Adverse childhood experiences differently affect Theory of Mind brain networks in schizophrenia and healthy controls.

Patients with schizophrenia (SZ) show impairments in both affective and cognitive dimensions of theory of mind (ToM). SZ are also particularly vulnerable to detrimental effect of adverse childhood experiences (ACE), influencing the overall course of the disorder and fostering poor social functioning. ACE associate with long-lasting detrimental effects on brain structure, function, and connectivity in regions involved in ToM. Here, we investigated whether ToM networks are differentially affected by ACEs in healthy controls (HC) and SZ, and if these effects can predict the disorder clinical outcome. 26 HC and 33 SZ performed a ToM task during an fMRI session. Whole-brain functional response and connectivity (FC) were extracted, investigating the interaction between ACEs and diagnosis. FC values significantly affected by ACEs were entered in a cross-validated LASSO regression predicting Positive and Negative Syndrome Scale (PANSS), Interpersonal Reactivity Index (IRI), and task performance. ACEs and diagnosis showed a widespread interaction at both affective and cognitive tasks, including connectivity between vmPFC, ACC, precentral and postcentral gyri, insula, PCC, precuneus, parahippocampal gyrus, temporal pole, thalamus, and cerebellum, and functional response in the ACC, thalamus, parahippocampal gyrus and putamen. FC predicted the PANSS score, the fantasy dimension of IRI, and the AToM response latency. Our results highlight the crucial role of early stress in differentially shaping ToM related brain networks in HC and SZ. These effects can also partially explain the clinical and behavioral outcomes of the disorder, extending our knowledge of the effects of ACEs.

The Neural Representations of Emotional Experiences Are More Similar Than Those of Neutral Experiences.

Stimuli that evoke the same feelings can nevertheless look different and have different semantic meanings. Although we know much about the neural representation of emotion, the neural underpinnings of emotional similarity are unknown. One possibility is that the same brain regions represent similarity between emotional and neutral stimuli, perhaps with different strengths. Alternatively, emotional similarity could be coded in separate regions, possibly those sensitive to emotional valence and arousal. In behavior, the extent to which people consider similarity along emotional dimensions when they evaluate the overall similarity between stimuli has never been investigated. Although the emotional features of stimuli may dominate explicit ratings of similarity, it is also possible that people neglect emotional dimensions as irrelevant to that judgment. We contrasted these hypotheses in (male and female) healthy controls using two measures of similarity and two picture databases of complex negative and neutral scenes, the second of which provided exquisite control over semantic and visual attributes. The similarity between emotional stimuli was greater than between neutral stimuli in the inferior temporal cortex, the fusiform face area, and the precuneus. Additionally, only the similarity between emotional stimuli was significantly represented in early visual cortex, anterior insula and dorsal anterior cingulate cortex. Intriguingly, despite the stronger neural similarity between emotional stimuli, the same participants did not rate them as more similar to each other than neutral stimuli. These results contribute to our understanding of how emotion is represented within a general conceptual workspace and of the overgeneralization bias in anxiety disorders.SIGNIFICANCE STATEMENT We tested differences in similarity between emotional and neutral scenes. Arousal and negative valence did not increase similarity ratings. When conditions were equated on semantic similarity, participants rated emotional stimuli as similar to each other as neutral ones. Despite this equivalence, the similarity among the neural representations of emotional compared with neutral stimuli was higher in regions, which also expressed similarity between neutral stimuli and in unique regions. We report a striking difference between behavioral and neural similarity; strong neural similarity between emotional pictures did not influence similarity judgements in the same participants in the behavioral rating task after the scan. These findings may have an impact on research about the neural representations of emotional categories and the overgeneralization bias in anxiety disorders.

The Emotional Facet of Subjective and Neural Indices of Similarity.

Emotional similarity refers to the tendency to group stimuli together because they evoke the same feelings in us. The majority of research on similarity perception that has been conducted to date has focused on non-emotional stimuli. Different models have been proposed to explain how we represent semantic concepts, and judge the similarity among them. They are supported from behavioural and neural evidence, often combined by using Multivariate Pattern Analyses. By contrast, less is known about the cognitive and neural mechanisms underlying the judgement of similarity between real-life emotional experiences. This review summarizes the major findings, debates and limitations in the semantic similarity literature. They will serve as background to the emotional facet of similarity that will be the focus of this review. A multi-modal and overarching approach, which relates different levels of neuroscientific explanation (i.e., computational, algorithmic and implementation), would be the key to further unveil what makes emotional experiences similar to each other.

A Glutamate Transporter EAAT1 Gene Variant Influences Amygdala Functional Connectivity in Bipolar Disorder.

Bipolar disorder (BD) is a severe illness characterized by recurrent depressive and manic episodes and by emotional dysregulation. Altered cortico-limbic connectivity could account for typical symptoms of the disorder such as mood instability, emotional dysregulation, and cognitive deficits. Functional connectivity positively associated with glutamatergic neurotransmission. The inactivation of glutamate is handled by a series of glutamate transporters, among them, the excitatory amino acid transporter 1 (EAAT1) which is modulated by a SNP rs2731880 (C/T) where the C allele leads to increased EAAT1 expression and glutamate uptake. We hypothesized that rs2731880 would affect cortico-limbic functional connectivity during an implicit affective processing task. Sixty-eight BD patients underwent fMRI scanning during implicit processing of fearful and angry faces. We explored the effect of rs2731880 on the strength of functional connectivity from the amygdalae to the whole brain. A significant activation in response to emotional processing was observed in two main clusters encompassing the right and left amygdala. Amygdalae to whole-brain functional connectivity analyses revealed a significant interaction between rs2731880 and the task (emotional stimuli vs geometric shapes) for the functional connections between the right amygdala and right subgenual anterior cingulate cortex. Post-hoc analyses revealed that T/T patients showed a significant negative connectivity between the amygdala and anterior cingulate cortex compared to C carriers. T/T subjects also performed significantly better in the face-matching task than rs2731880*C carriers. Our findings reveal an EAAT1 genotype-associated difference in cortico-limbic connectivity during affective regulation, possibly identifying a neurobiological underpinning of emotional dysfunction in BD.

Mild adverse childhood experiences increase neural efficacy during affective theory of mind.

Adverse childhood experiences (ACEs) affect the development of social cognition (and identify a risk factor for several physical and mental disorders). Theory of Mind (ToM) is a key predictor of social functioning, mental health, and quality of life. No previous study explored the effect of mild ACEs on the neural correlates of ToM in healthy humans. In 23 healthy participants, we used brain blood oxygen level-dependent fMRI to study the effect of ACEs on the neural responses to tasks targeting affective and cognitive ToM. Results pointed out an association between ACEs and a lower neural response in the vermis of the cerebellum (r = -.85), precentral gyrus, and inferior frontal operculum (putative Mirror Neural System, r = -.78) during affective ToM. A lower recruitment of these brain regions, paralleled by the same performance, could express an increased neural efficacy in inferring affective mental states driven by previous experience, in this case, ACEs.

A Homer 1 gene variant influences brain structure and function, lithium effects on white matter, and antidepressant response in bipolar disorder: A multimodal genetic imaging study.

BACKGROUND: The Homer family of postsynaptic scaffolding proteins plays a crucial role in glutamate-mediated synaptic plasticity, a phenotype associated with Bipolar Disorder (BD). Homer is a target for antidepressants and mood stabilizers. The AA risk genotype of the Homer rs7713917 A>G SNP has been associated with mood disorders and suicide, and in healthy humans with brain function. Despite the evidence linking Homer 1 gene and function to mood disorder, as well as its involvement in animal models of depression, no study has yet investigated the role of Homer in bipolar depression and treatment response. METHODS: We studied 199 inpatients, affected by a major depressive episode in course of BD. 147 patients were studied with structural MRI of grey and white matter, and 50 with BOLD functional MRI of emotional processing. 158 patients were treated with combined total sleep deprivation and light therapy. RESULTS: At neuroimaging, patients with the AA genotype showed lower grey matter volumes in medial prefrontal cortex, higher BOLD fMRI neural responses to emotional stimuli in anterior cingulate cortex, and lower fractional anisotropy in bilateral frontal WM tracts. Lithium treatment increased axial diffusivity more in AA patients than in G*carriers. At clinical evaluation, the same AA homozygotes showed a worse antidepressant response to combined SD and LT. CONCLUSIONS: rs7713917 influenced brain grey and white matter structure and function in BD, long term effects of lithium on white matter structure, and antidepressant response to chronotherapeutics, thus suggesting that glutamatergic neuroplasticity and Homer 1 function might play a role in BD psychopathology and response to treatment.

Corticolimbic Connectivity Mediates the Relationship between Adverse Childhood Experiences and Symptom Severity in Borderline Personality Disorder.

The interaction between biological and environmental factors (especially adverse childhood experiences, ACEs) plays a crucial role in the development and maintenance of borderline personality disorder (BPD). These factors act influencing BPD core features such as pervasive instability in affect regulation, impulse control, social cognition, and interpersonal relationships. In line with this perspective, abnormalities in social cognition and related neurobiological underpinnings could mediate the relationship between ACEs and psychopathological manifestations in adulthood. In a sample of 14 females, functional connectivity (FC) analyses were performed modeling the interaction between ACEs and corticolimbic dysregulation during emotional processing and its relationship with BPD symptom severity. ACEs were associated with a dampening of the negative FC between (1) the right amygdala (Amy) and right dorsolateral prefrontal cortex (DLPFC) and between (2) the left Amy and bilateral DLPFC, right precuneus, left cerebellum and left dorsomedial prefrontal cortex during emotional processing. The connectivity between right Amy and DLPFC mediates the relationship between childhood adversities and BPD symptomatology. Furthermore, the negative FC between Amy and DLPFC, postcentral gyrus, the vermis of cerebellum and precuneus was also associated with BPD symptom severity, with a weaker negative coupling between Amy and these regions being related to a worse BPD psychopathology. Our results confirm the role of ACEs in contributing to social cognition impairments in BPD and related symptomatology from a neurobiological perspective.