The primary findings of this study were of FA and Radial Diffusivity abnormalities in the Frontal CC fibers, and Mode abnormalities in the Parietal CC fibers in 19 SZ patients relative to 19 matched healthy controls. Furthermore, the severity of patients' symptoms of Reality Distortion (i.e., hallucinations and delusions) were found to be positively correlated with FA and negatively correlated with Radial Diffusivity in the Frontal CC fibers. In light of the FA reductions and Radial Diffusivity increases which were observed in the SZ patients in this CC segment, these results suggest that the most severely psychotic patients were the least abnormal in terms of their FA and Radial Diffusivity in these fibers.
Whilst FA reductions in the genu of the CC in SZ patients have been reported previously (38
), including in patients with first-episode SZ (40
) (see (10
) for reviews), their microstructural underpinnings have not been well established. FA reductions have been found to occur in response to axon death, myelin damage, damage to the axon membrane, and reduced ‘fiber coherence’ (i.e., more variable fiber trajectories within a WM bundle) (10
). While there is little evidence to suggest the presence of any substantial degree of abnormal neuron death in SZ patients (e.g., see (43
)), there is, in contrast, a growing body of evidence suggesting that SZ patients exhibit abnormalities in both their myelin and in the integrity of their axon membranes (44
). Distinguishing between these two distinct neuropathologies was one motivation behind the development of the diffusion indices Axial and Radial Diffusivity. In a series of animal studies, Song (19
) demonstrated that while damage to the myelin of the optic nerve resulted in increased Radial (but unchanged Axial) Diffusivity, damage to the axonal membrane of the optic nerve (but preservation of the myelin) resulted in reduced Axial but unchanged Radial Diffusivity (31
). The results of these studies support the claim that Radial Diffusivity is a putative measure of myelin integrity while Axial Diffusivity is a putative measure of axonal integrity. Hence the results of the present study in which the SZ patients were observed to exhibit abnormally increased Radial Diffusivity but unchanged Axial Diffusivity, relative to controls, in the Frontal CC fibers, suggests that the FA abnormalities in these fibers were more likely underpinned by myelin abnormalities as opposed to damage to the axon membrane.
If the observed diffusion abnormalities in the Frontal CC fibers were indeed the result of myelin damage, then this might be expected to result in slowed impulse conduction (46
). Furthermore, it might also seem likely that those SZ patients with the most profound diffusion abnormalities (and hence presumably the most severe conduction delays) would exhibit the most severe psychopathology. Such a relationship, however, was not observed in the present study. On the contrary, those SZ patients with the most subnormal levels of FA (and most supranormal levels of Radial Diffusivity) exhibited the least
severe symptoms of Reality Distortion. Far from being an unprecedented finding, this seemingly paradoxical result of a positive
correlation between FA and psychotic symptom severity has been reported many times previously, including in the CC (17
), cingulum bundle (17
), arcuate fasciculus (17
), superior longitudinal fasciculus (14
) and inferior fronto-occipital fasciculus (16
). It was also notable that, in the present study, the most severely psychotic patients did not show abnormally
high levels of FA, but instead exhibited FA values lower than the healthy controls but higher than the less-psychotic patients (see ). What is the explanation for this seemingly paradoxical finding that the more floridly psychotic a SZ patient, the less severe their FA abnormalities?
To the extent that axonal conduction delays can be inferred from diffusivity abnormalities in DTI, these results suggest that while some amount of neural desynchronization may be necessary for the development of psychotic symptoms, too much desynchronization may in fact preclude the development of highly systematized hallucinations and delusions such as would score highly on a clinical rating scale such as the PANSS. This idea has some support in the WM literature. For example, while psychotic symptoms have been commonly reported in patients with the degenerative demyelinating disease metachromatic leukodystrophy (48
), they are more likely to occur in the early stages of the disease when myelin pathologies are relatively minor compared to the late stages of the disease when severe demyelination is apparent (49
). If it is true that psychotic symptoms represent the brain's attempt to incorporate disjointed neural activity into a coherent (albeit pathological) framework (50
), then perhaps this “pathological integration” is only possible up to a certain level of temporal desynchronization. In other words, while mild asynchronies between the activities of spatially discrete brain regions might give rise to psychotic symptoms (such as, for example, between the different brain regions stimulated by a primary discharge and its corollaries (51
)), severe asynchronies (such as might be caused by severe WM damage) might not be incorporable into a coherent phenomenological framework and thus not give rise to psychotic symptoms. Such severe WM damage could instead result in something of a ‘cognitive shutdown’ which could underlie the negative symptoms of SZ. This would explain the negative
correlation between FA and negative symptom severity that has been observed previously in SZ patients (16
), and for which there was a non-significant trend in the present study. Testing these hypotheses could potentially provide a fruitful avenue for future research.
Our finding of abnormally increased Mode (i.e., abnormally prolate diffusion ellipsoids) in the Parietal CC fibers in the SZ patients has not (to our knowledge) been reported previously. Mode is a relatively recently-developed measure which provides independent and complementary information to the stalwart index of FA (13
). In terms of its physiological determinants, Mode has been found to decrease in the presence of fiber crossings (13
). Thus one explanation as to why the SZ patients exhibited abnormally increased Mode but normal levels of FA in the parietal CC fibers might be that the patients evince abnormalities in a fiber bundle adjacent to these CC fibers (e.g., the cingulum bundle, as recently suggested by Mandah et al., (53
)), resulting in a reduction in the density of fiber crossings, and hence elevated Mode, in this region of the CC. Our finding of diffusion abnormalities in the Parietal CC fibers is also consistent with the results of several early-onset studies which have reported parietal lobe white matter to be among the first cerebral areas to evince structural abnormalities in patients with schizophrenia – abnormalities that have been argued to contribute to the emergence of psychotic symptoms through their effects on frontal-parietal connectivity (54
A limitation of the present study relates to the fact that all of the SZ patients were suffering from chronic schizophrenia and had been at least intermittently (and in many cases chronically) exposed to neuroleptic medications. This is relevant in light of evidence from primate studies suggesting that exposure to both typical and atypical neuroleptics can influence brain structure in and of itself (56
). Notwithstanding the fact that a) patients' chlorpromazine-equivalent medication dosages were statistically controlled for in the present study, and b) there were no significant correlations between patients' CPZ-equivalent medication dosages and their FA, Mode, or Radial Diffusivity in any of the 6 CC segments (see Supplement 1
), replicating these results in a population of first-episode, neuroleptic-naive SZ patients would strengthen confidence into their validity, and would be a worthwhile aim for future research. A second limitation relates to the fact that all the patients were male. Whilst this was advantageous in the sense that it increased the homogeneity of the sample and thus the power, it obviously limited the extent to which the results can be generalized to females.
In summary, the main findings of this study were of FA reductions and Radial Diffusivity increases in Frontal CC fibers (consistent with dysmyelination) and Mode increases in Parietal CC fibers (consistent with a relative absence of crossing fibers) in 19 patients with schizophrenia relative to 19 matched healthy controls. Significant correlations were also observed between patients' FA and Radial Diffusivity in the Frontal fibers and the severity of their psychotic symptoms, such that patients with the most abnormal levels of FA and Radial Diffusivity exhibited the least severe symptoms of Reality Distortion. This result, we suggest, provides support for those theories which emphasize neural timing abnormalities in the etiology of psychotic symptoms.