Protected: Maxim Hoekmeijer

Lack of motivation (apathy), chronic insomnia, difficulty envisioning a positive future, and suicidal thoughts and behaviors (suicidality) are symptoms or phenomena that appear across psychiatric conditions, such as depression, schizophrenia, or anxiety. Through a transdiagnostic lens, these common psychiatric symptoms were studied in this thesis, focusing on shared mechanisms of specific symptoms across different diagnoses rather than in the context of a single diagnosis. Such a transdiagnostic approach can facilitate the identification of the relevance of symptom presence and progression for the course of psychiatric problems and can facilitate the development of targeted interventions and preventive strategies. A transdiagnostic approach focusing on understanding a specific symptom across prevalent psychiatric disorders or nonclinical populations (e.g., studying the neuropsychological mechanisms of motivation deficits in both clinical and nonclinical populations), instead of examining the phenomenology and underlying mechanisms of a typical symptom in a specific disorder (e.g., studying psychological and neural links of suicidal ideation and behavior in patients with major depressive disorder). A transdiagnostic approach further allows for the exploration of the common etiology and psychopathology related to the brain mechanisms underlying the symptoms in the context of general psychopathology. Furthermore, it allows us to examine the specificity of a symptom for a certain clinical population in comparison to other clinical and non-clinical populations, thereby, providing novel insights into the understanding of the common or specific mechanisms for a certain symptom in different psychiatric disorders. This thesis investigated neurophysiological and psychological links of three common psychiatric symptoms: suicidality (including suicidal ideation and behavior), apathy (a reduction in motivation), and insomnia, through relevant emotional and cognitive processes.

The Research Domain Criteria (RDoC) framework, introduced in 2009, guides researchers to study mental health by integrating multiple levels and types of data, including brain circuits, physiology, behavior, paradigms, and self-report experiences, across six key functional domains (e.g., negative emotional valence, positive emotional valence, cognitive control, social processing, arousal/regulation, and sensory-motor systems). The RDoC recommends a transdiagnostic or dimensional approach to studying a range of phenomena from normal to abnormal, prioritizing objective experimental evidence over categorical diagnostic guidelines based on the consensus of psychiatry experts, and emphasizes the study of underlying pathological mechanisms and psychological processes underlying psychiatric symptoms. The RDoC framework was applied in this thesis to explore the neurophysiological markers of suicidality, apathy, and insomnia. We studied these common psychiatric symptoms in the domains of positive emotional valence, cognitive control, arousal and regulation, and sensorimotor functional systems using neural circuitry, physiology, behavioral, and self-report measures within the RDoC framework. Specifically, we investigated the psychological processes of positive future thinking, and its neural mechanisms associated with suicidality in psychiatric disorders. Inhibitory control was linked to brain network connectivity associated with apathy symptom severity in schizophrenia, as well as motor activity and interview-based apathy measures in schizophrenia. Notably, apathy occurs in a variety of other clinical conditions, such as major depressive disorder, Alzheimer's disease, and Parkinson's disease, as well as in non-clinical populations. Though this thesis primarily examines the manifestation of apathy in schizophrenia, it can still provide insights with transdiagnostic relevance. Finally, we assessed the effectiveness of eHealth psychosocial interventions in improving insomnia symptoms across various populations. The following summarizes the specific questions we examined in each section as well as our findings.

Question 1: Does vividness of imagination and brain activation while thinking about positive future scenarios in patients with a psychiatric disorder and with the presence of recent suicide attempts differ from matched patients who never attempted suicide and non-psychiatric controls? Are the neural correlates of positive future-oriented thinking associated with the risk factors of suicide?

People with severe psychiatric disorders are at high risk for Suicide. Chapter 2 aimed to understand whether the neural capacity to vividly picturing positive future scenarios differed between people with psychiatric disorders with a presence or absence of a recent suicide attempt in the past six months. We compared how vividly patients with recent suicide attempts, patients without attempts, and non-psychiatric individuals imagined positive future events (e.g., having a happy vacation) and neutral events (e.g., commuting to work). All people with psychiatric disorders on average showed difficulties imagining vivid positive scenarios compared to non-psychiatric individuals, which was accompanied by higher activity of the left fronto-opercular regions associated with increased cognitive control to maintain the mental representations while envisioning positive and neutral future events. No differences between people with psychiatric problems with or without a recent suicide attempt were observed. However, brain activity in areas linked to reward processing and emotion regulation (i.e., the orbitofrontal cortex and frontal pole) was weaker when imagining positive events compared to neutral events in patients with high levels of hopelessness. This blunted brain response was related to severity suicidal ideation, through hopelessness, and especially in patients with a recent suicide attempt. This study provides evidence for a complex interplay between positive future-oriented thinking, reward processing, emotion regulation and suicidality, and interventions targeting these brain regions and associated functioning, and fostering hope might reduce suicide risk.

Question 2: Is apathy associated with impaired inhibitory control in schizophrenia? Do reductions in motor activity relate to apathy and impaired inhibitory control?

In patients with schizophrenia, apathy is one of the typical, highly prevalent, negative symptoms affecting cognitive functioning and quality of life. Apathy, characterized by a lack of motivation and interest in work or any activities of daily living, passivity, and withdrawal behavior, is common in clinical and non-clinical populations. Apathy can be defined as a lack of self-initiated goal-directed behaviour and is thought to be underpinned in systems related to cognitive control (i.e. functions needed to envision and obtain a goal), reward processing (seeing relevance of a certain goal), and auto-activation (the ability to set oneself into action). In the cognitive domain, inhibiting goal-irrelevant actions is a key cognitive control function for goal-directed behavior. However, whether apathy and the associated motor activity reduction are related to inhibition-related neural networks is unclear. Chapter 3 studied the associations of inhibitory control measured with a Go/No-Go task in people with schizophrenia with apathy at both behavioral and neural network level. We found that patients with higher levels of apathy displayed reduced motor activity levels, lower overall accuracy rate in inhibitory control, particularly more inhibitory errors, lower drift rates for Go-condition (indicating lower processing efficiency when making decisions about responses), and more negative stimulus sensitivity values (indicating lower discrimination of stimuli). On the neural network level, patients with schizophrenia and higher levels of apathy showed lower involvement of the ventral attention network associated with stimuli-driven attentional processing, and default mode network related to error processing and self-efficiency during inhibitory control. Weaker coupling of the ventral attention network and the default mode network were associated with higher levels of apathy in patients during the inhibition task. These networks imply maintaining attention to the task and allocating cognitive resources in response to external demands. Alterations in inhibition-related neural networks may explain the difficulty in inhibiting irrelevant response when chasing a goal. Motor activity levels and variability were shown to be unrelated to neural network activity during the task. Therefore, motor activity may be relevant to an auto-activation dimension underpinning apathy, but less relevant for a cognitive dimension, including inhibitory control.

Question 3: Can actigraphy-derived motor activity provide information about levels of apathy in people with schizophrenia after accounting for confounding factors such as weight, sleep, medication, and depressive symptoms?

In Chapter 4, we assessed the association between levels of apathy and motor activity. We compared a range of motor activity metrics in patients with schizophrenia with and without severe apathy symptoms and a group of non-psychiatric controls. Spontaneous motor activity was collected using wrist-worn activity trackers (i.e., actigraphy device) for two weekend days, during which activities were shown to be less driven by external obligations or therapy. Results showed that patients with severe apathy moved less, took fewer steps, and had less variation in motor activity. These associations were independent of age, smoking, body weight, positive symptoms, mediation use, and depressive symptoms. The average number of steps in the most active ten-hour period was the strongest predictor of apathy severity. Our study supports the application of actigraphy devices as an additional assessment in clinical screening and identifies patients with high apathy who require additional diagnosis and treatment.

Question 4: To what extent are eHealth-based psychosocial interventions for insomnia effective? Is the effectiveness different for specific populations? What intervention characteristics and specific factors influence treatment effectiveness?

Chapter 5 evaluated the existing evidence on the effectiveness of eHealth-based psychosocial interventions for insomnia in adults. We found that eHealth-based interventions effectively reduced insomnia severity and improved sleep quality compared to control groups who did not receive intervention. While eHealth-based psychotherapy was as effective as face-to-face treatment in reducing insomnia symptoms, face-to-face treatment showed a greater advantage in improving sleep quality. Greater improvements in insomnia severity were observed in studies including experienced therapist guidance, having participants with higher baseline insomnia severity, and having longer intervention durations. In addition, eHealth interventions for insomnia improved mood and quality of life, suggesting that better sleep can have ripple effects on mental health. This systematic review suggested that eHealth-based interventions can be considered a promising treatment for insomnia and supports wider dissemination. Blended eHealth interventions involving minimal therapist guidance can be tailored to better serve individuals with specific needs.

This thesis investigated the brain and behavioral mechanisms associated with suicide, apathy, and insomnia, providing novel insights into the identification of symptoms and the development of prevention and intervention strategies. Future research should include larger samples and combine objective and subjective measurements in studying these symptoms. Longitudinal or momentary assessments are needed to clarify the causal relationships between symptoms and their neuropsychological correlates, and symptom dynamics. In addition, neuromodulation studies targeting identified brain regions as potential markers in this thesis are needed to further examine potential pathways and ameliorative effects on specific symptoms.