Probing the Effect of Psychosis on Brain Volume
8 May 2013. Schizophrenia is associated with volume reductions in a variety of brain regions, notably the hippocampus and frontal cortex (Glahn et al., 2008). Two recent longitudinal imaging studies attempt to refine this understanding by examining the effect of psychosis on brain volume at different timepoints of the illness. In a study published in Neuron on April 10, a team led by Holly Moore and Scott Small of New York’s Columbia University found hypermetabolism in the CA1 subfield of the hippocampus in patients at high risk for schizophrenia. After onset of psychosis, the abnormal metabolism spread to the subiculum and was accompanied by atrophy. Studies in mouse models implicated glutamate as the driver of these abnormalities.
In a second study, published online in the American Journal of Psychiatry April 5, Nancy Andreasen of the University of Iowa in Iowa City and colleagues imaged the brains of first-episode patients for several years following illness onset, finding that the duration of illness as well as treatment with antipsychotics was correlated with a decrease on several cortical brain volume measures.
Progressive hippocampal abnormalities
People with schizophrenia, on average, show volume reductions in the CA1 subfield of the hippocampus (Kühn et al., 2012). Small’s group at Columbia has previously shown that this subfield is overactive in schizophrenia subjects, and that these abnormalities hint at the transition from prodromal to full-blown psychosis (see SRF related news story). In the new Neuron study, first author Scott Schobel and colleagues extended their earlier findings by mapping hippocampal metabolism and structure using magnetic resonance imaging (MRI) in the same clinical high-risk subjects—25 patients with sub-threshold psychotic symptoms such as unusual thought content, suspiciousness, and conceptual disorganization. Participants were imaged twice, once while experiencing sub-threshold symptoms and again an average of 2.5 years later, after 40 percent of the subjects had been diagnosed with a psychotic disorder. Cerebral blood volume (CBV), indicative of metabolism, and structure were measured in several subfields: the entorhinal cortex, dentate gyrus, CA1, CA3, and the subiculum.
In at-risk subjects, hippocampal hypermetabolism was observed in CA1 alone, in the absence of any structural changes. However, after onset of psychosis, hypermetabolism had spread to the subiculum and was accompanied by volume loss in CA1 and the subiculum, most prominently in the anterior left hippocampus. Similar to the group’s earlier findings, CA1 CBV strongly predicted the amount of time before a patient developed psychosis. In fact, CA1 CBV was a better predictor of later psychosis than the degree of sub-threshold psychotic symptoms. Initial CA1 CBV values also predicted hippocampal atrophy at follow up. Taken together, these data suggest that hippocampal dysfunction progresses during the transition from prodromal to full-blown psychosis.
Modeling hippocampal dysfunction in mice
To examine the mechanisms underlying the hippocampal abnormalities observed in people with sub-threshold symptoms and those with diagnosed psychosis, Schobel and colleagues measured CBV following acute administration of the NMDA glutamate receptor antagonist ketamine (which models many of the symptoms of schizophrenia) in mice. Similar to the results observed in humans with psychosis, acute ketamine exposure produced hypermetabolism in CA1 and the subiculum. Chronic administration of ketamine for one month, given during adolescence and early adulthood (corresponding to the time period of greatest psychosis risk in humans) also led to increases in CA1 CBV, as well as volume loss in the ventral portion of the hippocampus.
To confirm that glutamate mediated the effect of ketamine on hippocampal CBV (since the drug is also known to act at other receptor types), the researchers measured extracellular glutamate response using an amperometric biosensor, and found that acute ketamine increased hippocampal glutamate in the CA1 and subiculum. This effect, along with the increases in hippocampal CBV, was abolished when mice were pretreated with the metabotropic glutamate receptor 2/3 (mGluR2/3) agonist LY379268, a drug known to reduce glutamate release, suggesting that glutamate was necessary for the ketamine-induced hippocampal hypermetabolism. Similar results were obtained after chronic ketamine treatment. In addition, chronic ketamine exposure, but not pretreatment, with LY379268 decreased the density of parvalbumin-containing interneurons, consistent with several animal models of the disease and reminiscent of alterations observed in schizophrenia (see SRF related news story; Lodge et al., 2009).
In an accompanying commentary, University of Pittsburgh’s Bita Moghaddam places the findings in the context of other recent data from high-risk patients suggesting an elevated dopamine synthesis capacity in the striatum and an altered relationship between striatal dopamine synthesis capacity and hippocampal glutamate levels (Egerton et al., 2013; Stone et al., 2010). Given that the striatum receives extensive projections from the hippocampus, Moghaddam suggests that the current findings may indicate that elevated hippocampal glutamate levels cause the observed dopamine abnormalities observed during the prodromal phase.
“In addition to clarifying mechanisms of disease, the results of our study have several clinical implications,” conclude the study authors. “CA1 hypermetabolism may be a possible state-specific biomarker of prodromal and early psychotic disorders.” Because hypermetabolism was found in at-risk patients prior to the atrophy that occurred after psychosis onset, their results support the importance of early detection and treatment prior to any loss of brain tissue.
Brain volume, relapse, and antipsychotics
In the second study, Andreasen and colleagues investigated brain tissue loss in schizophrenia over time in 202 first-episode patients followed for at least five years, obtaining over 600 MRI scans total. A total of 157 patients experienced at least one relapse (1.7 on average), while the remainder had no relapses or continued to be symptomatic, such that relapses were not detectable.
Total cerebral volume, cerebral white matter volume, and frontal lobe volume were significantly negatively related to relapse duration (the sum of all relapses in the time period between two scans), indicating that greater relapse duration is associated with tissue loss in some brain regions. By contrast, no relationship between relapse number and brain volume was observed. However, antipsychotic treatment (measured in dose-years of haloperidol equivalents) also negatively affected several brain volume measures including total cerebral volume, frontal lobe volume, temporal lobe volume, and the ventricle-to-brain volume ratio.
These data suggest that extended periods of relapse have a detrimental effect on the brain, as does treatment with antipsychotics, the main tool used in preventing relapses. The implication would seem to be that relapse prevention is important, but should be achieved with the lowest antipsychotic dose possible. However, as noted by the authors, their data do not necessarily indicate that relapse duration causes tissue loss. An alternative explanation may be that brain tissue loss and relapse duration are both associated with another variable—illness severity, for example—so that patients with a more severe form of the illness have more and longer relapses as well as lower volumes of some brain regions.—Allison A. Curley.
Andreasen NC, Liu D, Ziebell S, Vora A, Ho BC. Relapse Duration, Treatment Intensity, and Brain Tissue Loss in Schizophrenia: A Prospective Longitudinal MRI Study. Am J Psychiatry. 2013 Apr 5; Abstract
Moghaddam B. A mechanistic approach to preventing schizophrenia in at-risk individuals. Neuron. 2013 Apr 10 ; 78(1):1-3. Abstract
Schobel SA, Chaudhury NH, Khan UA, Paniagua B, Styner MA, Asllani I, Inbar BP, Corcoran CM, Lieberman JA, Moore H, Small SA. Imaging patients with psychosis and a mouse model establishes a spreading pattern of hippocampal dysfunction and implicates glutamate as a driver. Neuron. 2013 Apr 10 ; 78(1):81-93. Abstract