Disrupted upregulation of salience network connectivity during acute stress in siblings of schizophrenia patients

BACKGROUND: An adaptive neural stress response is essential to adequately cope with a changing environment. It was previously argued that sympathetic/noradrenergic activity during acute stress increases salience network (SN) connectivity and reduces executive control network (ECN) connectivity in healthy controls, with opposing effects in the late aftermath of stress. Altered temporal dynamics of these networks in response to stress are thought to play a role in the development of psychopathology in vulnerable individuals. METHODS: We exposed male healthy controls (n = 40, mean age = 33.9) and unaffected siblings of schizophrenia patients (n = 39, mean age = 33.2) to the stress or control condition of the trier social stress test and subsequently investigated resting state functional connectivity of the SN and ECN directly after and 1.5 h after stress. RESULTS: Acute stress resulted in increased functional connectivity within the SN in healthy controls, but not in siblings (group × stress interaction pfwe < 0.05). In the late aftermath of stress, stress reduced functional connectivity within the SN in both groups. Moreover, we found increased functional connectivity between the ECN and the cerebellum in the aftermath of stress in both healthy controls and siblings of schizophrenia patients. CONCLUSIONS: The results show profound differences between siblings of schizophrenia patients and controls during acute stress. Siblings lacked the upregulation of neural resources necessary to quickly and adequately cope with a stressor. This points to a reduced dynamic range in the sympathetic response, and may constitute a vulnerability factor for the development of psychopathology in this at-risk group

Altered Relationship between Cortisol Response to Social Stress and Mediotemporal Function during Fear Processing in People at Clinical High Risk for Psychosis: A Preliminary Report

Evidence suggests that people at Clinical High Risk for Psychosis (CHR) have a blunted cortisol response to stress and altered mediotemporal activation during fear processing, which may be neuroendocrine–neuronal signatures of maladaptive threat responses. However, whether these facets are associated with each other and how this relationship is affected by cannabidiol treatment is unknown. We examined the relationship between cortisol response to social stress and mediotemporal function during fear processing in healthy people and in CHR patients. In exploratory analyses, we investigated whether treatment with cannabidiol in CHR individuals could normalise any putative alterations in cortisol-mediotemporal coupling. 33 CHR patients were randomised to 600 mg cannabidiol or placebo treatment. Healthy controls (n = 19) did not receive any drug. Mediotemporal function was assessed using a fearful face-processing functional magnetic resonance imaging paradigm. Serum cortisol and anxiety were measured immediately following the Trier Social Stress Test. The relationship between cortisol and mediotemporal blood-oxygen-level-dependent haemodynamic response was investigated using linear regression. In healthy controls, there was a significant negative relationship between cortisol and parahippocampal activation (p = 0.023), such that the higher the cortisol levels induced by social stress, the lower the parahippocampal activation (greater deactivation) during fear processing. This relationship differed significantly between the control and placebo groups (p = 0.033), but not between the placebo and cannabidiol groups (p = 0.67). Our preliminary findings suggest that the parahippocampal response to fear processing may be associated with the neuroendocrine (cortisol) response to experimentally induced social stress, and that this relationship may be altered in patients at clinical high risk for psychosis.</p

The human cerebellum in reward anticipation and outcome processing: An activation likelihood estimation meta-analysis

The cerebellum generates internal prediction models and actively compares anticipated and actual outcomes in order to reach a desired end state. In this process, reward can serve as a reinforcer that shapes internal prediction models, enabling context-appropriate behavior. While the involvement of the cerebellum in reward processing has been established in animals, there is no detailed account of which cerebellar regions are involved in reward anticipation and outcome processing in humans. To this end, an activation likelihood estimation meta-analysis of functional neuroimaging studies was performed to investigate cerebellar functional activity patterns associated with reward anticipation and outcome processing in healthy adults. Results showed that reward anticipation (k = 31) was associated with regional activity in the bilateral anterior lobe, bilateral lobule VI, left Crus I and the posterior vermis, while reward outcome (k = 16) was associated with regional activity in the declive and left lobule VI. These findings demonstrate distinct involvement of the cerebellum in reward anticipation and outcome processing as part of a predictive coding routine

Neural basis of genetic vulnerability to bipolar disorder

Abnormalities of reward processing, decision-making and emotion processing are core features of bipolar I disorder (BD). These processes are closely linked with fronto-striatal and midbrain circuitry. I sought to test whether dysfunctions of these pathways were present in BD and whether they related to genetic vulnerability to illness or resilience. I recruited twenty-five BD I patients each with their unaffected sibling, and compared them to 24 healthy age- and gender-matched controls. In chapter 1, I provide a research background and literature review. Chapter 2 describes the neuropsychological assessments which demonstrated trait-related deficits in working memory with slower processing speed representing an endophenotype. Chapter 3 describes the implicit/ explicit facial emotion processing task performed during event-related functional MRI (erfMRI). Pairwise comparisons demonstrated implicit processing was associated with increases in lingual gyrus and insula activations and explicit processing elicited reduced fusiform activations in patients compared with controls. Increased posterior cingulate activations and reductions in putamen and cerebellar activity were found in siblings compared to controls, and reductions in parietal activations were noted in siblings compared to their ill relatives. These findings suggest over-activations in regions involved in facial expression recognition and attentional shifting (lingual and insula respectively) and deactivations in a region important for the perception and recognition of faces (fusiform) represent correlates of disease expression. Additionally regional deactivations associated with category learning and attentional processing (parietal, putamen and cerebellar) and increased activations in a region involved in emotional salience (posterior cingulate) may represent adaptive responses associated with resilience. Chapter 4 describes an instrumental reward-learning task performed during erfMRI. Data were analysed at whole brain level and using a priori region of interest analyses in ventral striatum/midbrain and prefrontal cortex (PFC). Results included increased ventral striatum activation in association with the difference between observed and expected rewarding outcomes (the prediction error (PE)) in patients compared to controls. Decreased prefrontal activations were seen in the patient and sibling groups compared to controls in association with the learning of the value of the conditioned stimulus. These findings suggest that i) PE associated circuitry (striatal) overactivation, and ii) prefrontal deactivations underlie the genetic vulnerability to BD

Disrupted upregulation of salience network connectivity during acute stress in siblings of schizophrenia patients

BACKGROUND: An adaptive neural stress response is essential to adequately cope with a changing environment. It was previously argued that sympathetic/noradrenergic activity during acute stress increases salience network (SN) connectivity and reduces executive control network (ECN) connectivity in healthy controls, with opposing effects in the late aftermath of stress. Altered temporal dynamics of these networks in response to stress are thought to play a role in the development of psychopathology in vulnerable individuals. METHODS: We exposed male healthy controls (n = 40, mean age = 33.9) and unaffected siblings of schizophrenia patients (n = 39, mean age = 33.2) to the stress or control condition of the trier social stress test and subsequently investigated resting state functional connectivity of the SN and ECN directly after and 1.5 h after stress. RESULTS: Acute stress resulted in increased functional connectivity within the SN in healthy controls, but not in siblings (group × stress interaction pfwe < 0.05). In the late aftermath of stress, stress reduced functional connectivity within the SN in both groups. Moreover, we found increased functional connectivity between the ECN and the cerebellum in the aftermath of stress in both healthy controls and siblings of schizophrenia patients. CONCLUSIONS: The results show profound differences between siblings of schizophrenia patients and controls during acute stress. Siblings lacked the upregulation of neural resources necessary to quickly and adequately cope with a stressor. This points to a reduced dynamic range in the sympathetic response, and may constitute a vulnerability factor for the development of psychopathology in this at-risk group

Convergence of Aberrant Electrophysiological Correlates of Salience, Affective Processing and Stress Reactivity in Patients with Schizophrenia

Patients with schizophrenia exhibit debilitating deficits in attention and affective processing, which are often resistant to treatment and associated with poor functional outcomes. Attentional and affective processing relies on a distributed neural network of fronto-limbic circuits, which enable cognitive control and affective processing, and assist in their interaction to regulate emotional responses. Despite evidence of intact affective valence processing, schizophrenia patients are often unable to employ cognitive change strategies to reduce attentional capture by emotionally salient stimuli, or modulate neurophysiological responses to aversive stimuli. Aberrant neurophysiological correlates of orienting to task-relevant emotional stimuli are also present in unaffected first-degree relatives of schizophrenia patients, suggesting they may represent vulnerability markers. However, less is known about the attentional processing of emotionally salient, task-irrelevant information in these groups, which is examined in Experiment 1 (Chapter 2). Results suggest that despite intact novelty detection, schizophrenia patients and relatives shared deficiencies in attentional processing of emotionally salient information. First-degree relatives exhibited a unique enhancement of the electrophysiological correlate underlying salience evaluation, possibly indicating a compensatory engagement of neural circuitry. While fronto-limbic circuits are fundamental for affective processing and its modulation by higher order cognitive control, this network also plays a critical role in stress regulation, and is disproportionally affected by the deleterious effects of stress. To understand the efficiency and resilience of fronto-limbic circuitry in adapting and recovering from stress exposure in schizophrenia, Experiment 2 (Chapter 3) investigated the effect of an acute experimental psychosocial stressor on neurophysiological indices of fronto-limbic-mediated emotional regulation processes. Results suggest that stress exposure modified electrophysiological correlates of affective processing in patients and controls. Furthermore, patients demonstrated aberrant fronto-limbic oscillatory indices of affective processing, as indicated by exaggerated neural excitability and inefficient frontal cognitive control, and maladaptive stress function. This imbalance between heightened neural responsivity and inefficient frontal regulation may reflect an atypical arousal state that may in turn interfere with fronto-limbic processing and promote symptomatology. Elucidating the neurophysiological correlates underlying salience detection, affective processing, and their modification by stress, will be crucial for identifying vulnerability markers, and for developing innovative treatment strategies targeting the fronto-limbic circuitry to relieve psychopathology.Doctor of Philosoph