Brain Patterns May Flag Risk for Schizophrenia

Deborah Brauser

October 03, 2018

A specific pattern of brain circuitry may help predict whether patients at risk for psychosis will go on to develop schizophrenia, new imaging research suggests.

Dr Tyrone Cannon

In a study of 182 patients deemed to be at clinical high risk for psychosis, findings from functional MRI (fMRI) scans indicated a significant association between increased connectivity in the cerebello-thalamo-cortical network at baseline and later development of the disorder.

Investigators note that this display of "an intrinsic 'trait-like' abnormality in brain architecture" was more pronounced in patients who converted to schizophrenia than those who did not. The abnormality was also associated with symptoms of disorganization and was predictive of conversion time to psychosis.

In a second patient sample, only those with a previous diagnosis of schizophrenia were found to have this pattern of hyperconnectivity. Those with a diagnosis of bipolar disorder or of attention-deficit/hyperactivity disorder (ADHD), as well as their healthy peers, did not show this pattern.

"What's new is that we used a method to assess how the connectivity of different brain networks operate across a whole set of tasks, not just one separate task condition or paradigm," senior author Tyrone D. Cannon, PhD, professor of psychology and psychiatry at Yale University, New Haven, Connecticut, told Medscape Medical News.

"What's interesting about the detected pattern is that very large components of it are related to these integrated brain regions that are involved in error monitoring and in timing and coordination of information flow," said Cannon.

"We were pleasantly surprised because those particular sets of regions, and their particular roles, could help us understand why people with psychotic illnesses have such troubles with thought, belief, and perception," he added.

The findings were published online September 21 in Nature Communications.

Major Challenges

"Understanding the fundamental alterations in brain functioning that lead to psychotic disorders remains a major challenge in clinical neuroscience," the investigators write.

"In particular, it is unknown whether any state-independent biomarkers can potentially predict the onset of psychosis and distinguish patients from healthy controls, regardless of paradigm," they add.

To combat that, they assessed multiparadigm fMRI data from two different cohorts: the North American Prodrome Longitudinal Study (NAPLS-2) and the Consortium for Neuropsychiatric Phenomics (CNP) study.

The NAPLS-2 project, which recruited participants from eight sites in the United States and Canada, provided data on 302 participants, including 120 who acted as healthy controls (HCs). The remaining 182 were at clinical high risk for psychosis at baseline. Of these, 19 went on to convert to psychosis, and 163 did not convert.

"At risk" was defined as having had a "recent emergence of some psychotic-type features that collectively portend a high risk for psychosis within about a 2-year window from the time that they're initially ascertained," Cannon explained.

All of the participants underwent fMRI scans for five paradigms: resting state, verbal working memory, episodic memory retrieval, episodic memory encoding, and emotional face matching.

Significant Connectivity

After controlling for variables such as age, sex, and IQ, "we observed a highly significant group effect on a connected network including a total of 84 edges linking pairs of 62 nodes covering multiple brain regions in the cerebellum, thalamus, and cerebral cortex," the investigators report (P = .005).

"In particular, the regions in the identified network belonged to seven functional systems," they add. These included the subcortical-cerebellar, sensorimotor, visual, auditory, default-mode, frontoparietal, and attentional systems.

Connectivity between these regions was significantly higher in the patients at risk for psychosis than for the HC group — and the effect was even higher in the patients who converted to schizophrenia vs those who did not. This suggests "a paradigm-independent connectivity alteration that precedes onset of psychosis," the researchers write.

After averaging paradigm "connectivity matrices," there was a significant group effect for functional connectivity of the cerebello-thalamo-cortical network during all five paradigms (P < .04).

Using the Scale of Prodromal Symptoms, the investigators also found a significant association between network connectivity and disorganization symptoms in the patients at risk for psychosis (P = .02), but not in the HC group (P = .41).

"These findings suggest that the observed hyperconnectivity may be related to bizarre thought and behavior in individuals with prodromal symptoms," note the researchers.

There was also a significant correlation between connectivity in the network and number of months to conversion (P = .04), suggesting that higher connectivity was linked to shorter conversion time.

Supplementary analyses of 11 patients who converted, 40 patients who did not convert, and 40 of their healthy peers, all of whom were unmedicated, also showed significant group differences in connectivity of the identified network (P < .001). Again, the strongest association was in those who converted to schizophrenia, then those who did not, then the HC group.

In a subsample of NAPLS-2 participants followed for at least 24 months, for the group of 19 patients who converted, the mean association with cross-paradigm connectivity in the network was significantly greater than for the group of 103 patients who did not convert (P = .004).

Verification Study Cohort

After discovery of the functional network among the NAPLS-2 consortium, the investigators then sought network verification among 262 participants in the CNP study. This sample included 123 individuals who made up the HC group, as well as 50 patients with schizophrenia, 49 with bipolar disorder, and 40 with ADHD.

All completed some or all of seven paradigms, including a "balloon-analogue" risk-taking task, a color-shape task, and a "go–no go" stop signal task.

After controlling for age, sex, IQ, and dosage of antipsychotic medication, there was a significant group effect on cross-paradigm connectivity in the network (P = .025). This was mostly caused by the differences found between the group with schizophrenia and the HC group (P = .02).

"Moreover, there tended to be a gradient elevation of the degree of hyperconnectivity in the identified network with the increase of prevalence of psychotic symptoms in the populations," the researchers write.

In other words, the highest elevation in connectivity was in the group of patients with schizophrenia, followed by the groups of patients with bipolar disorder and with ADHD, respectively. The lowest elevation was in the HC group.

There was also a significant association between network hyperconnectivity and scores on the thought disorder subscale of the Scale for the Assessment of Positive Symptoms (P = .035).

"First Evidence"

Overall, the findings from the two cohorts provide "the first evidence for cerebello-thalamo-cortical hyperconnectivity as a state-independent neural trait for psychosis prediction and characterization," the investigators write.

"Future research is encouraged to replicate these findings and to investigate the nuanced role of this circuitry in relation to cognitive, symptomatic, and other features of psychotic illness," they add.

Asked whether there were any clinical implications from the findings, including the possibility of influencing treatment decisions, Cannon answered, "I hope it gets to that.

"At this stage, I'd say its major clinical import is that we could potentially use functional MRI as an adjunctive assessment tool to help predict who is most at risk for developing psychosis. And in that sense, then yes, it could provide the rationale for providing more treatment for those at higher risk," he said.

For now, "we're still at a stage of verifying these predictive patterns in a research mode," he added.

The investigators are currently assessing whether the connectivity pattern deteriorates with the development of more severe symptoms. They also want to evaluate whether treatment can correct the connectivity pattern "in a way that would support the resolution of symptoms," Cannon said.

The study was funded by a NARSAD Young Investigator Grant, by grants from the National Institutes Health, and by the Staglin Music Festival for Mental Health and the International Mental Health Research Organization. Dr Cannon reported having served as a consultant for Boehringer-Ingelheim Pharmaceuticals and Lundbeck A/S. The other study authors have reported no relevant financial relationships.

Nat Commun. Published online September 21, 2018. Full article

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