The neurobiology of conversion to psychosis – emerging findings from the SHARP study

The clinical high risk (CHR) phase of schizophrenia when cognitive and social functioning begin to decline is associated with an imminent risk for psychosis. Imaging data (structural MRI, diffusion-weighted MRI, resting-state functional MRI) and event-related potentials from a sample of CHR individuals taking part in the SHARP (Shanghai At-Risk for Psychosis) study, most of whom had never taken an antipsychotic, were presented at IEPA 2018. They provide important preliminary insights into the neurobiology of conversion to psychosis.

Decreased main language network cortical thickness in CHR-C individuals

Language circuits are among the earliest affected by schizophrenia

Elisabetta del Re, Assistant Professor in Psychiatry, Harvard Medical School, MA, presented an analysis of structural MRIs for a variety of selected brain regions from 22 individuals with clinical high risk (CHR) who had converted to psychosis (CHR-C), 130 with CHR who had not converted to psychosis (CHR-NC) and 92 healthy controls (HCs).

Significant group differences were observed in cortical thickness in the main language network brain regions.

In individuals with CHR-C, correlations between cortical thickness and surface area were distinct from those for HCs and individuals with CHR-NC.

Cellular changes precede the onset of psychosis

Free-water diffusion MRI enables an evaluation of the extracellular space, by modeling extracellular free water and water, explained Ofer Pasternak, Assistant Professor in Psychiatry and Radiology, Harvard Medical School, MA. Extracellular pathologies such as inflammation, atrophy, density and vascular changes can therefore be distinguished from cellular changes such as deformation and demyelination.

Cellular changes may result from altered neurodevelopmental processes

Professor Pasternak described the use of diffusion MRI to explore white matter alterations in 50 individuals with CHR from the SHARP study and 50 HCs.

The results suggest that cellular changes precede the onset of psychosis and may result from altered neurodevelopmental processes. No differences were observed in free water, but Professor Pasternak predicts that free water will be observed as an acute response closer to the time of onset of psychosis.

Abnormal functional connectome organization precedes onset of psychosis

A study of baseline connectome organization of 251 participants in the SHARP study — 23 individuals with CHR-C, 135 with CHR-NC, and 93 HCs — was presented by Guusje Collin, Postdoctoral Research Fellow, Harvard Medical School, MA.

Functional connectome reorganization may accompany transition to psychosis

The modular connectome organization of CHR-C individuals was significantly less similar to HCs than for CHR-NCs. Abnormalities were most pronounced in brain regions commonly associated with schizophrenia, and conversion to psychosis was three times higher in CHR individuals with abnormal baseline connectome organization.

dMMN amplitude is reduced in CHR individuals with psychosis

Mismatch negativity (MMN) is a component of the event-related potential (ERP) that tracks neural changes in milliseconds as an interface between behavioral output and neurophysiological mechanisms, explained Yingying Tang, Shanghai Mental Health Center, Shanghai, China. It is one of the most robust and replicable findings in schizophrenia and is a candidate biomarker for predicting transition to psychosis.

dMMN amplitude may act as a predictor of remission

Dr Tang presented a study of auditory MMNs in 106 individuals with CHR (at 1-year follow-up 18 were CHR-C, 88 were CHR-NC) and 90 HCs:

  • individuals with CHR, particularly those who had not remitted or those who converted to psychosis 1 year later, had reduced duration of MMN (dMMN) amplitudes
  • individuals with CHR whose psychotic symptoms remitted had relatively intact dMMN amplitudes at baseline

dMMN amplitude is therefore sensitive to remission from psychotic symptoms and may act as a predictor of remission, and also a target for early intervention.