Selected Publications

A Prefrontal Thalamocortical Readout for Conflict-Related Executive Dysfunction in Schizophrenia

Anna Huang

Cell Reports Medicine

Executive dysfunction is a key aspect of schizophrenia, often linked to deficits in the dorsolateral prefrontal cortex (dlPFC). This study developed a task to engage the human dlPFC and its interaction with the mediodorsal thalamus (MD), revealing that individuals with schizophrenia show specific performance deficits when attention is directed by conflicting cues, reminiscent to that observed in mice after MD inactivation. These performance deficits correlate with lateralized MD-dlPFC functional connectivity, providing a neural marker that predicts susceptibility to conflict during working memory tasks. Additionally, in healthy subjects, this MD-dlPFC network predicts behavior during a probabilistic reversal task, suggesting potential biomarkers for executive function in schizophrenia informed by animal circuit studies.

Cerebellar structure and cognitive ability in Psychosis 

Alexandra Moussa-Tooks

Biological Psychiatry

Smaller cerebellar gray matter volume has been found in schizophrenia spectrum disorders. However, the course of these deficits across illness stage, specificity to schizophrenia (vs. psychosis more broadly), and relationship to clinical phenotypes, primarily cognitive impairment, remain unclear. Using gold standard methods to quantify cerbellum structure on structural magnetic resonance images in a large cohort of individuals with psychosis (n=357) and health people (n=217) we found that smaller cerebellar volume was limited to patients with low premorbid cognitive functioning. These effects were more pronounced in areas of cerebellum involved in cognitive function. Our results implicated atypical neurodevelopment of the cerebellum and suggest further research examining the impact of early-life risk factors for psychosis on the development of the cerebellum and cognition is warranted.

Development of thalamocortical structural connectivity in typically developing and psychosis spectrum youth

Suzanne Avery

Biological Psychiatry: CNNI

Thalamocortical white matter connectivity is disrupted in psychosis and is hypothesized to play a role in its etiology and associated cognitive impairment. Attenuated cognitive symptoms often begin in adolescence, during a critical phase of white matter and cognitive development. However, little is known about the development of thalamocortical white matter connectivity and its association with cognition. To address these knowledge gaps, we examined thalamocortical white matter connectivity in youths aged 8-22 years. Total connectivity of the thalamus was weakly associated with age and unrelated to psychopathology or cognition. However, microstructural integrity of thalamocortical tracts, indexed by fractional anisotropy, increased with age, was higher in males, and was lowest in youths on the psychosis spectrum. Moreover, greater white matter integrity in connections linking thalamus to prefrontal and posterior parietal cortices correlated with better cognitive function. The findings highlight the significance of thalamocortical white matter microstructure in cognitive development and its potential as a risk marker for psychosis. 

Altered bed nucleus of the stria terminalis and amygdala responses to threat in combat veterans with PTSD

Brandee Feola

Journal of Traumatic Stress

Fear involves responses to immediate, predictable threats and is mediated by the amygdala, while anxiety involves responses to potential, unpredictable threat and is driven by the bed nucleus of the stria terminalis (BNST). PTSD has been linked to fear brain network amygdala, but it remains unknown how the anxiety network is altered. Our study found that veterans with PTSD showed stronger activation in the BNST and greater connectivity between the BNST, amygdala, and other brain regions linked to fear and anxiety. In contrast, veterans without PTSD had stronger brain connections in neutral conditions, suggesting a potential neural marker of resilience to PTSD. These findings highlight how disruptions in the fear and anxiety networks may contribute to PTSD and could help identify new targets for treatment.

Altered Brain and Physiological Stress Response in Early Psychosis 

Brandee Feola

Schizophrenia Research

Stress is proposed to be a crucial factor in the onset and presentation of psychosis. The early stage of psychosis provides a window into how stress interacts with the emergence of psychosis. Yet, how people with early psychosis respond to stress remains unclear. In this study, we report preliminary evidence that people with early psychosis showed heightened response to stressful and non-threatening situations, across multiple levels of stress responses. Our findings suggest a novel perspective on stress alterations in early psychosis and highlight the importance of considering both stressful and non-stressful situations.  

Characterizing effects of age, sex and psychosis symptoms on thalamocortical functional connectivity in youth 

Anna Huang

Neuroimage

This study investigated the developmental and sex effects on thalamocortical functional networks in youth, using a large sample from the Philadelphia Neurodevelopmental Cohort. We examined cortical functional connectivity of seven thalamic nuclear groups, identifying age-related decreases in functional connectivity with sensory/motor areas and increases with prefrontal and parietal areas, particularly in thalamic motor and sensory nuclei. Sex differences were noted, with females showing greater connectivity with the visual cortex and males with the inferior frontal and orbitofrontal cortices. Effects of clinical symptomatology were analyzed by separating youth into three groups based on their clinical symptoms; typically developing youth (n = 298), psychosis spectrum youth (n = 320), and youth with other psychopathologies (n = 482). Youth with psychosis spectrum symptoms exhibited decreased thalamic connectivity with premotor and prefrontal cortices, and higher symptoms correlated with lower connectivity between the prefrontal cortex and mediodorsal thalamus, providing insights into neurodevelopmental disruptions.

Brain function during stages of working memory in schizophrenia and psychotic bipolar disorder

Anna Huang

Neuropsychopharmacology

Working memory (WM) is impaired in psychotic disorders and linked to functional outcome. WM is composed of multiple processes, including encoding and maintenance, and the delineation of the neurobiology of these sub-processes has not been well characterized in schizophrenia and psychotic bipolar disorder. Using fMRI, we found that both schizophrenia and psychotic bipolar disorder groups demonstrate encoding- and maintenance-related impairments in the posterior parietal cortex (PPC) and frontal eye fields (FEF). BOLD response in the PPC and FEF, during encoding and maintenance respectively, was associated with task performance. Encoding-related activation in the PPC also correlated with general neuropsychological functioning independent of group. Our results are consistent with PPC dysfunction in WM impairment and suggest interventions targeting neural activation in PPC may improve WM and neuropsychological functioning across psychotic disorders.  

Data-driven, connectome-wide analysis identifies psychosis specific brain correlates of fear and anxiety

Brandee Feola

Molecular Psychiatry

Negative emotions, such as fear and anxiety, play important roles in psychosis, yet the brain basis of negative emotions is relatively unknown. We examined the brain basis of fear and anxiety in people with psychosis utilizing a data-driven approach using the Human Connectivity Early Psychosis Project (HCP-EP). Our results validated decades of hypothesis driven studies demonstrating the amygdala, hippocampus, and insula are pivotal for fear and anxiety. Importantly, our study also discovered a psychosis specific association between an amygdala/ hippocampus cluster and the ventromedial prefrontal cortex (vmPFC), with stronger connectivity linked to more severe anxiety symptoms in the psychosis group, but not in controls. The study suggests that the amygdala, hippocampus, and insula play key roles in fear and anxiety, and identifies a unique brain pattern in psychosis that could inform new treatment approaches.

Lifespan development of thalamic nuclei and characterizing thalamic nuclei abnormalities in schizophrenia using normative modeling

Anna Huang

Neuropsychopharmacology

Thalamic abnormalities are implicated in schizophrenia and other neurodevelopmental disorders, but understanding their etiology and impact on illness phenotypes is challenging due to unknown developmental trajectories and individual differences. This study used normative models from the Human Connectome Project Lifespan datasets to characterize thalamic nuclei volume development and applied these models to an independent clinical cohort with schizophrenia. The models revealed diverse non-linear age effects, with association nuclei showing negative effects in youth and older age, while sensorimotor nuclei volumes remained stable until older age. Up to 18% of individuals with schizophrenia had abnormally small mediodorsal and pulvinar volumes, which correlated with cognitive impairment severity, highlighting the importance of normative modeling for identifying individuals and advancing precision medicine.

Thalamic nuclei volumes in psychotic disorders and youth with psychosis spectrum symptoms

Anna Huang

American Journal of Psychiatry

The study investigated thalamic structural abnormalities in psychosis and their relationship to cognitive function. Using a validated method for segmenting thalamic nuclei and voxel-based morphometry, we examined a sample of 472 adults and 1,393 youths from the Philadelphia Neurodevelopmental Cohort. The findings revealed that individuals with psychosis had smaller volumes in the pulvinar, mediodorsal, and ventrolateral nuclei compared to healthy controls, with similar reductions in pulvinar volume observed in youths with psychosis spectrum symptoms. Additionally, smaller pulvinar volumes were positively correlated with general cognitive function, suggesting that thalamic association nuclei abnormalities are linked to both psychosis risk and cognitive impairment.