Limbic self-neuromodulation as a novel treatment option for emotional dysregulation in premenstrual dysphoric disorder (PMDD); a proof-of-concept study.

AIM: To assess the efficacy of a novel neurofeedback (NF) method, targeting limbic activity, to treat emotional dysregulation related to premenstrual dysphoric disorder (PMDD). METHODS: We applied a NF probe targeting limbic activity using a functional magnetic resonance imaging-inspired electroencephalogram model (termed Amyg-EFP-NF) in a double-blind randomized controlled trial. A frontal alpha asymmetry probe (AAS-NF), served as active control. Twenty-seven participants diagnosed with PMDD (mean age = 33.57 years, SD = 5.67) were randomly assigned to Amyg-EFP-NF or AAS-NF interventions with a 2:1 ratio, respectively. The treatment protocol consisted of 11 NF sessions through three menstrual cycles, and a follow-up assessment 3 months thereafter. The primary outcome measure was improvement in the Revised Observer Version of the Premenstrual Tension Syndrome Rating Scale (PMTS-OR). RESULTS: A significant group by time effect was observed for the core symptom subscale of the PMTS-OR, with significant improvement observed at follow-up for the Amyg-EFP group compared with the AAS group [F(1, 15)=4.968, P = 0.042]. This finding was specifically robust for reduction in anger [F(1, 15) = 22.254, P < 0.001]. A significant correlation was found between learning scores and overall improvement in core symptoms (r = 0.514, P = 0.042) suggesting an association between mechanism of change and clinical improvement. CONCLUSION: Our preliminary findings suggest that Amyg-EFP-NF may serve as an affordable and accessible non-invasive treatment option for emotional dysregulation in women suffering from PMDD. Our main limitations were the relatively small number of participants and the lack of a sham-NF placebo arm.

Somatic engagement alters subsequent neurobehavioral correlates of affective mentalizing.

Socio-emotional encounters involve a resonance of others' affective states, known as affect sharing (AS); and attribution of mental states to others, known as theory-of-mind (ToM). Empathy necessitates the integration of both processes, yet their interaction during emotional episodes and subsequent generation of inferences on others' affective states has rarely been tested. To address this, we developed a novel experimental design, wherein we manipulated AS by presenting nonverbal emotionally negative movies twice-each time accompanied by one of two soundtracks that accentuated either somatic cues or externally generated sounds. Movies were followed by questions addressing affective-ToM (emotional inferences), cognitive-ToM (inferences on beliefs and knowledge), and non-ToM aspects. Results revealed a neural differentiation between AS, affective-ToM, and cognitive-ToM. AS movies activated regions that have been implicated in emotional (e.g., amygdala) and somatosensory processing, and synchronized brain activity between participants in the latter. Affective-ToM activated the middle insula, limbic regions, and both ventral and dorsal portions of the medial prefrontal cortex (ventral medial prefrontal cortex [VMPFC] and dorsal medial prefrontal cortex [DMPFC], respectively), whereas cognitive-ToM activated posteromedial and lateral-prefrontal and temporal cortices. Critically, AS movies specifically altered neural activation in AS and ToM-related regions during subsequent affective-ToM inferences, most notably in the DMPFC. Moreover, DMPFC-VMPFC connectivity correlated with affective-ToM accuracy, when such questions followed AS movies. Our results associate empathic processes with designated neural activations and shed light on how neuro-behavioral indices of affective ToM are shaped by preceding somatic engagement.

Repeated oral ketamine for out-patient treatment of resistant depression: randomised, double-blind, placebo-controlled, proof-of-concept study.

BACKGROUND: Ketamine has been demonstrated to improve depressive symptoms.AimsEvaluation of efficacy, safety and feasibility of repeated oral ketamine for out-patients with treatment-resistant depression (TRD). METHOD: In a randomised, double-blind, placebo-controlled, proof-of-concept trial, 41 participants received either 1 mg/kg oral ketamine or placebo thrice weekly for 21 days (ClinicalTrials.gov Identifier: NCT02037503). Evaluation was performed at baseline, 40 and 240 min post administration and on days 3, 7, 14 and 21. The main outcome measure was change in Montgomery-Åsberg Depression Rating Scale (MADRS). RESULTS: Twenty-two participants were randomised to the ketamine group, and 19 to the control, with 82.5% (n = 33) completing the study. In the ketamine group, a decrease in depressive symptoms was evident at all time points, whereas in the control group a decrease was evident only 40 min post administration. The reduction in MADRS score on day 21 was 12.75 in the ketamine group versus 2.49 points with placebo (P < 0.001). Six participants in the ketamine group (27.3%) achieved remission compared with none of the controls (P < 0.05). The number needed to treat for remission was 3.7. Side-effects were mild and transient. CONCLUSIONS: Repeated oral ketamine produced rapid and persistent amelioration of depressive symptoms in out-patients with TRD, and was well tolerated. These results suggest that add-on oral ketamine may hold significant promise in the care of patients suffering from TRD in the community.Declaration of interestNone.

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

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

Global functional connectivity deficits in schizophrenia depend on behavioral state.

Schizophrenia is a devastating psychiatric illness characterized by deterioration of cognitive and emotional processing. It has been hypothesized that aberrant cortical connectivity is implicated in the disease (Friston, 1998), yet previous studies of functional connectivity (FC) in schizophrenia have shown mixed results (Garrity et al., 2007; Jafri et al., 2008; Lynall et al., 2010). We measured FC using fMRI in human schizophrenia patients and healthy controls during two different tasks and a rest condition, and constructed a voxel-based global FC index. We found a striking FC decrease in patients compared with controls. In the task conditions, relatively weaker FC was specific to regions of cortex not active during the task. In the rest condition, the FC difference between patients and controls was larger and allowed a case-by-case separation between individuals of the two groups. The results suggest that the relative reduction of FC in schizophrenia is dependent on the state of cortical activity, with voxels not activated by the task showing higher levels of FC deficiency. This novel finding may shed light on previous reports of FC in schizophrenia. Whether this neural characteristic is related to the development of the disorder remains to be established.

Obsessive musical hallucinations in a schizophrenia patient: psychopathological and FMRI characteristics.

Obsessive-compulsive symptoms (OCS) are relatively common and clinically significant phenomena in schizophrenia patients, suggesting the existence of a separate schizo-obsessive subgroup of the disorder. Although a majority of schizo-obsessive patients have typical ego-dystonic OCS, a meaningful proportion exhibits diagnostically challenging psychopathological phenomena, psychotic in content and obsessive in form. We report the clinical and functional magnetic resonance imaging characteristics of a schizophrenia patient who developed auditory hallucinations with musical content and obsessive in form. We suggest that "obsessive musical hallucinations", that integrate both psychotic and obsessive-compulsive disorder (OCD)-related features, may be mediated by the brain networks believed to be involved in OCD and in auditory musical hallucinations.

A functional magnetic resonance imaging investigation of prefrontal cortex deep transcranial magnetic stimulation efficacy in adults with attention deficit/hyperactive disorder: A double blind, randomized clinical trial.

ADHD is one of the most prevalent neurocognitive disorders. Deep Transcranial Magnetic Stimulation (dTMS) is a non-invasive neuromodulation tool that holds promise in treatment of neurocognitive disorders. Hypoactivity of the prefrontal cortex (PFC) has been observed in ADHD. This study examined the clinical, cognitive, and neural effects of dTMS to the PFC in adults with ADHD by using functional magnetic resonance imaging (fMRI). High frequency repetitive dTMS was applied to either the right or left PFC in 62 adults with ADHD in a randomized, double blind, placebo controlled protocol with 3 study groups: 2 treatment arms (rPFC, or lPFC) and a Sham arm. The study included 15 dTMS/cognitive training treatment sessions. Clinical effects were assessed with the Conners Adult ADHD Rating Scale (CAARS) self-report and the Clinical Global Impression score (CGI) as primary outcome measures. Self-report/observer questionnaires and computerized cognitive testing were also performed to assess clinical and cognitive effects. Neural effects were assessed with fMRI using working-memory (WM) and resting-state paradigms. While the study did not show improvement in the primary endpoints, significant improvements were observed in the CAARS (self-report) inattention/memory sub-scale, as well as increased activations in the rDLPFC, right parietal-cortex and right insula/IFG during WM conditions after treatment in the right stimulation group. Increased rDLPFC activation was associated with larger symptom improvement in the right stimulation group. This study indicates that dTMS is effective in modulating attention related brain networks, and is a feasible technique that may improve attention symptoms in adults with ADHD.

Diminished neural sensitivity to irregular facial expression in first-episode schizophrenia.

INTRODUCTION: Blunted, inappropriate affective-social behavior is a hallmark of early schizophrenia, possibly corresponding to reduced ability to recognize and express emotions. It is yet unknown if this affective deficiency relates to disturbed neural sensitivity to facial expressions or to overall face processing. In a previous imaging study, healthy subjects showed less suppression of the fusiform gyrus (FG) to repeated presentation of the same transfigured-bizarre face relative to regular face. We assumed that the FG in schizophrenia will show reduced repetition related sensitivity to transfigured-bizarre faces, while having overall normal response to faces. METHODS: Ten first-episode patients with schizophrenia and 10 controls rated the bizarreness of upright and inverted faces. In an fMRI study, another group of 17 first-episode patients with schizophrenia and 12 controls viewed regular and transfigured-bizarre faces in blocks. Each block contained regular- or transfigured-bizarre faces of either different or same individual, presented in an upright or inverted orientation. RESULTS: Patients in comparison with controls rated irregular faces as less bizarre. The FG, in patients and controls exhibited similar response to inverted faces, suggesting normal face processing. In contrast, the FG only in patients, showed similar suppression to repeated transfigured-bizarre and regular faces. Finally, the FG in patients compared with controls showed reduced functional connectivity with the amygdala and prefrontal cortex. CONCLUSION: Patients with schizophrenia already at first-episode, showed reduced behavioral and neural sensitivity to bizarre facial expressions. Possibly, this deficiency is related to disturbed modulations of emotion-related face processing in the FG by the amygdala and prefrontal cortex.

Reduced language lateralization in first-episode schizophrenia: an fMRI index of functional asymmetry.

Patients with schizophrenia exhibit a decrease or loss of normal anatomical brain asymmetry that also extends to functional levels. We applied functional magnetic resonance imaging (fMRI) to investigate language lateralization in patients with schizophrenia during their first episode of illness, thus excluding effects of chronic illness and treatment. Brain regions activated during language tasks of verb generation and passive music listening were explored in 12 first-episode patients with schizophrenia and 17 healthy controls. Regions of interest corresponded to Broca's area in the inferior frontal gyrus (IFG) and Wernicke's area in the superior temporal sulcus (STS). Patients with schizophrenia had significantly smaller lateralization indices in language-related regions than controls. A similar effect was observed in their IFG and STS regions. There was no difference between the groups in the auditory cortex for the music task. Patients with schizophrenia demonstrated greater activation than the controls in temporal regions: the difference was larger in patients with more severe positive symptom subscores. In conclusion, patients with schizophrenia demonstrated loss of normal functional brain asymmetry, as reflected in diminished lateralization of language-related activation in frontal and temporal regions. This phenomenon was already present during their first episode of psychosis, possibly reflecting developmental brain abnormalities of the illness.

Social affective context reveals altered network dynamics in schizophrenia patients.

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.

Abnormal neural hierarchy in processing of verbal information in patients with 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.

Differential stimuli and task effects in the amygdala and sensory areas.

Whether the amygdala responds in a stimulus- or a task-specific way, and how it corresponds to such effects in sensory cortices is dubious. Eighteen volunteers participated in a functional magnetic resonance imaging study in which they were asked to identify either emotion or gender in visually presented scenes, faces, and sentences. Amygdala and the lateral occipital complex showed similar stimulus effect with greater activation to scenes than to faces and sentences, whereas the superior temporal complex responded preferentially to sentences. No task effect was observed in the amygdala, whereas lateral occipital complex and superior temporal complex showed left lateralized selectivity to the emotional task. These results suggest that the amygdala is more sensitive to stimulus than explicit task parameters when processing emotion.

Does co-morbid obsessive-compulsive disorder modify the abnormal language processing in schizophrenia patients? An FMRI study.

BACKGROUND: Impaired language processing is one of the most replicated findings in functional brain studies of schizophrenia (SCH). This is demonstrated by reduced activations in left prefrontal language areas (i.e., BA44/45, the inferior frontal gyrus, IFG) presented as decreased language lateralization. This finding was documented both in chronic as well as in first-episode SCH patients, arguing for a neurobiological marker for SCH. In a previous study, we demonstrated the specificity of this finding to SCH patients when compared to obsessive-compulsive disorder (OCD) patients in whom language processing was similar to healthy controls. Since a sizable proportion of SCH patients also meet DSM-IV criteria for OCD, we further sought to elucidate whether OCD attenuates abnormal prefrontal language lateralization in this unique group of schizo-obsessive patients compared to their non-OCD-SCH counterparts. METHODS: We used functional magnetic resonance imaging (fMRI) to investigate regional activation and language lateralization in the left and right IFG and inter-hemispheric functional connectivity (FC) during a language task of auditory verb generation in 14 SCH patients with OCD, compared to 17 SCH patients without OCD, 13 OCD patients and 14 healthy controls. RESULTS: No between-group differences were found in the behavioral measurements of word generation. However, while OCD patients were indistinguishable from healthy volunteers, a similarly reduced lateralization in the IFG and diminished inter-hemispheric FC was noted in the two SCH groups with and without OCD. CONCLUSION: The co-occurrence of OCD in SCH does not attenuate abnormal processing of language as reflected by regional IFG activity and FC. These results further support the notion that these language processing abnormalities are characteristic of SCH and that SCH-OCD combined psychopathology is more akin to SCH than to OCD.

Machine learning fMRI classifier delineates subgroups of schizophrenia patients.

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.

Diminished language lateralization in schizophrenia corresponds to impaired inter-hemispheric functional connectivity.

INTRODUCTION: A consistent brain imaging finding in schizophrenia is decreased language-asymmetry, already evident in first episode patients, thus arguing for a biomarker of the disorder. Nonetheless, its specificity to schizophrenia is questionable. Furthermore, while previous studies suggested that enhanced right hemisphere activation underlies this diminished asymmetry, the mechanism for this anomaly is yet unknown. This study aimed to examine the role of inter-hemispheric relations in such abnormality through functional connectivity analysis driven by left inferior frontal gyrus (IFG) activation. To test for disorder specificity we compared schizophrenia patients not only to healthy controls but also to patients with obsessive compulsive disorder (OCD). METHODS: Functional magnetic resonance imaging (fMRI) was applied during an auditory verb generation task in the 3 groups. Language-related activation in BA44/45 located in the IFG was used for regional estimation of brain asymmetry and for assessment of inter-hemispheric functional connectivity. RESULTS: Schizophrenia, but not OCD patients showed reduced language asymmetry in the IFG relative to healthy controls and diminished functional connectivity between the left and right IFG. Importantly, decreased inter-hemispheric functional connectivity in the IFG was related to more negative symptoms among the schizophrenia patients. CONCLUSIONS: Diminished language-related asymmetry in the IFG seems to be an early disorder specific neural marker of schizophrenia, supporting its pathogenic role. The relation of this regional abnormality to reduced inter-hemispheric functional connectivity and symptom severity supports the role of large-scale brain disorganization in schizophrenia. This may relate to the known structural abnormalities of the corpus callosum leading to functional hemispheric dysconnection.

Functional and structural neural indices of risk aversion in obsessive-compulsive disorder (OCD).

Obsessive-compulsive disorder (OCD) patients suffer from risk aversion, which may be mediated by their exaggerated response to threat and diminished response to reward. In this study, 13 OCD patients and 13 healthy matched controls underwent functional magnetic resonance imaging (fMRI) while playing an interactive risky choice game encompassing distinct intervals of threat and reward; as well as anatomical diffusion tensor imaging (DTI). Compared to healthy controls OCD patients were reluctant to make risky choices during the game. Furthermore, they displayed higher amygdala activation to threat; lower nucleus accumbens (Nacc) activation to reward and reduced functional connectivity of the amygdala and Nacc to two frontal regions, the orbito-frontal cortex (OFC) and the dorsal anterior cingulate cortex (dACC), respectively. OCD patients also displayed reduced structural integrity in clusters within the uncinate and cingulum fiber tracts. Finally, these deficits in limbic-frontal connectivity pathways, both at the functional and structural level, were associated with severity of OCD symptoms, as well as with each other. Our results thus suggest that risk aversion in OCD is mediated by abnormal limbic responses to threatening and rewarding stimuli, as well as by deficient functional and structural limbic-frontal connectivity. Such deficiency characterization may aid in identifying neural predictors for treatment response and localizing individual targets for direct neural intervention treatments.

Never resting region--mPFC in schizophrenia.

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

Neurofunctional view of psychiatry: clinical brain imaging revisited.

PURPOSE OF REVIEW: Despite an exponential increase in the use of brain imaging in neuroscience, it has as yet hardly been integrated into clinical psychiatry. Our aim is to examine the potentials and perspectives of functional brain imaging in the diagnosis and treatment of mental disorders. RECENT FINDINGS: This review focuses on functional MRI in probing neural activation and on diffusion tensor imaging in delineating functionally related fibre-track organization. As a case study, it examines the state-of-the-art in applying these methods in schizophrenia by referring to several hurdles in the common clinical practice of psychiatry. First, we evaluate the ability of functional brain imaging to target various neuropathological mechanisms such as neurodegeneration, disrupted development and dysconnection. Then we discuss the use of brain-imaging genomics in identifying disease-specific genetic-based neuroendophenotypes. Lastly, we describe the current effort in using brain imaging to designate the most effective and least adverse treatment for patients with schizophrenia. SUMMARY: By examining the use of advanced MRI techniques in schizophrenia, we show both the remarkable variety of functional inferences, as well as their possible implications in clinical psychiatry. We advocate the need for extending the view on neuropathology from region-based to network-based, for integrating neurogenomic features as biological markers for illness definition and for relying on neural parameters to guide effective individual treatment.