• Hallucinations: A Functional Network Model of How Sensory Representations Become Selected for Conscious Awareness in Schizophrenia

      Hare, Stephanie M (Frontiers Media S.A., 2021-11-23)
      Hallucinations are conscious perception-like experiences that are a common symptom of schizophrenia spectrum disorders (SSD). Current neuroscience evidence suggests several brain areas are involved in the generation of hallucinations including the sensory cortex, insula, putamen, and hippocampus. But how does activity in these regions give rise to aberrant conscious perceptions that seemingly invade ongoing conscious experience? Most existing models assume that sensory representations are sometimes spontaneously activated in the brain, and that these spontaneous activations somehow play a causal role in the generation of hallucinations. Yet, it remains unclear how these representations become selected for conscious processing. No existing theory of hallucinations has specified such a "selection mechanism." Global Workspace (GW) theorists argue that the brain's interconnected processors select relevant piece(s) of information for broadcasting to other brain processors, rendering the information accessible to consciousness; this process known as "ignition" is associated with synchronized activity across distributed cortical and subcortical brain regions. Yet, it remains unclear how certain information and representations become selected for conscious processing. While GW theorists maintain that attention plays an important role, they have not delineated a formal "selection mechanism." This paper specifies a selection mechanism based upon two central hypotheses: (1) a functional network called the "salience network" plays a critical role in selecting sensory representations for conscious broadcast to the GW in normal (healthy) perception; (2) sensory representations become abnormally selected for conscious broadcast to the GW (instead of being filtered out of consciousness) in individuals with SSD that experience hallucinations.
    • Local versus long-range connectivity patterns of auditory disturbance in schizophrenia

      Hare, Stephanie M; Adhikari, Bhim M; Du, Xiaoming; Garcia, Laura; Bruce, Heather; Kochunov, Peter; Simon, Jonathan Z; Hong, L Elliot (Elsevier B.V., 2021-01-22)
      Auditory hallucinations are a debilitating symptom of schizophrenia. Effective treatment is limited because the underlying neural mechanisms remain unknown. Our study investigates how local and long-range functional connectivity is associated with auditory perceptual disturbances (APD) in schizophrenia. APD was assessed using the Auditory Perceptual Trait and State Scale. Resting state fMRI data were collected for N=99 patients with schizophrenia. Local functional connectivity was estimated using regional homogeneity (ReHo) analysis; long-range connectivity was estimated using resting state functional connectivity (rsFC) analysis. Mediation analyses tested whether local (ReHo) connectivity significantly mediated associations between long-distance rsFC and APD. Severity of APD was significantly associated with reduced ReHo in left and right putamen, left temporoparietal junction (TPJ), and right hippocampus-pallidum. Higher APD was also associated with reduced rsFC between the right putamen and the contralateral putamen and auditory cortex. Local and long-distance connectivity measures together explained 40.3% of variance in APD (P < 0.001), with the strongest predictor being the left TPJ ReHo (P < 0.001). Additionally, TPJ ReHo significantly mediated the relationship between right putamen – left putamen rsFC and APD (Sobel test, P = 0.001). Our findings suggest that both local and long-range functional connectivity deficits contribute to APD, emphasizing the role of striatum and auditory cortex. Considering the translational impact of these circuit-based findings within the context of prior clinical trials to treat auditory hallucinations, we propose a model in which correction of both local and long-distance functional connectivity deficits may be necessary to treat auditory hallucinations.
    • Mapping local and long-distance resting connectivity markers of TMS-related inhibition reduction in schizophrenia

      Hare, Stephanie M; Du, Xiaoming; Adhikari, Bhim M; Chen, Shuo; Mo, Chen; Summerfelt, Ann; Kvarta, Mark D; Garcia, Laura; Kochunov, Peter; Elliot Hong, L (Elsevier Inc., 2021-04-30)
      Short interval intracortical inhibition (SICI) is a biomarker for altered motor inhibition in schizophrenia, but the manner in which distant sites influence the inhibitory cortical-effector response remains elusive. Our study investigated local and long-distance resting state functional connectivity (rsFC) markers of SICI in a sample of N = 23 patients with schizophrenia and N = 29 controls. Local functional connectivity was quantified using regional homogeneity (ReHo) analysis and long-range connectivity was estimated using seed-based rsFC analysis. Direct and indirect effects of connectivity measures on SICI were modeled using mediation analysis. Higher SICI ratios (indicating reduced inhibition) in patients were associated with lower ReHo in the right insula. Follow-up rsFC analyses showed that higher SICI scores (indicating reduced inhibition) were associated with reduced connectivity between right insula and hubs of the corticospinal pathway: sensorimotor cortex and basal ganglia. Mediation analysis supported a model in which the direct effect of local insular connectivity strength on SICI is mediated by the interhemispheric connectivity between insula and left sensorimotor cortex. The broader clinical implications of these findings are discussed with emphasis on how these preliminary findings might inform novel interventions designed to restore or improve SICI in schizophrenia and deepen our understanding of motor inhibitory control and impact of abnormal signaling in motor-inhibitory pathways in schizophrenia.
    • Multiple dimensions of stress vs. genetic effects on depression

      Kvarta, Mark D; Bruce, Heather A; Chiappelli, Joshua; Hare, Stephanie M; Goldwaser, Eric L; Sewell, Jessica; Sampath, Hemalatha; Lightner, Samantha; Marshall, Wyatt; Hatch, Kathryn; et al. (Springer Nature, 2021-04-29)
      Many psychiatric disorders including depression involve complex interactions of genetics and environmental stressors. Environmental influence is challenging to measure objectively and account for in genetic studies because the necessary large population samples in these studies involve individuals with varying cultures and life experiences, clouding genetic findings. In a unique population with relative sociocultural homogeneity and a narrower range of types of stress experiences, we quantitatively assessed multiple stress dimensions and measured their potential influence in biasing the heritability estimate of depression. We quantified depressive symptoms, major lifetime stressors, current perceived stress, and a culturally specific community stress measure in individuals with depression-related diagnoses and community controls in Old Order Amish and Mennonite populations. Results showed that lifetime stressors measured by lifetime stressor inventory (R2 = 0.06, p = 2 × 10-5) and current stress measured by Perceived Stress Scale (R2 = 0.13, p < 1 × 10-6) were both associated with current depressive symptoms quantified by Beck Depression Inventory in community controls, but current stress was the only measure associated with current depressive symptoms in individuals with a depression diagnosis, and to a greater degree (R2 = 0.41, p < 1 × 10-6). A novel, culturally specific community stress measure demonstrated internal reliability and was associated with current stress but was not significantly related to depression. Heritability (h2) for depression diagnosis (0.46 ± 0.14) and quantitative depression severity as measured by Beck Depression Inventory (0.45 ± 0.12) were significant, but h2 for depression diagnosis decreased to 0.25 ± 0.14 once stressors were accounted for in the model. This quantifies and demonstrates the importance of accounting for environmental influence in reducing phenotypic heterogeneity of depression and improving the power and replicability of genetic association findings that can be better translated to patient groups.