- Email: [email protected]
White Matter Density in Patients with Schizophrenia, Bipolar Disorder and Their Unaffected Relatives
BRIEF REPORT
White Matter Density in Patients with Schizophrenia, Bipolar Disorder and Their Unaffected Relatives Andrew M. McIntosh, Dominic E. Job, T. William J. Moorhead, Lesley K. Harrison, Stephen M. Lawrie, and Eve C. Johnstone Background: This study sought to assess white matter density in patients and relatives with histories of bipolar disorder and/or schizophrenia. Methods: Subjects included those with schizophrenia from families affected by schizophrenia alone, those with bipolar disorder from families affected by bipolar disorder alone and those with bipolar disorder from families affected by both bipolar disorder and schizophrenia. Unaffected relatives of the three patient groups were also recruited. Subjects underwent an MRI brain scan which was analyzed using a white-matter optimized technique. Results: Subjects with schizophrenia and bipolar disorder showed reduced white matter density in the anterior limb of the internal capsule which was not found in unaffected relatives. Reductions were found in frontal subgyral white matter density in affected subjects with a family history of schizophrenia only. Conclusions: Abnormal anterior internal capsule white matter may provide a structural substrate for both disorders. Key Words: Schizophrenia, bipolar disorder, VBM, MRI, relatives
S
tructural brain imaging has revealed abnormalities of gray (Shenton et al 2001) and white matter (Wright et al 1995; Ananth et al 2002) in schizophrenia. These reductions frequently implicate frontothalamic circuits (Paillere-Martinot et al 2001) and have support from functional imaging studies (Andreasen et al 1996; Lawrie et al 2002). In bipolar disorder, results from region of interest studies are equivocal (McDonald et al 2004) although there is some evidence of qualitative white matter abnormality (Videbech 1997) and cortical-striatal-thalamic involvement (Sheline 2003). We have shown anterior thalamic gray matter reductions in both bipolar disorder and schizophrenia using Voxel-based Morphometry (VBM, McIntosh et al 2004). The anterior thalamic nucleus is connected to the frontal lobe via the anterior limb of the internal capsule (ALIC) and may be abnormal and associated with reduced connectivity in bipolar subjects. We examined the ALIC in a cohort of patients and relatives shown to have thalamic abnormalities. Unaffected relatives were also scanned to ascertain if deficits were related to genetic liability, the presence of illness or both. Attention was focused on frontal subgyral white matter and the ALIC. We hypothesized that ALIC reductions would be found in all patients and their unaffected relatives, but that subgyral reductions would be specific to schizophrenia.
Methods and Materials Subjects Recruitment procedures and patient characteristics are detailed elsewhere (McIntosh et al 2004). Briefly, patients with a clinical diagnosis of schizophrenia or bipolar disorder were identified from hospital notes. Where patients were known to have at least one close relative with psychosis, the notes were
From the Division of Psychiatry (AMM, DEJ, TWJM, LKH, SML, ECJ), University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, United Kingdom. Address reprint requests to Dr. Andrew M. McIntosh, Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, EH10 5HF, UK; E-mail: [email protected]. Received October 29, 2004; revised March 11, 2005; accepted March 24, 2005.
0006-3223/05/$30.00 doi:10.1016/j.biopsych.2005.03.044
retrieved and DSM-IV operational criteria were applied using the Operational Criteria Checklist (McGuffin et al 1991). Patients with at least one first or second degree family member with schizophrenia or bipolar disorder were asked if any of their well relatives would also be prepared to take part. Well relatives without a personal history of schizophrenia or major affective disorder were invited to participate. Subjects were recruited into one of the following groups. Schizophrenic Subjects from Schizophrenic Families. This group consisted of people with schizophrenia with at least one close (first or second degree) relative with schizophrenia. Unaffected Subjects from Schizophrenic Families. This group consisted of healthy people with at least two close relatives with schizophrenia. Bipolar Subjects from Bipolar Families. This group consisted of people with bipolar I disorder with at least one close relative with bipolar disorder. Unaffected Subjects from Bipolar Families. This group consisted of unaffected people with at least two close relatives with bipolar disorder. Bipolar Subjects from Mixed Families. This group consisted of people with bipolar I disorder with at least one close relative with schizophrenia. Unaffected Subjects from Mixed Families. This group consisted of unaffected people with at least one close relative with schizophrenia and one with bipolar disorder. Control Subjects. This group consisted of people with no personal or family history of schizophrenia or bipolar disorder. Control subjects were recruited from the social contacts and nongenetic relatives of the above groups wherever possible. All people fulfilling study inclusion criteria were interviewed using the Present State Examination (Wing et al 1974) to supplement case note information and to confirm the diagnostic status of affected and unaffected subjects. All patients, relatives and controls gave informed consent to their participation. The study methods followed local and national guidelines on the ethical conduct of research, and the study protocol and consent procedures were approved by Lothian’s regional ethics committee and by the Royal Edinburgh Hospital management board. Image Acquisition and Analysis Details of the MRI sequences used are given in detail in our earlier paper. A white matter optimized technique was used BIOL PSYCHIATRY 2005;58:254 –257 © 2005 Society of Biological Psychiatry
BIOL PSYCHIATRY 2005;58:254 –257 255
A.M. McIntosh et al Table 1. Demographic Characteristics of Subjects Providing Useable MRI Data Group
n
R Hand Preference n (%)
Male n (%)
Height Mean (SD)
Age Mean (SD)
NART IQ Mean (SD)
Control SCZ from SCZ Family UA from SCZ Family BPD from BPD Family UA from BPD Family BPD from MIX Family UA from MIX Family
49 26 24 26 22 19 26
46 (93.9) 23 (88.5) 20 (83.3) 24 (92.3) 21 (95.5) 19 (100) 24 (92.3)
23 (46.9) 13 (50) 11 (45.8) 14 (53.9) 9 (40.9) 7 (36.8) 14 (53.9)
1.72 (.1) 1.70 (.1) 1.67 (.1) 1.70 (.1) 1.70 (.1) 1.69 (.1) 1.71 (.1)
35.27 (11.1) 36.85 (13.7) 38.92 (12.9) 40.5 (12.1) 34.73 (12.6) 39.74 (9.2) 34.12 (13.0)
110.5 (8.7) 100.5 (12.3) 102.7 (10.2) 111.1 (10.9) 105.6 (10.3) 105.7 (11.0) 105.0 (9.8)
MRI, magnetic resonance imaging; NART IQ, National Adult Reading Test Intelligence Quotient; SCZ, schizophrenia patients; UA, unaffected subjects; BPD, bipolar disorder; MIX, family of both affected and unaffected members.
(Good et al 2001). First, a study-specific white matter template was made from all T1 MRI scans. Images were spatially normalized to the generic T1 template using linear normalization and nearest neighbor interpolation. A mean image was then calculated and smoothed using an 8 mm kernel. All native space images were then normalized to the studyspecific white matter template using 12-parameter linear affine and nonlinear transformations. Images were segmented into white, gray and CSF. White matter images were then smoothed using a 12 mm kernel. Unmodulated, smoothed images were used for the statistical analyses to reflect tissue density. Statistical Analysis Variables with a possible relationship to brain anatomy (height, sex, age, handedness and white matter voxels) were used as covariates in the subsequent imaging analysis (Job et al 2002). Average images were compared between groups using t-contrasts with correction for multiple comparisons (Worsley et al 1998) in SPM99. Analysis was restricted to a small volume correction image (SVC) for frontal subgyral white matter (sphere coordinates ⫽ ⫾ 22, 40, 6, diameter ⫽ 11 mm) and the ALIC (sphere coordinates ⫽ ⫾ 18, 12, 6, diameter ⫽ 11 mm). This image was constructed from the average of all normalised images, smoothed with an 8 mm kernel, thresholded at 80% and binarized to give a SVC image for subgyral and ALIC white matter (6.7 resels). The extent and location of between-group differences are illustrated using statistical parametric maps, thresholded at p ⬍ .01 uncorrected.
Analyses were restricted to those which looked for reductions relative to controls and were within volume of the SVC. Results were reported where they reached a significance level of p ⬍ .05 corrected. To ensure that differences were not due to misattribution of gray matter, the white matter and gray matter contrast images were superimposed and checked for overlap.
Results Seventy four patients provided complete clinical data and near complete neuropsychological data and 71 patients provided a useable MRI scan of the brain. From the families of eligible patients, a further 160 unaffected family members were identified. Eighty relatives met study inclusion criteria and 72 provided a useable MRI scan of the brain. Fifty-four potential control subjects were identified and interviewed using the Schedule for Affective Disorders and Schizophrenia, lifetime version (SADS-L). Three controls were excluded because of previous illness, and 49 provided useable imaging data (see Table 1). Imaging Results Patients versus Controls. Differences in white matter density were found between schizophrenic subjects and controls in several areas, particularly in the left subgyral white matter and left ALIC (Figure 1, Table 2). Patients with bipolar disorder from bipolar families showed significant reductions only in left ALIC (Figure 2, Table 3). No decreases in white matter density were found between bipolar patients from mixed families and controls. To examine the specificity of white matter differences to each disease phenotype, differences between schizophrenic patients and controls were masked with the contrast image comparing bipolar subjects from bipolar families and controls and secondly the contrast image comparing bipolar subjects from mixed families versus controls (Cabeza et al 2004). Each masking image was thresholded at p ⫽ .05 (uncorrected). Masking with the Table 2. White Matter Differences Between Schizophrenic Patients and Controls Voxel p Corrected
Figure 1. Differences in white matter density between schizophrenic subjects and controls. These statistical parametric maps illustrate the areas of significant difference between controls and each group projected onto an averaged image of the brain from all 192 study participants (thresholded at p ⬍ .01).
.01 .011 .012 .045 a
x, y, z (mm) Talairach Coordinates ⫺25 ⫺12 31 ⫺15
35 37 44 4
15 4 6 7
Region of Difference Left subgyral frontal white mattera Genu of corpus callosum/left cingulum Right subgyral frontal white matterb Left anterior internal capsule
Nearest gray matter BA 10. Nearest gray matter BA 10.
b
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256 BIOL PSYCHIATRY 2005;58:254 –257
A.M. McIntosh et al Table 4. Differences in White Matter Density between Unaffected Subjects from Mixed Families and Controls Voxel p corrected
x, y, z (mm) Talairach Coordinates
Region of Difference
Results After Frontal White Matter Small Volume Correction .02 .049
30 16
43 47
9 0
Right superior frontal gyral white matter Right medial frontal gyral white matter
Nearest gray matter to both regions is BA10.
Figure 2. Differences in white matter density between bipolar subjects from bipolar families and controls. These statistical parametric maps illustrate the areas of significant difference between controls and each group projected onto an averaged image of the brain from all 192 study participants (thresholded at p ⬍ .01).
bipolar from mixed families versus controls image removed all areas of significant white matter density reduction reflecting similar deficits in patients with bipolar disorder from mixed families which did not reach voxel-wise significance. Relatives versus Controls. No differences were observed between the unaffected relatives of schizophrenic subjects and controls or between unaffected subjects from bipolar families and controls. Unexpectedly, unaffected relatives from mixed families showed two areas of significant reduction- in right superior frontal subgyral white matter, and in right medial frontal gyral white matter (see Table 4).
Discussion White matter reductions were found in frontal subgyral and ALIC white matter in schizophrenic subjects compared to controls. Reductions in ALIC but not frontal subgyral white matter were found in bipolar patients from bipolar families. Areas of frontal subgyral white matter reduction were shown to be specific to patients with schizophrenia (Cabeza et al 2004). No white matter reductions relative to controls were found in the unaffected relatives of either schizophrenic or bipolar patients in families affected by one disorder. This study extends that of Zhou et al (2003) finding ALIC volume reductions in schizophrenia, extends their result to density reductions in familial Bipolar I disorder and shows that the reductions are not present in unaffected relatives. This suggests a pattern of abnormal frontothalamic connectivity common to both functional psychotic disorders, and complements the finding of anterior thalamic volume reduction found in the sample. Deficits in prefrontal subgyral white matter density were also demonstrated in the unaffected subjects from mixed families, but not the unaffected subjects from other groups. This might suggest that the effects of genetic liability to schizophrenia and bipolar disorder are additive or perhaps due to the larger size of this Table 3. White Matter Differences Between Bipolar Subjects from Bipolar Families and Controls x, y, z (mm) Talairach Coordinates
Voxel p corrected .036
⫺8
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8
Region of Difference 5
Left anterior internal capsule
group in comparison to the other unaffected relative groups. The right prefrontal subgyral white matter reductions may reflect the tendency for bipolar subjects from mixed families to be more ‘schizophrenic-like’ in terms of symptoms and neuropsychology (McIntosh et al 2005). This study suggests that decreased frontothalamic white matter may underlie disintegrated activity between these regions in psychosis. Although there is considerable imaging literature to support this result in schizophrenia, such evidence is lacking in respect of bipolar illness. Whilst these results confirm or extend those of some (Suzuki et al 2002; Zhou et al 2003; Hulshoff Pol et al 2004), although not all VBM studies (Sigmundsson et al 2001) in respect of schizophrenia, using a white matter optimised technique cannot distinguish axons from other tissue types and may stretch the assumptions of VBM (e.g. normality). Evidence of increased numbers of white matter hyperintensities (Videbech 1997), together with our findings, highlight the importance of white matter investigation in bipolar illness. We would like to thank all who participated in the study, the Medical Research Council for funding the principal investigator through a Clinical Training Fellowship and the Stanley Medical Research Institute for financial support in respect of the scans. Ananth H, Popescu I, Critchley HD, Good CD, Frackowiak RSJ, Dolan RJ (2002): Cortical and subcortical gray matter abnormalities in schizophrenia determined through structural magnetic resonance imaging with optimized volumetric voxel-based morphometry. Am J Psychiatry 159: 1497–1505. Andreasen NC, O’Leary DS, Cizadlo T, Arndt S, Rezai K, Ponto LL, et al (1996): Schizophrenia and cognitive dysmetria: a positron-emission tomography study of dysfunctional prefrontal-thalamic-cerebellar circuitry. Proceedings of the National Academy of Sciences of the United States of America 93:9985–9990. Cabeza R, Daselaar SM, Dolcos F, Prince SE, Budde M, Nyberg L (2004): Task-independent and Task-specific Age Effects on Brain Activity during Working Memory, Visual Attention and Episodic Retrieval. Cereb Cortex 14:364 –375. Good CD, Johnsrude IS, Ashburner J, Henson RN, Friston KJ, Frackowiak RS (2001): A voxel-based morphometric study of ageing in 465 normal adult human brains. Neuroimage 14:t-36. Hulshoff Pol HE, Schnack HG, Mandl RC, Cahn W, Collins DL, Evans AC, Kahn RS (2004): Focal white matter density changes in schizophrenia: reduced inter- hemispheric connectivity. NeuroImage 21:27–35. Job DE, Whalley HC, McConnell S, Glabus M, Johnstone EC, Lawrie SM (2002): Structural gray matter differences between first-episode schizophrenics and normal controls using voxel-based morphometry. Neuroimage 17: 880 – 889. Lawrie SM, Buechel C, Whalley HC, Frith CD, Friston KJ, Johnstone EC (2002): Reduced frontotemporal functional connectivity in schizophrenia associated with auditory hallucinations. Biological Psychiatry 51:1008 –1011. McDonald C, Zanelli J, Rabe-Hesketh S, Ellison-Wright I, Sham P, Kalidindi S, et al (2004): Meta-analysis of magnetic resonance imaging brain morphometry studies in bipolar disorder. Biological Psychiatry 56:144 – 417.
A.M. McIntosh et al McGuffin P, Farmer A, Harvey I (1991): A polydiagnostic application of operational criteria in studies of psychotic illness. Development and reliability of the OPCRIT system. Archives of General Psychiatry 48:764 –770. McIntosh AM, Harrison LK, Forrester K, Lawrie SM, Johnstone EC (2005): Neuropsychological impairments in patients with schizophrenia, bipolar disorder and their unaffected relatives. British Journal of Psychiatry 186:378 –385. McIntosh AM, Job D, Moorhead TWJ, Harrison LK, Forrester K, Lawrie SM, Johnstone EC (2004): Voxel-Based morphometry of patients with schizophrenia or bipolar disorder and their unaffected relatives. Biological Psychiatry 56:544 –552. Paillere-Martinot M, Caclin A, Artiges E, Poline JB, Joliot M, Mallet L, et al (2001): Cerebral gray and white matter reductions and clinical correlates in patients with early onset schizophrenia. Schizophrenia Research 50:19 –26. Sheline YI (2003): Neuroimaging studies of mood disorder effects on the brain. Biological Psychiatry 54(3):338 –52. Shenton ME, Dickey CC, Frumin M, McCarley RW (2001): A review of MRI findings in schizophrenia. Schizophrenia Research 49:1–52. Sigmundsson T, Suckling J, Maier M, Williams S, Bullmore E, Greenwood K, et al (2001): Structural abnormalities in frontal, temporal, and limbic regions and interconnecting white matter tracts in schizophrenic patients
BIOL PSYCHIATRY 2005;58:254 –257 257 with prominent negative symptoms. American Journal of Psychiatry 158:234 –243. Suzuki M, Nohara S, Hagino H, Kurokawa K, Yotsutsuji T, Kawasaki Y, et al (2002): Regional changes in brain gray and white matter in patients with schizophrenia demonstrated with voxel-based analysis of MRI. Schizophrenia Research 55:41–54. Videbech P (1997): MRI findings in patients with affective disorder: a metaanalysis. Acta Psychiatrica Scandinavica 96:157–168. Wing JK, Cooper JE, Sartorius N (1974): The Description and Classification of Psychiatric Symptoms. An instruction manual for the PSE and Catego systems. Cambridge University Press, Cambridge. Worsley KJ, Cao J, Paus T, Petrides M, Evans AC (1998): Applications of random field theory to functional connectivity. Human Brain Mapping 6:364 –367. Wright IC, McGuire PK, Poline JB, Travere JM, Murray RM, Frith CD, et al (1995): A voxel-based method for the statistical analysis of gray and white matter density applied to schizophrenia. Neuroimage 2:244 –252. Zhou S, Suzuki M, Hagino H, Takahashi T, Kawasaki Y, Nohara S, et al (2003): Decreased volume and increased asymmetry of the anterior limb of the internal capsule in patients with schizophrenia. Biological Psychiatry 54: 427– 436.
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White Matter Density in Patients with Schizophrenia, Bipolar Disorder and Their Unaffected Relatives Andrew M. McIntosh, Dominic E. Job, T. William J. Moorhead, Lesley K. Harrison, Stephen M. Lawrie, and Eve C. Johnstone Background: This study sought to assess white matter density in patients and relatives with histories of bipolar disorder and/or schizophrenia. Methods: Subjects included those with schizophrenia from families affected by schizophrenia alone, those with bipolar disorder from families affected by bipolar disorder alone and those with bipolar disorder from families affected by both bipolar disorder and schizophrenia. Unaffected relatives of the three patient groups were also recruited. Subjects underwent an MRI brain scan which was analyzed using a white-matter optimized technique. Results: Subjects with schizophrenia and bipolar disorder showed reduced white matter density in the anterior limb of the internal capsule which was not found in unaffected relatives. Reductions were found in frontal subgyral white matter density in affected subjects with a family history of schizophrenia only. Conclusions: Abnormal anterior internal capsule white matter may provide a structural substrate for both disorders. Key Words: Schizophrenia, bipolar disorder, VBM, MRI, relatives
S
tructural brain imaging has revealed abnormalities of gray (Shenton et al 2001) and white matter (Wright et al 1995; Ananth et al 2002) in schizophrenia. These reductions frequently implicate frontothalamic circuits (Paillere-Martinot et al 2001) and have support from functional imaging studies (Andreasen et al 1996; Lawrie et al 2002). In bipolar disorder, results from region of interest studies are equivocal (McDonald et al 2004) although there is some evidence of qualitative white matter abnormality (Videbech 1997) and cortical-striatal-thalamic involvement (Sheline 2003). We have shown anterior thalamic gray matter reductions in both bipolar disorder and schizophrenia using Voxel-based Morphometry (VBM, McIntosh et al 2004). The anterior thalamic nucleus is connected to the frontal lobe via the anterior limb of the internal capsule (ALIC) and may be abnormal and associated with reduced connectivity in bipolar subjects. We examined the ALIC in a cohort of patients and relatives shown to have thalamic abnormalities. Unaffected relatives were also scanned to ascertain if deficits were related to genetic liability, the presence of illness or both. Attention was focused on frontal subgyral white matter and the ALIC. We hypothesized that ALIC reductions would be found in all patients and their unaffected relatives, but that subgyral reductions would be specific to schizophrenia.
Methods and Materials Subjects Recruitment procedures and patient characteristics are detailed elsewhere (McIntosh et al 2004). Briefly, patients with a clinical diagnosis of schizophrenia or bipolar disorder were identified from hospital notes. Where patients were known to have at least one close relative with psychosis, the notes were
From the Division of Psychiatry (AMM, DEJ, TWJM, LKH, SML, ECJ), University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, United Kingdom. Address reprint requests to Dr. Andrew M. McIntosh, Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, EH10 5HF, UK; E-mail: [email protected]. Received October 29, 2004; revised March 11, 2005; accepted March 24, 2005.
0006-3223/05/$30.00 doi:10.1016/j.biopsych.2005.03.044
retrieved and DSM-IV operational criteria were applied using the Operational Criteria Checklist (McGuffin et al 1991). Patients with at least one first or second degree family member with schizophrenia or bipolar disorder were asked if any of their well relatives would also be prepared to take part. Well relatives without a personal history of schizophrenia or major affective disorder were invited to participate. Subjects were recruited into one of the following groups. Schizophrenic Subjects from Schizophrenic Families. This group consisted of people with schizophrenia with at least one close (first or second degree) relative with schizophrenia. Unaffected Subjects from Schizophrenic Families. This group consisted of healthy people with at least two close relatives with schizophrenia. Bipolar Subjects from Bipolar Families. This group consisted of people with bipolar I disorder with at least one close relative with bipolar disorder. Unaffected Subjects from Bipolar Families. This group consisted of unaffected people with at least two close relatives with bipolar disorder. Bipolar Subjects from Mixed Families. This group consisted of people with bipolar I disorder with at least one close relative with schizophrenia. Unaffected Subjects from Mixed Families. This group consisted of unaffected people with at least one close relative with schizophrenia and one with bipolar disorder. Control Subjects. This group consisted of people with no personal or family history of schizophrenia or bipolar disorder. Control subjects were recruited from the social contacts and nongenetic relatives of the above groups wherever possible. All people fulfilling study inclusion criteria were interviewed using the Present State Examination (Wing et al 1974) to supplement case note information and to confirm the diagnostic status of affected and unaffected subjects. All patients, relatives and controls gave informed consent to their participation. The study methods followed local and national guidelines on the ethical conduct of research, and the study protocol and consent procedures were approved by Lothian’s regional ethics committee and by the Royal Edinburgh Hospital management board. Image Acquisition and Analysis Details of the MRI sequences used are given in detail in our earlier paper. A white matter optimized technique was used BIOL PSYCHIATRY 2005;58:254 –257 © 2005 Society of Biological Psychiatry
BIOL PSYCHIATRY 2005;58:254 –257 255
A.M. McIntosh et al Table 1. Demographic Characteristics of Subjects Providing Useable MRI Data Group
n
R Hand Preference n (%)
Male n (%)
Height Mean (SD)
Age Mean (SD)
NART IQ Mean (SD)
Control SCZ from SCZ Family UA from SCZ Family BPD from BPD Family UA from BPD Family BPD from MIX Family UA from MIX Family
49 26 24 26 22 19 26
46 (93.9) 23 (88.5) 20 (83.3) 24 (92.3) 21 (95.5) 19 (100) 24 (92.3)
23 (46.9) 13 (50) 11 (45.8) 14 (53.9) 9 (40.9) 7 (36.8) 14 (53.9)
1.72 (.1) 1.70 (.1) 1.67 (.1) 1.70 (.1) 1.70 (.1) 1.69 (.1) 1.71 (.1)
35.27 (11.1) 36.85 (13.7) 38.92 (12.9) 40.5 (12.1) 34.73 (12.6) 39.74 (9.2) 34.12 (13.0)
110.5 (8.7) 100.5 (12.3) 102.7 (10.2) 111.1 (10.9) 105.6 (10.3) 105.7 (11.0) 105.0 (9.8)
MRI, magnetic resonance imaging; NART IQ, National Adult Reading Test Intelligence Quotient; SCZ, schizophrenia patients; UA, unaffected subjects; BPD, bipolar disorder; MIX, family of both affected and unaffected members.
(Good et al 2001). First, a study-specific white matter template was made from all T1 MRI scans. Images were spatially normalized to the generic T1 template using linear normalization and nearest neighbor interpolation. A mean image was then calculated and smoothed using an 8 mm kernel. All native space images were then normalized to the studyspecific white matter template using 12-parameter linear affine and nonlinear transformations. Images were segmented into white, gray and CSF. White matter images were then smoothed using a 12 mm kernel. Unmodulated, smoothed images were used for the statistical analyses to reflect tissue density. Statistical Analysis Variables with a possible relationship to brain anatomy (height, sex, age, handedness and white matter voxels) were used as covariates in the subsequent imaging analysis (Job et al 2002). Average images were compared between groups using t-contrasts with correction for multiple comparisons (Worsley et al 1998) in SPM99. Analysis was restricted to a small volume correction image (SVC) for frontal subgyral white matter (sphere coordinates ⫽ ⫾ 22, 40, 6, diameter ⫽ 11 mm) and the ALIC (sphere coordinates ⫽ ⫾ 18, 12, 6, diameter ⫽ 11 mm). This image was constructed from the average of all normalised images, smoothed with an 8 mm kernel, thresholded at 80% and binarized to give a SVC image for subgyral and ALIC white matter (6.7 resels). The extent and location of between-group differences are illustrated using statistical parametric maps, thresholded at p ⬍ .01 uncorrected.
Analyses were restricted to those which looked for reductions relative to controls and were within volume of the SVC. Results were reported where they reached a significance level of p ⬍ .05 corrected. To ensure that differences were not due to misattribution of gray matter, the white matter and gray matter contrast images were superimposed and checked for overlap.
Results Seventy four patients provided complete clinical data and near complete neuropsychological data and 71 patients provided a useable MRI scan of the brain. From the families of eligible patients, a further 160 unaffected family members were identified. Eighty relatives met study inclusion criteria and 72 provided a useable MRI scan of the brain. Fifty-four potential control subjects were identified and interviewed using the Schedule for Affective Disorders and Schizophrenia, lifetime version (SADS-L). Three controls were excluded because of previous illness, and 49 provided useable imaging data (see Table 1). Imaging Results Patients versus Controls. Differences in white matter density were found between schizophrenic subjects and controls in several areas, particularly in the left subgyral white matter and left ALIC (Figure 1, Table 2). Patients with bipolar disorder from bipolar families showed significant reductions only in left ALIC (Figure 2, Table 3). No decreases in white matter density were found between bipolar patients from mixed families and controls. To examine the specificity of white matter differences to each disease phenotype, differences between schizophrenic patients and controls were masked with the contrast image comparing bipolar subjects from bipolar families and controls and secondly the contrast image comparing bipolar subjects from mixed families versus controls (Cabeza et al 2004). Each masking image was thresholded at p ⫽ .05 (uncorrected). Masking with the Table 2. White Matter Differences Between Schizophrenic Patients and Controls Voxel p Corrected
Figure 1. Differences in white matter density between schizophrenic subjects and controls. These statistical parametric maps illustrate the areas of significant difference between controls and each group projected onto an averaged image of the brain from all 192 study participants (thresholded at p ⬍ .01).
.01 .011 .012 .045 a
x, y, z (mm) Talairach Coordinates ⫺25 ⫺12 31 ⫺15
35 37 44 4
15 4 6 7
Region of Difference Left subgyral frontal white mattera Genu of corpus callosum/left cingulum Right subgyral frontal white matterb Left anterior internal capsule
Nearest gray matter BA 10. Nearest gray matter BA 10.
b
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A.M. McIntosh et al Table 4. Differences in White Matter Density between Unaffected Subjects from Mixed Families and Controls Voxel p corrected
x, y, z (mm) Talairach Coordinates
Region of Difference
Results After Frontal White Matter Small Volume Correction .02 .049
30 16
43 47
9 0
Right superior frontal gyral white matter Right medial frontal gyral white matter
Nearest gray matter to both regions is BA10.
Figure 2. Differences in white matter density between bipolar subjects from bipolar families and controls. These statistical parametric maps illustrate the areas of significant difference between controls and each group projected onto an averaged image of the brain from all 192 study participants (thresholded at p ⬍ .01).
bipolar from mixed families versus controls image removed all areas of significant white matter density reduction reflecting similar deficits in patients with bipolar disorder from mixed families which did not reach voxel-wise significance. Relatives versus Controls. No differences were observed between the unaffected relatives of schizophrenic subjects and controls or between unaffected subjects from bipolar families and controls. Unexpectedly, unaffected relatives from mixed families showed two areas of significant reduction- in right superior frontal subgyral white matter, and in right medial frontal gyral white matter (see Table 4).
Discussion White matter reductions were found in frontal subgyral and ALIC white matter in schizophrenic subjects compared to controls. Reductions in ALIC but not frontal subgyral white matter were found in bipolar patients from bipolar families. Areas of frontal subgyral white matter reduction were shown to be specific to patients with schizophrenia (Cabeza et al 2004). No white matter reductions relative to controls were found in the unaffected relatives of either schizophrenic or bipolar patients in families affected by one disorder. This study extends that of Zhou et al (2003) finding ALIC volume reductions in schizophrenia, extends their result to density reductions in familial Bipolar I disorder and shows that the reductions are not present in unaffected relatives. This suggests a pattern of abnormal frontothalamic connectivity common to both functional psychotic disorders, and complements the finding of anterior thalamic volume reduction found in the sample. Deficits in prefrontal subgyral white matter density were also demonstrated in the unaffected subjects from mixed families, but not the unaffected subjects from other groups. This might suggest that the effects of genetic liability to schizophrenia and bipolar disorder are additive or perhaps due to the larger size of this Table 3. White Matter Differences Between Bipolar Subjects from Bipolar Families and Controls x, y, z (mm) Talairach Coordinates
Voxel p corrected .036
⫺8
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8
Region of Difference 5
Left anterior internal capsule
group in comparison to the other unaffected relative groups. The right prefrontal subgyral white matter reductions may reflect the tendency for bipolar subjects from mixed families to be more ‘schizophrenic-like’ in terms of symptoms and neuropsychology (McIntosh et al 2005). This study suggests that decreased frontothalamic white matter may underlie disintegrated activity between these regions in psychosis. Although there is considerable imaging literature to support this result in schizophrenia, such evidence is lacking in respect of bipolar illness. Whilst these results confirm or extend those of some (Suzuki et al 2002; Zhou et al 2003; Hulshoff Pol et al 2004), although not all VBM studies (Sigmundsson et al 2001) in respect of schizophrenia, using a white matter optimised technique cannot distinguish axons from other tissue types and may stretch the assumptions of VBM (e.g. normality). Evidence of increased numbers of white matter hyperintensities (Videbech 1997), together with our findings, highlight the importance of white matter investigation in bipolar illness. We would like to thank all who participated in the study, the Medical Research Council for funding the principal investigator through a Clinical Training Fellowship and the Stanley Medical Research Institute for financial support in respect of the scans. Ananth H, Popescu I, Critchley HD, Good CD, Frackowiak RSJ, Dolan RJ (2002): Cortical and subcortical gray matter abnormalities in schizophrenia determined through structural magnetic resonance imaging with optimized volumetric voxel-based morphometry. Am J Psychiatry 159: 1497–1505. Andreasen NC, O’Leary DS, Cizadlo T, Arndt S, Rezai K, Ponto LL, et al (1996): Schizophrenia and cognitive dysmetria: a positron-emission tomography study of dysfunctional prefrontal-thalamic-cerebellar circuitry. Proceedings of the National Academy of Sciences of the United States of America 93:9985–9990. Cabeza R, Daselaar SM, Dolcos F, Prince SE, Budde M, Nyberg L (2004): Task-independent and Task-specific Age Effects on Brain Activity during Working Memory, Visual Attention and Episodic Retrieval. Cereb Cortex 14:364 –375. Good CD, Johnsrude IS, Ashburner J, Henson RN, Friston KJ, Frackowiak RS (2001): A voxel-based morphometric study of ageing in 465 normal adult human brains. Neuroimage 14:t-36. Hulshoff Pol HE, Schnack HG, Mandl RC, Cahn W, Collins DL, Evans AC, Kahn RS (2004): Focal white matter density changes in schizophrenia: reduced inter- hemispheric connectivity. NeuroImage 21:27–35. Job DE, Whalley HC, McConnell S, Glabus M, Johnstone EC, Lawrie SM (2002): Structural gray matter differences between first-episode schizophrenics and normal controls using voxel-based morphometry. Neuroimage 17: 880 – 889. Lawrie SM, Buechel C, Whalley HC, Frith CD, Friston KJ, Johnstone EC (2002): Reduced frontotemporal functional connectivity in schizophrenia associated with auditory hallucinations. Biological Psychiatry 51:1008 –1011. McDonald C, Zanelli J, Rabe-Hesketh S, Ellison-Wright I, Sham P, Kalidindi S, et al (2004): Meta-analysis of magnetic resonance imaging brain morphometry studies in bipolar disorder. Biological Psychiatry 56:144 – 417.
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