Brain Connections Go Awry Before Psychosis Onset

Megan Brooks

August 12, 2015

Young people at clinical high risk (CHR) for psychosis show a particular pattern of neural disruption in communication involving the thalamus and the rest of the brain, new research shows.

"Critically, the pattern we observed in individuals at risk for psychosis was also observed in a more severe form in people who fully converted to psychosis later," lead author Alan Anticevic, PhD, of the Department of Psychiatry, Yale University, New Haven, Connecticut, told Medscape Medical News.

"The key clinical implication is that this evidence provides a possible method to understand what patterns of brain communication may predict future emergence of psychosis. This may point to neural treatment targets that could be amenable to earlier intervention (prior to full-blown psychosis onset)," he said.

The study by Dr Anticevic, senior author Tyrone Cannon, PhD, who is also from Yale and is principal investigator of the North American Prodrome Longitudinal Study, and colleagues was published online August 12 in JAMA Psychiatry.

Prognostic Brain Patterns

The researchers generated whole-brain thalamic functional connectivity maps for 243 people who experienced early warning symptoms of psychosis (the CHR group, which included 21 patients who converted to full-blown psychosis) and 154 healthy control individuals and followed them for 2 years.

They observed a widespread decrease in functional connectivity between the thalamus and prefrontal and cerebellar regions in the CHR group, which was more pronounced in the 21 individuals who developed full-blown psychosis. The CHR group also displayed hyperconnectivity between thalamus and sensory areas of the brain, which again was most evident in those who converted to full-blown psychosis.

"This study establishes that thalamocortical dysconnectivity is present in CHR states before psychosis onset," the investigators write. The patterns they uncovered are consistent with prior observations by the Yale team (and others) in patients with schizophrenia, they note.

In this latest study, the magnitude of thalamic dysconnectivity in both hyperconnected and hypoconnected regions correlated significantly with prodromal symptom severity, they point out.

This "fascinating result" in which both thalamocortical disconnectivity patterns correlated with the baseline levels of psychotic symptoms "opens the theoretical door to future translational interventions targeting abnormal functional brain connectivity on CHR patients," writes Paolo Fusar-Poli, MD, PhD, RCPsych, from the Department of Psychosis Studies, King's College London, United Kingdom, in a linked editorial.

The investigators caution that the relatively small number of patients in the study sample who converted (n = 21) "limits firm conclusions about whether this particular imaging phenotype is a true clinical predictor of conversion."

Dr Fusar-Poli agrees, noting that "nearly 40 years of inconclusive neuroimaging research in psychosis...should caution us against excessive enthusiasm when weighing the clinical effect of the findings by Anticevic et al."

Dr Fusar-Poli says external validation in large samples is needed to ensure that thalamocortical dysconnectivity can be consistently replicated in other CHR cohorts. Of "highest concern," he says, is that only 21 (8.6%) of the 243 baseline CHR patients had converted to frank psychosis after 2 years. A similar "low transition" rate (8%) was seen in the largest randomized clinical trial conducted on CHR patients.

"It seems alarming that 2 of the largest CHR research studies currently published reported an 8% transition risk at 2 years, which is dangerously too close to the 3% lifetime risk of psychosis observed in the general population. This finding clearly advocates for future studies elucidating the epidemiology of CHR," Dr Fusar-Poli writes.

"The near decade will be crucial to definitively tell us whether and to what extent the translational promises of Anticevic et al's findings and of neuroimaging methods in early psychosis have been kept," he concludes.

The study was supported by grants from the National Institute of Mental Health and the National Institutes of Health, the Brain and Behavior Research Foundation, and the Commonwealth Research Center. The authors and Dr Fusar-Poli have disclosed no relevant financial relationships.

JAMA Psychiatry. Published online August 12, 2015. Full text, Editorial

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