White Matter Integrity and Cognitive Impairment in First-Episode

Article

White Matter Integrity and Cognitive Impairment in First-Episode Psychosis Rocío Pérez-Iglesias, M.D., Ph.D. Diana Tordesillas-Gutiérrez, M.Sc. Philip K. McGuire, F.R.C.Psych., Ph.D. Gareth J. Barker, Ph.D. Roberto Roiz-Santiañez, M.Sc. Ignacio Mata, M.D., Ph.D. Enrique Marco de Lucas, M.D. Jose Manuel Rodríguez-Sánchez, Ph.D. Rosa Ayesa-Arriola, M.Psych. Jose L. Vazquez-Barquero, M.D., Ph.D. Benedicto Crespo-Facorro, M.D., Ph.D.

Objective: Impaired cognitive function has been identified as a core feature of schizophrenia. However, a significant proportion of patients do not show any cognitive deficits. The aim of this study was to assess if there were differences in white matter integrity between patients with and without cognitive impairment. Method: A diffusion tensor imaging study and neurocognitive assessment were conducted in 49 patients with firstepisode psychosis and 41 healthy comparison subjects. Subjects were assessed using the Continuous Performance Test, the Grooved Pegboard Test, the Rey Auditory Verbal Learning Test, and the Trail M aking Test Part B. For each test, the patient sample was subdivided according to performance, with those scoring more than one standard deviation below the normative mean categorized as impaired. For each cognitive domain, white matter fractional anisotropy in deficit and nondeficit subgroups was compared using a voxel-based analysis. A nonparametric statistical method, controlling for multiple comparisons, was applied.

Results: Impairment on the Trail M aking Test Part B was associated with reduced fractional anisotropy in the right/left anterior thalamic radiation and inferior frontooccipital fasciculus, forceps minor, and left superior and inferior longitudinal fasciculi. Patients exhibiting Grooved Pegboard Test impairment showed reduced fractional anisotropy in the forceps minor, inferior fronto-occipital fasciculus, anterior thalamic radiation, and corticospinal and corticopontine tracts. Impaired performance on the Rey Auditory Verbal Learning Test and Continuous Performance Test was not associated with significant differences in fractional anisotropy. Conclusions: Deficits in executive and motor functioning in patients with firstepisode psychosis are associated with reductions in white matter integrity in the major fasciculi that connect the frontal and temporal cortices as well as in pathways connecting cortical and subcortical regions. Their presence at the onset of illness, in minimally medicated patients, indicates that these findings are not attributable to effects of chronic illness or its treatment. (Am J Psychiatry 2010; 167:451–458)

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mpaired cognitive function has been identified as a core feature of schizophrenia (1). Functional MRI studies have consistently provided evidence of disturbed cognitive function in patients with schizophrenia relative to comparison subjects (2–4), but the pathological processes underlying such impaired cognitive function are not known. Disruptions of white matter networks have been proposed as a potential mechanism for cognitive dysfunction in schizophrenia and in other neurological pathologies such as dementia (5), multiple sclerosis (6) and traumatic brain injury (7). However, not all patients with schizophrenia show a cognitive impairment. Within the diagnostic category of schizophrenia in DSM-IV there may be a wide range in cognitive performance, from relatively intact cognition to severe deficits. Whether this corresponds to different pathophysiological processes is unclear. In a recent study, Wexler et al. (8) found that relative to healthy comparison

subjects, neuropsychologically impaired patients had significantly smaller white matter volumes in several regions, whereas patients with no cognitive deficit (within 0.5 SD of healthy comparison subjects) did not differ from healthy subjects. The authors suggest that white matter pathology may play a primary role in the cognitive deficits, and that the differences observed between the two subgroups might correspond to differences in the disease process. Diffusion tensor imaging has been proven to be a useful technique for detecting structural abnormalities in the white matter of individuals with cognitive impairment (9– 13). In schizophrenia, only a few studies have investigated the association between white matter connections and cognitive performance (14–20). The findings to date have been inconclusive, perhaps due to the wide heterogeneity in the study populations and in the imaging methodologies used. In the present study, using a voxel-based analysis method, we investigated white matter integrity—in patients

This article is discussed in an editorial by Dr. Kubicki (p. 373). Am J Psychiatry 167:4, April 2010

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COGNITIVE IMPAIRMENT IN FIRST-EPISODE PSYCHOSIS TAB L E 1 . Cognitive Performance of First-Episode Psychosis Patients Compared With Healthy Volu nteers and b y Defi cit Classifi cation Subject Group Patients (N=49) Mean Test Value

Domaina

SD

Deficit Classificationb

Comparison Subjects (N=41) Mean Test Value

SD

Analysis p

Patients With No Deficit Mean z Score

SD

Patients With Deficit Mean z Score

SD

Analysis p

Attention 68.17 14.93 78.34 1.99