Structural findings in schizophrenia

Initial post-mortem analysis of brain abnormalities led to conflicting and negative results (e.g. Row-land & Mettler, 1949; Haug, 1962; Southard, 1915). The emergence of magnetic resonance imaging (MRI) has stimulated researchers to investigate structural brain deficits related to schizophrenia and a number of reviews can be found in the literature (e.g. Buckley, 1998; Chua & McKenna, 1995;

B.1.2 : Introduction - Structural findings in schizophrenia

Gur & Pearlson, 1993; McCarley et al, 1999a; Pearlson and Marsh, 1993; Pfefferbaum and Zipursky, 1991; Shenton et al., 1997, 2001; Kasai et al., 2002). This paragraph follows the exten-sive review by Shenton et al. (2001), which is based on 193 peer-reviewed studies.

The majority of studies failed in detecting any whole brain volume differences between

schizophrenic patients and matched normal controls (e.g. Bilder et al., 1994; Cannon et al., 1998;

Vita et al., 1995). One of the most robust findings is the enlargements of the lateral and third ventri-cles in schizophrenic patients (e.g. Buchsbaum et al., 1997; Cannon et al., 1998; DeLisi et al., 2004^; Kelsoe et al., 1998; Sanfilipo et al., 2000a; Staal et al., 2000). With regard to the frontal cortex find-ings are more ambiguous. There is evidence for reduced frontal lobe volume (e.g. Buchanan et al., 1998; Goldstein et al., 1999; Kuperberg et al., 2003), but several studies found no difference be-tween frontal lobe volumes of schizophrenic patients and controls (e.g. Baaré et al., 1999; Corey-Bloom et al., 1995; Wible et al., 1995).

Only few studies have focused on volumetric measurements of the parietal lobe and there are no clear conclusions. Niznikiewicz et al. (2000) reported a reversal of the normal (left > right) lateral-ization of the angular gyrus for male patients with schizophrenia. Such a reversed asymmetry in male schizophrenic patients was also shown by Frederikse and coworkers (2000) for the inferior parietal lobe.

Several subcortical structures have been under investigation. The corpus callosum, a white matter fiber tract connecting the two hemispheres, is of particular interest as Crow (1997, 1998) has sug-gested that cognitive deficits in schizophrenia might originate from disturbed interhemispheric com-munication. Though some studies reported negative results (e.g. Chua et al., 2000; Sachdev & Bro-daty, 1999), the majority of studies (e.g. Hoff et al., 1994; Pol et al., 2004;Tibbo et al., 1998; Ue-matsu & Kaiya, 1988) found a decreased volume of the corpus callosum in schizophrenia. Unfortu-nately, none of these studies tried to relate morphological findings to cognitive functioning.

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largement of the cavum septum pellucidum (CSP) is one of the most robust findings (e.g. DeLisi et al., 1993; Kasai et al., 2004; Kwon et al., 1998). Rakic and Yakovlev (1968) have suggested that large CSP reflect developmental abnormalities of surrounding structures (hippocampus, corpus cal-losum).

The basal ganglia structures (including the caudate, putamen, globus pallidus) are of particular in-terest as neuroleptic medication acts on receptors within these structures. Decreased caudate volume was found in previously unmedicated schizophrenic patients (Corson et al., 1999; Keshavan et al., 1998; Shihabuddin et al., 1998). In contrast, treatment with conventional neuroleptics led to an in-crease in caudate volume (Chakos et al, 1994; Corson et al, 2002;Keshavan et al., 1994; Shihabud-din et al., 1998).

The vast majority of morphological research in schizophrenia has studied the temporal lobes. Find-ings on whole temporal lobe volume are equivocal and all studies found the normal overall right >

left asymmetry to be preserved in schizophrenic patients (e.g. Bilder et al., 1994; Kawasaki et al., 1993). However, examining the temporal lobe as a whole might leave more subtle, regional mor-phological changes undiscovered and indeed, focusing on sub-areas of the temporal lobe led to new insights in schizophrenia. Numerous studies measuring gray matter volume in the superior temporal gyrus (STG) demonstrated a volume decrease (e.g. Gur et al., 2000; Kasai et al., 2003a; Menon et al., 1995; Shenton et al. 1992). Shapleske et al. (1999) have reviewed MRI studies of the planum temporale (PT), a subregion of the STG critical for the processing of language (Nakada et al., 2001). In normal subjects the PT in the left hemisphere is larger compared to the right PT and for schizophrenia this asymmetry is reduced. This is most likely caused by a reduction of the left-hemi-spheric PT volume (Barta et al., 1997; Kwon et al., 1999)

In addition to the STG, medial temporal lobe structures including the amygdala-hippocampal

com-B.1.2 : Introduction - Structural findings in schizophrenia

plex² and the parahippocampal gyrus have been examined. Results suggest volume reduction in the amygdala-hippocampal complex in chronic as well as first-episode schizophenia (e.g. Bogerts, et al., 1990; Heckers & Konradi, 2002, Hirayasu et al., 1998; Velakoulis et al., 1999; Whitworth et al., 1998).

Only a few longitudinal studies have addressed the time course of structural deficits in schizophre-nia. There is evidence for an increase of ventricular volumes over time (e .g. DeLisi et al.,1997, 1998; 2004; Nair et al., 1997), however some other studies found ventricular size to be static (e.g.

Vita et al., 1994; Jaskiw et al., 1994).

Compared to healthy controls, Gur et al. (1998) found a volume reduction of frontal and temporal lobes for patients with schizophrenia after a mean interval of 30 months. A more fine-grained analy-sis was done by Mathalon and coworkers (2001) who compared 2 structural MRI scans, on average 4 years apart. Beyond an expansion of cerebrospinal fluid volume, they found a gray matter decline in the right frontal lobe and bilaterally in the posterior part of the superior temporal lobe. A decline in volume of the left Heschl Gyrus and the left PT after an average time period of 1.5 years was re-ported by Kasai et al. (2003b).

Longitudinal studies were also conducted with subjects with childhood-onset schizophrenia (COS).

Jacobsen et al. (1998) found a reduction of temporal lobe structures (bilateral superior temporal gyrus, posterior superior temporal gyrus, right anterior superior temporal gyrus and left hippocam-pus) for COS patients. Moreover, a reduction of temporal gray matter during the course of 2 years was demonstrated by Rapoport et al. (1999). Patients with COS showed a decline of brain matter in frontal and parietal regions. Giedd et al. (1999) examined COS patients and at a 2-year-follow-up the volume of the amygdala had decreased, while the size of the lateral ventricles had increased. A study by Thompson and coworkers (2001) measured brain volumes at three time points with 2 year

2The amygdala and the hippocampus are combined in most MRI studies, because they are difficult to separate in the coronal slices obtained in most MRI studies.

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B.1.2 : Introduction - Structural findings in schizophrenia

intervals between. By applying a three-dimensional mapping technique to individual brain scans, it was possible to analyze “gray matter loss rates” on a fine-grained level. Gray matter loss started early in parietal regions and progressed later in the temporal lobes. The prefrontal cortex was only affected during later stages of the disease.

In sum, schizophrenia is related to structural changes (mainly loss of gray matter) in a variety of brain regions. Among the most robust findings are: a) enlargement of the lateral ventricles, b) re-duced STG and c) medial temporal lobe volume. Further subcortical structures (particularly the basal ganglia), the parietal (mainly the inferior part) as well as the frontal cortex showed abnormali-ties in several studies. However, One should be cautious in interpreting these deficits as specific to schizophrenia, as especially medial temporal regions were also shown to be abnormal in other dis-eases. A reduction of the caudate volume was also reported for depressive patients (Krishnan et al., 1992). The volume reduction of the amygdala-hippocampal complex is also non-specific to

schizophrenia and was observed in depression (e.g. Dreverts et al., 1992), bipolar patients (e.g. Hi-rayasu et al., 1998) and post-traumatic stress disorder (e.g. Gurvits et al., 1996). Moreover, enlarge-ment of the CSP was also found in a group of psychotic bipolar patients (Kwon et al., 1998).