A new network-based neuroimaging study seeks to identify biomarkers across the spectrum of impairment in schizophrenia.
Negative symptoms in schizophrenia are important predictors of functional outcome in schizophrenia. The deficit syndrome, or “deficit schizophrenia,” refers to patients with primary, enduring negative symptoms, including blunted affect, apathy, anhedonia, and asociality. There is evidence-in terms of risk factors, neuroimaging, response to treatment, and disease course-that the deficit schizophrenia may represent a separate disease within the syndrome of schizophrenia. However, clinical heterogeneity has hindered neurobiological studies of neural correlates in schizophrenia.
Toward identification of biomarkers across the spectrum of impairment in schizophrenia, Wheeler and colleagues1 performed a network-based neuroimaging study of 128 patients with schizophrenia and 130 matched controls, as well as 39 patients with bipolar I disorder and 43 matched controls, over a 5-year period at three clinical sites. The authors hypothesized that patients with deficit schizophrenia would have alterations in cortical network properties (primarily in frontal and parietal brain regions) compared with patients with non-deficit schizophrenia and controls, and not present in bipolar I disorder.
Based on clinical rating scales of psychotic symptoms, patients in the highest quartile of the validated “Proxy for the Deficit Syndrome” were classified as having deficit schizophrenia, and those in the lowest quartile as having non-deficit schizophrenia. All subjects underwent magnetic resonance brain imaging. Mean cortical thickness was calculated at 52 distinct brain regions, from which network-level properties were assessed using graph theoretical approaches.
For each subject group, the average age was between 41 and 51, the average age of illness onset was between 23 and 27, and slightly more than half of all subjects were male. Patients with deficit schizophrenia had significantly stronger frontoparietal and frontotemporal network coupling than both patients with non-deficit schizophrenia and controls. By contrast, patients with non-deficit schizophrenia and bipolar I disorder did not show significant differences in coupling compared with controls. The cortical networks formed by patients with deficit schizophrenia showed an increased density of connections compared with both patients with non-deficit schizophrenia and controls. By contrast, there were no differences in network density between patients with bipolar I disorder and controls.
Using brain connectomics, the authors found a highly correlated structural brain network in patients with deficit schizophrenia. This is the first study with graph theory-based results to associate heterogeneity in clinical and neuroimaging findings in schizophrenia. They found evidence that deficit schizophrenia is characterized by distinct impairments in neural circuitry.
The authors suggested that the increased density in structural coupling networks may reflect altered early neurodevelopment in patients with deficit schizophrenia. This suggested decreased differentiation of distinct brain regions during development, resulting in a disruption in healthy synchronized brain maturation. The identified abnormal brain regions include the mirror neuron system, which are important in processing of emotion and social cognition.
Potential limitations of the study were that patients were evaluated at 3 different clinical sites with different MRI acquisition parameters. The authors also noted that alterations in brain structure could be an epiphenomenon of antipsychotic medication effects, although exposure did not differ between patients with deficit and non-deficit schizophrenia. These findings represent an important step toward novel therapeutic approaches for negative symptoms and social cognition in schizophrenia.
Dr Miller is Assistant Professor in the Department of Psychiatry and Health Behavior at Georgia Regents University and Schizophrenia Section Editor for Psychiatric Times.
1. Wheeler AL, Wessa M, Szeszko PR, et al. Further neuroimaging evidence for the deficit subtype of schizophrenia: a cortical connectomics analysis. JAMA Psychiatry. 2015;72:446-455.