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Decreased cortical gray and cerebral white matter in male patients with familial bipolar I disorder
Journal of Affective Disorders 82 (2004) 475 – 485 www.elsevier.com/locate/jad
Preliminary communication
Decreased cortical gray and cerebral white matter in $ male patients with familial bipolar I disorder Kevin A. Davis a, Andreana Kwon a, Valerie A. Cardenas b,c, Raymond F. Deicken a,b,d,* a b
Psychiatry Service, Veterans Affairs Medical Center, San Francisco, CA 94121, USA Magnetic Resonance Unit, Veterans Affairs Medical Center, San Francisco, CA, USA c Department of Radiology, University of California, San Francisco, CA, USA d Department of Psychiatry, University of California, San Francisco, CA, USA Received 3 April 2003; accepted 1 March 2004
Abstract Background: Previous MRI studies of bipolar disorder have failed to consistently demonstrate cortical gray or cerebral white matter tissue loss, as well as sulcal or ventricular enlargement. The inconsistencies are most likely due to the clinical and gender heterogeneity of the study populations as well as the different MRI acquisition and processing techniques. The objective of this study was to determine if there was a cortical gray matter and cerebral white matter deficit as well as sulcal and ventricular enlargement in a homogeneous sample of euthymic male patients with familial bipolar I disorder. Methods: MRI tissue segmentation was utilized to obtain cortical gray matter, cerebral white matter, ventricular cerebrospinal fluid (CSF), and sulcal CSF volumes in 22 euthymic males with familial bipolar I disorder and 32 healthy male control subjects. Results: Relative to the controls, the familial bipolar I patients demonstrated: (1) significant reductions of both cortical gray matter and cerebral white matter volumes; and (2) significant increases in both sulcal and ventricular CSF volumes. In the bipolar group, there was a significant negative correlation between cortical gray matter volume and sulcal CSF volume. Limitations: Small sample size, retrospective interviews, possible medication effects. Conclusions: These results provide evidence for significant cortical gray matter and cerebral white matter deficits and associated sulcal and ventricular enlargement in euthymic males with familial bipolar I disorder. D 2004 Elsevier B.V. All rights reserved. Keywords: Bipolar disorder; Cortical gray matter; Magnetic resonance imaging; Brain
1. Introduction Previous MRI investigations of bipolar disorder have been inconclusive in determining whether $ Previous presentation: Presented at the 32nd annual meeting of the Society for Neuroscience, Orlando, FL, Nov. 2 – 7, 2002. * Corresponding author. Psychiatry Service, 116-N Veterans Affairs Medical Center, 4150 Clement Street, San Francisco, CA 94121, USA. Tel.: +1-415-221-4810x4350; fax: +1-415-750-6648. E-mail address: [email protected] (R.F. Deicken).
0165-0327/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2004.03.010
there is: (1) decreased cortical gray matter volume; (2) decreased cerebral white matter volume; (3) increased lateral ventricular volume; or (4) increased sulcal volume. Although two previous studies (Lim et al., 1999; Lopez-Larson et al., 2002) using MRI tissue segmentation techniques found global reductions of cortical gray matter, most MRI investigations have failed to corroborate such reductions in bipolar disorder (Strakowski et al., 1993; Harvey et al., 1994; Schlaepfer et al., 1994; Dupont et al.,
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1995; Pearlson et al., 1997; Zipursky et al., 1997; Brambilla et al., 2001a). In fact, two studies found trends for increased total cortical gray matter volumes (Kieseppa et al., 2003; Sharma et al., 2003). More commonly, MRI studies have demonstrated tissue volume reductions in specific cortical regions such as the prefrontal (Sax et al., 1999; Strakowski et al., 1999; Lopez-Larson et al., 2002) or subgenual anterior cingulate (Drevets et al., 1998; Sharma et al., 2003) cortex. As for cerebral white matter volumes, no decrease was observed in five studies (Zipursky et al., 1997; Lim et al., 1999; Brambilla et al., 2001a; Lopez-Larson et al., 2002; Sassi et al., 2002) as compared to one study in first-episode manic patients that noted a decreasing trend in white matter volumes (Strakowski et al., 1993). However, a recent study of bipolar I patients and their healthy co-twins noted significantly decreased left hemisphere white matter volumes in the bipolar patients and healthy co-twins compared to controls, however, significantly decreased right hemisphere white matter volumes only in the bipolar I patients and not the co-twins compared to the controls (Kieseppa et al., 2003). Finally, despite a lack of consistent evidence of sulcal and ventricular enlargement (Soares and Mann, 1997), previous meta-analyses have shown significant effect sizes for both sulcal and ventricular enlargement (Elkis et al., 1995; Strakowski et al., 2000). To further complicate interpretation of these findings, ventricular enlargement has been reported in first-episode mania (Strakowski et al., 1993); noted to be positively correlated with the number of prior illness episodes (Brambilla et al., 2001b; Strakowski et al., 2002); and larger in familial compared to non-familial bipolar patients (Brambilla et al., 2001b). The overall inconsistency of findings for these generalized structural measures across studies is most likely due to the inclusion of clinically heterogeneous samples of bipolar patients who varied with respect to clinical subtype, familial subtype, affective state (euthymia, depression, hypomania, and mania), medication status, history of comorbid alcohol or substance abuse/dependence, and gender. For example, all of the previously cited MRI studies except for two included a mixture of both
men and women in different clinical states, with some differentiating between familial and non-familial patients. Six studies (Brambilla et al., 2001a; Lopez-Larson et al., 2002; Strakowski et al., 2002; Kieseppa et al., 2003; Sharma et al., 2003) used DSM-IV criteria to distinguish between bipolar I and bipolar II disorder, whereas the remaining studies utilized DSM-III-R criteria which does not specify bipolar II as a diagnostic category. Two studies used identical MRI tissue segmentation protocols (Zipursky et al., 1997; Lim et al., 1999) but one study examined male inpatients (Lim et al., 1999) whereas the other study examined predominantly female bipolar outpatients (Zipursky et al., 1997). Furthermore, the MRI slice thickness in 10 of the 15 MRI volumetric studies cited above ranged from 3 to 6 mm with and without slice gaps, resulting in varying degrees of partial volume artifact. This coupled with different morphometric voluming algorithms could easily account for the discrepancies. The identification of structural brain abnormalities that may be trait markers and therefore, potential endophenotypes for bipolar I disorder has become an increasingly important objective of neuroimaging research in recent years. In order to identify structural brain abnormalities that may serve as potential endophenotypes for bipolar I disorder, it is imperative that such abnormalities be attributable to the disease itself, without potential confounds due to comorbidity with other major psychiatric disorders and/or substance abuse. Therefore, this study examined a homogeneous population of euthymic male patients with familial bipolar I disorder order, in an effort to reduce the potential confounds of bipolar subtype, gender, and clinical state on the MRI measures, and because there is emerging evidence that abnormalities in brain structure and function may be more prominent in familial compared to non-familial mood disorders (Drevets et al., 1998; Ongu¨r et al., 1998; Hirayasu et al., 1999; Brambilla et al., 2001b; Sharma et al., 2003). More specifically, quantitative MRI tissue segmentation methods were utilized to determine if: (1) cortical gray matter and cerebral white matter volumes were decreased; and (2) sulcal and ventricular volumes were increased in the bipolar I group compared to controls.
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2. Methods 2.1. Subjects Study subjects were recruited from the San Francisco Veterans Affairs Medical Center, University of California, San Francisco Langley Porter Psychiatric Institute, outpatient community mental health clinics, and the local community by newspaper advertisement. Twenty-two male patients who met inclusion DSM-IV diagnostic criteria for bipolar I disorder (mean F SD age = 43.1 F 11.4 years) and 32 male control subjects (mean F SD age = 37.8 F 10.8 years) gave written informed consent for participation in the study after the procedures had been fully explained. The age range of subjects for inclusion in the study was 18 – 60 years. Mean F SD years of education was 15.2 F 2.4 for the bipolar patients and 16.6 F 4.2 for the control group. Mean F SD years of average parental education was 14.3 F 2.6 for the bipolar patients and 14.6 F 2.9 for the control subjects. All subjects were right handed as determined by the Annett Handedness Scale (Annett, 1970). The procedures were approved by the University of California, San Francisco Committee on Human Research. The diagnosis of bipolar I disorder was confirmed using the Structured Clinical Interview for DSM-IV (SCID) Axis I, Patient Version (First et al., 1995) by a board-certified psychiatrist (RFD) who has extensive experience in the use of this instrument with excellent intrarater and interrater reliabilities (kappa>0.9). None of bipolar I patients had a history of head injury, organic mental disorder, neurological disorder, cerebrovascular disease, schizophrenia, anxiety disorder, or current or past history of alcohol or substance abuse/dependence. The bipolar patients had all been euthymic for at least 2 months before the study as documented by: (1) clinical history and interview, and (2) separate scores of 6 or less on both the Young Mania Rating Scale and the Hamilton Depression Rating Scale administered on the same day as the MRI study. Bipolar patients were stable on medication regimens which included lithium (n = 6), divalproex (n = 7), topiramate (n = 1), gabapentin (n = 1), olanzapine (n = 3), risperidone (n = 2), quetiapine (n = 1), bupropion (n = 4), sertraline (n = 3), citalopram (n = 1), fluoxetine (n = 2), paroxetine (n = 1), mirtazapine (n = 1). Family history was obtained from infor-
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mation provided by the patient and first degree relatives using diagnostic criteria from the SCID for major depressive disorder and bipolar disorder. Familial bipolar disorder was defined as having a first degree relative (parent, sibling, offspring) with a current or prior diagnosis of bipolar disorder or major depression. Control subjects were also assessed using the SCID to rule out any other major Axis I diagnoses including both past and present substance abuse/dependence. None of the control subjects had any history of significant medical illness, head injury, neurological disorder, major Axis I psychiatric disorder, major Axis I psychiatric disorder in first-degree relatives, or current or past history of alcohol or substance abuse/dependence. Fifty-four percent of patients and controls screened to participate were excluded by the subject recruiter based on retrospective accounts of substance use prior to their participation in the study. The demographic and clinical variables are summarized in Table 1. Table 1 Demographic and clinical variables in male familial Bipolar I disorder patients and controls Variable
Bipolar I (n = 22)
Controls (n = 32)
Gender, n, male Age, mean F SD, years Race, N, Caucasian Height, mean F SD, inches Handedness, n, left handed History of substance abuse or dependence, n Medications, n Mood stabilizer Lithium Divalproex Other Antidepressant Antipsychotics Illness duration, mean F SD years Education, mean F SD years Parental education, mean F SD years Young mania rating scale score, mean F SD Hamilton depression rating scale score, mean F SD
22 43.1 F 11.4 11 67.3 F 4.5 0 0
32 37.8 F 10.8 16 69.0 F 4.9 0 0
6 8 2 13 7 22.5 F 11.8
N/A N/A N/A N/A N/A N/A
14.6 F 2.4
16.3 F 4.2
14.3 F 2.5
14.2 F 2.6
0.8 F 1.6
N/A
0.5 F 1.1
N/A
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2.2. MR image acquisition All MRI studies were performed at the Magnetic Resonance Unit of the San Francisco Veterans Affairs Medical Center on a Siemens 1.5 T Magnetom VISION system equipped with a standard quadrature head coil. A vacuum-molded head holder was used to minimize motion of the subject’s head. Each subject was numerically coded for blind measurement and data processing. MRI sequences included: (1) T1-weighted scout views in the sagittal, coronal, and axial planes. (2) Axial T2-weighted images from double spin echo (DSE) (TR/TE1/ TE2 = 3000/20/80 ms, resolution 1 1.4 mm2 resolution, 3 mm slice thickness), oriented minus 10j off a plane parallel to the intercommissural line. (3) Coronal T1-weighted images from 3D MP-RAGE (TR/TI/TE = 10/250/4 ms, resolution 1 1 mm2 resolution, 1.4 mm slice thickness), oriented perpendicular to the DSE. The MRI scans from both controls and patients were evaluated by a board certified neuroradiologist to determine if any abnormalities were present. 2.3. Image analysis The MRI tissue segmentation and volumetric methods have been previously described in detail (with reliabilities) and successfully validated (Cardenas et al., 2001) using an MRI simulator and digital brain phantoms developed at the Montreal Neurological Institute (Collins et al., 1998; Kwan et al., 1999) with percentage volume differences of less than 5% and spatial distribution overlaps greater than 0.94 (1.0 is perfect). The DSE study is in the axial plane with 3 mm interleaved slices. The 3D T1 study uses the Siemens MP-RAGE sequence which gathers 1.4 mm thick coronal slices with a 0.97 0.97 mm in plane pixel size. Analysis begins with the first pass auto-segmentation which separates the brain into gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF). In-house software is used to: (1) remove the skull and meninges from the images, (2) coregister each of the interleaves of the spin-echo images to T1 images reformatted to the axial plane, (3) perform RF inhomogeneity correction in 3D, (4) define seeds (based on peaks in the 3D histogram of T1 pixel intensities) for the K-
means cluster analysis, and (5) transfer the data to statistical software which performs the actual cluster analysis. The initial process is followed by computer-assisted editing of the data to separate cortical from subcortical gray matter, ventricular CSF from sulcal CSF, and to reclassify white matter incorrectly classified in the first pass into a category of white matter with an abnormal MRI signal or white matter signal hyperintensity (WMSH). This is followed by manual delineation of the boundaries of cortical regions, subcortical structures, the cerebellum, and the hippocampi. The intracranial volume (ICV) was determined by summing the total number of pixels within the intracranial vault including all GM, WM, ventricular/sulcal CSF and the cerebellum. Prior to this calculation and all other analysis, the skull, meninges, orbits, and brainstem were removed from the images. 2.4. Statistical analysis All MRI volumetric measures were normally distributed by the Shapiro-Wilks test. Analysis of variance (ANOVA) was used to examine the demographic variables as well as the MRI brain measures (cortical gray matter, cerebral white matter, sulcal CSF, ventricular CSF, and WMSH) as the dependent variables and group as the between-subjects variable. To control for head size and age effects, intracranial volume and age were used as covariates in the ANOVA analyses. Finally, regression analysis and Pearson correlation coefficients were used to examine the association between age, illness duration, and MRI brain measures. The criterion of significance level was set at p = 0.05 for both the ANOVA as well as the regression and correlation analyses.
3. Results No abnormalities were noted on the MRI images of the patients or the control group. There were no significant group differences between patients and control subjects for age, years of education, years of parental education, or ICV. As shown in Table 2, relative to the control group, the bipolar patients demonstrated: (1) significantly reduced cortical GM
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Table 2 MRI tissue segmentation voluming results (mean F SD cm3) in male familial Bipolar I disorder patients and controls MRI brain measure
Intracranial volume (ICV) Sulcal CSF Ventricular CSF Cortical gray matter Cerebral white matter White matter signal hyperintensities a
Bipolar I (n = 22)
1433.96 F 108.46 235.57 F 85.97 35.37 F 21.02 610.39 F 60.55 514.18 F 54.03 0.31 F 0.30
Controls (n = 32)
1469.47 F 105.88 184.89 F 42.64 25.99 F 9.23 671.58 F 61.44 547.88 F 48.01 0.34 F 0.45
ANOVAa F (df)
p-value
1.41 (1,52) 8.91 (1,50) 11.72 (1,50) 10.00 (1,50) 5.22 (1,50) 0.15 (1,50)
0.240 0.004 0.001 0.003 0.027 0.809
Except for ICV, ANOVA results for MRI brain measures show main effect of group with age and ICV as covariates.
and cerebral white matter; (2) significantly increased sulcal and ventricular CSF; and (3) no significant group differences in the ICV or volume of WMSH. Pearson correlation coefficients revealed that cortical GM was negatively correlated with: (1) age in both the control (r = 0.672, p < 0.0001) and bipolar (r = 0.445, p = 0.037) groups, and (2) sulcal CSF in the bipolar (r = 0.575, p = 0.004) but not control (r = 0.136, p = 0.462) groups. Cortical GM was also positively correlated with cerebral WM in both the control (r = 0.471, p = 0.006) and bipolar (r = 0.667, p = 0.001) groups. Sulcal CSF was positively correlated with: (1) age in the bipolar (r = 0.584, p = 0.004) but not control (r = 0.253; p = 0.165) groups; (2) ventricular CSF in the bipolar (r = 0.546, p = 0.008) but not control (r = 0.291, p = 0.106) groups. Ventricular CSF was positively correlated with age in the bipolar (r = 0.455, p = 0.032) but not control (r = 0.074, p = 0.688) groups. In the bipolar group only, WMSH was positively correlated with age (r = 0.452, p = 0.034), sulcal CSF (r = 0.463, p = 0.029), and ventricular CSF (r = 0.548, p = 0.007) but not cortical GM (r = 0.089, p = 0.699) or cerebral WM (r = 0.043, p = 0.853). Furthermore, there were no significant partial correlations in the bipolar group between any of the MRI brain measures and years of illness after adjusting for the effects of age. With regard to mood stabilizing medication, there were no significant correlations between lithium or divalproex medication dosages and any of the MRI brain measures. We were unable to analyze whether antidepressant dosages (in addition to mood stabilizer dosages) or the length of time on any medications correlated with any of the MRI brain measures due to a lack of the appropriate data.
4. Discussion To our knowledge, this is the first report to demonstrate a significant reduction in global cortical gray matter volume and cerebral white matter volume in a relatively homogeneous population of males with familial bipolar I disorder. The finding of significantly reduced cortical gray matter volume is consistent with a previous study (Lim et al., 1999) which examined nine chronically ill, medicated male bipolar inpatients compared to 16 male control subjects. The reduction is also consistent with one study (Lopez-Larson et al., 2002) including 17 medicated bipolar inpatients (65% male) and 12 controls subjects (67% male). All of the other studies included both men and women and found no significant reduction in total cortical gray matter volume. Given that the present study of male outpatients, one prior study (Lim et al., 1999) which examined male bipolar inpatients, and one prior study (Lopez-Larson et al., 2002) which examined mostly male bipolar inpatients are the only three studies to date that have found a global reduction in cortical gray matter, the question arises as to whether the cortical gray matter deficit may be more prevalent in men than in women. It is not clear exactly which regions of the cortex are primarily responsible for the observed cortical gray matter deficit. Recent neuropathological studies provide evidence for reduced dorsolateral prefrontal cortex neuronal size (Cotter et al., 2002) and neuronal and/or glial cell densities (Rajkowska et al., 2001); reduced anterior cingulate cortex neuronal density (Benes et al., 2001; Bouras et al., 2001); and more pronounced anterior cingulate glial cell loss in familial bipolar disorder (Ongu¨r et al., 1998). MRI studies of prefrontal cortex have reported volume reductions
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(Sax et al., 1999; Lopez-Larson et al., 2002) as well as no change in volume (Strakowski et al., 1999). Similarly, MRI studies of the subgenual anterior cingulate cortex have noted both reduced subgenual volume (Drevets et al., 1997; Sharma et al., 2003); and no reduction in subgenual volume (Brambilla et al., 2002). MRI investigations of other cortical regions are clearly needed in more homogeneously defined bipolar cohorts to ascertain whether there are differences in regional neuropathology between the different bipolar subtypes. The significant increases in both sulcal CSF and ventricular CSF volumes are in agreement with previous meta-analyses showing significant effect sizes for both sulcal and ventricular enlargement (Elkis et al., 1995; Strakowski et al., 2000). More importantly, the robust negative correlation between cortical gray matter and sulcal CSF volumes suggests that the increasing volume of sulcal CSF is predominantly due to loss of cortical tissue volume. This relationship between sulcal CSF and cortical volumes is consistent with a previous study which found that increased sulcal CSF volume predicted cortical gray matter deficits in patients with schizophrenia, Alzheimer’s disease, and chronic alcoholism (Symonds et al., 1999). However, the study by Symonds et al. (1999) also found that sulcal CSF volumes predicted cerebral white matter deficits in these same patient groups, whereas this study found no correlation between sulcal CSF volumes and cerebral white matter volumes in either bipolar or control groups. Ventricular CSF volume was also increased in the bipolar group but was not correlated with either cortical gray matter or cerebral white matter volumes in the bipolar and control groups. This suggests that the ventricular enlargement in familial bipolar I disorder may be more closely associated with tissue deficits involving subcortical structures. The reduction in cerebral white matter volume is consistent with the strong trend for white matter loss reported in first episode mania (Strakowski et al., 1993), and a recent study of bipolar I patients and their healthy co-twins (Kieseppa et al., 2003) which noted: (1) significantly decreased left and right hemisphere white matter volumes in the bipolar patients compared to controls, and (2) significantly decreased left hemisphere white matter volumes in the healthy co-twins compared to controls. These white matter
volume deficits in conjunction with the most consistent MRI finding of abnormally increased WMSH in bipolar disorder (Altshuler et al., 1995) suggests potentially altered white matter connectivity. The occurrence of left hemisphere cerebral white matter volume deficits in both bipolar I patients and their healthy co-twins further underscores the importance of utilizing quantitative MRI tissue volume measurements to search for potential new endophenotypes. Given the high heritability of bipolar disorder, it is perhaps not surprising that a number of MRI studies comparing familial to non-familial bipolar disorder have shown more prominent brain abnormalities in the familial group (Drevets et al., 1998; Ongu¨r et al., 1998; Hirayasu et al., 1999; Brambilla et al., 2001b; Sharma et al., 2003), which could be interpreted as biological evidence of increased genetic liability for the disorder. The lack of increased WMSH volume in the bipolar group may at first appear to be inconsistent with the increased WMSH prevalence noted in many (Altshuler et al., 1995) but not all MRI studies (Brown et al., 1992; Strakowski et al., 1993; Krabbendam et al., 2000). However, the one study (Dupont et al., 1995) that quantitatively assessed WMSH volume found it to be increased in bipolar disorder compared to controls but significantly associated with onset after adolescence. Two other studies found increased prevalence of subcortical WMSH in patients with lateonset mania (McDonald et al., 1991) and no difference in WMSH prevalence between relatively young mood disorder patients with mild to moderate illness severity and controls (Sassi et al., 2003). Furthermore, increased WMSH prevalence has been observed in ‘‘poor outcome’’ bipolar patients (defined as having been ill for 2 years or more despite adequate therapy, and having had periods of remission lasting 8 weeks or less during which time they still had functional impairment) but not ‘‘good outcome’’ bipolar patients (defined as euthymic for at least 8 weeks and having shown full recovery and return to premorbid functioning after any illness episode) compared to controls (Moore et al., 2001). Using the age of 29 as the cutoff to define ‘‘early onset’’ versus ‘‘late onset’’ bipolar disorder (Taylor and Abrams, 1981), 21 out of 23 patients in this study would be classified as ‘‘early onset’’ and the majority would also be defined as ‘‘good outcome’’ patients based on their current and
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past history of stability on medications. Therefore, the combination of both ‘‘early onset’’ and ‘‘good outcome’’ that characterized most of the bipolar patients in the current study may have contributed to not finding an increased volume of WMSH in this particular cohort. White matter volume reductions may be a reflection of the underlying neuronal and glial cell pathology that is emerging in studies of bipolar disorder. The white matter is comprised of myelinated axons of neurons and glial cells, the latter being comprised of astrocytes, oligodendrocytes, and microglia. Recent neuropathology studies have documented glial reductions in the anterior cingulate and dorsolateral prefrontal cortex regions (Ongu¨r et al., 1998; Cotter et al., 2001; Rajkowska et al., 2001) in bipolar disorder. Furthermore, proton and phosphorous magnetic resonance spectroscopy studies of bipolar patients have reported: (1) reduced N-acetylaspartate (NAA) in the dorsolateral prefrontal gray and white matter in adults (Winsberg et al., 2000; Deicken et al., 2001) and children (Chang et al., 2003); (2) increased choline (Moore et al., 2000a) in the anterior cingulate region but decreased (Cecil et al., 2002; Chang et al., 2003) in the orbitofrontal region; (3) phosphomonoesters (PME) and phosphodiesters (PDE) in the frontal and temporal lobe gray and white matter (Kato et al., 1993, 1995; Deicken et al., 1995a,b). The NAA reductions suggest dorsolateral prefrontal cortex neuronal pathlogy as well as frontal white matter axonal pathology, whereas the choline, PME, and PDE alterations provide evidence for trait dependent abnormalities of membrane phospholipid metabolism. Finally, a recently published study which utilized microarray techniques to investigate bipolar brains from the Stanley brain collection revealed that expression profiles of most known oligodendrocyte-related and myelin-related genes were greatly reduced in bipolar disorder and several transcription factors known to coordinate myelin gene expression demonstrated corresponding alterations (Tkachev et al., 2003). Therefore, the combination of WMSH, membrane phospholipid abnormalities, axonal dysfunction or damage, reduced glial cells, and decreased expression of oligodendrocyte-related and myelin-related genes is providing more cohesive evidence for white matter pathological involvement in bipolar disorder.
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The causal relationship between bipolar disorder and the reduced cortical gray and white matter volumes as well as increased ventricular and sulcal CSF has yet to be determined. If these findings represent neurodevelopmental abnormalities, originating either from genetic or environmental risk factors, alterations would most likely be manifest at an early stage of the disorder. Support for this notion comes from studies of: (1) first-episode mania that have reported a decrease in subgenual cingulate cortex volumes (Hirayasu et al., 1999), increased lateral and third ventricle as well as putamen volumes (Strakowski et al., 1993, 2002), and increased WMSH; (2) adolescent bipolar I subjects which revealed increased lateral ventricular, frontal sulcal, and temporal sulcal volumes (Friedman et al., 1999) suggesting that this finding may be present at the onset of illness; and (3) studies of BPI children and adolescents demonstrating an increased presence of WMSH (Botteron et al., 1995; Lyoo et al., 2002; Pillai et al., 2002). It should be noted that this study attempted to minimize the potential effects of comorbid conditions on brain structural abnormalities that may be trait markers and potential endophenotypes. Therefore, patients with a history of substance abuse or substance dependence were excluded because it is not clear for any given individual, when the effects of alcohol and substance abuse begin to have a significant effect on brain structure. Therefore, the study findings may not be generalizable to the 40 – 48% of male bipolar patients with alcohol or substance abuse comorbidities (Hendrick et al., 2000). However, the intent of this study was to identify any alterations in tissue volume for cortical gray matter, cerebral white matter, and ventricular and sulcal CSF that are central nervous system manifestations of the disease itself. Such pathological alterations that can be directly attributed to the disease without the confound of substance abuse or dependence stand an increased likelihood of being identified as potential endophenotypes which can then better inform genetic studies. The current results and interpretations are limited by the relatively small sample size and the consequent reduced statistical power, the retrospective nature of obtaining past psychiatric and medical histories, as well as the possible confounding effects of medication. All bipolar subjects participating in the study were on mood stabilizers and antidepressants for at
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least 2 months, but detailed medication histories going back in time more than several years could not be remembered accurately by the patients and/or corroborated by treating clinicians or family members. Therefore, we are unable to determine if the specific length of time on medication or other confounding factors correlated with the MRI brain measures. Although there were no significant associations between the cortical gray matter volume and either divalproex or lithium dosages, there is no convincing evidence to date that chronic exposure to these mood stabilizers in humans would result in cortical gray matter deficits. On the contrary, recent studies of healthy volunteers and bipolar patients demonstrated that four weeks of lithium administration significantly increased total gray matter content in the bipolar patients (Moore et al., 2000b,c). Total gray matter volumes were found to be increased in lithium treated bipolar patients compared with untreated patients and healthy controls in one study, suggesting that lithium exerts neurotrophic effects on the brain (Sassi et al., 2002). A study of bipolar I twins and their co-twins found a positive correlation between frontal gray matter volume and the use of lithium, with a significant effect size for doses of 1000 mg per day (Kieseppa et al., 2003). There is also evidence that valproate activates pathways that regulate BDNF; robustly increases trophic factors like bcl-2 and growth cone associated protein (GAP-43); and promotes neurite outgrowth in as well as prolongs survival of human neuroblastoma cells (Manji et al., 2000). As for medications other than mood stabilizers, chronic administration of several different classes of antidepressants increases neurogenesis in the adult rodent hippocampus (Jacobs et al., 2000; Malberg et al., 2000; Duman et al., 2001; Manev et al., 2001), and this may be related to antidepressant induced upregulation of hippocampal CREB and BDNF (Nibuya et al., 1995, 1996; Thome et al., 2000). However, one previous study showing a reduction in total gray matter volume reported that current antidepressant exposure was associated with smaller right inferior gray matter volumes (Lopez-Larson et al., 2002). Recent reviews of the neuropathological effects of antipsychotics in rats and humans (Harrison, 1999; Konradi and Heckers, 2001) concluded that they appear to induce synaptic plasticity or reorganization in the striatum and lamina VI of the frontal
cortex, however, there is no good evidence that antipsychotics cause neuronal loss or gliosis. Nevertheless, a larger cumulative dosage of antipsychotic medication has been associated with progressive decreases in frontal lobe volume in recent longitudinal studies of patients with first-episode schizophrenia (Gur et al., 1998; Madsen et al., 1999; Cahn et al., 2002). Therefore, if antipsychotics can potentially induce synaptic reorganization, and chronic administration of antidepressants, lithium, and valproate can potentially promote neurogenesis, then cortical gray matter volume in bipolar disorder might be expected to increase rather than decrease as a consequence of chronic medication treatment.
Acknowledgements This research was supported by a 1998 Stanley Foundation Research Award and NIH grant MH62102 (Dr. Deicken) (RFD).
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Preliminary communication
Decreased cortical gray and cerebral white matter in $ male patients with familial bipolar I disorder Kevin A. Davis a, Andreana Kwon a, Valerie A. Cardenas b,c, Raymond F. Deicken a,b,d,* a b
Psychiatry Service, Veterans Affairs Medical Center, San Francisco, CA 94121, USA Magnetic Resonance Unit, Veterans Affairs Medical Center, San Francisco, CA, USA c Department of Radiology, University of California, San Francisco, CA, USA d Department of Psychiatry, University of California, San Francisco, CA, USA Received 3 April 2003; accepted 1 March 2004
Abstract Background: Previous MRI studies of bipolar disorder have failed to consistently demonstrate cortical gray or cerebral white matter tissue loss, as well as sulcal or ventricular enlargement. The inconsistencies are most likely due to the clinical and gender heterogeneity of the study populations as well as the different MRI acquisition and processing techniques. The objective of this study was to determine if there was a cortical gray matter and cerebral white matter deficit as well as sulcal and ventricular enlargement in a homogeneous sample of euthymic male patients with familial bipolar I disorder. Methods: MRI tissue segmentation was utilized to obtain cortical gray matter, cerebral white matter, ventricular cerebrospinal fluid (CSF), and sulcal CSF volumes in 22 euthymic males with familial bipolar I disorder and 32 healthy male control subjects. Results: Relative to the controls, the familial bipolar I patients demonstrated: (1) significant reductions of both cortical gray matter and cerebral white matter volumes; and (2) significant increases in both sulcal and ventricular CSF volumes. In the bipolar group, there was a significant negative correlation between cortical gray matter volume and sulcal CSF volume. Limitations: Small sample size, retrospective interviews, possible medication effects. Conclusions: These results provide evidence for significant cortical gray matter and cerebral white matter deficits and associated sulcal and ventricular enlargement in euthymic males with familial bipolar I disorder. D 2004 Elsevier B.V. All rights reserved. Keywords: Bipolar disorder; Cortical gray matter; Magnetic resonance imaging; Brain
1. Introduction Previous MRI investigations of bipolar disorder have been inconclusive in determining whether $ Previous presentation: Presented at the 32nd annual meeting of the Society for Neuroscience, Orlando, FL, Nov. 2 – 7, 2002. * Corresponding author. Psychiatry Service, 116-N Veterans Affairs Medical Center, 4150 Clement Street, San Francisco, CA 94121, USA. Tel.: +1-415-221-4810x4350; fax: +1-415-750-6648. E-mail address: [email protected] (R.F. Deicken).
0165-0327/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2004.03.010
there is: (1) decreased cortical gray matter volume; (2) decreased cerebral white matter volume; (3) increased lateral ventricular volume; or (4) increased sulcal volume. Although two previous studies (Lim et al., 1999; Lopez-Larson et al., 2002) using MRI tissue segmentation techniques found global reductions of cortical gray matter, most MRI investigations have failed to corroborate such reductions in bipolar disorder (Strakowski et al., 1993; Harvey et al., 1994; Schlaepfer et al., 1994; Dupont et al.,
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1995; Pearlson et al., 1997; Zipursky et al., 1997; Brambilla et al., 2001a). In fact, two studies found trends for increased total cortical gray matter volumes (Kieseppa et al., 2003; Sharma et al., 2003). More commonly, MRI studies have demonstrated tissue volume reductions in specific cortical regions such as the prefrontal (Sax et al., 1999; Strakowski et al., 1999; Lopez-Larson et al., 2002) or subgenual anterior cingulate (Drevets et al., 1998; Sharma et al., 2003) cortex. As for cerebral white matter volumes, no decrease was observed in five studies (Zipursky et al., 1997; Lim et al., 1999; Brambilla et al., 2001a; Lopez-Larson et al., 2002; Sassi et al., 2002) as compared to one study in first-episode manic patients that noted a decreasing trend in white matter volumes (Strakowski et al., 1993). However, a recent study of bipolar I patients and their healthy co-twins noted significantly decreased left hemisphere white matter volumes in the bipolar patients and healthy co-twins compared to controls, however, significantly decreased right hemisphere white matter volumes only in the bipolar I patients and not the co-twins compared to the controls (Kieseppa et al., 2003). Finally, despite a lack of consistent evidence of sulcal and ventricular enlargement (Soares and Mann, 1997), previous meta-analyses have shown significant effect sizes for both sulcal and ventricular enlargement (Elkis et al., 1995; Strakowski et al., 2000). To further complicate interpretation of these findings, ventricular enlargement has been reported in first-episode mania (Strakowski et al., 1993); noted to be positively correlated with the number of prior illness episodes (Brambilla et al., 2001b; Strakowski et al., 2002); and larger in familial compared to non-familial bipolar patients (Brambilla et al., 2001b). The overall inconsistency of findings for these generalized structural measures across studies is most likely due to the inclusion of clinically heterogeneous samples of bipolar patients who varied with respect to clinical subtype, familial subtype, affective state (euthymia, depression, hypomania, and mania), medication status, history of comorbid alcohol or substance abuse/dependence, and gender. For example, all of the previously cited MRI studies except for two included a mixture of both
men and women in different clinical states, with some differentiating between familial and non-familial patients. Six studies (Brambilla et al., 2001a; Lopez-Larson et al., 2002; Strakowski et al., 2002; Kieseppa et al., 2003; Sharma et al., 2003) used DSM-IV criteria to distinguish between bipolar I and bipolar II disorder, whereas the remaining studies utilized DSM-III-R criteria which does not specify bipolar II as a diagnostic category. Two studies used identical MRI tissue segmentation protocols (Zipursky et al., 1997; Lim et al., 1999) but one study examined male inpatients (Lim et al., 1999) whereas the other study examined predominantly female bipolar outpatients (Zipursky et al., 1997). Furthermore, the MRI slice thickness in 10 of the 15 MRI volumetric studies cited above ranged from 3 to 6 mm with and without slice gaps, resulting in varying degrees of partial volume artifact. This coupled with different morphometric voluming algorithms could easily account for the discrepancies. The identification of structural brain abnormalities that may be trait markers and therefore, potential endophenotypes for bipolar I disorder has become an increasingly important objective of neuroimaging research in recent years. In order to identify structural brain abnormalities that may serve as potential endophenotypes for bipolar I disorder, it is imperative that such abnormalities be attributable to the disease itself, without potential confounds due to comorbidity with other major psychiatric disorders and/or substance abuse. Therefore, this study examined a homogeneous population of euthymic male patients with familial bipolar I disorder order, in an effort to reduce the potential confounds of bipolar subtype, gender, and clinical state on the MRI measures, and because there is emerging evidence that abnormalities in brain structure and function may be more prominent in familial compared to non-familial mood disorders (Drevets et al., 1998; Ongu¨r et al., 1998; Hirayasu et al., 1999; Brambilla et al., 2001b; Sharma et al., 2003). More specifically, quantitative MRI tissue segmentation methods were utilized to determine if: (1) cortical gray matter and cerebral white matter volumes were decreased; and (2) sulcal and ventricular volumes were increased in the bipolar I group compared to controls.
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2. Methods 2.1. Subjects Study subjects were recruited from the San Francisco Veterans Affairs Medical Center, University of California, San Francisco Langley Porter Psychiatric Institute, outpatient community mental health clinics, and the local community by newspaper advertisement. Twenty-two male patients who met inclusion DSM-IV diagnostic criteria for bipolar I disorder (mean F SD age = 43.1 F 11.4 years) and 32 male control subjects (mean F SD age = 37.8 F 10.8 years) gave written informed consent for participation in the study after the procedures had been fully explained. The age range of subjects for inclusion in the study was 18 – 60 years. Mean F SD years of education was 15.2 F 2.4 for the bipolar patients and 16.6 F 4.2 for the control group. Mean F SD years of average parental education was 14.3 F 2.6 for the bipolar patients and 14.6 F 2.9 for the control subjects. All subjects were right handed as determined by the Annett Handedness Scale (Annett, 1970). The procedures were approved by the University of California, San Francisco Committee on Human Research. The diagnosis of bipolar I disorder was confirmed using the Structured Clinical Interview for DSM-IV (SCID) Axis I, Patient Version (First et al., 1995) by a board-certified psychiatrist (RFD) who has extensive experience in the use of this instrument with excellent intrarater and interrater reliabilities (kappa>0.9). None of bipolar I patients had a history of head injury, organic mental disorder, neurological disorder, cerebrovascular disease, schizophrenia, anxiety disorder, or current or past history of alcohol or substance abuse/dependence. The bipolar patients had all been euthymic for at least 2 months before the study as documented by: (1) clinical history and interview, and (2) separate scores of 6 or less on both the Young Mania Rating Scale and the Hamilton Depression Rating Scale administered on the same day as the MRI study. Bipolar patients were stable on medication regimens which included lithium (n = 6), divalproex (n = 7), topiramate (n = 1), gabapentin (n = 1), olanzapine (n = 3), risperidone (n = 2), quetiapine (n = 1), bupropion (n = 4), sertraline (n = 3), citalopram (n = 1), fluoxetine (n = 2), paroxetine (n = 1), mirtazapine (n = 1). Family history was obtained from infor-
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mation provided by the patient and first degree relatives using diagnostic criteria from the SCID for major depressive disorder and bipolar disorder. Familial bipolar disorder was defined as having a first degree relative (parent, sibling, offspring) with a current or prior diagnosis of bipolar disorder or major depression. Control subjects were also assessed using the SCID to rule out any other major Axis I diagnoses including both past and present substance abuse/dependence. None of the control subjects had any history of significant medical illness, head injury, neurological disorder, major Axis I psychiatric disorder, major Axis I psychiatric disorder in first-degree relatives, or current or past history of alcohol or substance abuse/dependence. Fifty-four percent of patients and controls screened to participate were excluded by the subject recruiter based on retrospective accounts of substance use prior to their participation in the study. The demographic and clinical variables are summarized in Table 1. Table 1 Demographic and clinical variables in male familial Bipolar I disorder patients and controls Variable
Bipolar I (n = 22)
Controls (n = 32)
Gender, n, male Age, mean F SD, years Race, N, Caucasian Height, mean F SD, inches Handedness, n, left handed History of substance abuse or dependence, n Medications, n Mood stabilizer Lithium Divalproex Other Antidepressant Antipsychotics Illness duration, mean F SD years Education, mean F SD years Parental education, mean F SD years Young mania rating scale score, mean F SD Hamilton depression rating scale score, mean F SD
22 43.1 F 11.4 11 67.3 F 4.5 0 0
32 37.8 F 10.8 16 69.0 F 4.9 0 0
6 8 2 13 7 22.5 F 11.8
N/A N/A N/A N/A N/A N/A
14.6 F 2.4
16.3 F 4.2
14.3 F 2.5
14.2 F 2.6
0.8 F 1.6
N/A
0.5 F 1.1
N/A
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2.2. MR image acquisition All MRI studies were performed at the Magnetic Resonance Unit of the San Francisco Veterans Affairs Medical Center on a Siemens 1.5 T Magnetom VISION system equipped with a standard quadrature head coil. A vacuum-molded head holder was used to minimize motion of the subject’s head. Each subject was numerically coded for blind measurement and data processing. MRI sequences included: (1) T1-weighted scout views in the sagittal, coronal, and axial planes. (2) Axial T2-weighted images from double spin echo (DSE) (TR/TE1/ TE2 = 3000/20/80 ms, resolution 1 1.4 mm2 resolution, 3 mm slice thickness), oriented minus 10j off a plane parallel to the intercommissural line. (3) Coronal T1-weighted images from 3D MP-RAGE (TR/TI/TE = 10/250/4 ms, resolution 1 1 mm2 resolution, 1.4 mm slice thickness), oriented perpendicular to the DSE. The MRI scans from both controls and patients were evaluated by a board certified neuroradiologist to determine if any abnormalities were present. 2.3. Image analysis The MRI tissue segmentation and volumetric methods have been previously described in detail (with reliabilities) and successfully validated (Cardenas et al., 2001) using an MRI simulator and digital brain phantoms developed at the Montreal Neurological Institute (Collins et al., 1998; Kwan et al., 1999) with percentage volume differences of less than 5% and spatial distribution overlaps greater than 0.94 (1.0 is perfect). The DSE study is in the axial plane with 3 mm interleaved slices. The 3D T1 study uses the Siemens MP-RAGE sequence which gathers 1.4 mm thick coronal slices with a 0.97 0.97 mm in plane pixel size. Analysis begins with the first pass auto-segmentation which separates the brain into gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF). In-house software is used to: (1) remove the skull and meninges from the images, (2) coregister each of the interleaves of the spin-echo images to T1 images reformatted to the axial plane, (3) perform RF inhomogeneity correction in 3D, (4) define seeds (based on peaks in the 3D histogram of T1 pixel intensities) for the K-
means cluster analysis, and (5) transfer the data to statistical software which performs the actual cluster analysis. The initial process is followed by computer-assisted editing of the data to separate cortical from subcortical gray matter, ventricular CSF from sulcal CSF, and to reclassify white matter incorrectly classified in the first pass into a category of white matter with an abnormal MRI signal or white matter signal hyperintensity (WMSH). This is followed by manual delineation of the boundaries of cortical regions, subcortical structures, the cerebellum, and the hippocampi. The intracranial volume (ICV) was determined by summing the total number of pixels within the intracranial vault including all GM, WM, ventricular/sulcal CSF and the cerebellum. Prior to this calculation and all other analysis, the skull, meninges, orbits, and brainstem were removed from the images. 2.4. Statistical analysis All MRI volumetric measures were normally distributed by the Shapiro-Wilks test. Analysis of variance (ANOVA) was used to examine the demographic variables as well as the MRI brain measures (cortical gray matter, cerebral white matter, sulcal CSF, ventricular CSF, and WMSH) as the dependent variables and group as the between-subjects variable. To control for head size and age effects, intracranial volume and age were used as covariates in the ANOVA analyses. Finally, regression analysis and Pearson correlation coefficients were used to examine the association between age, illness duration, and MRI brain measures. The criterion of significance level was set at p = 0.05 for both the ANOVA as well as the regression and correlation analyses.
3. Results No abnormalities were noted on the MRI images of the patients or the control group. There were no significant group differences between patients and control subjects for age, years of education, years of parental education, or ICV. As shown in Table 2, relative to the control group, the bipolar patients demonstrated: (1) significantly reduced cortical GM
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Table 2 MRI tissue segmentation voluming results (mean F SD cm3) in male familial Bipolar I disorder patients and controls MRI brain measure
Intracranial volume (ICV) Sulcal CSF Ventricular CSF Cortical gray matter Cerebral white matter White matter signal hyperintensities a
Bipolar I (n = 22)
1433.96 F 108.46 235.57 F 85.97 35.37 F 21.02 610.39 F 60.55 514.18 F 54.03 0.31 F 0.30
Controls (n = 32)
1469.47 F 105.88 184.89 F 42.64 25.99 F 9.23 671.58 F 61.44 547.88 F 48.01 0.34 F 0.45
ANOVAa F (df)
p-value
1.41 (1,52) 8.91 (1,50) 11.72 (1,50) 10.00 (1,50) 5.22 (1,50) 0.15 (1,50)
0.240 0.004 0.001 0.003 0.027 0.809
Except for ICV, ANOVA results for MRI brain measures show main effect of group with age and ICV as covariates.
and cerebral white matter; (2) significantly increased sulcal and ventricular CSF; and (3) no significant group differences in the ICV or volume of WMSH. Pearson correlation coefficients revealed that cortical GM was negatively correlated with: (1) age in both the control (r = 0.672, p < 0.0001) and bipolar (r = 0.445, p = 0.037) groups, and (2) sulcal CSF in the bipolar (r = 0.575, p = 0.004) but not control (r = 0.136, p = 0.462) groups. Cortical GM was also positively correlated with cerebral WM in both the control (r = 0.471, p = 0.006) and bipolar (r = 0.667, p = 0.001) groups. Sulcal CSF was positively correlated with: (1) age in the bipolar (r = 0.584, p = 0.004) but not control (r = 0.253; p = 0.165) groups; (2) ventricular CSF in the bipolar (r = 0.546, p = 0.008) but not control (r = 0.291, p = 0.106) groups. Ventricular CSF was positively correlated with age in the bipolar (r = 0.455, p = 0.032) but not control (r = 0.074, p = 0.688) groups. In the bipolar group only, WMSH was positively correlated with age (r = 0.452, p = 0.034), sulcal CSF (r = 0.463, p = 0.029), and ventricular CSF (r = 0.548, p = 0.007) but not cortical GM (r = 0.089, p = 0.699) or cerebral WM (r = 0.043, p = 0.853). Furthermore, there were no significant partial correlations in the bipolar group between any of the MRI brain measures and years of illness after adjusting for the effects of age. With regard to mood stabilizing medication, there were no significant correlations between lithium or divalproex medication dosages and any of the MRI brain measures. We were unable to analyze whether antidepressant dosages (in addition to mood stabilizer dosages) or the length of time on any medications correlated with any of the MRI brain measures due to a lack of the appropriate data.
4. Discussion To our knowledge, this is the first report to demonstrate a significant reduction in global cortical gray matter volume and cerebral white matter volume in a relatively homogeneous population of males with familial bipolar I disorder. The finding of significantly reduced cortical gray matter volume is consistent with a previous study (Lim et al., 1999) which examined nine chronically ill, medicated male bipolar inpatients compared to 16 male control subjects. The reduction is also consistent with one study (Lopez-Larson et al., 2002) including 17 medicated bipolar inpatients (65% male) and 12 controls subjects (67% male). All of the other studies included both men and women and found no significant reduction in total cortical gray matter volume. Given that the present study of male outpatients, one prior study (Lim et al., 1999) which examined male bipolar inpatients, and one prior study (Lopez-Larson et al., 2002) which examined mostly male bipolar inpatients are the only three studies to date that have found a global reduction in cortical gray matter, the question arises as to whether the cortical gray matter deficit may be more prevalent in men than in women. It is not clear exactly which regions of the cortex are primarily responsible for the observed cortical gray matter deficit. Recent neuropathological studies provide evidence for reduced dorsolateral prefrontal cortex neuronal size (Cotter et al., 2002) and neuronal and/or glial cell densities (Rajkowska et al., 2001); reduced anterior cingulate cortex neuronal density (Benes et al., 2001; Bouras et al., 2001); and more pronounced anterior cingulate glial cell loss in familial bipolar disorder (Ongu¨r et al., 1998). MRI studies of prefrontal cortex have reported volume reductions
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(Sax et al., 1999; Lopez-Larson et al., 2002) as well as no change in volume (Strakowski et al., 1999). Similarly, MRI studies of the subgenual anterior cingulate cortex have noted both reduced subgenual volume (Drevets et al., 1997; Sharma et al., 2003); and no reduction in subgenual volume (Brambilla et al., 2002). MRI investigations of other cortical regions are clearly needed in more homogeneously defined bipolar cohorts to ascertain whether there are differences in regional neuropathology between the different bipolar subtypes. The significant increases in both sulcal CSF and ventricular CSF volumes are in agreement with previous meta-analyses showing significant effect sizes for both sulcal and ventricular enlargement (Elkis et al., 1995; Strakowski et al., 2000). More importantly, the robust negative correlation between cortical gray matter and sulcal CSF volumes suggests that the increasing volume of sulcal CSF is predominantly due to loss of cortical tissue volume. This relationship between sulcal CSF and cortical volumes is consistent with a previous study which found that increased sulcal CSF volume predicted cortical gray matter deficits in patients with schizophrenia, Alzheimer’s disease, and chronic alcoholism (Symonds et al., 1999). However, the study by Symonds et al. (1999) also found that sulcal CSF volumes predicted cerebral white matter deficits in these same patient groups, whereas this study found no correlation between sulcal CSF volumes and cerebral white matter volumes in either bipolar or control groups. Ventricular CSF volume was also increased in the bipolar group but was not correlated with either cortical gray matter or cerebral white matter volumes in the bipolar and control groups. This suggests that the ventricular enlargement in familial bipolar I disorder may be more closely associated with tissue deficits involving subcortical structures. The reduction in cerebral white matter volume is consistent with the strong trend for white matter loss reported in first episode mania (Strakowski et al., 1993), and a recent study of bipolar I patients and their healthy co-twins (Kieseppa et al., 2003) which noted: (1) significantly decreased left and right hemisphere white matter volumes in the bipolar patients compared to controls, and (2) significantly decreased left hemisphere white matter volumes in the healthy co-twins compared to controls. These white matter
volume deficits in conjunction with the most consistent MRI finding of abnormally increased WMSH in bipolar disorder (Altshuler et al., 1995) suggests potentially altered white matter connectivity. The occurrence of left hemisphere cerebral white matter volume deficits in both bipolar I patients and their healthy co-twins further underscores the importance of utilizing quantitative MRI tissue volume measurements to search for potential new endophenotypes. Given the high heritability of bipolar disorder, it is perhaps not surprising that a number of MRI studies comparing familial to non-familial bipolar disorder have shown more prominent brain abnormalities in the familial group (Drevets et al., 1998; Ongu¨r et al., 1998; Hirayasu et al., 1999; Brambilla et al., 2001b; Sharma et al., 2003), which could be interpreted as biological evidence of increased genetic liability for the disorder. The lack of increased WMSH volume in the bipolar group may at first appear to be inconsistent with the increased WMSH prevalence noted in many (Altshuler et al., 1995) but not all MRI studies (Brown et al., 1992; Strakowski et al., 1993; Krabbendam et al., 2000). However, the one study (Dupont et al., 1995) that quantitatively assessed WMSH volume found it to be increased in bipolar disorder compared to controls but significantly associated with onset after adolescence. Two other studies found increased prevalence of subcortical WMSH in patients with lateonset mania (McDonald et al., 1991) and no difference in WMSH prevalence between relatively young mood disorder patients with mild to moderate illness severity and controls (Sassi et al., 2003). Furthermore, increased WMSH prevalence has been observed in ‘‘poor outcome’’ bipolar patients (defined as having been ill for 2 years or more despite adequate therapy, and having had periods of remission lasting 8 weeks or less during which time they still had functional impairment) but not ‘‘good outcome’’ bipolar patients (defined as euthymic for at least 8 weeks and having shown full recovery and return to premorbid functioning after any illness episode) compared to controls (Moore et al., 2001). Using the age of 29 as the cutoff to define ‘‘early onset’’ versus ‘‘late onset’’ bipolar disorder (Taylor and Abrams, 1981), 21 out of 23 patients in this study would be classified as ‘‘early onset’’ and the majority would also be defined as ‘‘good outcome’’ patients based on their current and
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past history of stability on medications. Therefore, the combination of both ‘‘early onset’’ and ‘‘good outcome’’ that characterized most of the bipolar patients in the current study may have contributed to not finding an increased volume of WMSH in this particular cohort. White matter volume reductions may be a reflection of the underlying neuronal and glial cell pathology that is emerging in studies of bipolar disorder. The white matter is comprised of myelinated axons of neurons and glial cells, the latter being comprised of astrocytes, oligodendrocytes, and microglia. Recent neuropathology studies have documented glial reductions in the anterior cingulate and dorsolateral prefrontal cortex regions (Ongu¨r et al., 1998; Cotter et al., 2001; Rajkowska et al., 2001) in bipolar disorder. Furthermore, proton and phosphorous magnetic resonance spectroscopy studies of bipolar patients have reported: (1) reduced N-acetylaspartate (NAA) in the dorsolateral prefrontal gray and white matter in adults (Winsberg et al., 2000; Deicken et al., 2001) and children (Chang et al., 2003); (2) increased choline (Moore et al., 2000a) in the anterior cingulate region but decreased (Cecil et al., 2002; Chang et al., 2003) in the orbitofrontal region; (3) phosphomonoesters (PME) and phosphodiesters (PDE) in the frontal and temporal lobe gray and white matter (Kato et al., 1993, 1995; Deicken et al., 1995a,b). The NAA reductions suggest dorsolateral prefrontal cortex neuronal pathlogy as well as frontal white matter axonal pathology, whereas the choline, PME, and PDE alterations provide evidence for trait dependent abnormalities of membrane phospholipid metabolism. Finally, a recently published study which utilized microarray techniques to investigate bipolar brains from the Stanley brain collection revealed that expression profiles of most known oligodendrocyte-related and myelin-related genes were greatly reduced in bipolar disorder and several transcription factors known to coordinate myelin gene expression demonstrated corresponding alterations (Tkachev et al., 2003). Therefore, the combination of WMSH, membrane phospholipid abnormalities, axonal dysfunction or damage, reduced glial cells, and decreased expression of oligodendrocyte-related and myelin-related genes is providing more cohesive evidence for white matter pathological involvement in bipolar disorder.
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The causal relationship between bipolar disorder and the reduced cortical gray and white matter volumes as well as increased ventricular and sulcal CSF has yet to be determined. If these findings represent neurodevelopmental abnormalities, originating either from genetic or environmental risk factors, alterations would most likely be manifest at an early stage of the disorder. Support for this notion comes from studies of: (1) first-episode mania that have reported a decrease in subgenual cingulate cortex volumes (Hirayasu et al., 1999), increased lateral and third ventricle as well as putamen volumes (Strakowski et al., 1993, 2002), and increased WMSH; (2) adolescent bipolar I subjects which revealed increased lateral ventricular, frontal sulcal, and temporal sulcal volumes (Friedman et al., 1999) suggesting that this finding may be present at the onset of illness; and (3) studies of BPI children and adolescents demonstrating an increased presence of WMSH (Botteron et al., 1995; Lyoo et al., 2002; Pillai et al., 2002). It should be noted that this study attempted to minimize the potential effects of comorbid conditions on brain structural abnormalities that may be trait markers and potential endophenotypes. Therefore, patients with a history of substance abuse or substance dependence were excluded because it is not clear for any given individual, when the effects of alcohol and substance abuse begin to have a significant effect on brain structure. Therefore, the study findings may not be generalizable to the 40 – 48% of male bipolar patients with alcohol or substance abuse comorbidities (Hendrick et al., 2000). However, the intent of this study was to identify any alterations in tissue volume for cortical gray matter, cerebral white matter, and ventricular and sulcal CSF that are central nervous system manifestations of the disease itself. Such pathological alterations that can be directly attributed to the disease without the confound of substance abuse or dependence stand an increased likelihood of being identified as potential endophenotypes which can then better inform genetic studies. The current results and interpretations are limited by the relatively small sample size and the consequent reduced statistical power, the retrospective nature of obtaining past psychiatric and medical histories, as well as the possible confounding effects of medication. All bipolar subjects participating in the study were on mood stabilizers and antidepressants for at
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least 2 months, but detailed medication histories going back in time more than several years could not be remembered accurately by the patients and/or corroborated by treating clinicians or family members. Therefore, we are unable to determine if the specific length of time on medication or other confounding factors correlated with the MRI brain measures. Although there were no significant associations between the cortical gray matter volume and either divalproex or lithium dosages, there is no convincing evidence to date that chronic exposure to these mood stabilizers in humans would result in cortical gray matter deficits. On the contrary, recent studies of healthy volunteers and bipolar patients demonstrated that four weeks of lithium administration significantly increased total gray matter content in the bipolar patients (Moore et al., 2000b,c). Total gray matter volumes were found to be increased in lithium treated bipolar patients compared with untreated patients and healthy controls in one study, suggesting that lithium exerts neurotrophic effects on the brain (Sassi et al., 2002). A study of bipolar I twins and their co-twins found a positive correlation between frontal gray matter volume and the use of lithium, with a significant effect size for doses of 1000 mg per day (Kieseppa et al., 2003). There is also evidence that valproate activates pathways that regulate BDNF; robustly increases trophic factors like bcl-2 and growth cone associated protein (GAP-43); and promotes neurite outgrowth in as well as prolongs survival of human neuroblastoma cells (Manji et al., 2000). As for medications other than mood stabilizers, chronic administration of several different classes of antidepressants increases neurogenesis in the adult rodent hippocampus (Jacobs et al., 2000; Malberg et al., 2000; Duman et al., 2001; Manev et al., 2001), and this may be related to antidepressant induced upregulation of hippocampal CREB and BDNF (Nibuya et al., 1995, 1996; Thome et al., 2000). However, one previous study showing a reduction in total gray matter volume reported that current antidepressant exposure was associated with smaller right inferior gray matter volumes (Lopez-Larson et al., 2002). Recent reviews of the neuropathological effects of antipsychotics in rats and humans (Harrison, 1999; Konradi and Heckers, 2001) concluded that they appear to induce synaptic plasticity or reorganization in the striatum and lamina VI of the frontal
cortex, however, there is no good evidence that antipsychotics cause neuronal loss or gliosis. Nevertheless, a larger cumulative dosage of antipsychotic medication has been associated with progressive decreases in frontal lobe volume in recent longitudinal studies of patients with first-episode schizophrenia (Gur et al., 1998; Madsen et al., 1999; Cahn et al., 2002). Therefore, if antipsychotics can potentially induce synaptic reorganization, and chronic administration of antidepressants, lithium, and valproate can potentially promote neurogenesis, then cortical gray matter volume in bipolar disorder might be expected to increase rather than decrease as a consequence of chronic medication treatment.
Acknowledgements This research was supported by a 1998 Stanley Foundation Research Award and NIH grant MH62102 (Dr. Deicken) (RFD).
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