MRI Findings May Identify a Biomarker in People with Schizophrenia who Will Develop Psychosis

Lay Summary

MRI findings may identify a biomarker in people with schizophrenia who will develop psychosis

Investigators will use a type of fMRI imaging to see whether disconnections in a specific brain network are a biomarker for identifying clinically high risk schizophrenia patients who will develop a first episode of psychosis. Alternatively, these changes may be a cause of the “conversion” to psychosis, occurring at the time this conversion occurs.

People who are at clinically high risk of schizophrenia exhibit extreme social isolation and other cognitive and behavioral problems. About one-quarter of these clinically high risk people “convert” to psychosis, which is characterized as having emotions and thoughts indicative of a break with reality. The investigators made observations in patients, then conducted animal model studies to try to identify physiological signs of conversion to psychosis, and now will test their findings in patients.

In their animal model studies, the investigators used “resting-state functional connectivity MRI” (rs-fcfMRI)—where animals were at rest rather than performing any specific task—and found structural abnormalities in connections between two areas in the basal ganglia: the “dorsal caudate nucleus” and the “globus pallidus.” These abnormal connections can affect the needed regulatory balance between excitatory (dopamine) and inhibitory (GABA) neurotransmission. They found that the indirect pathway used by GABA to send inhibitory signals reduced or blocked the direct pathway used by dopamine to transmit its excitatory signals.

Now they will translate these animal model findings into a clinical study. They will determine whether abnormal connectivity between the dorsal caudate nucleus and globus pallidus is a biomarker that predicts conversion to psychotic disorder among patients at clinical high risk, or whether this abnormal connectivity is a cause of psychosis and occurs at the time of conversion.

The investigators hypothesize that dis-connectivity between these two brain areas will occur only in high risk patients who then go on to convert to psychosis. This would support the biomarker possibility. Secondarily, they hypothesize, if this reduction in connectivity is not evident in high risk individuals prior to conversion, reduced connectivity will manifest during conversion to psychosis, consistent with being a causal neural process of psychosis.

They will enroll 60 clinically high risk patients, of whom at least 15 are expected to convert to psychosis within two years; and 25 healthy volunteer adults. All participants will undergo a baseline (pre) and post rs-fcMRI scan so that investigators can see whether changes in connectivity occur only in patients who convert to psychosis (biomarker hypothesis) or whether the changes occur as part of psychosis (causal hypothesis).

This second scan will be undertaken in any patient converting to psychosis immediately following this event to compare the patient’s pre-post connectivity changes; also at those times, a healthy volunteer will be scanned for comparison of any “normal” connectivity changes occurring over that same time period. All remaining (“non-converted”) high risk patients and healthy volunteers will undergo the second scan two years from the start of the study.

In this way, investigators will be able to determine: 1) normally occurring brain connectivity changes, if any, over time in the two brain areas of interest in healthy volunteers; 2) whether there are connectivity changes in about 25 percent of the clinically high risk patients that differ from this “norm (biomarker):” or 3) whether these connectivity changes are seen only in high risk patients after they convert to psychosis (causal process).

Significance: Determining whether altered connectivity is a biomarker of conversion to psychosis or is a causal process of psychosis, is anticipated to lead to new methods to prevent or treat psychosis.

Abstract

Functional Connectomics of Clinical High Risk for Psychosis: Development of a Novel Prognostic Marker

The pathophysiology of psychosis and psychotic disorders such as schizophrenia remains unknown. Recent work in a mouse model of schizophrenia, the dopamine 2 receptor overexpressing (D2R-OE) mouse, which was designed to model the well-established enhanced dopamine function in the associative striatum observed in patients with schizophrenia has revealed a highly plastic D2R-mediated increase in axonal collaterals projecting from D1R-containing medium spiny neurons in the dorsal striatum to the external segment of the globus pallidus (GPe). Preliminary study of unmedicated patients with schizophrenia motived by this animal model and using resting-state functional connectivity fMRI (rs-fcMRI) has suggested that this neuropathology, which in mice is responsive to treatment with haloperidol, may also be presents in patients. Specifically, these patients exhibit a decrease in rs-fcMRI between the dorsal caudate nucleus (DCa) and the GPe, which was expected based on the fact that the excess collaterals observed in the D2R-OE mice are GABA-ergic (inhibitory). This Dana Foundation David Mahoney Neuroimaging Program application seeks to extend the study of this potential biomarker of psychosis to patients in the prodromal phase of the illness, who are at clinical high risk for psychosis (CHR), with the aim of determining whether 1) CHR patients who later convert to a full psychotic disorder exhibit altered DCa-GPe connectivity relatives to patients who do not convert, or 2) whether the emergence of this neural abnormality is concurrent with the emergence of frank psychotic symptoms, which would be consistent with a causal neural mechanism of psychotic symptoms. Specifically, 60 CHR patients, 15 of whom are expected to convert to a full psychotic disorder based on historical conversion rates in our prodromal clinic, and 25 healthy controls will undergo a baseline rs-fcMRI scan and a follow-up scan following conversion to a psychotic disorder or after 2 years, or (for control participants) at a time interval matching that of a CHR patient who converts to psychosis. Imaging will be carried out using state-of-the-art high temporal- and spatial-resolution multiband fMRI, with 2 mm isotropic voxels and an 850 ms TR, primarily in order to accurately image small subcortical regions-of-interest such as the GPe and GPi (the internal segment of the pallidum), which will be obtained from anatomical tracings along with 5 striatal subregions in each hemisphere, as well as the thalamus. These ROIs will all be entered together in a network (partial correlation) model in order to specifically identify any alteration in converted CHR patients in DCa-GPe connectivity after accounting for the densely interconnected nature of basal ganglia-thalamocortical loops. If successful, this project has the potential to either 1) identify a neural marker of risk for conversion to a psychotic disorder, or to 2) identify a causal neural mechanism of psychosis, either of which could be transformative for attempts to develop novel treatments, or even preventions, for this debilitating illness.