Mapping Structural Alterations of the Corpus Callosum during Brain Development and Degeneration

To determine whether there was a regionally selective pattern of callosal change accompanying AD pathology, the morphology of the callosum at the mid-sagittal plane was analyzed using a 5-sector partition which is relatively simple to apply (Fig. 1(a); Duara et al. (1991); Larsen et al., 1992). This resulted in an approximate segregation of callosal fibers belonging to distinct cortical regions (see Section 2). Since individual data were standardized by digital transformation into Talairach stereotaxic space (Talairach and Tournoux, 1988), regional cross-sectional areas of callosal subdivisions were determined both before and after stereotaxic transformation. When areas of specific sectors were compared between groups, the isthmus of the callosum was of particular interest, since fibers crossing in this area selectively innervate the temporo-parietal regions at risk for early neuronal loss in AD (Brun and Englund, 1981).

Localized Atrophy. Consistent with this hypothesis, a severe and significant reduction in the area of the callosal isthmus was found in AD relative to controls, reflecting a dramatic 24.5% decrease from 98.0 ± 8.6 mm² in controls to 74.0 ± 5.3 mm² in AD (p < 0.025; Fig. 7(b)). By contrast, the terminal sectors (1 and 5) of the callosum, corresponding to fibers crossing in the rostrum and splenium respectively, did not undergo a significant area reduction, with almost identical values in the control and patient group of 160.9 ± 9.6 mm² and 158.6 ± 14.3 mm² respectively for the rostral sector (p > 0.1), and 148.7 ± 8.6 mm² and 150.8 ± 6.8 mm² respectively for the splenial sector (p > 0.1). An observed 16.6% mean area loss in AD for the central midbody sector showed only a trend toward significance (p < 0.1), and an apparent 13.4% depression in mean anterior midbody area was statistically insignificant (p > 0.1), because of substantial inter-group overlap in the values of these parameters in the early stages of Alzheimer's Disease.

Fig. 7. Average Boundary Representations of the Callosum in (a) Normal Elderly Subjects (N=10), (b) Alzheimer's Disease patients (N=10). Average boundary representations of the midsagittal callosum in normal controls and patients with mild Alzheimer’s Disease (MMSE ~ 19.7 ± 5.7) indicate a severe reduction in the area of the isthmus in AD relative to controls, accompanied by a pronounced inflection in shape (white arrow) in the neighborhood of stereotaxic location (0.0,-25.0,19.0). The overlying sector representing the isthmus (2nd of 5, top panel), underwent a 24.5% reduction in area in AD compared with controls (p < 0.025).

Fig. 8. Maps of Stereotaxic Variability at the Corpus Callosum in Patients with Alzheimer’s Disease and in Elderly Normal Subjects. Separate maps of local variability were constructed for (bottom) Alzheimer's patients, and (top) control subjects, expressing (in color) the r.m.s. variation of callosal points in each subject group around an average boundary representation of the callosum, at the midsagittal plane of Talairach stereotaxic space. Unlike the asymmetry and variability maps in Fig. 9, these are strictly 2-dimensional maps, since the midsagittal analysis of callosal morphology is conducted in a single vertical plane. Average boundary representations have therefore been thickened for visualization purposes only. Two trends are apparent. Although the variability measure peaks at the rostrum, this may be an artifact, due to the difficulties of defining an unambiguous anatomical limit for the inferior aspect of the rostrum. Nevertheless, the pronounced rise in variability at the rostral midbody in AD, (bottom), may reflect disease-related enlargement of the third ventricle, which forms its inferior boundary.

Average Boundary Representations and Variability Maps. Selective changes in the CC accompanying AD pathology were examined in more detail by partitioning midsagittal sector outlines into upper and lower sectors. Average boundary representations (Fig. 7) and local variability maps (Fig. 8) were then made for the callosum in both subject groups. In both control and AD subjects, sectors showed a distinctly heterogeneous profile of variability in stereotaxic space (Fig. 8(a),(b)), with confidence limits on two-dimensional variation at the midsagittal plane varying from an SD of 2.0-3.3 mm at the inferior splenium, central midbody and genu, to 4.6-5.0 mm at the posterior aspect of the rostrum. Intriguingly, at the isthmus, where a significant area reduction was apparent in AD, the average callosal representations showed a slight reduction in thickness in AD relative to controls (Fig. 7(b)). In addition, a pronounced inflection in shape was demonstrated towards the inferior limit. This feature can be seen in Fig. 7(b), at stereotaxic location (0.0,-25.0,19.0). This morphology has also been observed in studies of callosal shape in schizophrenia (DeQuardo et al., 1996; Bookstein, 1997).

Sylvian Fissure Asymmetries. In view of the severe reduction in size at the isthmus, perisylvian areas where fibers in the isthmus originate were examined to determine whether their patterns of 3-dimensional variability and asymmetry were altered in the disease. Methods for mapping patterns of 3D cortical variation and asymmetry are discussed in detail in (Thompson et al., 1998); analysis of digital anatomic maps in normal aging and Alzheimer's Disease suggested a range of global and local disease-related differences (Fig. 9). Confidence limits on 3D cortical variation in controls showed a marked increase from 2-4 mm at the callosum to a peak of 12-13 mm at the external cerebral surface. In AD however, while variability was marginally higher than in controls at the callosal surface, the variability across the surface of the Sylvian fissure rose extremely sharply from an SD of 6.0 mm rostrally to 19.6 mm caudally on the left, and from 5.0 mm rostrally to 9.0 mm caudally on the right.

Although there is a substantial literature on Sylvian fissure cortical surface asymmetries (Eberstaller, 1884; Cunningham, 1892; Geschwind and Levitsky, 1968; Davidson and Hugdahl, 1994) and their relation to functional lateralization (Strauss et al., 1983), handedness (Witelson and Kigar, 1992), language function (Davidson and Hugdahl, 1994), asymmetries of associated cytoarchitectonic fields (Galaburda and Geschwind, 1981) and their thalamic projection areas (Eidelberg and Galaburda, 1982), no prior studies had mapped the spatial profile of asymmetries in 3 dimensional space. When Sylvian fissure asymmetries were mapped in 3 dimensions, the marked rostral and vertical extent asymmetries in controls (left posterior limit 9.7 mm more caudal than right; p < 0.0005) were severely increased in AD (left limit 16.6 mm more caudal than right; p < 0.0002), and between-hemisphere differences in the anterior-posterior position of the Sylvian fissure's posterior limit were also found to be significantly greater in Alzheimer's Disease than in matched controls (p < 0.05). Local maps (Fig. 10) also revealed a sharp rise in 3-dimensional asymmetry in AD, reaching 21.8 mm at the posterior limit of the left Sylvian fissure, compared with 15.4 mm in controls.

Asymmetric Progression of Alzheimer's Disease. Greater variability of the left perisylvian surface and greater Sylvian fissure asymmetry in AD suggests that AD pathology asymmetrically disrupts the anatomy of temporo-parietal cortex. In AD, Sylvian fissure CSF volume has also been shown to rise, relative to controls, more sharply on the left than the right (left volume: 31.5% higher in AD than controls (p < 0.02; N=32) but right volume only 20.4% higher (p < 0.09; Wahlund et al., 1993). Underlying atrophy and possible left greater than right degeneration of perisylvian gyri may widen the Sylvian fissure, superimposing additional individual variation and asymmetry on that already seen in normal aging (Fig. 9). Significant left greater than right metabolic dysfunction and cognitive impairment have been reported in both PET (Loewenstein et al., 1989; Siegel et al., 1996) and neuropsychiatric (Capitani et al., 1990) studies of AD, and in PET studies of related amnestic disorders (Corder et al., 1997). Recent PET studies have also examined cognitively normal subjects who are 'at risk' for AD in the sense that they experience mild memory complaints and have at least two relatives with AD (Small et al., 1995). Left greater than right metabolic impairment also appears in these subjects, and the deficit has been shown to be significantly more asymmetric in at-risk subjects carrying the apolipoprotein type 4 allele (ApoEe 4; a risk factor for familial AD) relative to those subjects without ApoEe 4 (Small et al., 1995). Accentuated patterns of structural asymmetry and variation found here in Alzheimer's Disease support these findings, suggesting either that (1) the left hemisphere is more susceptible than the right to neurodegeneration in AD, or that (2) left hemispheric impairment results in greater structural change and lobar metabolic deficits (Loewenstein et al., 1989).

Callosal Deficits in Alzheimer's Disease. An anatomically-specific relationship was observed in this and other studies (Lyoo et al., 1997) between putative fiber loss in callosal regions and the dynamic progression of cortical and lobar atrophy characteristic of AD. Size reduction and shape inflection were observed in callosal regions that map association areas at risk of selective metabolic loss and incipient atrophy in early stages of AD (Figs. 4 and 6). Greater resilience was observed in splenial sectors, which map the parieto-occipital and calcarine surfaces which are comparatively resistant to neuronal loss in AD (Pearson et al., 1985). Severe and regionally-selective areal loss and focal shape inflection at the isthmus may reflect disease-related disruption of the commissural system connecting bilateral temporal and parietal cortical zones, since these regions are known to be at risk for early metabolic dysfunction, perfusion deficits and selective neuronal loss in AD (DeCarli et al., 1996).

Differences between Normal Aging and Dementia. As noted earlier, controversy exists over whether different callosal regions undergo selective changes in aging and dementia (Yoshii et al., 1990), and even whether effects in dementia are significant compared to age-matched controls (Biegon et al., 1994). As found in Biegon et al. (1994), Black et al. (1996) and Kaufer et al. (1997), we did not find total callosal area to be significantly depressed in AD (mean ± SD: 525.9 ± 116.8 mm²) relative to controls (575.4±108.8 mm²; p > 0.05). These values (determined prior to stereotaxic normalization) are in broad agreement with, but marginally higher than, previously determined callosal area values (Biegon et al., 1994) of 562 ± 98 mm² in elderly controls (n=13; MR slice thickness: 10 mm; age: 64.8 ± 9.0 yrs.) and 480 ± 133 mm² in AD (p > 0.05; n=20; age: 70.1 ± 7.4 yrs., with slightly lower MMSE scores of 17 ± 7.2, and a range of 9-25). Both our data and those of Biegon et al. (1994), Black et al. (1996) and Kaufer et al. (1997) do not fully agree with earlier reports that total callosal area discriminated between AD and control subjects (Hofmann et al., 1995; p < 0.05), and that combined callosal area was significantly reduced in AD (by 7.0% relative to controls; p < 0.05; Yoshii et al., 1994). If selective AD-related atrophy occurs in specific callosal sectors (Black et al., 1996), when areas of these sectors are pooled with that of other more robust regions, they may or may not be significantly reduced, depending on disease severity.

Alzheimer's Disease and Schizophrenia. The finding that the same highly circumscribed site at the callosum (Fig. 8) shows a comparable shape inflection in schizophrenia (DeQuardo et al., 1996; Bookstein, 1997) is intriguing. Due to differences in the etiology of the two diseases, fiber deficiency at this site in schizophrenia may be associated with a neurodevelopmental disruption of the sulco-gyral organization of temporal lobe fibers that cross in this region (see Section 8; Kikinis et al., 1994). In AD, however, a similarly-localized fiber deficiency may result from temporo-parietal neuronal loss, associated with the early perfusion and cognitive performance deficits in AD. As noted already, a massive perinatal loss of callosal axons, lasting from the 35th gestational week to the end of the first post-natal month (Clarke et al., 1989; La Mantia and Rakic, 1990) leads to a restricted pattern of adult callosal connections, but controversy exists over whether callosal area is further reduced in normal aging relative to young normal controls (Biegon et al., 1994; cf. Doraiswamy et al., 1991). Callosal area reductions in AD may have functional significance, as smaller partial callosal size often reflects a focal decrease in the number of small diameter (< 3 µm) fibers (Aboitiz et al., 1992) or decreased myelin deposition, associated with decreased conduction velocity and longer interhemispheric transmission times. These and other callosal studies, interpreted in the context of (1) the temporo-parietal perfusion deficits and temporal neuronal loss typical in early AD, and (2) correlations between reduced association cortex metabolism and cognitive performance, suggest that neuronal loss and white matter abnormalities in AD may partially exert their effect through disruption of long cortico-cortical pathways (DeCarli et al., 1996). Earlier reports of CC alterations in clinically mild AD (Vermersch et al., 1994; Hoffman et al., 1995; Janowsky et al., 1996), support these observations and further highlight the selective vulnerability of callosal regions in AD.

Other Dementia Subtypes. Recent reports suggest that the pattern of callosal atrophy may differ in different subtypes of dementia, at least in the early stages of each disease. Using the Witelson partition (1989; Fig. 1(c)), Lyoo et al. (1997) observed that mildly demented (MMSE > 21) subjects with Alzheimer's Disease exhibited significant area reductions at the posterior midbody, isthmus and splenium (N=49; Fig. 1(c)), while subjects with mild vascular dementia (according to DSM-III and Hachinski diagnostic criteria, and with MMSE > 21; N=21) had only a significantly smaller genu relative to normal controls (N=36). This finding is consistent with prior reports that the anterior vasculature is preferentially affected in vascular dementia (Freedman and Albert, 1985; Ishii et al., 1986). Observed post mortem, patients with vascular dementia also have a reduced axon density specific to the anterior callosum (Yamanouchi et al., 1990; N=5). Nonetheless, all callosal sectors exhibit significant size reductions in the more severe stages of both diseases (MMSE < 21; Lyoo et al., 1997). In view of the distinct etiologies of different types of dementia, further neuroimaging studies are required to clarify the relation between structural and functional deficits throughout the dynamic course of each disease.

Callosal Morphometry. People with schizophrenia exhibit subtle and diffuse alterations in cerebral structure as revealed by evidence from post mortem and in vivo imaging studies. None of these neuroanatomical abnormalities, however, have been shown to be requisite for diagnosis (Stevens, 1998). Nevertheless, technological advances in structural and functional imaging protocols and improvements in quantitative methods for measuring brain morphology and activation continue to increase the sensitivity with which deviation of neuroanatomic and functional norms can be detected. In spite of novel imaging techniques and applications, morphometric findings in schizophrenic populations frequently lack consensus and fail to expose reliable patterns of structural variation within and across schizophrenia subtypes compared to normal. In fact, the reported morphometric differences appear to be as variable as patient symptomatology. Imaging studies designed to detect macroscopic alteration of callosal morphology have yielded mixed results. There is however a fair amount of experimental evidence suggesting that transcallosal connectivity plays an important role in the schizophrenia syndrome. Furthermore, schizophrenia fits the profile of a misconnection syndrome, reflecting dysfunctional callosal connections from homologous regions of cortex, especially those between the sometimes asymmetric areas of association cortex (Crow, 1998). In the following sections we will discuss: (1) how maldevelopment of the callosum may relate to other structural neuropathology reported in schizophrenia; (2) theoretical issues that relate symptomatology in schizophrenia to callosal abnormality; (3) empirical evidence from neuroimaging and neuropsychological studies suggesting structural alterations of the callosum and related behavioral deficits; and finally (4) methodological issues related to detecting structural abnormalities of the callosum in this population.

Callosal Links to Structural Neuropathology in Schizophrenia. Diffuse structural abnormalities have been reported in neuroimaging, cytoarchitectural, epidemiological and behavioral studies of schizophrenic populations. Converging evidence supports the idea of schizophrenia as a circuit disease, stemming from aberrant neurodevelopmental events (e.g., Carpenter et al., 1993; Pilowsky et al., 1993; Waddington et al., 1993; Nopoulos et al., 1995; Weinberger et al., 1995; Buchanan, 1997). The disruption of neurodevelopmental events involving mechanisms such as abnormal neuronal migration, growth retardation, aberrant myelination, neuronal pruning and/or apoptosis occurring prenatally or through development are thought to account for the diversity of structural findings in schizophrenia (Waddington et al., 1993; Nopoulos et al., 1995). The fact that pruning and myelination in the corpus callosum continue into early adulthood and that interhemispheric coherence develops up until late adolescence may also have some relevance to the age of onset (Njiokiktjien et al., 1994). Furthermore, myelination begins prenatally and has been shown to be susceptible to malnutrition, asphyxia, exotoxins and endotoxins of infectious origin (Njiokiktjien et al., 1994; Bishop and Wahlsten, 1997). It may be no coincidence that influenza epidemics or other viral infections during the second trimester, a critical period for neurodevelopment and obstetric complications, lead to an increase in schizophrenic births (Swayze et al., 1990; Waddington et al., 1993, Woodruff et al., 1995).

A clearer picture of callosal dysfunction in schizophrenia emerges by considering structural abnormalities in the context of their functional circuitry. After all, no brain region acts in isolation and alterations in circuitry potentially lead to structural abnormalities, and vice versa. In spite of primary confounds such as schizophrenia heterogeneity and different methodological approaches, there are some suggestive neurodevelopmental abnormalities frequently reported in schizophrenia populations involving neural systems linked by the callosal commissure. The major players include frontal, temporo-limbic and midline circuits (Cassanova, 1990; Andreasen et al., 1994, 1996; Bogerts, 1997; Goldman-Rakic and Selemon, 1998). As the primary channel of interhemispheric communication, the corpus callosum plays an important role in these systems by reciprocally connecting homologous regions of neocortex. This means that an abnormality in prefrontal or temporal cortices, for example, is likely to influence callosal morphology, and a disturbance in callosal development is likely to have reciprocal affects on these cortical regions.

Callosal Development in Schizophrenia. As noted earlier, the development of the corpus callosum and the neopallium occurs in parallel, with the embryonic callosum first connecting nonolfactory cortex, then extending anteriorly to connect frontal cortices, and then posteriorly to join other lobes as they develop. Recent evidence, however, suggests that the callosum develops bidirectionally (Kier et al., 1996; see Section 4). Nevertheless there is no question that the corpus callosum develops in the hippocampal primordium in close relationship with the developing lobes.

Imaging studies indicate that median reductions in prefrontal cortex make these regions about 5.5% smaller in schizophrenic patients. Reductions are primarily due to a loss in gray rather than white matter (Lawrie and Abukmeil, 1998). Superior and rostral portions of the hippocampal formation also undergo regressive changes in association with callosal development. While findings regarding volume decreases in limbic structures remain equivocal in schizophrenic patients, results in homogeneous samples (males with positive symptoms) are more conclusive (Shenton et al., 1992; Flaum et al., 1995; Menon et al., 1995; Barta et al., 1997; Marsh et al., 1997). Morphological alteration of the superior temporal gyrus in schizophrenic patients has also been reported (e.g., Nestor et al., 1993). This gyrus has particular relevance to callosal circuitry, because it has been identified as the approximate site of Wernicke's language area, and marks the planum temporale on its superior banks (Geschwind et al., 1985; Galaburda et al., 1990). To focus on language-related cortex in schizophrenic patients, investigators have measured the asymmetry of the planum temporale and Sylvian fissure in MR images. Once again, results are mixed with some studies reporting a decreased asymmetry in schizophrenic patients (Hoff et al., 1992; Kikinis et al., 1994; Petty et al., 1995) and others not (De Lisi et al., 1994; Kleinschmidt et al., 1994; Frangou et al., 1997). While corpus callosum morphometry and planum asymmetry have not been compared in the same schizophrenic sample, data from normal populations indicate that morphology in these areas are related (Aboitiz et al., 1992). In summary, imaging studies examining temporal and limbic structures report a modest reduction in temporal lobe volume, with larger volume reductions in the hippocampus, amygdala and superior temporal gyrus, and some reports of abnormal asymmetries of the planum temporale and Sylvian fissure.

Towards the end of embryonic callosal development the area between the corpus callosum and the fornix becomes very thin, and forms the septum pellucidum, where the cavum septi pellucidi may develop. MRI and post mortem studies have related presence of cavum septi pellucidi to psychosis. This developmental anomaly is especially prevalent in schizophrenia groups, and relates to other schizophrenia structural abnormalities (Degreef et al., 1992; Nopoulos et al., 1996). In addition, the corpus callosum forms the rostral boundary and roof of the superior horn of the lateral ventricles. Cerebral ventricular enlargement is the most robust structural anomaly reported in schizophrenic patients. Median figures from many studies indicate the most substantial enlargement is in the ventricular body (Lawrie and Abukmeil, 1998). While finding no difference in corpus callosum area, thickness, or length in twins discordant for schizophrenia, Cassanova et al. (1990) used a statistical analysis of a Fourier expansion series to demonstrate differences in callosal shape between discordant twins. The shape difference was especially apparent in the middle and anterior segments of the callosum. The displacement of the corpus callosum in the vertical plane of schizophrenic patients, representing a shape difference between populations has been replicated, and reflects the increased size of the lateral ventricular body (Narr et al., unpublished findings). Finally, thalamic abnormalities along with other midline structure alterations such as cavum septum pellucidi (Nopoulos et al., 1996) and increased incidence of callosal agenesis (Swayze et al., 1990) suggests the role of neurodevelopmental abnormalities and the disruption of midline circuitry in schizophrenia.

Callosal Connectivity in Schizophrenia. Considering the major role the corpus callosum plays in hemispheric transmission, it is conceivable that the corpus callosum must be involved in schizophrenia neuropathology. Crow (1998) proposes that schizophrenic etiology arises from a component of callosal connectivity associated with the evolution of language, arguing that language and psychoses have a common evolutionary origin. He supports this view by pointing out that age of onset, relative constancy of incidence across societies, and affliction during reproductive and healthy phases of life are characteristics of schizophrenia, and this disease may not be selected out because of its association with language specialization. While this misconnection hypothesis is difficult to test, evidence is cited of abnormalities in the "last to evolve" fiber pathways (for example, perisylvian temporal and dorsolateral prefrontal cortex) and reports of callosal morphologic change over time in schizophrenic patients. Additionally, some studies have reported a link between schizophrenia and dyslexia, representing schizophrenia etiology as tied to language lateralization and callosal connectivity (Stein, 1994; Horrobin et al., 1995). There are however studies that directly dispute the misconnection hypothesis; for example, Bartley et al. (1993) found no evidence of altered asymmetry in language areas in monozygotic twins discordant for schizophrenia, and other studies have not found altered planum asymmetry in schizophrenic patients (De Lisi et al., 1994; Kleinschmidt et al., 1994; Frangou et al., 1997).

David (1994) discusses different views regarding how abnormal interhemispheric transmission accounts for typical schizophrenic phenomena, such as hallucinations and thought alienation. One view suggests that cognitive activity within the right hemisphere would be experienced as alien by the left hemisphere if the two hemispheres were not in full communication (Nasrallah et al., 1985). Another model of interhemispheric abnormality in schizophrenia assumes that excessive connectivity between the two hemispheres, perhaps due to insufficient pruning during development, causes confusion as to whether stimuli are of external or internal origin (Randall, 1983). Clinical studies have also reported cases of psychosis in patients with complete or partial callosal agenesis (David, 1994). As mentioned above, callosal agenesis and other callosal abnormalities are thought to have increased incidence in schizophrenia (Swayze et al., 1990; Degreef et al., 1992; Nopoulos et al., 1996).

Post Mortem and Imaging Studies. The most direct evidence of structural callosal abnormalities in schizophrenia comes from post mortem and imaging studies. Experimental neuropsychology also contributes with specific behavioral measures designed to assess impairments in interhemispheric communication implicating callosal abnormality. Findings of altered callosal morphology in schizophrenic patients appear complex and tempered by a number of variables including sex, symptoms, disease course and age of onset. In fact, there appears little consensus on whether the corpus callosum is larger or smaller in this population. In spite of conflicting evidence, a meta-analysis by Woodruff et al. (1995) found a modest reduction of callosal size across 11 studies with heterogeneous schizophrenic samples. To complicate matters further, structural differences are confounded by employment of different measurement techniques, making it difficult to compare results across studies. If one thing is clear from this body of research, it is that the story of callosal abnormality in schizophrenia is as complicated as other facets of the disease.

Early post mortem studies report an increase in callosal size in schizophrenia (Bigelow et al., 1983), but this finding has not always been replicated (Brown et al., 1986). Advances in imaging procedures have made it easier to study the corpus callosum in vivo but studies continue to report mixed results for different callosal parameters. For example, some studies have found total callosal area to be smaller (e.g. Rossi et al., 1989; Woodruff et al., 1993), larger (e.g., Nasrallah et al., 1986) or not significantly different (e.g., Uematsu and Kaiya, 1988) in schizophrenic patients compared to controls. Other studies measuring callosal thickness have similarly reported increases (e.g. Nasrallah et al., 1986), decreases (e.g., DeQuardo et al., 1996), and no difference across groups. As discussed earlier (Section 2), efforts have been made to parcellate the callosum into sections, to isolate malformation of specific callosal channels (see Fig. 1). Here again results conflict, perhaps in part due to variations in methods, and the different schizophrenia subgroups tested. For example, roughly equivalent estimates of the anterior corpus callosum connecting frontal cortices have been reported as thicker or larger in area (Nasrallah et al., 1986; Uematsu and Kaiya, 1988), smaller in area (Woodruff et al., 1993, Jacobsen et al., 1997) or not different (Woodruff et al., 1997) in patients. Posterior and middle callosal regions in schizophrenic patients have also been found reduced (DeQuardo et al., 1996; Woodruff et al., 1993, Jacobsen et al., 1997), thicker (Nasrallah et al., 1986) or to have similar distributions with normal controls (Smith et al., 1987; Uematsu et al., 1988; Woodruff et al., 1997).

Gender Interactions. Results mentioned above and elsewhere indicate an incredible range of callosal morphometric findings in schizophrenic populations. Although failure to replicate findings may be attributable to the heterogeneity of the patient groups examined, discrepancies may also result from structural differences between sexes in schizophrenic groups. As noted in Section 3, there is an ongoing controversy concerning sex differences in callosal structure, and it appears that brain size has a larger influence over callosal morphology than does gender (Rauch et al., 1994; Jäncke et al., 1997; see Section 3). Larger callosal size found in females relative to brain or skull size results directly from their smaller brain size, and this relative difference persists irrespective of sex. Even if no sex difference is present in normal callosal morphology (cf. Bishop and Wahlsten, 1997), this does not preclude sex effects from interacting with morphometric abnormalities in schizophrenic populations. Male and female schizophrenics may, in general, follow a different course of illness. There is typically a later age of onset in female schizophrenics and hereditary factors may be unevenly distributed between the sexes (De Lisi et al., 1989; Waddington, 1993). Callosal structural alterations in schizophrenic patients may therefore reflect gender differences or gender interactions. Hoff et al. (1994), for example, found that females with first episode schizophrenia had smaller total callosal area compared to controls. These findings partially replicated data from a study by Hauser et al. (1989) where chronic female schizophrenic patients showed smaller anterior callosal widths compared to normals. In contrast, Nasrallah found increased thickness of the anterior and middle corpus callosum in females, while Raine et al. (1990) found increased thickness in the callosum of female schizophrenics compared to normal females and decreased callosal thickness in male patients compared to male controls. A similar trend towards a ‘reversed’ sex difference in anterior and posterior callosal size was reported by Colombo et al. (1993).

Clinical Variables. Clinical and psychopathological heterogeneity in schizophrenic patients may account for inconsistencies in results when assessing structural morphology (Colombo et al., 1993). For example, patients with negative symptoms are shown to have smaller callosal sizes relative to patients with positive symptoms or to controls (Gunther et al., 1991; Woodruff et al., 1993). It has also been suggested, however, that patients with negative symptoms have thicker corpus callosums (Coger and Serafetinides, 1990; Jacobsen et al., 1997). Early onset schizophrenic patients have been shown to have larger total, anterior and posterior callosal areas as compared to controls (Coger and Serafetinides, 1990; Jacobsen et al., 1997). These results are consistent with the post mortem data of Bigelow et al. (1983) that found early onset chronic schizophrenic patients to have significantly greater callosal thickness than later onset patients. In addition, auditory hallucinations have been related to callosal size (David et al.,1995). Lastly, one study suggested that an elongated anterior callosum related to unfavorable prognosis, because large callosal size suggested poor heterosexual relations, reduced numbers of hospitalizations, low academic grades and mild anxiety-depression syndrome (Uematsu and Kaiya, 1988). Clearly, more information is needed to establish the role of these factors in relation to callosal morphometry in schizophrenia. Finally, almost all studies used solely right-handed subjects in their analyses, or matched for handedness across groups. Controlling for handedness is important since handedness appears a predictor of neuroanatomic asymmetry, and bears a relationship to callosal morphology (Bartley et al., 1993; Clarke and Zaidel, 1994). Most studies also reported no influence of age in their findings of callosal pathology. Even though the effects of aging and callosal development are still under investigation (Sections 4-6), these results may not be surprising as most studies controlled for age in some degree and used primarily adult samples.

Structure/Function Correlations. To assess the relationship between callosal structure and function in schizophrenia, several investigators correlated measures of interhemispheric transfer and hemispheric specialization with callosal morphometry (Raine et al., 1990; Colombo et al., 1993; Woodruff et al., 1996). Tests of interhemispheric transfer include measures of visual, tactile, auditory, and cognitive transfer. Such tests have been derived from studies assessing the absence of callosal relay in split-brain patients. Patients with surgical transection of the corpus callosum exhibit impairments such as left hand anomia in tactile tasks, inability to identify false speech sounds presented to the right ear, and deficits in matching stimuli across visual fields (Gazzaniga, 1995). Similar impairments in schizophrenic patients would therefore imply abnormalities in callosal relay. Raine and colleagues (1990) were one of the first groups to employ concurrent structural and functional callosal measures in a schizophrenia sample. Behavioral measures included verbal and nonverbal dichotic listening protocols and crossed versus uncrossed conditions in finger sequence repetition, tactile and WAIS-R block design tasks. None of these tasks detected deficits in interhemispheric processing in patients, and attempts were not made to correlate scores with the sex interaction of callosal morphometry detected across groups. A neuropsychological battery with unilateral and bilateral conditions employed by Hoff et al. (1993) revealed an association of larger callosal size with better cognitive function but no relationship was noted in female schizophrenic patients who exhibited significantly smaller callosal area or across genders in the schizophrenic group. Similar non-significant results of interhemispheric transfer have been reported in studies assessing behavioral measures alone (e.g., Schrift et al., 1986; Ditchfield et al., 1990). In another of the few studies simultaneously assessing structural and functional abnormality of the callosum in schizophrenic patients there were no deficits reported in interhemispheric transfer for an auditory comprehension task assessing transfer of speech information (Colombo et al., 1993). However, the degree of left versus right ear response in the monaural condition in this paradigm was significantly correlated with posterior callosal size in male schizophrenics.

Color Naming and Matching. Although studies assessing interhemispheric transfer have yielded unpromising results in schizophrenic patients, more interesting results have stemmed from studies assessing color naming and matching. Here patients show impairments in left visual field color naming, reflecting impairments in callosal transfer. Impairments are greater in across field color matching relative to within-field matching (McKeever et al., 1979; David, 1989). In a similar vein, a lateralized version of the color-word Stroop task administered to schizophrenic patients revealed that the reaction time difference across visual fields for congruent and incongruent color word pairs was increased (David et al., 1994). This suggests a hypoconnection of facilitation and interference between hemispheres. Using a version of the color-word Stroop task, Woodruff and colleagues (1997) found that bilateral facilitation was greater and interference less in schizophrenic patients. Furthermore, these investigators included simultaneous morphometric analysis of the corpus callosum in their sample. However, they found a positive correlation between facilitation and posterior callosal area, and a complimentary negative correlation between interference and posterior callosal area only when both patient and control groups were combined.

In general, tests of interhemispheric transfer in schizophrenic patients have yielded disappointing results as far as a misconnection hypothesis is concerned. Studies including morphometric measures and those assessing behavioral measures alone have so far yielded no consistent deficit in interhemispheric transfer specific to this population but instead have indicated a more particular left hemisphere deficit (Schrift et al., 1986; Ditchfield et al., 1990). Functional imaging studies, however, have revealed decreased activity in the corpus callosum in disorganized schizophrenic patients (Schroder et al., 1995). Evidence of different regional cerebral activation patterns in each clinically defined subgroup serves to emphasize the importance of studying homogeneous patient groups. Bilateral hyperactivation has also been reported in schizophrenic patients with primarily positive symptoms in a sensorimotor task and this subgroup also exhibited increased callosal size (Gunther et al., 1991). Many methodological problems however, occur in research assessing interhemispheric communication. Until more evidence is obtained, especially in regard to measuring structural and functional correlates, no solid conclusions can be drawn about interhemispheric impairment in schizophrenic patients.

Methodological Issues. Morphometric analysis of structural differences in schizophrenic brains from post mortem and in vivo imaging studies is a relatively dirty task. That is, many extraneous variables interact to threaten validity of results. Since the schizophrenia syndromes may arise from multiple pathophysiological mechanisms it is not always clear how to reduce patient heterogeneity when examining particular and connected morphometric anomalies. As indicated above, differences in sex, chronicity, symptomatology, age of onset, handedness and age may all influence callosal morphology in schizophrenia groups. Other factors that may interfere with analysis include the incidence of perinatal insult, educational level, IQ, height, social status, premorbid adjustment, treatment history and response, and the duration and course of illness (Carpenter et al., 1993). Further difficulties arise from the large variability present in normal populations regarding callosal structure and the significant overlap with patient distributions. Interactions of these variables increasingly complicate the endeavor to examine structural alteration of the corpus callosum and its relationship with other neuroanatomic abnormalities in schizophrenia.

Some solutions to these problems may include the ability to compare images from individual patients with those of an appropriately matched average from normal brain archives. This is now becoming possible, as a probabilistic reference system for the human brain is being compiled whereby variables such as age, sex and handedness may be matched (Mazziotta et al., 1995; Thompson et al., 1997, 1998; see Section 9). Correcting for head size differences appears all-important when studying the nature of callosal structural neuropathology (Steinmetz et al., 1995; Jäncke et al., 1997), especially in view of sex differences in head size. Furthermore, while schizophrenic patients are shown to have decreased cranial and cerebral size, that does not necessarily hold true for other cerebral structures. To illustrate this point, no callosal structural abnormalities were revealed in childhood onset schizophrenic patients (Jacobsen et al., 1997). However, after adjusting for the smaller cerebral volume of the schizophrenics, larger total, anterior and posterior corpus callosum areas were detected in patients. Unfortunately not all studies assessing callosal structure abnormalities in schizophrenia have adjusted for brain size. Transforming images into Talairach standardized space (Talairach et al., 1967; Talairach and Tournoux, 1988) or correcting for both measured cortical volumes and head positioning in the MR scanner are suggested to allow for proper morphometric comparison of neuroanatomical regions across populations.

Patient Homogeneity. In a meta-analysis of heterogeneous schizophrenic patients, Woodruff and colleagues (1995) noted the huge variability in magnitude and direction of callosum size in the patient groups. To address the problem of patient heterogeneity, the most simple solution is to study homogeneous groups. Unfortunately, this has a trade-off with the ability to generalize results. Some investigators suggest that besides matching for demographic variables either the type of course of illness or the evaluation of outliers should be used when assessing morphology in schizophrenia brains (Stevens, 1998). Others argue that neuroanatomy should be examined in the context of separate symptom complexes that may or may not alter regional anatomy (Carpenter et al., 1993). Furthermore, as noted in Section 3, large sample sizes are required to assess the relationships of structural brain abnormalities as exist in neural circuits, especially as callosal abnormality in schizophrenia appears to have a small to medium effect size (Woodruff et al., 1995).

Results are further complicated by different protocols used to divide the callosum into sub-regions (see Fig. 1) and in the measures used to obtain maximal or minimal callosal thickness (see Fig. 1(d)). Even though research in monkeys shows that the corpus callosum is organized by sensory modality (Pandya & Seltzer, 1986), there are no neuroanatomical landmarks by which to partition these areas. While some investigators have investigated how different partitioning protocols influence validity of results (e.g., Allen et al., 1991), different methods make it difficult to compare results across studies. Furthermore, most analyses have only looked at traditional morphometric parameters that include midsagittal area, maximum and minimum width and length (Fig. 1). More recent techniques allow the analysis of curvature, shape and fractal complexity (Thompson et al., 1996a,b). Methods which involve the creation of parametric meshes rendered from traces of regional surface anatomy enable the visualization of very local variability and group differences across the surfaces of individual structures (Thompson et al., 1996, 1997; see Section 9). Additionally, even fewer studies have related callosal morphometric differences to data from other brain regions. Since callosal function depends on the integrity of the cortical regions it connects, it does not make sense to study this region in isolation. Tissue segmentation protocols indicate a gray matter volume loss in the cortices of schizophrenic patients (e.g., Lim et al., 1995; Sullivan et al., 1996). Considering the mixed findings of callosal abnormality it is still not clear whether white matter sparing in schizophrenia includes the traversing callosal fibers or whether disconnection or misconnection occurs. Finally, only one study to our knowledge has looked at changes in callosal morphology in schizophrenic patients across time (De Lisi et al., 1995).

There are also difficulties in interpreting the nature of interhemispheric deficits in schizophrenic patients and their relationship to callosal structure. Part of the problem appears because even in normals many behavioral tests of interhemispheric transfer have often not been found to be related to measurements of callosal structure (Clarke and Zaidel, 1994). In post mortem studies, Aboitiz et al. (1992) noted that only the numbers of small diameter fibers thought to relay cognitive information across hemispheres relate to callosal size while large diameter fibers conducting sensory and motor information do not. Considering that most of the interhemispheric tasks employed in the schizophrenia studies reviewed involved mainly the transfer of sensory information (visual, tactile and auditory transfer), it may not be surprising that these measures did not correlate well with callosal structural abnormalities, although abnormalities were detected in imaging activation tasks (Gunther et al., 1991; Schroder et al., 1995). Also, many trials are required to assess small differences in reaction time for stimuli presented within versus between hemispheres. In these types of behavioral paradigms, results may also be compromised by patient distractibility. Finally, the fine temporal resolution of EEG studies augments the power to detect differences in processing time across the hemispheres, and these studies have reported abnormal interhemispheric transfer time in schizophrenic patients (e.g., Weisbrod et al., 1997; Heidrich and Strik, 1997).

The large body of research dedicated to studying callosal abnormality in schizophrenic patients at the structural and behavioral levels has thus far been unable to reach a consensus. As improvements in imaging analysis techniques provide enhanced detection of subtle differences, and as more is learned about callosal structure and function in normal populations, a clearer picture of callosal abnormality in schizophrenia is likely to emerge.

Probabilistic atlasing is a research strategy whose goal is to generate anatomical templates that retain quantitative information on inter-subject variations in brain architecture (Mazziotta et al., 1995; Thompson et al., 1997; Thompson and Toga, 1998). A digital probabilistic atlas of the human brain, incorporating precise statistical information on positional variability of important functional and anatomic interfaces, may help to address many of the methodologic difficulties we have observed in detecting alterations in callosal anatomy. As the database of subjects on which probabilistic atlases are based increases in size and content, the digital, electronic form of the atlas provides efficiency in statistical and computational comparisons between individuals or groups. In addition, the population on which probabilistic atlases are based can be stratified into subpopulations by age, gender, handedness, or other demographic factors, by stage of development or to represent different disease types. A probabilistic framework for structural brain data solves many of the limitations of a fixed atlas in representing highly variable anatomy. A statistical confidence limit, rather than an absolute representation of neuroanatomy may also be more appropriate for representing particular subpopulations.

Warping Algorithms can Create Probabilistic Atlases. As noted earlier, when applied to two different 3D brain scans, a non-linear registration or warping algorithm calculates a deformation map (Fig. 2,3) which matches up brain structures in one scan with their counterparts in the other. The deformation map indicates 3-dimensional patterns of anatomic differences between the two subjects. By defining probability distributions on the space of deformation transformations which drive the anatomy of different subjects into correspondence (Grenander, 1976; Amit et al., 1991; Grenander and Miller, 1994; Thompson and Toga, 1997; Thompson et al., 1997), statistical parameters of these distributions can be estimated from databased anatomic data to determine the magnitude and directional biases of anatomic variation. Encoding of local variation can then be used to assess the severity of structural variants outside of the normal range, which, in brain data, may be a sign of disease (Thompson et al., 1997).

3D Anatomic Variability Maps: Elderly Normal Subjects (N=10)	3D Anatomic Variability Maps: Alzheimer's Disease Subjects (N=10)
3D Anatomic Asymmetry Maps: Elderly Normal Subjects (N=10)	3D Anatomic Asymmetry Maps: Alzheimer's Disease Subjects (N=10)

Encoding Brain Variation. The random vector field approach is a general strategy to construct population-based atlases of the brain (Thompson and Toga, 1997; Thirion et al., 1998). Briefly, given a 3D MR image of a new subject, a warping algorithm (Thompson and Toga, 1996) calculates a set of high-dimensional volumetric maps, elastically deforming this image into structural correspondence with other scans, selected one by one from an anatomic image database. Target scans are selected from subjects matched for age, handedness, gender, and other demographic factors (Thompson et al., 1997, 1998). The resulting family of volumetric warps provides empirical information on patterns of local anatomic variation. A probability space of random transformations, based on the theory of anisotropic Gaussian random fields (Thompson et al., 1997), is then used to encode the variations. Specialized continuum-mechanical approaches are required to encode information on complex variations in gyral and sulcal topography from one individual to another (Thompson et al., 1997; Thompson and Toga, 1998). Confidence limits in stereotaxic space are determined, for points in the new subject's brain, enabling the creation of color-coded probability maps to highlight and quantify regional patterns of deformity.

Callosal Anatomy. Although probabilistic systems are under development for the population-based analysis of callosal data (Thompson et al., 1998), their ability to resolve callosal differences in small groups of subjects with dementia is indicated in Fig. 7. In one validation experiment (Thompson et al., 1997; Fig. 10), probability maps were created to highlight abnormal deviations in the callosal anatomy of a specific subject. The medical history of the subject in question indicated the presence of lung cancer, which had spread to the brain. Two metastatic tumors were present, one in each hemisphere. The first, and larger, tumor (volume: 95.2 cm³; see Fig. 10) was centered in the high putamen of the right hemisphere, while a second tumor (volume: 24.6 cm³) was located in the left occipital lobe. No other neuropathology was present, and the primary cause of death was cardiopulmonary arrest. The two regions of metastatic tissue induced marked distortions in the normal architecture of the brain. This effect was reflected both in the blockface imagery itself (Fig. 10, top) and in the values of the probability maps of structures proximal to the lesion sites (Figs. 10, bottom).

Fig. 10. Distortions in Brain Architecture induced by Tumor Tissue: Probability Maps for Ventral Callosum and Major Sulci in Both Hemispheres. Color-coded probability maps, (lower panel), quantify the impact of two focal metastatic tumors (illustrated in red; see also cryosection blockface, (top)) on the ventral callosal boundary, as well as the parieto-occipital and anterior and posterior calcarine sulci in both brain hemispheres.

Pathology Detection. To identify differences in brain structure between two groups, or between an individual subject and a database of demographically matched subjects, we define W_ij(x) as the deformation vector required to match the structure at position x in an atlas template with its counterpart in subject i of group j, and model the deformations as:

W_ij(x) = µ _j(x) + S (x)^1/2e _ij(x).

Here µ _j(x) is the mean deformation for group j, and S (x) is a non-stationary, anisotropic covariance tensor field, which relaxes the confidence threshold for detecting abnormal structure in regions where normal variability is extreme, S (x)^1/2 is the upper triangular Cholesky factor tensor field, and e _ij(x) is a trivariate random vector field whose components are independent stationary Gaussian random fields.

A T² or F statistic which indicates evidence of significant difference in deformations between the groups is calculated at each lattice location in a 3D image or parameterized 3D surface, to form a statistic image (Thompson et al., 1997). Specialized algorithms, using corrections for the metric tensor of the underlying surface, are required to calculate these fields at the cortex (Thompson and Toga, 1998). Under the null hypothesis of no abnormal deformations, the statistic image is approximated by a T² random field. The global maximum of the random deformation field, or derived tensor fields (Thompson et al., 1998), can be used to test the hypothesis of no structural change in disease (Worsley, 1994a,b; Cao and Worsley, 1998). Similar multivariate linear models can be used to test for the effect of explanatory variables (e.g., age, gender, clinical test scores) on a set of deformation field images.

Probabilistic atlases based on random deformation fields, and associated scalar fields derived using operators which emphasize specific deformational characteristics, have been used to assess gender-specific differences in the brain (Davatzikos, 1996; Cao and Worsley, 1998). These algorithms are currently being tested on databases of 3D MRI and high-resolution cryosection volumes with the goal of detecting structural abnormalities in schizophrenia (Moussai et al., 1998), and in neurodegenerative disorders such as Alzheimer's disease (Figs. 4-6; Thompson et al., 1997, 1998; Mega et al., 1998).

In summary, group-specific patterns of brain structure may go unnoticed in individual subjects or groups due to extreme variations in anatomy between subjects. Population-based brain atlases, however, linked with appropriate warping algorithms, can incorporate extensive regional information on structural variability, and show great promise in identifying group trends and characteristics, especially in disease states.

Extreme variations in callosal anatomy are found in normal and diseased populations. These variations complicate the design of systems to detect callosal anomalies in disease, and to clarify associations between callosal structure and sex, handedness, and a variety of behavioral and cognitive factors.

In many ways, static representations of brain structure are ill-suited to analyzing the dynamic processes of brain development and disease. The inherently changing morphology complicates attempts to compare callosal anatomy across subjects and groups, and interaction effects between age, sex and other demographic factors are also observed. The intense interest in brain development and disease mandates the design of mathematical systems to track anatomical changes over time, and map dynamic patterns of growth or degeneration. In this chapter, we introduced an approach to map patterns of growth at the callosum, emphasizing the regional complexity of growth patterns over a prolonged period.

In the near future, brain mapping techniques will provide the ability to map growth and degeneration in their full spatial and temporal complexity. In spite of the logistic and technical challenges, these mapping approaches hold tremendous promise for representing, analyzing and understanding the extremely complex dynamic processes that affect regional anatomy in the healthy and diseased brain.

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