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SIRS 2014—Associative Striatum Linked to Prodromal Psychosis

August 7, 2014. Researchers took a fresh look at the dopamine hypothesis of schizophrenia in an afternoon SIRS session on Monday, April 7. There is a conception in the field that when it comes to excess dopamine in schizophrenia, "all the action is in the mesolimbic pathway," said chair and discussant Anissa Abi-Dargham, Columbia University, New York City. Historically, researchers have focused on the ventral striatum, but a lot is going on in the dorsal or "associative" region of the structure, she continued. Recent positron emission tomography studies find that the associative striatum has the greatest dopamine excess, and suggest that it is also where dopaminergic abnormalities first appear during the prodromal period (see SRF related news report; SRF news report).

Columbia University's Tiziano Colibazzi presented multimodal imaging evidence suggesting that at baseline, individuals at clinical high risk for development of psychosis have aberrant connectivity between the associative striatum and the dorsolateral prefrontal cortex (DLPFC). Specifically, he reported that high-risk subjects exhibited low fractional anisotropy, indicative of disorganized fiber tracts, in connections between the striatum and the frontal cortex. Functional connectivity analyses indicated a higher degree of centrality in the thalamus of high-risk subjects�meaning that there are more connections to and from the thalamus in these subjects than in controls�and increased connectivity between the ventral rostral putamen and thalamus. In a cognitive control task in which subjects must inhibit a response in order to perform a goal-directed behavior, high-risk subjects displayed hyperactivity in the dorsal and ventral striatum and hypoactivity in the DLPFC.

Camilo de la Fuente-Sandoval, from Mexico City's Instituto Nacional de Neurolog�a y Neurocirug�a, discussed proton magnetic resonance spectroscopy findings in a cohort at high risk for psychosis. He reported elevated levels of associative striatum glutamate at baseline in these subjects, similar to findings in antipsychotic-na�ve first-episode patients. A subsequent measurement after two years revealed that those who transitioned to psychosis had higher levels of glutamate at baseline. GABA levels, as well as a combined measure of glutamate and glutamine, were also elevated in the associative striatum in a second cohort of high-risk subjects.

Oliver Howes, King's College London, United Kingdom, reviewed data on the elevated striatal dopamine synthesis capacity in the psychosis prodrome (see SRF related news report; SRF news report). The elevation is found only in the associative striatum, not in other striatal subdivisions, and is specific to those who later convert to schizophrenia. In addition, the elevated dopamine synthesis capacity is also observed in the substantia nigra, which projects to the associative striatum. Howes then discussed several possible methodological caveats for these observations and wondered if the results could be an artifact of volume differences or measurement variability in different striatal regions.

In the only animal studies of the session, Bita Moghaddam, University of Pittsburgh, Pennsylvania, presented data suggesting that the associative striatum in rats is "uniquely different in adolescents compared to adults." This is surprising, she said, because this region has always been used as a control region. In contrast to adults, adolescents show very robust dorsal striatum activation in response to reward. In the nucleus accumbens, on the other hand, neural activity is similar between adolescents and adults.

In addition, studies using amphetamine show that dopamine release in the adolescent dorsal striatum is blunted, said Moghaddam. This hypoactivity may be the result of the reduced levels of tyrosine hydroxylase (TH)�the enzyme that synthesizes dopamine�that are present in the dorsal striatum of adolescent rats. These data suggest that reduced striatal activity may be a normal component of adolescent development that is disrupted in those especially vulnerable to schizophrenia, Moghaddam added. The adolescent dorsal striatum is also sensitive to a dietary deficiency in omega-3 fatty acid, which has been implicated in schizophrenia, she said, citing decreased levels of TH in a rat model of omega-3 fatty acid deficiency (Bondi et al., 2014).

The bottom line from the session, concluded Abi-Dargham, is that "the associative striatum is one of the earliest structures that shows alterations" in the process of moving from the ill-defined high-risk state to psychosis. It is interesting that dopamine, glutamate, and GABA are all increased in this one structure, she added.—Allison A. Curley.

 
Comments on Related News
Related News: High Dopamine Levels in People With Evidence of Prodromal Schizophrenia

Comment by:  Anissa Abi-Dargham, SRF Advisor
Submitted 28 January 2009 Posted 28 January 2009

This paper introduces new knowledge and at the same time replicates many of the themes that have emerged in the area of dopamine research and schizophrenia. The new knowledge is that DA dysregulation precedes onset, and is present in the same anatomical area and with a similar magnitude to that observed in schizophrenia. It shows once again that the dopamine dysregulation in schizophrenia is one of the most replicated and consistent findings in the field.

The area of pathology within the striatum is, as described in schizophrenia, the associative, rather than the limbic or sensorimotor striatum (Kegeles et al., 2006). This represents the main area of projection of the DLPFC. Furthermore, this part of the striatum receives input from other limbic cortical areas (Haber et al., 2006) and may play a role in integrating emotions and cognition. Alterations in this integrative function could lead to misattributions or mislabelings leading to paranoia or “inappropriate” affect, in addition to the cognitive deficits.

The relationship...  Read more


View all comments by Anissa Abi-Dargham

Related News: Signs of Things to Come? Seeking Biomarkers for the Schizophrenia Prodrome

Comment by:  Thomas McGlashan
Submitted 21 January 2012 Posted 21 January 2012

Three very recent publications have detailed that biomarkers can identify and quantify high-risk or prodromally symptomatic subjects who subsequently undergo conversion to psychosis. McGuire and his group (Howes et al., 2011) used fluoro-dopa positron emission tomography scanning to measure dopamine synthesis. Koutsouleris et al. (Koutsouleris et al., 2011) used structural MRI data to develop a neuroanatomical classification system for predicting psychosis conversion, and Amminger et al. (Amminger et al., 2011) used capillary gas chromatography of erythrocyte membrane fatty acid levels to provide information about brain phospholipids. All measures were significantly successful in identifying high-risk or prodromally symptomatic subjects who went on to develop a first episode of psychosis.

These papers point to an exciting future in our efforts to elaborate easily identifiable risk factors that can pinpoint among clinically identified...  Read more


View all comments by Thomas McGlashan

Related News: SIRS 2014—Refining Schizophrenia Clinical Drug Trials

Comment by:  Anthony Grace, SRF Advisor (Disclosure)
Submitted 4 June 2014 Posted 4 June 2014

This was an important symposium, but I am concerned about the impression that these findings suggest a problem with translating data from animal models to the clinic. In order to translate effectively, one must use an animal model that recapitulates as much of the disease state as possible, and acute pharmacological challenges are inadequate for this. Developmental models should be a more effective screen. But perhaps more important, there is a very big difference between animal models and clinical trials: In animal models, the first therapeutic drug that the animal sees is the novel target compound. In contrast, clinical trials comprise patients that have been treated for antipsychotic drugs for decades, then withdrawn for only a single week before the test compound is evaluated.

It has been known for quite some time that repeated D2 antagonists change the brain in substantial ways. In our recent paper (Gill et al., 2014), we found that a GABAA alpha 5 compound that was highly effective in reversing dopamine neuron...  Read more


View all comments by Anthony Grace
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