing style by recruiting neural operations involved in both visceral (i.e. 'low') and cognitive (i.e. 'high') related processes of emotions.

Brain activity is continuously modulated, even at "rest". The alpha rhythm (8-12 Hz) has been known as the hallmark of the brain's idle-state. However, it is still debated if the alpha rhythm reflects synchronization in a distributed network or focal generator and whether it occurs spontaneously or is driven by a stimulus. This EEG/fMRI study aimed to explore the source of alpha modulations and their distribution in the resting brain. By serendipity, while computing the individually defined power modulations of the alpha-band, two simultaneously occurring components of these modulations were found. An 'induced alpha' that was correlated with the paradigm (eyes open/ eyes closed), and a 'spontaneous alpha' that was on-going and unrelated to the paradigm. These alpha components when used as regressors for BOLD activation revealed two segregated activation maps: the 'induced map' included left lateral temporal cortical regions and the hippocampus; the 'spontaneous map' included prefrontal cortical regions and the thalamus. Our combined fMRI/EEG approach allowed to computationally untangle two parallel patterns of alpha modulations and underpin their anatomical basis in the human brain. These findings suggest that the human alpha rhythm represents at least two simultaneously occurring processes which characterize the 'resting brain'; one is related to expected change in sensory information, while the other is endogenous and independent of stimulus change.