The Role of Amygdala Subregions in the Neurobiology of Social Anxiety Disorder

Social anxiety is characterised by fear and/or avoidance of social situations in which an individual may be scrutinised by others. Social anxiety is thought to exist as a spectrum, with individuals on the high-end experiencing frequent and severe anxiety in the context of social situations. When severe social anxiety is accompanied by distress and functional impairment, a diagnosis of social anxiety disorder (SAD) can be made. SAD is a prevalent and debilitating disorder that can be unremitting and pervasive in the absence of intervention. Current psychotherapeutic and pharmacotherapeutic treatments for SAD demonstrate limited efficacy in remitting symptoms. Therefore, it is important to achieve a better understanding of the neurobiological mechanisms implicated in this disorder and identify potential neural treatment targets to develop more efficacious treatments. This thesis aimed to further investigate the neurobiological mechanisms implicated in SAD (vs. controls) and the associations between neural functioning and social anxiety as a dimensional symptom, with a focus on the amygdala and four of its subregions (the amygdalostriatal, basolateral, centromedial, and superficial subregions). This was due to previous findings in the neuroimaging literature in SAD having consistently implicated the amygdala, albeit with mixed findings of both increased and decreased functioning in those with SAD compared to controls. In the literature to date, however, most studies had examined the amygdala as a singular homogenous region due to methodological limitations in being able to examine the functionally and structurally distinct subnuclei that make up this region. By examining the amygdala subregions through the use of multiband functional magnetic resonance imaging (fMRI), this thesis additionally sought to determine whether the mixed findings in the literature to date may be a result of amygdala subregion-specific activity and connectivity patterns. This was achieved through three research studies. Firstly, Study 1 involved a comprehensive systematic review that summarised the literature on resting-state neuroimaging in SAD with a focus on fMRI studies and findings specific to the amygdala and its subregions (Chapter 3). This was followed by two empirical studies which investigated the role of the amygdala and its subregions during resting-state (Study 2) and emotion processing (Study 3) fMRI paradigms (Chapters 5 and 6, respectively). Findings from the systematic review (Study 1) highlighted the mixed findings in the resting-state neuroimaging literature in SAD to date, along with methodological limitations relating to neuroimaging acquisition and analysis. The empirical studies sought to address these limitations and demonstrated differing amygdala subregion activity and connectivity patterns at rest and during emotion processing. In the resting-state fMRI study (Study 2), there were no statistically significant differences in functional connectivity of the amygdala and its subregions in those with SAD compared to controls. However, social anxiety severity was found to be positively associated with connectivity between the superficial subregion and the supramarginal gyrus. The superficial subregion, along with the basolateral and centromedial subregions, were also implicated in the task-based emotion processing fMRI study (Study 3). In response to happy, angry, and fearful faces, those with SAD (vs. controls) had hyperactivation of the superficial subregion, hypoconnectivity between the superficial subregion and the precuneus, and hyperconnectivity between the basolateral subregion and broader brain regions (i.e., the pre/postcentral gyrus and the supramarginal gyrus). Additionally, social anxiety severity was positively associated with superficial and centromedial activation. Overall, the findings from this thesis provide novel information to the current understanding of the neurobiology of SAD by demonstrating amygdala subregion-specific alterations. This has important implications for research, theory, and clinical practice that are detailed in the thesis discussion (Chapter 7). Briefly, in terms of research, findings from the thesis provide support for the continuing investigation of SAD using both dimensional and categorical approaches. This was evident by the findings from the two empirical papers which demonstrated positive associations between subregional activity and connectivity patterns and social anxiety severity. With regards to theory, differences in neural patterns that were observed at rest (Study 2) and during emotion processing (Study 3) provide support for distinct neurobiological models to be constructed based on whether those with SAD are in the absence or presence of social stimuli. This is in contrast to the most recently proposed neurobiological model of SAD which was informed by a combination of resting-state and task-based fMRI data. Finally, with regards to clinical practice, the findings from this thesis provide preliminary evidence of the superficial, basolateral, and centromedial subregions of the amygdala as being potential treatment targets that can be used to inform the development of more efficacious treatments for SAD

Connectivity differences between Gulf War Illness (GWI) phenotypes during a test of attention

One quarter of veterans returning from the 1990–1991 Persian Gulf War have developed Gulf War Illness (GWI) with chronic pain, fatigue, cognitive and gastrointestinal dysfunction. Exertion leads to characteristic, delayed onset exacerbations that are not relieved by sleep. We have modeled exertional exhaustion by comparing magnetic resonance images from before and after submaximal exercise. One third of the 27 GWI participants had brain stem atrophy and developed postural tachycardia after exercise (START: Stress Test Activated Reversible Tachycardia). The remainder activated basal ganglia and anterior insulae during a cognitive task (STOPP: Stress Test Originated Phantom Perception). Here, the role of attention in cognitive dysfunction was assessed by seed region correlations during a simple 0-back stimulus matching task (“see a letter, push a button”) performed before exercise. Analysis was analogous to resting state, but different from psychophysiological interactions (PPI). The patterns of correlations between nodes in task and default networks were significantly different for START (n = 9), STOPP (n = 18) and control (n = 8) subjects. Edges shared by the 3 groups may represent co-activation caused by the 0-back task. Controls had a task network of right dorsolateral and left ventrolateral prefrontal cortex, dorsal anterior cingulate cortex, posterior insulae and frontal eye fields (dorsal attention network). START had a large task module centered on the dorsal anterior cingulate cortex with direct links to basal ganglia, anterior insulae, and right dorsolateral prefrontal cortex nodes, and through dorsal attention network (intraparietal sulci and frontal eye fields) nodes to a default module. STOPP had 2 task submodules of basal ganglia–anterior insulae, and dorsolateral prefrontal executive control regions. Dorsal attention and posterior insulae nodes were embedded in the default module and were distant from the task networks. These three unique connectivity patterns during an attention task support the concept of Gulf War Disease with recognizable, objective patterns of cognitive dysfunction

Dimensions of Depression and Cerebellar Subregion Volumes in Older Adults

The present study examined the relationship between subthreshold depressive symptoms and gray matter volume in subregions of the posterior cerebellum in middle-aged to older adults. Structural magnetic resonance imaging data from 38 adults aged 51 to 80 years were analyzed along with participants’ responses to the Center for Epidemiologic Studies Depression Scale. Subscale scores for depressed mood, somatic symptoms, and lack of positive affect were calculated, and multiple regression analyses were used to examine the relationship between symptom dimensions and cerebellar volumes. Greater somatic symptoms of depression were significantly related to larger vermis VI volumes, as were total depressive scores. Exploratory analyses revealed that greater severity on the lack of positive affect subscale was related to larger vermis VIII volumes. These results support that depressive symptom profiles have unique relationships within the cerebellum that may be important as the field moves towards targeted treatment approaches for depression

The Neural Circuitry of Sensory Processing in Post-traumatic Stress Disorder

Background: Traumatic experiences can have severe emotional and psychological consequences, which may affect the capacity to process both internal and external sensory information. Such aberrations may have cascading effects in individuals with post-traumatic stress disorder (PTSD), where alterations in sensory processing may hinder the capacity for higher-order executive functions, including emotion regulation. Delineating the neural circuitry of subcortical and cortical structures thought to be central to sensory processing is therefore critical to the study of PTSD and may help to develop an understanding of the neurobiological mechanisms underlying this often debilitating disorder. Methods: Various neuroimaging approaches were employed to investigate sensory processing in PTSD, its dissociative subtype, and healthy controls. First, resting-state connectivity patterns of subcortical brainstem structures linked to interoceptive and exteroceptive sensory processing, including the periaqueductal gray and the vestibular nuclei, were examined (chapters 2 and 3). In addition, given that the insula is critical for relaying exteroceptive and interoceptive sensory information to other neurocognitive networks in the brain, resting-state whole brain seed-based connectivity patterns of different insula subregions were investigated (chapter 4). Furthermore, machine learning analyses were used to assess the utility of insula subregion resting-state connectivity patterns as a diagnostic predictor for classifying PTSD, its dissociative subtype, and healthy controls. Finally, a task-based paradigm using oculomotor stimuli with simultaneous traumatic autobiographical memory recall was employed to examine cortical brain structures involved in the convergence of exteroceptive and interoceptive sensory information (chapter 5). Results and Discussion: As compared to controls, widespread periaqueductal gray connectivity was observed with cortical structures associated with emotional reactivity and defensive responding in PTSD and its dissociative subtype at rest. In addition, as compared to controls, decreased vestibular nuclei connectivity with cortical structures essential to exteroceptive sensory processing and multisensory integration was observed in individuals with the PTSD dissociative subtype. Moreover, PTSD showed limited cortical insula subregion resting-state connectivity with frontal lobe structures involved in the central executive network, which may be associated with impairment of higher-order executive functions, including emotion regulation, in PTSD. Finally, exposure to simultaneous exteroceptive and interoceptive sensory stimuli through oculomotor eye movements performed simultaneous to traumatic memory recall engaged the dorsal attentional network and default-mode frontoparietal networks that have been demonstrated to work in tandem to facilitate connectivity with structures in the central executive network, including the dorsolateral and dorsomedial prefrontal cortex, necessary for multisensory integration and emotion regulation. This effect was greater in individuals with PTSD and may provide a neurobiological account for how oculomotion may influence the frontoparietal cortical representation of traumatic memories. Overall, the findings of this dissertation reveal that individuals with PTSD experience aberrations in the neural circuitry necessary for processing both interoceptive and exteroceptive sensory information. We hypothesize that these observed alterations in interoceptive and exteroceptive neural processing may underlie, in part, the emotion dysregulation and maladaptive responses to chronic stress, including hypervigilance and dissociative symptoms, observed in PTSD and its dissociative subtype

Emotional and behavioral symptoms in neurodegenerative disease: a model for studying the neural bases of psychopathology.

Disruptions in emotional, cognitive, and social behavior are common in neurodegenerative disease and in many forms of psychopathology. Because neurodegenerative diseases have patterns of brain atrophy that are much clearer than those of psychiatric disorders, they may provide a window into the neural bases of common emotional and behavioral symptoms. We discuss five common symptoms that occur in both neurodegenerative disease and psychopathology (i.e., anxiety, dysphoric mood, apathy, disinhibition, and euphoric mood) and their associated neural circuitry. We focus on two neurodegenerative diseases (i.e., Alzheimer's disease and frontotemporal dementia) that are common and well characterized in terms of emotion, cognition, and social behavior and in patterns of associated atrophy. Neurodegenerative diseases provide a powerful model system for studying the neural correlates of psychopathological symptoms; this is supported by evidence indicating convergence with psychiatric syndromes (e.g., symptoms of disinhibition associated with dysfunction in orbitofrontal cortex in both frontotemporal dementia and bipolar disorder). We conclude that neurodegenerative diseases can play an important role in future approaches to the assessment, prevention, and treatment of mental illness

Using novel imaging approaches in affective disorders : beyond current models

Depressie en angststoornissen, zoals major depressive disorder, paniekstoornis, sociale angststoornis en gegeneraliseerde angststoornis, vallen onder de meest voorkomende psychiatrische ziektebeelden. Door middel van neuroimaging onderzoek zoals structurele en functionele MRI (fMRI) is het mogelijk om op een non-invasieve manier de onderliggende neurobiologie van deze stoornissen in kaart te brengen. Op basis van dergelijk onderzoek werden ruim 15 jaar geleden enkele neurobiologische modellen opgesteld waarin werd voorgesteld dat het goed of juist niet goed hersengebieden een belangrijke bijdrage leverde aan het ontstaan en/of instandhouden van depressie en angst. In de loop der jaren zijn nieuwe MRI technieken ontwikkeld. Met behulp van structurele MRI en resting-state fMRI, waarmee connectiviteit tussen hersengebieden onderzocht kan worden, heb ik gekeken naar anatomische en functionele hersenafwijkingen bij volwassenen en jongeren met depressie en/of angststoornissen. Doel was te bepalen of de reeds bestaande neurobiologische modellen bevestigd danwel aangepast of aangevuld zouden kunnen worden met recent ontwikkelde onderzoeksmethoden. De resultaten van mijn studies bevestigden grotendeels de betrokkenheid van de hersengebieden in de modellen, maar wezen tevens op een rol voor uitgebreidere netwerken van hersengebieden dan in de modellen werd verondersteld.UBL - phd migration 201

Dimensions of psychosis: Elucidating the subclinical spectrum using neuroimaging markers

Psychosis unifies a collective of disorders characterised by symptom dimensions (Gaebel & Zielasek, 2015). Purposefully delimited clinical descriptors of schizophrenia spectrum and psychotic disorders (American Psychiatric Association, 2013) impose challenges on the identification of aetiological and clinically meaningful predictors. The disassembly of psychiatric diagnoses into their elementary symptom dimensions has helped formulate psychosis phenotypes fitted on a psychosis continuum (Verdoux & van Os, 2002). Aetiological models of psychosis may be studied through schizotypy and transient psychotic experiences (Barrantes-Vidal et al., 2015; Nelson, Fusar-Poli, & Yung, 2012), collectively termed subclinical psychosis phenotypes. The dimensional psychometric structures of these phenotypes varying in temporal stability (Linscott & van Os, 2013; Mason et al., 1995; Stefanis et al., 2002), and their implications might be further consolidated when paired with neuroimaging parameters (Siever & Davis, 2004). Three neuroimaging studies aimed to examine the relationship between subclinical psychotic phenotypes and neurobiology. Surface and volume-based morphometric (VBM) methods were implemented to examine the variety of cortical and subcortical signatures of different phenotype dimensions. Study 1 investigated whether cortical surface gyrification -a maker of genetic and developmental influences on cortical morphology (Docherty et al., 2015; Haukvik et al., 2012)- is associated with dimensional psychosis prone phenomena (Konings, Bak, Hanssen, van Os, & Krabbendam, 2006; Stefanis et al., 2002). Early cortical organisation contributes to cognitive capacities in later life (Gautam et al., 2015; Gregory et al., 2016; Papini et al., 2020). Given that cognitive deficits are present in psychosis prone and clinical samples to varying extents (Hou et al., 2016; Siddi et al., 2017), Study 1 also explored the mediating role of cognition (both as a general measure and intelligence quotient) as a psychosis endophenotype in the relationship between regional gyrification and PLE distress. Study 2 and Study 3 used VBM to investigate structural brain correlates for psychotic-like experiences (PLE) and trait psychosis phenotypes (schizotypy). Different PLE facets (quantity and distress severity) (Hanssen, Bak, et al., 2005; Ising et al., 2012) were used to estimate whole-brain grey matter volume, followed by interaction models in subsequent prefrontal regions of interest (Study 2). The medial temporal lobe includes the hippocampal subfields, which are regions of interest in psychosis pathophysiology (Lieberman et al., 2018; Mathew et al., 2014; Schobel et al., 2013). Based on a previous study in schizoytypy (Sahakyan et al., 2020), Study 3 examined the relationship between schizotypal trait dimensions (Mason et al., 1995) and PLE, and their interactions, and hippocampal subfields and the amygdala. The results of Study 1 showed that psychometrically assessed PLE were associated with reduced gyrification in parietal and temporal regions, indicating that psychosis proneness correlates with neurodevelopmental factors (Fonville et al., 2019; Liu et al., 2016). A lack of mediating pathways between regional gyrification and PLE suggested that cognition effects may emerge in larger samples (Mollon et al., 2016) and/or increasingly psychosis pone phenotypes. Elaborating on the distinction between PLE quantity versus distress, Study 2 showed that PLE load, but not distress severity, were associated with volume increases in prefrontal and occipitotemporal regions. At increased distress severity for perceptual abnormalities, PLE were associated with regional volume reductions of the superior frontal gyrus. Study 3 showed differential relationships between schizotypy dimensions and volumes of the MTL that are involved in the pathophysiology of schizophrenia. PLE per se did not associate with amygdala or hippocampal subfield volumes, but a positive association between the hippocampal subiculum and PLE was moderated by positive schizotypy. Study 3 underscored the enhanced usefulness of schizotypy as an endophenotype in psychosis research when its multidimensional organisation (Grant, 2015; Vollema & van den Bosch, 1995) is respected. The results support the use of psychosis symptom dimensions, showing different (positive and negative) neuroanatomical associations. While case-control studies in schizophrenia show consistent volume reductions of the prefrontal and temporal cortices (Haijma et al., 2013; Honea, Crow, Passingham, & Mackay, 2005), these findings contribute to more heterogeneous volumetric relationships in nonclinical individuals. Reduced regional cortical gyrification proposes a continuous distribution of neurodevelopmental impacts. Distress severity and schizotypy occasioned modulatory effects in prefrontal and hippocampal subfield volumes, respectively. Collectively, these three cross-sectional studies extend previous research suggesting that dimensional phenotypes show neuroanatomical variation supportive of a psychosis continuum possibly characterised by an underlying non-linearity (Bartholomeusz et al., 2017; Binbay et al., 2012; Johns & van Os, 2001)

Human subsystems of medial temporal lobes extend locally to amygdala nuclei and globally to an allostatic-interoceptive system.

In mammals, the hippocampus, entorhinal, perirhinal, and parahippocampal cortices (i.e., core regions of the human medial temporal lobes, MTL) are locally interlaced with the adjacent amygdala nuclei at the structural and functional levels. At the global brain level, the human MTL has been described as part of the default mode network and amygdala nuclei as parts of the salience network, with both networks collectively forming a large-scale brain system supporting allostatic-interoceptive functions. We hypothesized (i) that intrinsic functional connectivity of slow activity fluctuations would reveal human MTL subsystems locally extending to the amygdala; and (ii) that these extended local subsystems would be globally embedded in large-scale brain systems supporting allostatic-interoceptive functions. Capitalizing on resting-state fMRI data of three independent samples of cognitively healthy adults (one main and two replication samples: N ​= ​101, 60, and 29, respectively), we analyzed the functional connectivity of fluctuating ongoing BOLD-activity within and outside the amygdala-MTL in a data-driven way using masked independent component and dual-regression analyses. We found that at the local level, MTL subsystems extend to the amygdala and are functionally organized along the longitudinal amygdala-MTL axis. These subsystems are characterized by consistent involvement of amygdala, hippocampus, and entorhinal cortex, but variable participation of perirhinal and parahippocampal regions. At the global level, amygdala-MTL subsystems selectively connect to salience, thalamic-brainstem, and default mode networks – the major cortical and subcortical components of the allostatic-interoceptive system. These findings provide evidence for integrated amygdala-MTL subsystems in humans, which are embedded within a larger allostatic-interoceptive system

Neural mechanisms of visual awareness and their modulation by social threat

The human brain can extract an enormous wealth of visual information from our surroundings. However, only a fraction of this immense data set ever becomes available to the observer’s awareness. How and why certain information is selected for awareness are questions under active investigation. Following two introductory chapters, this thesis contains six inter-related experimental chapters, through which I will explore two key outstanding questions in this field, using bistable perceptual paradigms to study conscious and non-conscious visual processing in healthy human volunteers. The first major theme focuses on adding new insight into the brain regions and networks that facilitate transfer between non-conscious and conscious modes of visual processing. In Chapters 3 and 4 I will use fMRI, both in task-related and resting-state conditions, to delineate areas, and their interactions (in terms of effective connectivity), which are relevant for transition between different conscious perceptual experiences. In Chapter 5 I will focus on one specific region in the proposed perceptual transition-related network (the frontal eye field) and explore its causal role in access to awareness using repetitive TMS. The second key question explored in this thesis is how social cues in the visual environment influence non-conscious visual processing as well as transition to conscious vision. In Chapter 6 I will study behavioural effects of non-conscious social cues from faces, and the relationship of these effects to focal brain anatomy. Based on finding slower perceptuomotor performance when non-conscious faces contain threatening cues in Chapter 6, I hypothesise that a defensive freezing response is engaged in such situations. The final two experimental chapters will explore the correlates of putative human freezing in the context of non-conscious social threat: using fMRI and psychophysiological measurements to study effects on perceptual transition in Chapter 7, and relating TMS-induced motor-evoked potentials and concurrent psychophysiological measurements to non-conscious perceptuomotor performance in Chapter 8. Taken together, the presented findings shed new light on the network of brain regions involved in transition between non-conscious and conscious modes of visual processing. In addition, they uncover novel mechanisms through which socially relevant visual cues shape our awareness of the visual world, with particular emphasis on the engagement of defensive responses by socially threatening stimuli. The concluding chapter discusses the implications of these findings and explores relevant avenues for future work