Once someone becomes ill with schizophrenia, does the brain remain in a steady state, processing information in the same way? Or, does it change over the course of the disorder? A new study published online July 30th in Biological Psychiatry suggests the latter possibility: the patterns of brain activity in people in the first year of illness differed from that found in those who had been ill for several years. The findings suggest that some therapies may need to be fine-tuned to the stage of a person’s illness.

First author Alan Anticevic, Ph.D., 2012 NARSAD Young Investigator Grantee, with colleagues at Yale University School of Medicine and a research team at China Medical University in Shenyang, used brain imaging to scan and monitor functional connectivity in the prefrontal cortex (PFC), a brain region that supports higher executive functions such as reasoning, which is known to contribute to schizophrenia onset and progression. Recent studies have indicated that glutamate dysfunction—glutamate is the brain’s main excitatory neurotransmitter, essential for neural communication, memory formation and learning—may produce hyper-connectivity in the PFC, a condition linked to schizophrenia.

The researchers compared the effects of blocking a particular type of glutamate receptor (N-methyl-D-aspartate or NMDAR) on PFC functional connectivity in both healthy volunteers and those in various stages of schizophrenia. Building upon recent work showing widespread disruption of global brain connectivity in people with schizophrenia during what is called “resting state,” the researchers measured PFC functional connectivity during resting state after administering the medication ketamine that blocks glutamate receptor activity.

They found that individuals in the early stage of schizophrenia (28 people) showed higher-than-normal PFC connectivity during resting state in certain PFC areas while those with chronic schizophrenia (20 people) had lower-than-normal connectivity in certain PFC areas. This new work points to a more nuanced version of glutamate dysfunction and its impact on PFC connectivity in schizophrenia, suggesting more evidence for over-activity and hyper-connectivity in the early stages of illness and perhaps under-activity in certain areas in later stages of the illness.

Longitudinal studies that follow the brain states of the same person over the course of their illness will be critical to confirm this difference. In the meantime, the findings offer a possible explanation for recent failed clinical trials, which included people at all stages of schizophrenia. Perhaps people in earlier stages would be helped by medications that are not effective for people with later-stage illness.

Other NARSAD Grantees involved in this study included: Fei Wang, Ph.D. (2008 & 2012 NARSAD Young Investigator Grantee); Philip Corlett, Ph.D. (2008 NARSAD Young Investigator Grantee); Peter Thomas Morgan, M.D., Ph.D. (2004 NARSAD Young Investigator Grantee); Naomi Driesen, Ph.D. (2000 & 2003 NARSAD Young Investigator Grantee), and Foundation Scientific Council Member John Krystal, M.D. (three-time NARSAD Grantee).

Read the abstract of this research paper.

Learn more about this research from the Schizophrenia Research Forum.