This study found that FESZ exhibited GM abnormalities at baseline and showed widespread progressive GM reduction in frontal, temporal and parietal lobes over the first 1.5 years of illness. Distinctive features of this study were: 1) the congruence of longitudinal results using DARTEL-based VBM and ROI methodology; and 2) the correlation of patients’ levels of longitudinal GM reduction with the longitudinal changes in their clinical symptoms and basic cognitive functioning. We believe the richness of FESZ GM loss-symptom associations detected in this study is unique in the longitudinal literature, even though they were obtained by relatively liberal, exploratory analyses. This study thus emphasizes the clinical relevance of progression of gray matter loss in the period immediately following onset of schizophrenia.
First, the whole brain longitudinal analysis demonstrated GM volume loss in widespread brain regions in temporal, frontal, fronto-limbic, and parietal regions in the 21 FESZ compared with 23 HC.
In the frontal lobe, the longitudinal analysis uncovered widespread frontal GM reduction, consistent with our previous ROI analysis (Nakamura et al., 2007
) and other VBM longitudinal studies of FESZ (Theberge et al., 2007
; Whitford et al., 2006
). Progressive GM loss was found in all surface frontal gyri: superior, middle, inferior, precentral, and orbitofrontal. These findings are more extensive than the specific IFG loss previously reported (Whitford et al., 2006
), possibly due to improved sensitivity of the DARTEL methodology (Tahmasebi et al., 2009
), although other reasons like subject differences cannot be ruled out.
Within fronto-limbic regions, bilateral rostral and dorsal subregions and the left subgenual subregion of the ACG, and left PCG showed progressive volume reductions. These findings were consistent with our previous manual ROI analysis (Koo et al., 2008
Within the parietal lobe, the longitudinal analysis detected extensive progressive GM volume reductions in FESZ in bilateral postcentral and supramarginal gyri, and right angular and superior parietal gyri. The lateral parietal cortex, medial prefrontal cortex, ventral ACG and PCG are thought to be a part of the so-called default network (Raichle et al., 2001
; Whitfield-Gabrieli et al., 2009
), in which some functional MRI studies have reported hyperactivity in SZ (Garrity et al., 2007
; Whitfield-Gabrieli et al., 2009
). The structural abnormalities in frontal, frontal-limbic, and parietal regions detected in this study might contribute to functional abnormalities in the default network.
Second, the SVC analyses using both the current subjects and the same subjects as in our previous ROI analyses demonstrated similar results as the ROI analyses (Kasai et al., 2003a
; Koo et al., 2008
), thus supporting our new technology. Although it remains for us to confirm the congruence of VBM-ROI results in other brain regions, such as frontal and parietal regions, the present similarity of our VBM results with previous ROI analysis suggest the validity and reliability of our new method. As a final point, we mention that, to the best of our knowledge, there are no longitudinal VBM studies comparing their results with manual ROI results using the same subjects, although such comparisons would, in our opinion, be useful.
Finally, correlational analyses demonstrated many associations between the degree of GM reduction and clinical symptoms. While many associations indicated GM loss in temporal regions were related to positive symptoms and volume loss in frontal regions were related to negative symptoms, the data showed a more complex interplay between brain regions with volume reduction in the production of symptoms. Abnormalities were found in the STG/HG and postcentral gyrus, which have both early stage auditory and somatosensory processing functions and also in regions with more complex processing and top down control functions (frontal gyri). This is in accord with a conceptualization of schizophrenia as involving disturbances in both bottom up and top down stages of processing. Functionally the temporal lobe STG regions are substrates of auditory and language processing (Galaburda et al., 1978
), two domains which are often impaired in SZ. Several previous functional and structural neuroimaging studies indicated that cross-sectional temporal lobe abnormalities were related to positive symptoms (Bachmann et al., 2004
; Dierks et al., 1999
; Shenton et al., 1992
; Wible et al., 2001b
). Our data suggest that longitudinal temporal lobe GM loss is linked to worsening or less improvement in positive symptoms over time. Our previous ROI study showed HG volume reduction was associated with reduction in the auditory mismatch negativity to pitch (Salisbury et al., 2007
). Thus worsening in both positive symptoms and auditory pathophysiology appear to be associated with progressive temporal lobe GM reduction. Importantly, there was also support for the concept of a complex interplay of brain regions in positive symptom production, with both insula and pre- and post-central gyri showing positive symptom associations.
Frontal regions play important roles in the executive functions of attention, working memory, set shifting, and planning, as well as in learning and memory and regulation of emotion and social interaction (Gazzaniga, 2005
). Deficits in these functions may appear in schizophrenia as negative symptoms and cognitive dysfunction (Hirsch and Weinberger, 2003
). Several neuroimaging studies have, in fact, reported a relationship between cross-sectional frontal volume reductions and negative symptomatology and cognitive dysfunction (Mathalon and Ford, 2008
; Weinberger et al., 1986
; Wible et al., 2001a
; Wolkin et al., 1992
; Zipparo et al., 2008
). In terms of longitudinal studies, some previous studies have reported such relationships in FESZ. In the previous ROI studies, prefrontal GM declines have been reported to be associated with greater BPRS negative symptom scores (Mathalon et al., 2001
). With respect to insula, an ROI study (Takahashi et al., 2009a
) has reported associations of insular cortex progression and BPRS negative symptoms, similar to that reported here using VBM methodology. An association of right ACG volume reduction with the BPRS withdrawal-retardation factor (negative symptoms) was also found in our ROI study (Koo et al., 2008
), further suggesting the validity of our VBM approach. Thus, our results of the associations between negative symptoms and frontal and fronto-limbic progressive GM reductions were consistent with these previous findings. Reinforcing the notion of a complex regional interplay in symptom production was the STG GM volume reduction association with negative symptoms.
General cognitive changes as indexed by the MMSE were associated with widespread GM loss, although frontal associations predominated. The lack of domain-specific MMSE cognitive correlations suggests the MMSE correlations index a diffuse cognitive impairment that occurs over time in FESZ. We note that the MMSE has been validated in cognitive decline (Cockrell and Folstein, 1988
), but not in schizophrenia. Validation of its use in schizophrenia will thus require comparison with other more standard cognitive tests. Our data showing the strong MRI volumetric correlations suggest this comparison for validation might be worthwhile.
The precise neurobiological mechanism that underlies this progressive, perhaps neurodegenerative, change shown in the current longitudinal VBM analysis is unknown. However, recent studies have provided some evidence that neuropil reduction and not cellular loss has been shown to be the basis of GM loss in both temporal (Sweet et al., 2003
) and frontal regions (Selemon and Goldman-Rakic, 1999
) in patients with SZ. Such loss likely underlies the GM loss observed here. While the neurobiological mechanism underlying GM volume/neuropil loss is unknown, we have speculated that a cortical circuit abnormality (deficient recurrent inhibition as a result of γ-aminobutyric acid [GABA]-ergic abnormalities in parvalbumin-positive interneurons) and consequent excitotoxic reduction in neuropil might be responsible (McCarley et al., 1996
; McCarley et al., 1999a
). This model is compatible with glutamatergic hypofunction of pyramidal neurons’ recurrent collaterals on the N
-methyl-D-aspartate (NMDA) glutamate receptor on GABAergic interneurons (Coyle, 1996
), and is now recognized as a plausible mechanism (see review (Krystal et al., 2003
; Woo et al., 2010
)). Relevant to our model, a MRS study (Theberge et al., 2007
) found progressive glutamatergic abnormalities that were compatible with excitotoxicity, although also compatible with neuroplastic changes.
Limitations. First, the correlation analysis of this study must be labeled as exploratory and therefore needing confirmation in future planned studies because of the number of correlations calculated. However, taken as a whole, our GM volume and clinical correlation data do show statistically significant associations. We used 3 major clinical variables, 2 BPRS factors (positive and negative symptoms) and MMSE total score. These three variables were evaluated for association with GM changes in all regions showing significant FESZ>HC GM reduction, a total of 25 regions. Thus, 3 clinical variables × 25 regions =75 chances for significance, and at a p=.05 level a chance association would predict 3.75 occurrences of significance. We found 17 significant occurrences of significance, a number that is greater than expected at a p level<10-6 by the binomial theorem. Second, we must label the volume reduction in the cerebellum as questionable because of technical factors, since some images contained a few voxels with unusually high intensity in the cerebellum. Finally, we need to confirm the current VBM findings of the progressive GM volume reductions in the frontal and parietal regions using manually traced ROIs, studies that are now underway.