Diffusion tensor imaging findings from the present study strongly suggest that fronto–temporal connectivity through the UF, one of the most prominent fiber bundles connecting the frontal and temporal lobes, is altered in SPD, and that this alteration shows an interesting dissociation between the left UF area and verbal deficits on one hand and reduced right UF anisotropy and increased clinical symptoms on the other. Moreover, the observed DTI correlations with clinical and cognitive measures suggest that a disturbance in connectivity between different brain regions, rather than abnormalities within the separate regions themselves, might be responsible for some of the observed clinical symptoms and cognitive dysfunctions in SPD.
Compared with previous DTI findings on schizophrenia, findings of bilaterally abnormal UF integrity in male subjects with SPD are similar to findings reported in schizophrenia, although two previous DTI studies (Burns et al 2003
; Kubicki et al 2002a
) in schizophrenia showed reduced anisotropy in left UF; more specifically, reduced normal left > right asymmetries in UF anisotropy (Kubicki et al 2002a
) and a trend-level reduction in left UF anisotropy (Burns et al 2003
). In contrast, there were no significant differences in CB between SPDs and NCs, whereas we previously reported CB integrity disruption in schizophrenia (Kubicki et al 2003
), and two other studies (Sun et al 2003
; Wang et al 2004
) also demonstrated CB abnormalities in schizophrenia.
The fact that there is some overlap between findings in SPD and schizophrenia suggests that SPD might be a “forme fruste” or “milder” presentation of pathology among the schizophrenia spectrum disorders and supports a dimensional conceptualization of schizophrenia spectrum disorders, rather than a categorical classification, such as in DSM-IV. Accordingly, the similarity in findings for UF anisotropy in SPD and schizophrenia suggests that UF integrity disruption might be along a continuum of dysfunction. This lack of UF cohesion in the schizophrenia spectrum is reminiscent of classic disconnection syndromes (Mesulam 1985
), in that a lack of integration between two brain regions results in specific deficits. In schizophrenia and SPD, but unlike isolated lesions found in the classic disconnection syndromes, the deficits are more widespread and result in a larger range of abnormalities, as exemplified by the range of correlations described in this report.
One potential pathogenic explanation for this more widespread abnormality might come from postmortem data. On the basis of histochemical studies of postmortem brains of schizophrenic subjects, Deakin and Simpson (1997)
proposed that an abnormal amount of glutamatergic innervation from orbitofrontal cortex to anterior temporal cortex through UF might be an essential neurodevelopmental abnormality for schizophrenia. This glutamatergic excitotoxicity might result in reduced UF anisotropy in both schizophrenia and SPD populations.
In contrast, areas of dissimilarity between SPD and schizophrenia, such as observed for CB anisotropy, suggest that there might be certain protective factors operating in SPD that might contribute to more limited clinical symptoms compared with schizophrenia. More specifically, Siever and Davis (2004)
speculate that there is a “greater frontal capacity in SPD than schizophrenia.” Because CB projects disproportionately to the frontal lobe, the finding of disrupted CB in schizophrenia, but not in SPD, supports Siever and Davis’ hypothesis that the prefrontal cortex in SPD acts to “buffer” other brain regions against the decimating effects of an abnormal temporal lobe (Siever and Davis 2004
). Intact CB in SPD might therefore represent part of that prefrontal “buffer.”
Also noteworthy were the clinical correlations with DTI measures in SPDs, suggesting that altered temporal–frontal connectivity through the UF might play an important role in the phenomenology of SPD. Specifically, reduced FA in right UF was correlated with clinical symptoms, including ideas of reference (SIS), suspiciousness (SIS, SPQ), restricted affect (SPQ, BDI), anxiety (SPQ, STAI), and no close friends (SPQ). In contrast, cognitive correlations with DTI in SPDs showed that the left UF area was correlated with measures of general intelligence, verbal and visual memory, and executive functions. These latter correlations are consistent with previous neuropsychological findings in SPD, which have shown decrements in general intelligence (Mitropoulou et al 2002
; Voglmaier et al 2000
), in performance on the CVLT (Voglmaier et al 1997
), and in visual reproduction on the WMS-III (Mitropoulou et al 2002
), as well as poor performance on executive functions, such as the WCST and the Trail Making Test (Mitropoulou et al 2002
; Trestman et al 1995
), all of which provide further evidence that fronto–temporal disconnectivity through the left UF might play a crucial role in cognitive distortion in SPD. The Rey-Osterrieth Complex Figure test, however, demonstrated right-dominant correlations, possibly reflecting contributions of visual memory and visuo-spatial planning, which are required in this test.
Of interest to the present study, a recent DTI study of schizophrenia by Nestor et al (2004)
reported reduced left UF FA in schizophrenic subjects compared with control subjects, which was correlated with lower declarative–episodic verbal memory, whereas reduced left CB cross-sectional area correlated with errors in executive functions related to performance monitoring. The association between verbal memory and left UF is similar to that reported here for SPD. Moreover, results from the hierarchical multiple regression analyses in the present study provide evidence of dissociation between disruptions of left UF and reduced verbal memory on the one hand and right UF and SPQ traits on the other.
Anatomically, UF interconnects with anterior temporal and inferior frontal regions. More specific links include connecting amygdala and uncus with subcallosal regions (Ebeling and von Cramon 1992
; Kier et al 2004
; Klingler and Gloor 1960
). A human histochemical study has shown that UF also carries cholinergic fibers from the basal nucleus of Meynert, as a part of cholinergic pathway that supplies frontal, parietal, and temporal neocortices, and perisylvian division of frontoparietal operculum, insula, and superior temporal gyrus (Selden et al 1998
). Also of note, UF is closely related to the ventral visual pathway (Ungerleider et al 1989
), although dissection studies with monkeys reveal that UF dissection itself did not yield visual memory disturbances alone (Gaffan and Eacott 1995a
). Results from the present study, in light of these anatomical findings, suggest that UF-mediated neural circuits involving the amygdala might be attributed to emotional aspects of SPD pathophysiology. Altered cholinergic innervation through the UF with decreased anisotropy might also be relevant to cognitive distortion in SPD. In the present study, some visual memory tests, including visual reproduction and memory for faces in WMS-III and immediate and delayed recall in the Rey-Osterrieth complex figure test, demonstrated significant correlation with UF area, suggesting that the ventral visual pathway involved with UF might also be affected in SPD.
The present findings of significant reduction of anisotropy with a trend-level increase of mean diffusivity in UF could be attributed to 1) decreased density of axons; 2) decreased degree of myelination of axons; and/or 3) impaired axonal membranes. A recent postmortem study of UF in schizophrenia demonstrated that there were no differences in the number and density of fibers in UF between schizophrenic and control subjects (Highley et al 2002
). Additionally, there is growing evidence suggesting that glial cells, particularly oligodendrocytes, which form myelin sheaths around axons, are abnormal in schizophrenia (Davis et al 2003
; Hakak et al 2001
; Uranova et al 2001a
). Hakak and coworkers, in fact, reported abnormal expression of myelin-related genes in schizophrenia, which suggests a disruption in oligodendrocyte function (Hakak et al 2001
). Furthermore, Uranova and coworkers showed both qualitative and quantitative abnormalities in postmortem brains of schizophrenic subjects in the oligodendroglia of the prefrontal cortex and caudate nucleus (Uranova et al 2001a
). Also, a magnetization transfer imaging study revealed that decreased magnetization transfer ratio, a putative index of myelin or axonal density, was observed in frontal and temporal regions of schizophrenia (Foong et al 2000a
). Taken together, these findings suggest that UF anisotropy reduction might be attributed to oligodendrocyte dysfunction within the fronto–temporal circuitry. Because SPDs in our study also showed disturbed UF anisotropy, it is possible that a similar process might be occurring in SPD, although future studies focused on glial cells are needed to confirm such speculations.
We note several methodological issues in our study. One limitation is that DTI is more prone to artifact, including partial volume effects, chemical shift artifacts, bulk motion, and spatial distortion, compared with standard MRI acquisition protocols used for most volumetric studies, and thus such artifacts might have influenced our findings. The resolution of DTI is also low compared with most recent volumetric studies, and low spatial resolution can increase partial volume effects, which could decrease mean anisotropy, particularly within small ROIs; however, the LSDI (Gudbjartsson et al 1996
; Maier et al 1998
) protocol we used is less prone to chemical shift artifacts, bulk motion, and spatial distortions than is the conventional single-shot diffusion-weighted echo-planar protocol (Turner et al 1990
), although the LSDI sequence is four to six times slower (Kubicki et al 2004
). Moreover, with LSDI, motion artifact can be monitored for each voxel, and we demonstrated that motion artifact did not differ significantly between groups. Furthermore, to reduce partial volume effects, we took advantage of coronal image acquisitions that were perpendicular to both the densest portion of the UF at the temporal stem and the largest portion of the CB. We are thus confident that, given the current state-of-the-art technology, we controlled for the influence of possible artifacts due to the method we used.
Also of note, our group developed a directional threshold method for cross-sectional ROI definition of fiber bundles, such as UF and CB. The greatest advantage of this method is that it is based on directional information obtained only from the diffusion tensor, whereas conventional fixed ROI methods and exploratory voxel-based approaches discard this important information. There are limitations to this method, however. First, it works only for the unidirectional portion of fiber bundles and not for their dispersive portions or for fiber crossings. Therefore, we were limited to just one slice that included the densest portion at the anterior temporal stem to evaluate UF, and we excluded CB portions outside of the anterior and posterior boundaries defined by the genu and splenium of corpus callosum. Second, torque of the brains or any shape asymmetries that might exist between groups might affect the main direction of the bundle or threshold and thus might affect the anisotropy results, although all the DTI images were aligned to the AC-PC line with T1-weighted images to minimize these possibilities. Third, this method produces an additional variable, the cross-sectional area within the ROI defined by thresholding λ1z
magnitude; however, this cross-sectional area has not been well interpreted physiologically, although it is speculated that it might also yield a quantitative measure of connectivity between different brain regions because it includes information about fiber directionality (λ1z
) as well as bundle volume. In fact, many meaningful correlations were observed between the cross-sectional areas and cognitive measures in the present study in SPDs and in our previous study in schizophrenia (Nestor et al 2004
In summary, the present DTI study of SPD demonstrates fronto–temporal disconnectivity through the UF in association with cognitive distortion, social deficit, and restricted affectivity, and intact neocortical–limbic connection through CB, with the latter in marked contrast with what has been reported in schizophrenia. Also, the present study offers biological commonality and distinction between SPD and schizophrenia in terms of neural connectivity. More specifically, neural circuitry through the UF might be affected in both clinical entities, whereas CB integrity might be preserved in SPD. This method thus has the potential of elucidating further the neuropathology that underlies altered neural connectivity in SPD.