Diffusion-weighted MRI has linked impairment of white matter (WM) microstructure to worse cognitive performance in schizophrenia, especially slower processing speed. However, these studies have been limited to small samples.
To facilitate the creation of large datasets, the Psychiatry Neuroimaging Laboratory at Brigham and Women’s Hospital developed and validated a novel method to harmonize diffusion-weighted MRI data from different centers several years ago.
Johanna Seitz-Holland, PhD, a research fellow in the Department of Psychiatry at the Brigham, Marek Kubicki, MD, PhD, associate director of the Psychiatry Neuroimaging Laboratory, and colleagues recently became the first to investigate cognitive deficits in schizophrenia in a large-scale, thoroughly harmonized sample. Their dataset was international and came from 13 independent sites. In Molecular Psychiatry, they report deficits across cognitive domains, largely independent of age and sex and related to positive symptoms and WM microstructure.
Prevalence of Cognitive Deficits
Compared with healthy individuals, those with schizophrenia demonstrated worse performance in all eight cognitive domains studied: language, processing speed, vigilance, working memory, verbal memory, nonverbal memory, motor function, and executive function.
The effect sizes were medium to large; the largest was for processing speed. 20% to 50% of individuals with schizophrenia had results of more than one standard deviation below the mean.
Cognition and Demographics
The possibility that brain aging is accelerated in schizophrenia is fiercely debated. The only effect of age in this study was that younger and older individuals with schizophrenia demonstrated significantly more impairment in vigilance than middle-aged individuals.
The only significant effect of sex was on working memory, a domain in which males with schizophrenia were more severely impaired than females.
Cognition and Symptom Severity
Seven positive symptoms were examined: delusions, disorganization, hallucinations, excitement, grandiosity, suspiciousness, and hostility. Impairments in processing speed, vigilance, and verbal memory were significantly associated with greater severity of positive symptoms.
No correlations were observed between cognitive deficits and negative symptoms, perhaps because only two negative symptoms were studied: blunted affect and emotional withdrawal.
Cognition and Medication
Information about lifetime medication and duration of medication exposure was unavailable. However, on the day of MRI scanning, the researchers calculated the current chlorpromazine equivalent dosage. Higher daily dosages were related to better processing speed, working memory, and executive function but also to worse language performance.
Cognition and WM Microstructure
Whole-brain fractional anisotropy (FA, a measure of WM organization) was unrelated to cognitive performance in healthy individuals. In individuals with schizophrenia, higher FA (indicating a more organized WM microstructure) was associated with better performance in five domains: language, processing speed, working memory, verbal memory, and nonverbal memory.
Additional analyses suggested processing speed partially explains the association between a diagnosis of schizophrenia, WM microstructure, and three cognitive deficits: language, working memory, and nonverbal memory.
It’s not possible to deduce causality from cross-sectional data. Still, these findings suggest schizophrenia is characterized by widespread disruptions in WM microstructure that affect all aspects of cognitive functioning through processing speed.
Cognitive deficits in general and processing speed, in particular, might be vital biomarkers that could be used to assess brain functioning, treatment response, and disease outcome. Novel treatment strategies are needed that focus on cognitive training to improve processing speed and protect WM microstructure.