Socio-cognitive and Biological Responses to Maltreatment

Correlation between a history of emotional childhood maltreatment score (as assessed by a combined score of the Maltreatment and Abuse Chronology of Exposure [MACE-X] emotional subscales: parental verbal abuse, parental nonverbal emotional abuse, emotional neglect, peer verbal abuse) and emotion recognition (number of correctly identified emotions) as assessed by the Reading the Mind in the Eyes Test adult version (RMET). RMET use expressions from images of 28 adult faces, 50% male and 50% female. The task consist of two types of trials: emotion recognition and sex judgment. In the emotion recognition trials, participants select among four adjectives the one that best describes what the person in the image is thinking or feeling. This task is sensitive to subtle emotion processing deficits since it involves the recognition of a relatively wide range of complex mental states.

Correlation between a history of emotional childhood maltreatment score (Maltreatment and Abuse Chronology of Exposure scale; MACE-X) and emotion recognition (number of correctly identified emotions) as assessed the Reading the Mind in the Eyes Test child version (RME-C-T). RME-C-T uses high-quality pictures of 28 child faces. The task consist of two types of trials: emotion recognition and sex judgment. In the emotion recognition trials, participants select among four adjectives the one that best describes what the person in the image is thinking or feeling.

Correlation between a history of emotional childhood maltreatment score (Maltreatment and Abuse Chronology of Exposure scale; MACE-X) and cognitive empathy (number of correctly identified) as assessed by The Multifaceted Empathy Test (MET-core 2). MET-core 2 is an ecologically valid measure that allows separate assessment of cognitive and affective empathy. It consists of 40 photographs depicting people in emotionally charged situations and is designed to elicit strong emotional reactions. To assess cognitive empathy ("What is the person feeling?"), the mental states of the people in the photographs are selected from four mental state descriptors. To assess affective empathy ("How much are you feeling for the person?"), the level of empathic concern for the depicted individuals is rated on a 4-point Likert scale (from "not at all" to "very strong") for the same series of pictures.

Correlation between a history of emotional childhood maltreatment score (Maltreatment and Abuse Chronology of Exposure scale; MACE-X) and affective empathy (rating) as assessed by The Multifaceted Empathy Test (MET-core 2). MET-core 2 is an ecologically valid measure that allows separate assessment of cognitive and affective empathy. It consists of 40 photographs depicting people in emotionally charged situations and is designed to elicit strong emotional reactions. To assess cognitive empathy ("What is the person feeling?"), the mental states of the people in the photographs are selected from four mental state descriptors. To assess affective empathy ("How much are you feeling for the person?"), the level of empathic concern for the depicted individuals is rated on a 4-point Likert scale for the same series of pictures.

Correlation between a history of emotional childhood maltreatment score (Maltreatment and Abuse Chronology of Exposure scale; MACE-X) and brain morphometry (T1-weighted MRI). The research hypothesis is that increasing severity of a history of emotional childhood maltreatment will correlate with small limbic volumes (e.g. hippocampi, amygdala, thalamus). These changes in morphometry will be more pronounced in bipolar disorder compared to control participants.

Correlation between a history of emotional childhood maltreatment score (Maltreatment and Abuse Chronology of Exposure scale; MACE-X) and brain responses (task-based functional MRI). In control participant, the hypothesis is that increasing severity of a history of emotional childhood maltreatment will correlate with: i) low brain responses during RMET/RME-C-T (along with correct and rapid identification of negative emotions) in social cognitive brain regions (e.g. temporoparietal junction, medial prefrontal cortex, amygdala, insula); ii) high brain responses during MET-Core 2 (along with high cognitive and affective empathy abilities). In bipolard disorder, increasing severity of a history of emotional childhood maltreatment will correlate with: i) high brain responses during RMET/RME-C-T in social cognitive regions (along with incorrect and slow identification of negative emotions) ii) low brain responses during MET-Core 2 (along with low cognitive and affective empathy abilities).

Correlation between a history of emotional childhood maltreatment score (Maltreatment and Abuse Chronology of Exposure scale; MACE-X) and brain functional connectivity (resting-state functional MRI). The hypothesis is that increasing severity of a history of emotional childhood maltreatment will correlate low functional connectivity within the Theory-of-Mind (ToM) network. These changes in functional connectivity will be more pronounced in bipolar disorder compared to control participants. Both cognitive and affective ToM tasks involve the posterior temporoparietal junction, the posterior superior temporal sulcus, and the posterior cingulate cortex. While cognitive ToM involves the dorsolateral prefrontal cortex (PFC), dorsal striatum, dorsal anterior cingulate cortex (ACC), and dorsomedial PFC, affective ToM involves the inferior frontal gyrus, insula, ventral striatum, amygdala, temporal poles, ACC, and medial PFC.

Correlation between a history of emotional childhood maltreatment score (Maltreatment and Abuse Chronology of Exposure scale; MACE-X) and brain white matter values (diffusion MRI). The hypothesis is that increasing severity of a history of emotional childhood maltreatment will correlate with disruption (e.g. low fractional anisotropy values) in white matter tracts connecting social cognitive regions (e.g. superior longitudinal fasciculus, cingulum, uncinate fasciculus, corpus callosum). These changes in white matter will be more pronounced in bipolar disorder compared to control participants.

Correlation between a history of emotional childhood maltreatment score (Maltreatment and Abuse Chronology of Exposure scale; MACE-X) and inflammation (measured from blood samples). The hypothesis is that increasing severity of a history of emotional childhood maltreatment is correlated with higher inflammation levels (e.g. CRP, IL-1β, IL-6, TNF-α). High levels of inflammation will be more pronounced in bipolar disorder compared to control participants.

Correlation between a history of emotional childhood maltreatment score (Maltreatment and Abuse Chronology of Exposure scale; MACE-X) and telomere length (measured from blood samples). The hypothesis is that increasing severity of a history of emotional childhood maltreatment is correlated with telomere shortening. Telomere shortening will be more pronounced in bipolar disorder compared to control participants.

Correlation between a history of emotional childhood maltreatment score (Maltreatment and Abuse Chronology of Exposure scale; MACE-X) and mitochondrial bioenergetics and biogenesis (measured from blood samples). The hypothesis is that in control participants increasing severity of a history of emotional childhood maltreatment is correlated with high mitochondria function (e.g. high mitochondrial respiratory activity and density as a compensatory effect of chronic stress) whereas in bipolar disorder it will correlate with impairments in mitochondria function.

Correlation between a history of emotional childhood maltreatment score (Maltreatment and Abuse Chronology of Exposure scale; MACE-X) and gaze pattern (as studied with eye-tracking) within the eye region during the RMET. The hypothesis is that increasing severity of a history of emotional childhood maltreatment will correlate with reduced attention to the eye region. These changes will be more pronounced in bipolar disorder compared to control participants.

Change in the baseline and follow-up (3 to 6 months) assessments of self-reported childhood maltreatment (Maltreatment and Abuse Chronology of Exposure scale; MACE-X) data are used to study the illness effects in bipolar disorder and stability of assessments in control participants.

Change in the baseline and follow-up (3 to 6 months) assessment of emotion recognition (number of correctly identified emotions) as assessed the Reading the Mind in the Eyes Test child version (RME-C-T) is used to study the illness effects in bipolar disorder and stability of assessments in control participants.

Change in the baseline and follow-up (3 to 6 months) assessment of emotion recognition (number of correctly identified emotions) as assessed by the Reading the Mind in the Eyes Test adult version (RMET) is used to study the illness effects in bipolar disorder and stability of assessments in control participants.

Change in the baseline and follow-up (3 to 6 months) assessment of cognitive empathy (number of correctly identified) as assessed by The Multifaceted Empathy Test (MET-core 2) is used to study the illness effects in bipolar disorder and stability of assessments in control participants.

Change in the baseline and follow-up (3 to 6 months) assessment of affective empathy (rating) as assessed by The Multifaceted Empathy Test (MET-core 2) is used to study the illness effects in bipolar disorder and stability of assessments in control participants.

Change in the baseline and follow-up (3 to 6 months) assessments of brain responses during task-based fMRI (RME-C-T, RMET, MET-core-2) are used to study the illness effects in bipolar disorder and stability of assessments in control participant

Change in the baseline and follow-up (3 to 6 months) assessments of brain functional connectivity (resting-state fMRI) are used to study the illness effects in bipolar disorder and stability of assessments in control participants.

Change in the baseline and follow-up (3 to 6 months) assessments of brain white matter values (diffusion MRI) are used to study the illness effects in bipolar disorder and stability of assessments in control participants.

Change in the baseline and follow-up (3 to 6 months) assessments of brain morphometry (T1-weighted imaging) are used to study the illness effects in bipolar disorder and stability of parameters in control participants.

Change in the baseline and follow-up (3 to 6 months) telomere length (assessed from blood samples) are used to study the illness effects in bipolar disorder and stability of assessments in control participants.

Change in the baseline and follow-up (3 to 6 months) mitochondrial bioenergetics and biogenesis (assessed from blood samples) are used to study the illness effects in bipolar disorder and stability of assessments in control participants.

Change in the baseline and follow-up (3 to 6 months) of inflammatory (assessed from blood samples) parameters are used to study the illness effects in bipolar disorder and stability of assessments in control participants

The Mini-Symptom-Checklist (Mini-SCL) assesses symptomatic stress with 18 questions on a Likert scale ranging from 0 (not at all) to 4 (very strongly). Higher scores on the Mini-SCL indicate higher levels of psychological distress or symptom severity

The Brief Assessment of Cognition in Schizophrenia (BACS) is used to rule out impairment in non-social cognition, i.e. verbal memory, working memory, motor speed, verbal fluency, attention and processing speed, and executive functions. It has high reliability and has been validated in several languages. BACS raw values are converted into T values with a mean of 50 and a standard deviation of 10. In summary, while there isn't a fixed maximum or minimum score, lower BACS scores (especially when below -1 or -2 on the Z-score scale) are indicative of cognitive deficits. The BACS was originally developed for schizophrenia but has been used in individuals diagnosed with bipolar disorder who achieved lower scores in the composite and most subtest scores compared to control participants.

Any Diagnostic and Statistical Manual of Mental Disorders (DSM) 5 psychiatric disorders will be screened with Mini-International Neuropsychiatric Interview (M.I.N.I.) version 7.0.2 on the recruitment stage. The M.I.N.I. is a validated, structured, diagnostic interview tool with high diagnostic reliability, consisting of questions that parallel symptoms in the DSM. M.I.N.I. has 17 modules. Each question within a module is answered with a "yes" or "no". A "yes" answer contributes one point to the module's score. Clinicians sum the positive responses to determine the module score, which indicates whether the participant meets the diagnostic criteria for that particular disorder.

The Montgomery-Åsberg Depression Rating Scale (MADRS) is a 10-item questionnaire used to determine the degree of depressive symptoms in individuals diagnosed with bipolar disorder and subclinical depression in control participants. Each item yields a score ranging from 0 to 6, and the overall score ranges from 0 to 60. Higher MADRS scores indicate more severe depressive symptoms.

IQ is assessed with German multiple-choice vocabulary test (MWT-B). It assesses crystallized intelligence. It consists of 37 items of multiple choice (5 words) vocabulary test. One of the answers is correct. Maximum of 37 correct words corresponds to IQ=120.

Young Mania Rating Scale (YMRS) assesses the severity of manic symptoms with 11 items. The overall score ranges from 0 to 60 with higher scores indicating more severe mania. Each item is scored either on a 0 to 4 scale (7 items) or with twice the scaling weight from 0 to 8 (4 items).

Comorbid borderline personality disorder is assessed by Structured Clinical Interview for DSM-5 Personality Disorders (SCID-5-PD). It is used to assess comorbid borderline personality disorder traits (14 questions) which are often found in an interaction between bipolar disorder and childhood maltreatment. Higher scores indicate a greater severity of personality pathology.

The Toronto Alexithymia Scale (TAS) consists of 20 statements on a 5-point Likert scale which measure participants' difficulties in identifying or describing their own emotions (1=strongly disagree/5=strongly agree), and their externally oriented thinking style which allows reliable discrimination of alexithymic and non-alexithymic individuals. The TAS-20 has 3 subscales: Difficulty Describing Feelings, Difficulty Identifying Feeling, and Externally-Oriented Thinking. There are 5 items that are negatively keyed. The total alexithymia score is the sum of responses to all 20 items, while the score for each subscale factor is the sum of the responses to that subscale. The TAS-20 uses cutoff scoring: equal to or less than 51 = non-alexithymia, equal to or greater than 61 = alexithymia. Scores of 52 to 60 =possible alexithymia. MET and RMET performance correlates negatively with TAS scores, which is expected as empathetic traits facilitate and alexithymic traits impair emotion recognition.

The IRI consists of 28 statements on a 5-point Likert scale (scored from 0 to 4) which requires participants to decide on other-directed thoughts and feelings (Does not describe me well/Describes me very well), and is a widely used multidimensional measure of trait empathy. The measure has 4 subscales, each made up of 7 different items: Perspective taking (PT), Fantasy (FS), Empathic concern (EC), and Personal Distress (PD), where higher scores generally indicate a greater tendency towards empathy. MET and RMET performance correlates positively with IRI, which is expected as empathetic traits facilitate and alexithymic traits impair emotion recognition. EC and PD scales have been referred to as measuring affective empathy while the PT and FS scale are commonly referred to as measuring cognitive empathy.

The resource allocation task (RAT-6) measures prosociality with 6 decisions regarding the imaginary split of money between the participant and another person, where nine options are given. The set of responses can then be scored to yield a single score, the rank order of social preferences (altruistic, prosocial, individualistic, and competitive), and additionally contains a check for transitivity in revealed preferences. Given the angles that result from idealized SVO types, proper boundaries between categories can be derived by bisecting the respective adjacent ranges. Altruists would have an angle greater than 57.15◦; prosocials would have angles between 22.45◦ and 57.15◦; individualists would have angles between -12.04◦ and 22.45◦ ; and competitive types would have an angle less than -12.04◦. Mindreading performance predicts RAT performance which indicates its real consequences on social behavior.

BCEs is a 20-item self-report measure used retrospectively to assess positive childhood experiences from birth to age 18 years. BCEs scale evaluates multisystem positive experiences that serve as assets and resources for developing children. The BCEs scale also measures two primary dimensions of positive childhood experiences: 1) Common Protective Factors - assesses the presence of frequently reported protective childhood experiences, capturing internal and relational safety and security (e.g., having at least one safe caregiver, a good friend, a supportive teacher) and a positive, predictable quality of life, and 2) Discriminating Protective Factors - evaluates the presence of experiences such as beliefs that provide comfort, positive self-image, fair treatment, and regular access to restorative factors (like good sleep and time outdoors).

Traumatic exposure is assessed using the ITEM, which is a freely available checklist measuring 21 threatening life events. Sixteen events reflect the DSM-5 definition of trauma exposure (i.e., direct or indirect threat to life, or to physical or sexual safety). The other five events are psychologically threatening events that can be considered traumatic in line with ICD-11 guidelines. Respondents indicate if they experienced each event during three developmental periods (0-12 years, 13-18 years, and older than 18 years). Lifetime exposure to each event is indicated by a positive response in any of the developmental periods. Respondents identify their most distressing event (their index trauma), how many times this event occurred, and how long ago it first occurred.

The CTQ consists of 25 questions and three validity items which comprise five subscales: emotional, physical, and sexual abuse, as well as emotional and physical neglect. Each scale is represented with five items that are scored on a 5-point Likert scale (1=never true, 5=very often true) according to the frequency with which each event occurred.