Volumetric White Matter Abnormalities in First-Episode Schizophrenia: A Longitudinal, Tensor-Based Morphometry Study

Westmead Millennium Institute, Sydney, New South Wales, Australia
American Journal of Psychiatry (Impact Factor: 12.3). 08/2007; 164(7):1082-9. DOI: 10.1176/appi.ajp.164.7.1082
Source: PubMed


While schizophrenia has long been considered a disorder of brain connectivity, few studies have investigated white matter abnormalities in patients with first-episode schizophrenia, and even fewer studies have investigated whether there is progressive white matter pathology in the disease.
The authors obtained a T1-weighted structural magnetic resonance imaging (MRI) scan on 41 patients with first-episode schizophrenia. These first-episode schizophrenia patients were analyzed relative to 47 age- and sex-matched healthy comparison subjects who also underwent an MRI scan. Of the baseline participants, 25 first-episode schizophrenia patients and 26 comparison subjects returned 2 to 3 years later for a follow-up scan. To identify regional volumetric white matter differences between the two groups at baseline, voxel-based morphometry in statistical parametric mapping-2 (SPM2) was used, while tensor-based morphometry was used to identify the longitudinal changes over the follow-up interval.
The first-episode schizophrenia patients exhibited volumetric deficits in the white matter of the frontal and temporal lobes at baseline, as well as volumetric increases in the white matter of the frontoparietal junction bilaterally. Furthermore, these first-episode schizophrenia patients lost considerably more white matter over the follow-up interval relative to comparison subjects in the middle and inferior temporal cortex bilaterally.
These results indicate that patients with schizophrenia exhibit white matter abnormalities at the time of their first presentation of psychotic symptoms to mental health services and that these abnormalities degenerate further over the initial years of illness. Given the role that white matter plays in neural communication, the authors suggest that these white matter abnormalities may be a cause of the dysfunctional neural connectivity that has been proposed to underlie the symptoms of schizophrenia.

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    • "(2014), as opposed to structural abnormalities to the gray matter regions connected by these fasciculi per se. However, while a number of studies have identified WM abnormalities in patients with schizophrenia, including with electron microscopy (Uranova et al., 2007), structural MRI (Hulshoff Pol et al., 2004a; Hulshoff Pol et al., 2004b; Whitford et al., 2007) and Diffusion-Tensor Imaging (DTI) (Karlsgodt et al., 2008; Price et al., 2007; Skelly et al., 2008; Zalesky et al., 2011), there have been no studies (to our knowledge) that have specifically investigated the WM abnormalities associated with delusions of control. "
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    ABSTRACT: Background: Delusions of control are among the most distinctive and characteristic symptoms of schizophrenia. Several theories have been proposed that implicate aberrant communication between spatially disparate brain regions in the etiology of this symptom. Given that white matter fasciculi represent the anatomical infrastructure for long-distance communication in the brain, the present study investigated whether delusions of control were associated with structural abnormalities in four major white matter fasciculi. Methods: Ten schizophrenia patients with current delusions of control, 13 patients with no clinical history of delusions of control, and 12 healthy controls underwent a Diffusion-Tensor Imaging (DTI) scan. Deterministic tractography was used to extract the corpus callosum, superior longitudinal fasciculus, arcuate fasciculus, and cingulum bundle. The structural integrity of these four fasciculi was quantified with fractional anisotropy (FA) and compared between groups. Results: The patients with delusions of control exhibited significantly lower FA in all four fasciculi, relative to the healthy controls. Furthermore, the patients with delusions of control also exhibited significantly lower FA in the cingulum bundle relative to patients without a history of this symptom, and this difference remained significant when controlling for between-group differences in global SAPS score and medication dosage. Conclusions: The results suggest that structural damage to the cingulum bundle may be involved in the etiology of delusions of control, possibly because of its role in connecting the action initiation areas of the premotor cortex with the cingulate gyrus.
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    • "e l s e v i e r . c o m / l o c a t e / s c h r e s 2001; Kubicki et al., 2007; Whitford et al., 2007) and although many of these alterations have been reported in relatives of people with schizophrenia (Boos et al., 2007: meta-analysis), there is a relative paucity of studies investigating the neuroanatomical substrates of language in the illness. In the extant FHR literature (see Table 1), only four publications from two research groups (from Pittsburgh and Edinburgh) have reported on the neural substrates of language in FHR individuals. "
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    ABSTRACT: Neuroanatomical and cognitive alterations typical of schizophrenia (SZ) patients are observed to a lesser extent in their adolescent and adult first-degree relatives, likely reflecting neurodevelopmental abnormalities associated with genetic risk for the illness. The anatomical pathways for language are hypothesized to be abnormal and to underlie the positive symptoms of schizophrenia. Examining non-psychotic relatives at high familial risk (FHR) for schizophrenia may clarify if these deficits represent trait markers associated with genetic vulnerability, rather than specific markers resulting from the pathological process underlying schizophrenia.
    Full-text · Article · Aug 2012 · Schizophrenia Research
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    • "Post-mortem studies of chronic SZ support the existence of an ICM deficit with cytology data revealing cortical glial deficits in SZ due primarily to lower numbers of oligodendrocytes and myelin stain data confirming an ICM deficit that seems particularly prominent in the frontal lobes (Hof et al., 2002; Flynn et al., 2003; Hof et al., 2003; Chambers and Perrone-Bizzozero, 2004; Uranova et al., 2004; Vostrikov et al., 2007; Beasley et al., 2009; Parlapani et al., 2009; Schmitt et al., 2009; Uranova et al., 2011) (reviewed in Bartzokis, 2011). Imaging studies that assessed white matter volume (Bartzokis et al., 2003; Ho et al., 2003; Whitford et al., 2007; Cocchi et al., 2009) (reviewed in Bartzokis, 2002; Bartzokis, 2011) provided consistent evidence of a deficient myelination trajectory that, unlike the rising trajectory of healthy individuals, ceases its development during early adulthood. These divergent trajectories are consistent with post-mortem cytology data that show significant age-related increases in intracortical oligodendrocyte numbers in normal individuals and decreasing numbers in SZ (Vostrikov et al., 2007; Vostrikov and Uranova, 2011). "
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    ABSTRACT: Imaging and post-mortem studies suggest that frontal lobe intracortical myelination is dysregulated in schizophrenia (SZ). Prior MRI studies suggested that early in the treatment of SZ, antipsychotic medications initially increase frontal lobe intracortical myelin (ICM) volume, which subsequently declines prematurely in chronic stages of the disease. Insofar as the trajectory of ICM decline in chronic SZ is due to medication non-adherence or pharmacokinetics, it may be modifiable by long acting injection (LAI) formulations. Assess the effect of risperidone formulation on the ICM trajectory during a six-month randomized trial of LAI (RLAI) versus oral (RisO) in first-episode SZ subjects. Two groups of SZ subjects (RLAI, N=9; and RisO, N=13) matched on pre-randomization oral medication exposure were prospectively examined at baseline and 6 months later, along with 12 healthy controls (HCs). Frontal lobe ICM volume was assessed using inversion recovery (IR) and proton density (PD) MRI images. Medication adherence was tracked. ICM volume change scores were adjusted for the change in the HCs. ICM volume increased significantly (p=.005) in RLAI and non-significantly (p=.39) in the RisO groups compared with that of the healthy controls. A differential between-group treatment effect was at a trend level (p=.093). SZ subjects receiving RLAI had better medication adherence and more ICM increases (chi-square p<.05). The results suggest that RLAI may promote ICM development in first-episode SZ patients. Better adherence and/or pharmacokinetics provided by LAI may modify the ICM trajectory. In vivo MRI myelination measures can help clarify pharmacotherapeutic mechanisms of action.
    Full-text · Article · Jul 2012 · Schizophrenia Research
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