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Altered Connections Between Cortex and Striatum Mark Risk for Psychosis

September 17, 2013. Different signaling patterns between the cortex and striatum distinguish the brains of people with first-episode psychosis from those of control subjects, reports a study published online September 4 in JAMA Psychiatry. Moreover, the same circuit alterations are present in their healthy relatives.

Using resting-state functional magnetic resonance imaging (fMRI), Alex Fornito of Monash University in Melbourne, Australia, and colleagues at the University of Cambridge, U.K., examined patterns of co-activation between the striatum’s subregions and the cortical regions that target them. This revealed patterns of over- and under-coordination of activity in people with psychosis and those at genetic risk for it: In particular, dorsal regions of the striatum seemed decoupled from their cortical partners, whereas ventral regions showed overly tight connectivity with them, compared to healthy controls.

The striatum in focus
The findings suggest a vulnerability that may allow psychosis entry to the brain. Early on, prior to the development of full-blown psychosis, signs of aberrant brain signals can be detected in people at risk for psychosis (e.g., see SRF related news story). But it has been unclear whether this really indicates genetic risk or whether these abnormalities reflect the mild, intermittent psychotic experiences that put these people into the clinical at-risk category. In the new study, the researchers study people newly ill with psychosis, as well as their unaffected first-degree relatives; these people share some of the genetic risk for the disorder, but none of the psychosis. Anomalies detected in both groups, then, could reflect the risk state.

A recent study with this design implicates numerous brain networks (Khadka et al., 2013), and the new study focuses on the complicated connections between the striatum and cortex. The striatum has been seen as a locus of psychosis because its rich dopaminergic innervation makes it a candidate target of antipsychotic action. Previous work focused on the ventral parts of the striatum in psychosis, which receive inputs from limbic parts of the cortex as does the orbitofrontal cortex (OFC) involved in emotion and motivation. Recent studies, however, have suggested a role for the dorsal parts, also called the “associative” striatum, which receive inputs from cortical regions involved in cognition, such as the dorsolateral prefrontal cortex (DLPFC): Aberrant dopamine signaling localizes to the dorsal striatum in people showing mild signs of psychosis (see SRF related news story) and in people with schizophrenia (Kegeles et al., 2010; see also SRF Q&A with Anissa Abi-Dargham).

The new study examines the state of these dorsal and ventral striatal-cortical networks in psychosis and in people at genetic risk for psychosis. Using resting-state fMRI, the researchers measured the extent to which any two brain regions were simultaneously active while the study participant rested in the scanner: Regions that turn on and off in lockstep likely work together and are deemed to be functionally connected.

Seeds of psychosis
First author Alex Fornito and colleagues scanned 19 people with their first episode of psychosis, 25 of their unaffected first-degree relatives, and 26 healthy controls. The diagnoses of those with psychosis mainly consisted of schizophrenia or bipolar disorder. With the resulting images, the researchers selected six regions within the caudate and the putamen—the two main components of the striatum—spanning the dorsal and ventral parts. They then asked how activity in these predefined seed regions varied with activity in the rest of the brain.

To get at disease-related changes in how information flowed along the dorsal and ventral networks, the researchers compared those individuals with psychosis to controls. This revealed abnormally low functional connectivity in the dorsal network and abnormally high functional connectivity in the ventral network. Specifically, those with psychosis showed reduced connectivity between the dorsal caudate and DLPFC, but unusually heavy connectivity between the superior ventral caudate (sVC) and its limbic cortical partner, the OFC. The sVC also showed strong connectivity with the left DLPFC, a connection not seen at all in controls. This crossed connection suggests that the boundary between the ventral and dorsal systems is blurred in the brains of people who develop psychosis. A similar pattern held true for the dorsal and ventral parts of the putamen, and connectivity findings did not seem to vary with antipsychotic medication.

Risk regions
The unaffected relatives shared the same pattern of under-connectivity in the dorsal network and over-connectivity in the ventral network, suggesting this pattern marks a brain vulnerable to psychosis. Specifically, compared to controls, unaffected relatives showed weak functional connectivity between the dorsal caudate and DLPFC, and heavy connectivity between the sVC and the OFC. A similar gradient of connectivity was seen for the putamen regions. The magnitude of this over- and under-connectivity did not differ from that found in people with psychosis. Yet one key difference emerged: The unaffected relatives did not show a crossed connection between the ventral striatum and the DLPFC, which suggests that transitioning from risk to actual illness involves problems in additional circuits.

The researchers suggest that diminished dorsal connectivity triggers the ventral network problems; for example, enhanced dopamine signaling detected in dorsal striatum could promote noisy signals there, resulting in disjointed signaling between cortex and dorsal striatum, which could compromise top-down cognitive processes. This, in turn, may allow for runaway crosstalk between the ventral striatum and its cortical partners, which could lead to aberrant salience, a process that assigns importance to irrelevant stimuli and so could provide the grist for psychosis (Kapur, 2003).

Consistent with this, among people with psychosis, the weaker the connections between dorsal caudate and frontal cortical regions, the worse their psychotic symptoms, as measured by the positive symptom scores on the Brief Psychiatric Rating Scale (R = -0.53, p = 0.2). Although a positive correlation was also found between ventral corticostriatal network connectivity strength and positive symptom severity, this was not significant. The researchers also reported that lower connectivity between the dorsal caudate and the left DLPFC in particular correlated with worse negative symptom scores, which suggests this connection may be particularly relevant to schizophrenia.

Despite the tangle of connections between striatum and cortex, the research suggests some organization to the aberrant connectivity that appears in mental illness. This may stem from deviations in early brain development, which seems to follow a fairly basic blueprint (see SRF related news story). Future research will have to probe how genetic or environmental factors prod a vulnerable brain to full-blown illness.—Michele Solis.

Fornito A, Harrison BJ, Goodby E, Dean A, Ooi C, Nathan PJ, Lennox BR, Jones PB, Suckling J, Bullmore ET. Functional Dysconnectivity of Corticostriatal Circuitry as a Risk Phenotype for Psychosis. JAMA Psychiatry. 2013 Sep 4. Abstract

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