Effects of Childhood Maltreatment on Social Cognition and Brain Functional Connectivity in Borderline Personality Disorder Patients

Borderline personality disorder (BPD) is a chronic condition characterized by high levels of impulsivity, affective instability, and difficulty to establish and manage interpersonal relationships. However, little is known about its etiology and neurobiological substrates. In our study, we wanted to investigate the influence of child abuse in the psychopathology of BPD by means of social cognitive paradigms [the Movie for the Assessment of Social Cognition (MASC) and the reading the mind in the eyes test (RMET)], and resting state functional magnetic resonance imaging (rs-fMRI). For this, we recruited 33 participants, 18 BPD patients, and 15 controls. High levels of self-reported childhood maltreatment were reported by BPD patients. For the sexual abuse subdimension, there were no differences between the BPD and the control groups, but there was a negative correlation between MASC scores and total childhood maltreatment levels, as well as between physical abuse, physical negligence, and MASC. Both groups showed that the higher the level of childhood maltreatment, the lower the performance on the MASC social cognitive test. Further, in the BPD group, there was hypoconnectivity between the structures responsible for emotion regulation and social cognitive responses that have been described as part of the frontolimbic circuitry (i.e., amygdala). Differential levels of connectivity, associated with different types and levels of abuse were also observed

The relationship between performance in a theory of mind task and intrinsic functional connectivity in youth with early onset psychosis

Psychotic disorders are characterized by theory of mind (ToM) impairment. Although ToM undergoes maturational changes throughout adolescence, there is a lack of studies examining ToM performance and its brain functional correlates in individuals with an early onset of psychosis (EOP; onset prior to age 18), and its relationship with age. Twenty-seven individuals with EOP were compared with 41 healthy volunteers using the "Reading-the-Mind-in-the-Eyes" Test, as a measure of ToM performance. A resting-state functional MRI scan was also acquired, in which the default mode network was used to identify areas relevant to ToM processing employing independent component analysis. Group effects revealed worse ToM performance and less intrinsic functional connectivity in the medial prefrontal cortex in EOP relative to healthy volunteers. Group by age interaction revealed age-positive associations in ToM task performance and in intrinsic connectivity in the medial prefrontal cortex in healthy volunteers, which were not present in EOP. Differences in ToM performance were partially mediated by intrinsic functional connectivity in the medial prefrontal cortex. Poorer ToM performance in EOP, coupled with less medial prefrontal cortex connectivity, could be associated with the impact of psychosis during a critical period of development of the social brain, limiting normative age-related maturation

Epileptic Seizures are Reduced by Autonomic Biofeedback Therapy Through Enhancement of Fronto-limbic Connectivity: A Controlled Trial and Neuroimaging Study.

BACKGROUND: Thirty-percent of patients with epilepsy are drug-resistant, and might benefit from effective noninvasive therapeutic interventions. Evidence is accumulating on the efficacy of autonomic biofeedback therapy using galvanic skin response (GSR; an index of sympathetic arousal) in treating epileptic seizures. This study aimed to extend previous controlled clinical trials of autonomic biofeedback therapy with a larger homogeneous sample of patients with temporal lobe epilepsy. In addition, we used neuroimaging to characterize neural mechanisms of change in seizure frequency following the therapy. METHODS: Forty patients with drug-resistant temporal lobe epilepsy (TLE) (age: 18 to 70years old), on stable doses of anti-epileptic medication, were recruited into a controlled and parallel-group trial from three screening centers in the UK. Patients were allocated to either an active intervention group, who received therapy with GSR biofeedback, or a control group, who received treatment as usual. Allocation to the group was informed, in part, by whether patients could travel to attend repeated therapy sessions (non-randomized). Measurement of outcomes was undertaken by an assessor blinded to the patients' group membership. Resting-state functional and structural MRI data were acquired before and after one month of therapy in the therapy group, and before and after a one-month interval in the control group. The percentage change of seizure frequency was the primary outcome measure. The analysis employed an intention-to-treat principle. The secondary outcome was the change in default mode network (DMN) and limbic network functional connectivity tested for effects of therapy. The trial was registered with the National Institute for Health Research (NIHR) portfolio (ID 15967). FINDINGS: Data were acquired between May 2014 and October 2016. Twenty participants were assigned to each group. Two patients in the control group dropped out before the second scan, leaving 18 control participants. There was a significant difference in reduction of seizure frequency between the therapy and control groups (p50%. Neuroimaging analysis revealed that post-therapy seizure reduction was linearly correlated with enhanced functional connectivity between right amygdala and both the orbitofrontal cortex (OFC) and frontal pole (FP). INTERPRETATION: Our clinical study provides evidence for autonomic biofeedback therapy as an effective and potent behavioral intervention for patients with drug-resistant epilepsy. This approach is non-pharmacological, non-invasive and seemingly side-effect free

Dissociable relations between amygdala subregional networks and psychopathy trait dimensions in conduct‐disordered juvenile offenders

Psychopathy is a serious psychiatric phenomenon characterized by a pathological constellation of affective (e.g., callous, unemotional), interpersonal (e.g., manipulative, egocentric), and behavioral (e.g., impulsive, irresponsible) personality traits. Though amygdala subregional defects are suggested in psychopathy, the functionality and connectivity of different amygdala subnuclei is typically disregarded in neurocircuit-level analyses of psychopathic personality. Hence, little is known of how amygdala subregional networks may contribute to psychopathy and its underlying trait assemblies in severely antisocial people. We addressed this important issue by uniquely examining the intrinsic functional connectivity of basolateral (BLA) and centromedial (CMA) amygdala networks in relation to affective, interpersonal, and behavioral traits of psychopathy, in conduct-disordered juveniles with a history of serious delinquency (N 5 50, mean age 5 16.83 6 1.32). As predicted, amygdalar connectivity profiles exhibited dissociable relations with different traits of psychopathy. Interpersonal psychopathic traits not only related to increased connectivity of BLA and CMA with a corticostriatal network formation accommodating reward processing, but also predicted stronger CMA connectivity with a network of cortical midline structures supporting sociocognitive processes. In contrast, affective psychopathic traits related to diminished CMA connectivity with a frontolimbic network serving salience processing and affective responding. Finally, behavioral psychopathic traits related to heightened BLA connectivity with a frontoparietal cluster implicated in regulatory executive functioning. We suggest that these traitspecific shifts in amygdalar connectivity could be particularly relevant to the psychopathic phenotype, as they may fuel a self-centered, emotionally cold, and behaviorally disinhibited profile. Hum Brain Mapp 37:4017–4033, 2016

Brain functional correlates of theory of mind in neurodevelopmental disorders

[eng] Impairment in social functioning is a common diagnostic criteria for most psychiatric disorders (1,2). Multiples causes may be involved in the loss, or the lack of acquisition, of social skills in psychopathological conditions (3). Social cognition is progressively acquired during childhood and adolescence (4), coinciding with the age of onset of most psychiatric disorders (5) and especially neurodevelopmental disorders, which frequently exhibit impairment in theory of mind performance (6). Along the Introduction, the concept of theory of mind (ToM) (section 4.1) is presented, in addition to the role of functional neuroimaging (section 4.2) for studying the neural correlates underlying ToM (section 4.3). This is contextualized in neurodevelopment (subsections 4.1.1, 4.2.1 and 4.3.1). Secondly, the current knowledge about the impairments in ToM and its associated functional brain correlates is reviewed within three neurodevelopmental disorders (section 4.4): autism spectrum disorders (4.4.1), attention-deficit and hyperactivity disorder (4.4.2) and early-onset psychosis (4.4.3).[spa] La teoría de la mente o mentalización es un dominio cognitivo de la cognición social que se utiliza para designar la capacidad de atribuir emociones, pensamientos e intenciones a otras personas, y que son diferentes a los propios. La teoría de la mente es una habilidad que se adquiere progresivamente durante el neurodesarrollo hasta la edad adulta. Durante tareas que implican la teoría de la mente aumenta la actividad cerebral del córtex prefrontal medial, las uniones temporo-parietales bilaterales y córtex cingulado posterior/precuneus. La conectividad funcional entre estas áreas también incrementa durante las tareas de teoría de la mente. Esta red funcional de mentalización se superpone anatómicamente con la red de activación por defecto, que se activa durante los estados de reposo, en los que no se realiza ninguna actividad concreta. Con frecuencia, durante la divagación mental que caracteriza el estado de reposo, tienen lugar cogniciones de tipo social. Por ello, se han utilizado estudios de neuroimagen con tarea y de reposo para estudiar las bases neuronales de la teoría de la mente. Los déficits en teoría de la mente, tradicionalmente asociados con el trastorno del espectro autista, se han identificado también en otros trastornos del neurodesarrollo, como el trastorno por déficit de atención e hiperactividad y en la esquizofrenia. El trastorno por déficit de atención e hiperactividad es un diagnóstico frecuentemente comórbido a los trastornos del espectro del autismo, aunque las dificultades en teoría de la mente parecen ser menos marcadas en el primero. La esquizofrenia ha sido conceptualizada en las últimas décadas como un trastorno del neurodesarrollo, y algunos estudios apoyan que las dificultades en teoría de la mente son más marcadas cuando el primer episodio de psicosis se produce a edades más tempranas. Además, estos déficits en teoría de la mente podrían iniciarse antes de desarrollarse el primer episodio psicótico. Pese a esto, la literatura que evalúa el rendimiento en teoría de la mente en la presentación comórbida de trastorno del espectro autista con un trastorno por déficit de atención e hiperactividad, en la psicosis de inicio temprano (cuando el primer episodio psicótico tiene lugar durante la infancia o la adolescencia) o en los síndromes de alto riesgo de psicosis es más escasa. En este sentido, el efecto de la edad sobre la adquisición de habilidades de teoría de la mente en adolescentes dentro del espectro de la psicosis ha sido escasamente reportado y con resultados inconcluyentes. Aunque existe evidencia sobre los déficits neuronales que subyacen a los déficits en teoría de la mente de los sujetos con trastorno del espectro autista y los adultos con esquizofrenia, no hay estudios de resonancia magnética funcional que los evalúen en sujetos con trastorno por déficit de atención e hiperactividad, con o sin comorbilidad con el trastorno del espectro autista, en adolescentes con psicosis de inicio temprano o en adolescentes con alto riesgo clínico de psicosis. Dentro del espectro de la psicosis, tampoco se ha estudiado el efecto de la edad sobre los correlatos neuronales de teoría de la mente. Por lo tanto, se desconoce el impacto que ejercen sobre la conectividad cerebral algunos de los principales trastornos del neurodesarrollo, y si los déficits en teoría de la mente subyacen a vías neuronales similares o diferenciales entre diferentes trastornos del neurodesarrollo. El objetivo de esta tesis es evaluar los correlatos neuronales subyacentes a la teoría de la mente en adultos jóvenes con trastorno por déficit de atención e hiperactividad, con o sin comorbilidad con trastorno del espectro de autismo, y adolescentes con psicosis de inicio temprano y con alto riesgo clínico de psicosis

The Emotional Brain in Obsessive-Compulsive Disorder

Background Obsessive-compulsive disorder (OCD) is characterized by distressing obsessions and time-consuming compulsions. The disorder affects 1-3% and can be highly impairing to daily functioning and detrimental to the quality of life. Cognitive behavioral therapy is an effective treatment for 50-75% of people with OCD, leaving a considerable minority who do not benefit from the best available treatments we have today. Neuroimaging has related the disorder to the function and structure of cortico-striato-thalamo-cortical and fronto-limbic circuits. A better understanding of these circuits might contribute to a better understanding of the disorder, how current treatments change the brain, and how we can help non-responders with better treatments in the future. This is likely particularly true for fronto-limbic and affective circuits, given their role in the formation, maintenance, and extinction of fear as well as motivating behavior. The aim of this dissertation was, first, to investigate how OCD is related to brain activation during emotional processing of aversive stimuli. Secondly, we wanted to examine if unaffected siblings of OCD patients showed similar anxiety, brain activation, and connectivity during emotion provocation and regulation as their OCD-affected siblings compared to unrelated healthy controls. Lastly, we wanted to investigate if the resting-state network structure changes in OCD patients directly after the Bergen 4-Day Treatment (B4DT), a concentrated and exposure-based psychological therapy. Methods Paper I was a meta-analysis of 25 functional neuroimaging studies comparing OCD patients and healthy controls during emotion processing, when participants were exposed to aversive or neutral stimuli. In Paper II we used functional magnetic resonance imaging (fMRI) to investigate distress, brain activation, and fronto-limbic connectivity during emotion provocation and regulation of neutral, fear-related, and OCD-related stimuli in 43 unmedicated OCD patients, 19 unaffected siblings, and 38 healthy controls. In Paper III we used resting-state fMRI to study the network structure of 28 OCD patients (21 unmedicated) and 19 healthy controls the day before and three days after B4DT. We examined static and dynamic graph metrics at the global, subnetwork, and regional levels, as well as between-subnetwork connectivity. Results In Paper I, we found that OCD patients showed more activation than healthy controls in the orbitofrontal cortex (OFC), extending into the subgenual anterior cingulate cortex (sgACC) and ventromedial prefrontal cortex (vmPFC), bilateral amygdala (extending into the right putamen), left inferior occipital cortex, and right middle temporal gyrus during aversive versus neutral stimuli. Meta-regressions showed that medication status and comorbidity moderated amygdala, occipital and ventromedial prefrontal cortex hyperactivation, while symptom severity moderated hyperactivation in medial frontal prefrontal and superior parietal regions. In Paper II we showed that unaffected siblings resembled healthy controls in task-related distress, less amygdala activation/altered timing than OCD patients during emotion provocation. During OCD-related emotion regulation siblings showed no significant difference in dmPFC activation versus either OCD patients or healthy controls, but showed more temporo-occipital activation and dmPFC-amygdala connectivity compared to healthy controls. In Paper III we found that unmedicated OCD patients showed more frontoparietal-limbic connectivity before treatment than healthy controls. This, along with sgACC flexibility, was reduced in OCD patients directly after B4DT. Conclusions OCD patients show hyperactivation of the amygdala and related structures, but this characteristic is not directly shared with unaffected siblings during provocation or regulation of emotional information. However, siblings seem to show compensatory activation and connectivity in other areas. The rapid changes in frontoparietal-limbic connectivity and subgenual ACC flexibility suggests that concentrated treatment leads to a more independent and stable network state. OCD is related to subtle alterations in limbic activation and fronto-limbic connectivity during both emotional tasks and resting-state, which seems to vary with comorbidity and is sensitive to treatment

Neurobiological Underpinnings of Trauma-related Psychopathology

The understanding and treatment of trauma-related psychopathology is a crucial challenge in the field of global mental health today. The etiology and mechanisms of two common trauma-related symptoms – intrusive re-experiencing and dissociative symptomatology – are still not well understood. The present work aims to advance the understanding of these phenomena by investigating their neurobiological underpinnings in two disorders: depersonalization/derealization disorder (DPD), in which dissociation depicts the core feature, and the dissociative subtype of posttraumatic stress disorder (PTSD-D), in which dissociative symptomatology and intrusive re-experiencing co-occur and correlate in regard to their severity. Alterations in fiber tract networks in white matter, which are crucial for communicating between brain regions, have not yet been investigated in DPD or PTSD-D. In Study I, white matter network alterations were explored in 23 patients with DPD compared to 23 matched healthy controls. Results yielded relatively lower structural connectivity in left and right temporal regions in DPD, which have previously been associated with dissociative symptomatology in DPD and in other disorders. Furthermore, a trend indicated alterations in a fronto-limbic circuit, which a neurobiological model proposes underlies dissociation in DPD as well as PTSD-D. In Study II, we tested whether fronto-limbic circuits are also altered in PTSD-D (n=23) compared to ‘classic’ PTSD patients (n=19) using the same analysis pipeline as in Study I. No respective white matter changes were detected on a network level in PTSD-D. However, subsequent exploratory analyses revealed alterations in two subcortical networks comprising a limbic-thalamic circuit and low-level motor regions, respectively. The limbic-thalamic network is crucial for declarative and spatial mnemonic processes, which according to dual memory models play a crucial role for the development of intrusive memories. We tested the respective memory model in Study III and confirmed for the first time empirically, that spatial-contextual (allocentric) memory ability is negatively associated with severity of intrusive memories in 33 patients with PTSD. The findings of the present work indicate that (1) dissociation in DPD is underpinned by different alterations in structural connectivity than in PTSD-D and (2) dissociative and intrusive memories are associated with aberrations in similar sub-cortical circuits, supporting the notion that in PTSD-D, a lower state of consciousness exacerbates de-contextualization of the traumatic content, resulting in heightened intrusive symptomatology. Clinical implications of our findings are discussed

The UNC/UMN Baby Connectome Project (BCP): An overview of the study design and protocol development

The human brain undergoes extensive and dynamic growth during the first years of life. The UNC/UMN Baby Connectome Project (BCP), one of the Lifespan Connectome Projects funded by NIH, is an ongoing study jointly conducted by investigators at the University of North Carolina at Chapel Hill and the University of Minnesota. The primary objective of the BCP is to characterize brain and behavioral development in typically developing infants across the first 5 years of life. The ultimate goals are to chart emerging patterns of structural and functional connectivity during this period, map brain-behavior associations, and establish a foundation from which to further explore trajectories of health and disease. To accomplish these goals, we are combining state of the art MRI acquisition and analysis techniques, including high-resolution structural MRI (T1-and T2-weighted images), diffusion imaging (dMRI), and resting state functional connectivity MRI (rfMRI). While the overall design of the BCP largely is built on the protocol developed by the Lifespan Human Connectome Project (HCP), given the unique age range of the BCP cohort, additional optimization of imaging parameters and consideration of an age appropriate battery of behavioral assessments were needed. Here we provide the overall study protocol, including approaches for subject recruitment, strategies for imaging typically developing children 0–5 years of age without sedation, imaging protocol and optimization, a description of the battery of behavioral assessments, and QA/QC procedures. Combining HCP inspired neuroimaging data with well-established behavioral assessments during this time period will yield an invaluable resource for the scientific community