Sensory contributions to third visual pathway dysfunction in schizophrenia: correlation and causation

The National Institute of Mental Health awarded $1,463,483 to the Research Foundation For Mental Hygiene, Inc., operating through its Nathan S Kline Institute, on September 19, 2025, under the Mental Health Research Grants program (CFDA 93.242) to investigate sensory contributions to third visual pathway dysfunction in schizophrenia, with work performed in Orangeburg, New York through July 31, 2030.

The project examines neural mechanisms underlying social cognitive deficits in schizophrenia by developing and applying multimodal neuroimaging approaches—including event-related potentials and functional magnetic resonance imaging—to measure dysfunction in the third visual pathway, a primate-specific neural circuit specialized for processing social information. The research integrates naturalistic viewing fMRI, co-activation pattern state analysis, and personalized high-definition transcranial direct current stimulation concurrent with fMRI and EEG data acquisition to identify and reverse visual sensory-level dysfunction in schizophrenia patients. The project builds on prior work demonstrating interrelated impairments in motion-sensitive middle temporal cortex and posterior superior temporal cortex activation that correlate with impaired face emotion recognition, reduced sensitivity to face motion in social scenes, and altered connectivity within third visual pathway structures.

The Trustees of Columbia University in the City of New York, operating through its Health Sciences Division, serves as a sub-recipient on the award, sharing in delivery of the research activities.

Abstract

Schizophrenia (SZ) is associated with deficits in social cognitive function that represent a core feature of the disorder. At present, the neural mechanisms underlying these impairments remain relatively unknown and no specific treatments are available. A recent advance in the conceptualization of human social cognition is the description of a primate specific third visual pathway (TVP) that is specialized for processing of social information. This pathway preferentially utilizes motion input relayed through the primary visual (V1) and motion- sensitive middle temporal cortex (MT+) into the posterior superior temporal cortex (PSTS), an area known to respond to a variety of dynamic social cues including faces and bodies. This project builds from three convergent recent projects within our group. First, we have developed a multimodal ERP/FMRI approach sensitive to TVP dysfunction in SZ and have demonstrated significant interrelated impairments in both MT+ and PSTS activation which, in turn, correlate with impaired face emotion recognition (FER). Second, using naturalistic viewing FMRI (NV-FMRI) we have demonstrated that individuals with SZ show reduced sensitivity to face motion within a social scene and altered patterns of connectivity within TVP structures, including the pulvinar nucleus of the thalamus. Most recently, using CO-activation pattern (cap) state analysis, we have demonstrated decreased occupancy in SZ of states that are associated with increased activity in visual, face processing and TVP regions and increased occupancy of cap states associated with visual system deactivation. Finally, we have developed expertise in simultaneous application of personalized high-definition transcranial direct current stimulation (PHD-TDCS) concurrent with both FMRI and EEG data acquisition for reversal of visual sensory-level dysfunction in SZ. In preliminary within-subject data, we have observed that PHD-TDCS over MT+ significantly enhances not only MT+ activation to random-DOT kinematogram (RDK) stimuli, but also PSTS activation to dynamic face emotion stimuli. These activation changes are associated with correlated improvements in motion sensitivity and FER. Here, we will combine these three currently separate lines of investigation - sensory-level visual assessment, NV-FMRI, and PHD-TDCS - to 1) evaluate mechanisms underlying TVP and social cognitive dysfunction in SZ, and 2) develop potential approaches for future clinical TVP-targeted therapy. Participants will include 120 SZ and 30 healthy control volunteers, who will participate in baseline ERP and FMRI assessments of TVP function along with clinical measures of social function and global outcome. Directional analyses will investigate the relationship between baseline sensory-level visual dysfunction, higher-tier TVP dysfunction, social cognition and global outcome. SZ participants will additionally be randomized to active (CATHODAL) VS. Sham MT+-targeted PHD-TDCS. Convergent ERP and FMRI outcome measures will assess potential causality in the relationships between improved sensory-level motion processing and improved higher-tier TVP function. If successful, the project will provide crucial pilot data for longer term PHD-TDCS-enhanced social cognitive remediation approaches.