Amygdala Connectivity Differs Among Chronic, Early Course, and Individuals at Risk for Developing Schizophrenia

Abstract

Alterations in circuits involving the amygdala have been repeatedly implicated in schizophrenia neuropathology, given their role in stress, affective salience processing, and psychosis onset. Disturbances in amygdala whole-brain functional connectivity associated with schizophrenia have yet to be fully characterized despite their importance in psychosis. Moreover, it remains unknown if there are functional alterations in amygdala circuits across illness phases. To evaluate this possibility, we compared whole-brain amygdala connectivity in healthy comparison subjects (HCS), individuals at high risk (HR) for schizophrenia, individuals in the early course of schizophrenia (EC-SCZ), and patients with chronic schizophrenia (C-SCZ). We computed whole-brain resting-state connectivity using functional magnetic resonance imaging at 3T via anatomically defined individual-specific amygdala seeds. We identified significant alterations in amygdala connectivity with orbitofrontal cortex (OFC), driven by reductions in EC-SCZ and C-SCZ (effect sizes of 1.0 and 0.97, respectively), but not in HR for schizophrenia, relative to HCS. Reduced amygdala-OFC coupling was associated with schizophrenia symptom severity (r = .32, P < .015). Conversely, we identified a robust increase in amygdala connectivity with a brainstem region around noradrenergic arousal nuclei, particularly for HR individuals relative to HCS (effect size = 1.54), but not as prominently for other clinical groups. These results suggest that deficits in amygdala-OFC coupling could emerge during the initial episode of schizophrenia (EC-SCZ) and may present as an enduring feature of the illness (C-SCZ) in association with symptom severity but are not present in individuals with elevated risk for developing schizophrenia. Instead, in HR individuals, there appears to be increased connectivity in a circuit implicated in stress response.

Development of White Matter Microstructure and Intrinsic Functional Connectivity Between the Amygdala and Ventromedial Prefrontal Cortex: Associations With Anxiety and Depression

“…Finally, increased CM amygdala-rACC functional connectivity was associated with greater anxiety and depression in adulthood, while increased CM amygdala-anterior vmPFC structural connectivity was associated with greater anxiety and depression in childhood. Our results provide a novel view of developmental functional and structural connectivity within a neural circuit that has been implicated in a wide array of cognitive and emotional processes (79–82) and psychiatric disorders (18;36–38;44–46;83). …”

Aberrant Temporal Connectivity in Persons at Clinical High Risk for Psychosis

“…We speculate that this difference could be reflected in different patterns of dysconnectivity. For instance, symptoms could be related to failure of top-down cognitive control on subcortical nodes, in particular the amygdala (82) and hippocampus (83) and in fact, dysconnectivity in cognitive control networks has been shown in a variety of psychotic illnesses (84) (32). …”

Increased Resting-State Gamma-Band Connectivity in First-Episode Schizophrenia

“…Thus, the present results do not yield information on possible changes in structures such as the amygdala, thalamus, basal ganglia, and cerebellum, all of which have been implicated in connectivity disturbances in schizophrenia. [86][87][88][89][90][91][92] A cautionary note is also appropriate with regard to the chosen method of functional connectivity calculation: Although methods based on excluding same-phase signal components are currently the only available way of dealing with spurious interaction patterns due to signal mixing, and although these methods generally reveal connectivity structures much more clearly than uncorrected measures, 46,47 it should be kept in mind that this approach also discards true zero-phase interactions that are known to exist in the brain. 39 Finally, although the present study focused on the gamma band, oscillations of other frequency ranges have been also implicated in the pathophysiology of schizophrenia.…”