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Brief Report   |    
Morphometry of Individual Cerebellar Lobules in Schizophrenia
Russell T. Loeber, B.S.; Christina M.B. Cintron, B.S.; Deborah A. Yurgelun-Todd, Ph.D.
Am J Psychiatry 2001;158:952-954. doi:10.1176/appi.ajp.158.6.952

Abstract

OBJECTIVE: Previous imaging studies have described focal cortical changes in schizophrenia, with predominant findings of abnormalities in the temporal and frontal regions. The current study hypothesized that cerebellar regions involved in feedback and feed-forward loops with cortical regions affected in schizophrenia would also demonstrate structural changes. METHOD: Using magnetic resonance imaging, the authors measured the volume of individual cerebellar lobules in 19 patients with schizophrenia and 19 healthy comparison subjects. RESULTS: The inferior vermis was significantly smaller in the schizophrenic group than in the comparison group. Patients with schizophrenia also demonstrated a significantly smaller cerebellar asymmetry than the comparison subjects. CONCLUSIONS: The authors hypothesize that these morphometric changes may be developmental in origin and possibly related to cortical abnormalities.

Abstract Teaser
Figures in this Article

Cerebellar abnormalities, including irregular Purkinje cell arrangement and loss, were described in patients with schizophrenia as early as 1959 (1). More recent histological evidence has been inconclusive (2, 3), suggesting that marked Purkinje cell abnormalities are not the hallmark of cerebellar pathology in schizophrenia. Computerized tomography studies have provided data showing structural abnormalities, particularly vermal atrophy, in the cerebella of patients with schizophrenia (4, 5). Experiments applying magnetic resonance imaging (MRI) techniques have been inconclusive, some finding a greater vermal volume in patients with schizophrenia (6), others reporting no differences (7, 8), and still others finding smaller cerebellar volume in patients (9).

The current investigation examined volume measurements of individual cerebellar regions in patients with schizophrenia. We hypothesized that cerebellar regions connected with cortical regions associated with the pathophysiology of schizophrenia would have abnormal volumes. Furthermore, on the basis of the prevalence of cerebral asymmetry in schizophrenia (10), we hypothesized that the cerebellar hemispheres would exhibit a reversed pattern of asymmetry.

Nineteen subjects with schizophrenia blindly diagnosed according to DSM-III-R (15 men and four women; mean age=34 years, SD=6), and 19 psychiatrically well comparison subjects (15 men and four women; mean age=27, SD=6) participated in the study. Comparison subjects had no personal or family history of neurological illness and no axis I disorder. Other exclusion criteria for both patients and comparison subjects included any history of organic brain syndrome, head injury, or motor disturbance. The study was approved by the McLean Hospital Institutional Review Board. Written informed consent was obtained from all participating subjects.

MRI data were acquired with a 1.5-T GE Signa scanner (GE Medical Systems, Milwaukee) retrofit with an Advanced NMR Systems (Woburn,Mass.) whole-body echo-planar imaging coil. A spoiled gradient-recalled acquisition of T1-weighted images was used (TR=35 msec, TE=5 msec) with 1.5-mm thick contiguous coronal slices.

Images were filtered and segmentation was completed by applying a method based on visual inspection. Parcellation of the cerebellum was carried out with the aid of the high-resolution MRI cerebellar atlas of Schmahmann et al. (11). The cerebellum was divided into 18 individual regions. Three-dimensional reconstructions are shown in four orthogonal views in F1 to demonstrate the divisions made by tracing the fissures. The volume of each region was calculated as the sum of all pixels within the region across slices multiplied by the slice thickness and voxel aspect ratio. Reliability of these measures was confirmed by calculating the intraclass correlation coefficient for all regions of 10 subjects (r=0.95 for all regions; range=0.92–0.99). Lateralization of cerebellar hemisphere volume was examined as an index of asymmetry: (right–left)/(right+left). Following the analysis of this index, one patient with schizophrenia was dropped from all tests because of a value outside of two standard deviations from the mean.

Statistical analyses were performed with StatView (Abacus Concepts, Inc., Berkeley, Calif.). Differences between diagnostic groups in morphometric measures were analyzed by using analysis of covariance with total cerebral volume as the covariate. Indexes of asymmetry were compared by using a one-tailed Student’s t test because the direction of the change was hypothesized a priori. We hypothesized that differences in asymmetry would follow the pattern frequently observed for the cerebral cortex. Bonferroni correction was not performed.

The mean inferior vermal volume was smaller in the patients with schizophrenia than in the comparison subjects (F=5.32, df=1, 33, p<0.03). Although the differences between groups in mean superior vermal volume were not significant, total vermal volume was significantly smaller in the patients with schizophrenia (F=4.56, df=1, 33, p<0.05). The groups did not differ significantly in other regional mean volume measures or in total cerebellar volume.

Measures of laterality revealed a right-greater-than-left hemispheric volume asymmetry for both groups. However, this asymmetry measure was significantly smaller in the patients with schizophrenia (for comparison subjects, mean=1.73, SD=0.99; for patients with schizophrenia, mean=0.82, SD=1.23) (t=2.47, df=35, p<0.01).

This study found a smaller inferior vermal volume and total vermal volume in patients with schizophrenia than in comparison subjects without schizophrenia. Developmental studies have found that granule cell production in vermal lobules VI–VIII follows that of the rest of the vermis and that lobule VIII is the only vermal region to develop third-order sublobules, suggesting that cell production and volume expansion occur later and to a greater extent in the inferior vermis (12). Studies documenting smaller vermal volumes in childhood-onset schizophrenia (13), fragile X syndrome (14), and autism (15) have also implicated cerebellar changes as part of an anomalous developmental process. The current study findings are consistent with the perspective that the inferior vermis, a large part of which is composed of lobule VIII, may be associated with an anomalous developmental process in schizophrenia.

This study also found less laterality in the cerebellum of patients with schizophrenia than in normal subjects. The abnormal pattern of cerebellar asymmetry may be related to changes in the cerebral cortex. Apart from the change in inferior vermal volume, we did not observe focal morphologic changes, suggesting that the difference in overall cerebellar asymmetry in schizophrenia may be due to a subtle and diffuse loss of inputs from the left cerebral cortex. Altered cerebral asymmetry in schizophrenia is postulated to result from a primary genetic defect (16). The present study provides evidence that anomalous cerebellar asymmetry is also related to schizophrenia.

In conclusion, cerebellar changes that accompany schizophrenia appear localized to the vermis but are not regionally specific within the hemispheres. Vermal changes are consistent with earlier findings regarding the importance of this structure for emotion modulation and integration of information from both cerebral hemispheres. A relative loss of normal cerebellar asymmetry in the schizophrenic group may be related to differences in cortical asymmetries in these patients. The observed morphologic changes may result from the combined or individual influence of genetic predispositions or nonfamilial factors, such as early brain insults.

Received May 9, 2000; revisions received Aug. 11 and Dec. 18, 2000; accepted Dec. 20, 2000. From the Cognitive Neuroimaging Laboratory, McLean Brain Imaging Center; and Program in Behavioral Neuroscience, Boston University School of Medicine, Boston. Address reprint requests to Dr. Yurgelun-Todd, Cognitive Neuroimaging Laboratory, McLean Brain Imaging Center, 115 Mill St., Belmont, MA 02478; ytodd@mclean.harvard.edu (e-mail). Supported in part by a National Alliance for Research on Schizophrenia and Depression Young Investigator Award (Dr. Yurgelun-Todd) and National Research Service Award MH-12535 (Mr. Loeber).

 
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Figure 1.

Three-Dimensional Reconstructions of the Segmented and Parcellated Cerebellum Seen From Four Anglesa

aSymmetric regions are displayed in the same color, although the measurements for the right and left sides were performed independently.

Roizin L, True C, Knight M: Structural effects of tranquilizers. Res Publ Assoc Res Nerv Ment Dis  1959; 17:285–324
 
Reyes MG, Gordon A: Cerebellar vermis in schizophrenia. Lancet  1981; 2:700–701
 
Helmkamp CE, Bigelow LB, Paltan-Ortiz JD, Torrey EF, Kleinman JE, Herman MM: Evaluation of superior vermal Purkinje cell placement in mental illness. Biol Psychiatry 1999; 45:1370–  1375
 
Heath RG, Franklin DE, Walker CF, Keating JWJ: Cerebellar vermal atrophy in psychiatric patients. Biol Psychiatry  1982; 17:569–583
[PubMed]
 
Sandyk R, Kay SR, Merriam AE: Atrophy of the cerebellar vermis: relevance to the symptoms of schizophrenia. Int J Neurosci  1991; 57:205–212
[PubMed]
[CrossRef]
 
Nasrallah HA, Schwarzkopf SB, Olson SC, Coffman JA: Perinatal brain injury and cerebellar vermal lobules I–X in schizophrenia. Biol Psychiatry  1991; 29:567–574
[PubMed]
[CrossRef]
 
Staal WG, Hulshoff Pol HEH, Schnack HG, Hoogendoorn MLC, Jellema K, Kahn RS: Structural brain abnormalities in patients with schizophrenia and their healthy siblings. Am J Psychiatry  2000; 157:416–421
[PubMed]
[CrossRef]
 
Aylward EH, Reiss A, Barta PE, Tien A, Han W, Lee J, Pearlson GD: Magnetic resonance imaging measurement of posterior fossa structures in schizophrenia. Am J Psychiatry 1994; 151:1448–  1452
 
Seidman LJ, Faraone SV, Goldstein JM, Goodman JM, Kremen WS, Toomey R, Tourville J, Kennedy D, Makris N, Caviness VS, Tsuang MT: Thalamic and amygdala-hippocampal volume reductions in first-degree relatives of patients with schizophrenia: an MRI-based morphometric analysis. Biol Psychiatry  1999; 46:941–954
[PubMed]
[CrossRef]
 
Yurgelun-Todd DA, Kinney DK, Sherwood AR, Renshaw PF: Magnetic resonance in schizophrenia. Semin Clin Neuropsychiatry  1996; 1:4–19
[PubMed]
 
Schmahmann JD, Doyon J, Toga AW, Petrides M, Evans AC: MRI Atlas of the Human Cerebellum. Orlando, Fla, Academic Press, 2000
 
Altman J, Bayar SA: Development of the Cerebellar System in Relation to Its Evolution, Structure, and Functions. Boca Raton, Fla, CRC Press, 1997
 
Jacobsen LK, Giedd JN, Berquin PC, Krain AL, Hamburger SD, Kumra S, Rapoport JL: Quantitative morphology of the cerebellum and fourth ventricle in childhood-onset schizophrenia. Am J Psychiatry 1997; 154:1663–  1669
 
Reiss AL, Aylward E, Freund LS, Joshi PK, Bryan RN: Neuroanatomy of fragile X syndrome: the posterior fossa. Ann Neurol  1991; 29:26–32
[PubMed]
[CrossRef]
 
Courchesne E, Yeung-Courchesne R, Press GA, Hesselink JR, Jernigan TL: Hypoplasia of cerebellar vermal lobules VI and VII in autism. N Engl J Med 1988; 318:1349–  1354
 
Crow TJ, Ball J, Bloom SR, Brown R, Bruton CJ, Colter N, Frith CD, Johnstone EC, Owens DG, Roberts GW: Schizophrenia as an anomaly of development of cerebral asymmetry: a postmortem study and a proposal concerning the genetic basis of the disease. Arch Gen Psychiatry 1989; 46:1145–  1150
 

Figure 1.

Three-Dimensional Reconstructions of the Segmented and Parcellated Cerebellum Seen From Four Anglesa

aSymmetric regions are displayed in the same color, although the measurements for the right and left sides were performed independently.

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References

Roizin L, True C, Knight M: Structural effects of tranquilizers. Res Publ Assoc Res Nerv Ment Dis  1959; 17:285–324
 
Reyes MG, Gordon A: Cerebellar vermis in schizophrenia. Lancet  1981; 2:700–701
 
Helmkamp CE, Bigelow LB, Paltan-Ortiz JD, Torrey EF, Kleinman JE, Herman MM: Evaluation of superior vermal Purkinje cell placement in mental illness. Biol Psychiatry 1999; 45:1370–  1375
 
Heath RG, Franklin DE, Walker CF, Keating JWJ: Cerebellar vermal atrophy in psychiatric patients. Biol Psychiatry  1982; 17:569–583
[PubMed]
 
Sandyk R, Kay SR, Merriam AE: Atrophy of the cerebellar vermis: relevance to the symptoms of schizophrenia. Int J Neurosci  1991; 57:205–212
[PubMed]
[CrossRef]
 
Nasrallah HA, Schwarzkopf SB, Olson SC, Coffman JA: Perinatal brain injury and cerebellar vermal lobules I–X in schizophrenia. Biol Psychiatry  1991; 29:567–574
[PubMed]
[CrossRef]
 
Staal WG, Hulshoff Pol HEH, Schnack HG, Hoogendoorn MLC, Jellema K, Kahn RS: Structural brain abnormalities in patients with schizophrenia and their healthy siblings. Am J Psychiatry  2000; 157:416–421
[PubMed]
[CrossRef]
 
Aylward EH, Reiss A, Barta PE, Tien A, Han W, Lee J, Pearlson GD: Magnetic resonance imaging measurement of posterior fossa structures in schizophrenia. Am J Psychiatry 1994; 151:1448–  1452
 
Seidman LJ, Faraone SV, Goldstein JM, Goodman JM, Kremen WS, Toomey R, Tourville J, Kennedy D, Makris N, Caviness VS, Tsuang MT: Thalamic and amygdala-hippocampal volume reductions in first-degree relatives of patients with schizophrenia: an MRI-based morphometric analysis. Biol Psychiatry  1999; 46:941–954
[PubMed]
[CrossRef]
 
Yurgelun-Todd DA, Kinney DK, Sherwood AR, Renshaw PF: Magnetic resonance in schizophrenia. Semin Clin Neuropsychiatry  1996; 1:4–19
[PubMed]
 
Schmahmann JD, Doyon J, Toga AW, Petrides M, Evans AC: MRI Atlas of the Human Cerebellum. Orlando, Fla, Academic Press, 2000
 
Altman J, Bayar SA: Development of the Cerebellar System in Relation to Its Evolution, Structure, and Functions. Boca Raton, Fla, CRC Press, 1997
 
Jacobsen LK, Giedd JN, Berquin PC, Krain AL, Hamburger SD, Kumra S, Rapoport JL: Quantitative morphology of the cerebellum and fourth ventricle in childhood-onset schizophrenia. Am J Psychiatry 1997; 154:1663–  1669
 
Reiss AL, Aylward E, Freund LS, Joshi PK, Bryan RN: Neuroanatomy of fragile X syndrome: the posterior fossa. Ann Neurol  1991; 29:26–32
[PubMed]
[CrossRef]
 
Courchesne E, Yeung-Courchesne R, Press GA, Hesselink JR, Jernigan TL: Hypoplasia of cerebellar vermal lobules VI and VII in autism. N Engl J Med 1988; 318:1349–  1354
 
Crow TJ, Ball J, Bloom SR, Brown R, Bruton CJ, Colter N, Frith CD, Johnstone EC, Owens DG, Roberts GW: Schizophrenia as an anomaly of development of cerebral asymmetry: a postmortem study and a proposal concerning the genetic basis of the disease. Arch Gen Psychiatry 1989; 46:1145–  1150
 
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