Published online before print January 7, 2008, 10.1148/radiol.2462061469
(Radiology 2008;246:536-542.)
© RSNA, 2008
Corpus Callosum in Patients with Obsessive-Compulsive Disorder: Diffusion-Tensor Imaging Study1
Yukiko Saito, MD,
Kenji Nobuhara, MD, PhD,
Gaku Okugawa, MD, PhD,
Katsunori Takase, MD, PhD,
Tatsuya Sugimoto, MD,
Mami Horiuchi, MD,
Chiho Ueno, MD,
Minoru Maehara, MD,
Naoto Omura, MD,
Hiroaki Kurokawa, MD, PhD,
Koshi Ikeda, MD, PhD,
Noboru Tanigawa, MD, PhD,
Satoshi Sawada, MD, PhD, and
Toshihiko Kinoshita, MD, PhD
1 From the Departments of Neuropsychiatry (Y.S., K.N., G.O., K.T., T.S., M.H., C.U., T.K.) and Radiology (Y.S., M.M., N.O., H.K., K.I., N.T., S.S.), Kansai Medical University, 10-15 Fumizono-cho, Moriguchi City, Osaka, 570-8506, Japan. Received August 23, 2006; revision requested October 30; revision received March 2, 2007; accepted March 21; final version accepted July 5. Supported by grant 16591173 from the Ministry of Education Science and Culture of Japan.
Address correspondence to Y.S. (e-mail: saitoyu{at}takii.kmu.ac.jp).
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ABSTRACT
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Purpose: To prospectively examine microstructural white matter abnormalities in the corpus callosum (CC) of patients with obsessive-compulsive disorder (OCD), as compared with control subjects, and to investigate the relationship between diffusion-tensor (DT) imaging measures of the CC region and clinical symptoms of OCD.
Materials and Methods: Institutional review board approval was obtained, and each participant—or the participant's parent(s)—provided written informed consent. Sixteen patients with OCD (seven male, nine female; mean age, 28.7 years ± 9.8 [standard deviation]) and 16 matched healthy volunteers (control subjects) (seven male, nine female; mean age, 29.9 years ± 9.0) were examined. Mean diffusivity and fractional anisotropy (FA) were measured in five subdivisions of the CC. The paired t test was performed to compare the mean diffusivity or the FA in CC regions between the patients with OCD and the control subjects.
Results: There were no significant differences (rostrum, P = .15; genu, P = .88; rostral body, P = .12; isthmus, P = .77; splenium, P = .88) in mean diffusivity between the patients with OCD and the healthy volunteers. A significant reduction in FA was observed in the rostrum of the CC in patients with OCD compared with the rostral FA in the control subjects (P < .001). Higher FA in only the rostrum correlated significantly with lower Yale-Brown obsessive-compulsive scale score (r = –0.72, P = .002).
Conclusion: Study results support the widely held view that the orbital prefrontal region is involved in the pathophysiology of OCD and indicate that the orbitofrontal circuit influences symptom severity in patients with OCD.
© RSNA, 2008
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INTRODUCTION
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Obsessive-compulsive disorder (OCD) is characterized by intense, intrusive, and unwanted thoughts or ideas in association with urges to perform ritualistic behaviors (1). OCD is often chronically disabling, with concomitant impairments in interpersonal and occupational function, and patients with this disorder report having senseless and unpleasant symptoms (2). Obsessions and compulsions typically emerge around the 2nd to 3rd decade of life and often are resistant to psychodynamic therapeutic approaches; however, they are quite responsive to pharmacologic intervention (3).
Neuropsychologic studies have revealed cognitive impairments with OCD (4,5). The corpus callosum (CC), the largest interhemispheric white matter commissure connecting the cerebral hemispheres, has a crucial role in interhemispheric communication and cognitive processes (6). The subdivisions of the CC may be roughly associated with various cortical regions, although there is considerable overlap. The possibility of topographic organization of callosal fibers is based on experimental work with monkeys (7), autoradiographic study results (8,9), and clinical study results (10,11). The rostrum contains fibers from the orbitofrontal cortex (OFC), and the genu connects the lateral and medial surfaces of the frontal lobes. The body of the CC connects wide neocortical homotopic regions of the cerebral hemispheres, including the premotor, supplementary motor, motor, somatesthetic, and posterior parietal regions. The isthmus connects the superior temporal and posterior parietal regions, while the splenium connects the occipital and inferior temporal regions.
Neuroimaging study results have repeatedly implicated the OFC in the pathophysiology of OCD. The OFC, when measured at baseline (12,13) or during exposure (14) to triggering stimuli, is hyperactive in patients with OCD. Substantial reductions in OFC activity have been observed after successful pharmacologic and behavioral therapy (15). The consistency with which OFC hyperactivity has been observed in these studies suggests that the OFC may make a unique contribution to OCD. The OFC is positioned at a point of interface between the sensory association cortices, limbic structures, and subcortical regions involved in controlling the automatic and motor effector pathways (16). Although recent research on OCD has been focused on the neuroanatomic circuitry, including the circuitry in the OFC, the abnormalities of the white matter in the orbitofrontal region in patients with OCD have been examined in only a few studies.
Magnetic resonance (MR) diffusion-tensor (DT) imaging is used to noninvasively examine the molecular diffusion of water in vivo and to directly appreciate the anatomic integrity of neural fibers (axons and myelin) in white matter. Thus, DT imaging yields information about white matter tracts and their organization (17). Specifically, it yields an index of microstructural integrity through quantification of the magnitude and directionality of restricted tissue water mobility (diffusion anisotropy) in three dimensions. The magnitude and directionality are evaluated specifically by using measurements of mean diffusivity (DM), a measure of the magnitude of diffusion, and fractional anisotropy (FA), a measure of the directionality of diffusion. DT imaging has been used successfully to evaluate the white matter fiber integrity in patients with psychiatric diseases such as schizophrenia (18–20) and depression (21).
We hypothesized that OCD is associated with white matter integrity abnormalities in the orbitofrontal brain region. Thus, the purpose of our study was to prospectively examine the microstructural white matter abnormalities in the CC of patients with OCD, as compared with healthy control subjects, and to investigate the relationship between DT measures of the CC region and clinical symptoms of OCD.
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MATERIALS AND METHODS
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Patients
The study protocol was approved by our institutional review board, and written informed consent was obtained from all patients or their parents, depending on the age of the patient. All patients had received a diagnosis of OCD based on criteria listed in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (22). Between April 2004 and October 2005, 18 consecutive patients with OCD who met our study criteria were recruited for this investigation at our university hospital. We excluded patients who (a) had cardiac pacemakers, metallic clips, or other metallic implants or artifacts in their bodies; (b) had substantial medical illness or neurologic (eg, Tourette syndrome, Huntington disease, and Parkinson disease), pulmonary, cardiac, renal, hepatic, endocrine, or metabolic disorders; (d) had DSM-IV–defined dementia, delirium, schizophrenia, schizoaffective disorder, delusional disorder, brief reactive psychosis, or psychotic disorders not otherwise specified; (e) had DSM-IV–defined mental retardation; (f) had lacunar infarcts; (g) were currently or previously dependent on or abusers of DSM-IV–defined alcoholic or psychoactive substances; and/or (h) were pregnant. All patients with lacunar infarcts in any location were excluded. Thus, two patients found to have lacunar infarction were excluded from our study. The final study cohort included 16 patients (seven male, nine female; age range, 16–47 years; mean age, 28.7 years ± 9.8 [standard deviation]).
The final study cohort of 16 patients had a mean total Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) score of 26.0 ± 5.3, and their mean scores on the obsessive and compulsive subscales were 14.6 ± 3.5 and 11.4 ± 2.8, respectively. Their mean Hamilton Depression Rating Scale (HDRS) score was 5.3 ± 2.7. No patients had comorbid disorders such as major depression or panic disorder. Ten patients had doubting obsessions (wondering whether something was done) in association with checking compulsions (checking that it was done), whereas six patients had contamination obsessions (fear of germs) in association with washing compulsions.
All but three patients were receiving medication for their OCD symptoms at the time of the MR examination: Five patients were taking paroxetine hydrochloride only; two patients, a combination of paroxetine hydrochloride and benzodiazepines; and two patients, a combination of fluvoxamine maleate and benzodiazepines. One patient each was taking a combination of paroxetine hydrochloride, fluvoxamine maleate, and benzodiazepines; a combination of paroxetine hydrochloride and clomipramine hydrochloride; a combination of fluvoxamine maleate, benzodiazepines, and sulpiride; or a combination of fluvoxamine maleate, milnacipran hydrochloride, and benzodiazepines.
Control Subjects
Sixteen healthy volunteers (seven male, nine female; age range, 16–47 years; mean age, 29.9 years ± 9.0) matched one-to-one in age, sex, and handedness with the patients who had OCD participated in the study as control subjects after giving informed consent. Institutional review board approval was also obtained to examine these volunteers. Neither these volunteers nor their first-degree relatives had a history of psychiatric illness. They underwent MR imaging of the brain and were subsequently confirmed to have normal MR findings and no neurologic deficits at clinical examination.
Clinical Assessments
Only the 16 patients with OCD were examined with the Y-BOCS and the 17-item HDRS. Greater symptom severity results in higher Y-BOCS and HDRS scores. Both assessments were performed by one trained psychiatrist (Y.S., 5 years experience in psychiatry) at the initial visit, 2 weeks before the MR examinations.
MR Imaging Protocol
The MR examinations were performed with a 1.5-T unit (Signa Horizon LX; GE Medical Systems, Milwaukee, Wis). Head motion was minimized with restraining pads and tape before imaging. Echo-planar MR images were obtained in the patients with OCD and the control subjects and were checked for head motion. Sagittal short inversion time inversion-recovery (STIR) echo-planar images were acquired first, with a section clearly showing the anterior and posterior commissures. The superoinferior thickness of the rostrum in the sagittal plane was measured. Then, a series of transverse diffusion-weighted images with a diffusion-sensitizing gradient (b = 1000 sec/mm2) were obtained. Diffusion was measured along six noncolinear directions. We used single-shot spin-echo echo-planar sequences for DT analysis. All acquisitions were performed parallel to the anterior commissure–posterior commissure line with use of the following parameters: >17 000/>115.6 (repetition time msec/echo time msec), 128 x 128 matrix, 24 x 24-cm field of view, four signals acquired, 4.0-mm section thickness, and no intersection gap.
The diffusion-weighted images were transferred to a dedicated workstation (Sun Microsystems, Santa Clara, Calif), where the DT data were postprocessed by using Functool 2.2.49 software (GE Medical Systems). Echo-planar image distortion was corrected. The first step of this procedure entails correcting the distortions usually induced by the eddy current related to the large diffusion-sensitizing gradients. This correction algorithm is based on the maximization of mutual information to estimate the three parameters of a geometric distortion model inferred from the acquisition principle. The second step of the procedure involves replacing the standard least squares–based approach with the Geman-McLure M estimator approach to eliminate outlier-related artifacts.
DM and FA maps were then computed by using the DT data. The Functool software applies thresholding to apparent diffusion coefficient maps that may substantially affect mean region-of-interest (ROI) data. We were aware of this and took care to avoid it.
Diffusion eigenvectors and eigenvalues (
1, 2, and 3), which correspond to the main diffusion direction and the associated diffusivity, were calculated from the DT data. FA values, which yield information about the degree of diffusion anisotropy in white matter, and DM values, which yield information about the magnitude of diffusion, were then calculated:
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and
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ROI Selection and Analysis
The CC was clearly delineated in the midsagittal plane on the STIR brain MR images. The lack of anatomic landmarks on the midsagittal view of the CC made it difficult to define the corresponding cortical areas from which the fibers originate. Thus, seven callosal subdivisions were defined on the basis of the scheme of regional divisions of the CC proposed by Witelson and Kigar (23) (Fig 1a). We investigated the plane parallel to the anterior commissure–posterior commissure plane, including each subdivision of the CC, on the sagittal STIR images (Fig 1b). Each ROI consisted of manually traced 2-mm squares placed over the anatomic horizontal T2-weighted imaging plane, which was determined on the basis of the sagittal STIR image findings. The borderlines between the anterior middle and posterior middle bodies of the CC were not clearly defined in the transverse T2-weighted imaging planes. Therefore, the following five subdivisions of the CC were chosen as ROIs: the rostrum, genu, rostral body, isthmus, and splenium (Fig 2).
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Figure 1a: Regional subdivisions of CC in adult human based on (a) regional division scheme of the CC and (b) corresponding sagittal STIR MR image findings (3000/8.8/100 [repetition time msec/echo time msec/inversion time msec]). Anterior CC (ACC) and posterior CC (PCC) are extreme anterior and extreme posterior points of the CC, respectively, with anterior CC–posterior CC distance defined as the length of the CC. Anterior CC–posterior CC distance is used as linear axis to subdivide CC into anterior and posterior halves; anterior, middle, and posterior thirds; and posterior fifth region, which is roughly congruent with the splenium (region 7). Line perpendicular to axis at extreme anterior point on inner convexity of anterior CC is used to define rostrum (region 1) and extreme anterior division of CC, which is roughly congruent with the genu (region 2). Region 3, the rostral body, is defined as anterior third of CC minus regions 1 and 2. Region 4, the anterior middle body, is defined as anterior half minus anterior third. Region 5, the posterior middle body, is defined as posterior half minus posterior third. Region 6, the isthmus, is defined as posterior third minus posterior fifth. Regions 3–6 constitute CC body.
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Figure 1b: Regional subdivisions of CC in adult human based on (a) regional division scheme of the CC and (b) corresponding sagittal STIR MR image findings (3000/8.8/100 [repetition time msec/echo time msec/inversion time msec]). Anterior CC (ACC) and posterior CC (PCC) are extreme anterior and extreme posterior points of the CC, respectively, with anterior CC–posterior CC distance defined as the length of the CC. Anterior CC–posterior CC distance is used as linear axis to subdivide CC into anterior and posterior halves; anterior, middle, and posterior thirds; and posterior fifth region, which is roughly congruent with the splenium (region 7). Line perpendicular to axis at extreme anterior point on inner convexity of anterior CC is used to define rostrum (region 1) and extreme anterior division of CC, which is roughly congruent with the genu (region 2). Region 3, the rostral body, is defined as anterior third of CC minus regions 1 and 2. Region 4, the anterior middle body, is defined as anterior half minus anterior third. Region 5, the posterior middle body, is defined as posterior half minus posterior third. Region 6, the isthmus, is defined as posterior third minus posterior fifth. Regions 3–6 constitute CC body.
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Figure 2: Transverse T2-weighted MR images (left, b = 0 sec/mm2) and corresponding FA maps (right, b = 1000 sec/mm2) in patient with OCD (>17 000/>115.6, 4-mm section thickness). ROIs are drawn in rostrum (1), genu (2), rostral body (3), isthmus (4), and splenium (5) of CC. Right: Colors, demonstrated by using Functool 2.2.49 software, indicate various grades of white matter anisotropy. Blue indicates low grade of white matter anisotropy, and red indicates high grade of white matter anisotropy.
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Two trained physicians (Y.S., K.N.) conducted all FA measurements in consensus. These physicians have 5 (Y.S.) and 10 (K.N.) years experience in brain MR imaging research. They were blinded to the subject group when they performed the ROI analysis. For each subject, the ROIs were transferred onto FA maps and the FA was calculated for each selected CC ROI. The interoperator reliability between the two physicians in assessing the DT measures in 10 randomly selected subjects (five patients with OCD, five healthy volunteers) was also confirmed.
Statistical Analyses
The two physicians (Y.S., K.N.) were blinded to information about the images that they were analyzing. Interoperator reliability in assessing the DT measures was confirmed by using intraclass correlation coefficients. Data for 10 participants (five patients with OCD, five healthy volunteers) collected by one psychiatrist (K.N.) were used to compare the patient and control subject data. Mean DT values for each ROI, including 95% confidence intervals for the difference in mean values between the two groups (patients with OCD vs healthy volunteers), were calculated. The paired t test was used to compare DT values for the CC regions between the patients with OCD and the matched control subjects. Because five comparisons were performed for each DT measure, P values lower than .01 were considered significant on the basis of Bonferroni correction. The correlations between DT measures of the CC regions studied and Y-BOCS and HDRS scores were investigated by using Spearman rank correlation coefficients. All statistical analyses were performed by using SPSS statistical software (SPSS for Windows, release 11.5 J; SPSS, Chicago, Ill).
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RESULTS
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Our check of the raw echo-planar images for head motion revealed that the patients with OCD and the control subjects had kept equally still. The average superoinferior thickness of the rostrum measured in the sagittal plane for both groups was 6.875 mm. All intraclass correlation coefficients of DT measures were greater than 0.89 for every ROI, indicating excellent interoperator reliability.
There were no significant differences in DM between the patients with OCD and the healthy volunteers (Table 1). A significant reduction in FA was observed in the CC rostrum of the patients with OCD compared with the rostral FA in the control subjects (P < .001). FA in the other subdivisions did not differ significantly between the patients and the healthy volunteers (Table 2). Higher FA in only the rostrum correlated significantly with lower Y-BOCS score (r = –0.72, P = .002) (Fig 3). HDRS score did not correlate with FA in the rostrum (r = 0.06, P = .84). Because none of the patients with OCD had an HDRS score higher than 7, we found noncorrelation between HDRS score and FA in the rostrum.
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DISCUSSION
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Our study results indicate that in patients with OCD, there is abnormal white matter anisotropy in the rostrum of the CC and an inverse relationship between white matter anisotropy in the CC rostrum and severity of OCD symptoms. The reduced white matter anisotropy observed in our study suggests that patients with OCD possibly have microstructural abnormalities in the CC rostrum itself and fiber integrity abnormalities in the orbital prefrontal region that contains fibers extending into the rostrum. There is a large amount of experimental and clinical evidence that the OFC is involved in the mediation of emotional responses to biologically important stimuli (16). Results of animal studies suggest that hoarding, a common OCD symptom, is mediated by the ventromedial striatum, globus pallidus, and medial dorsal thalamus—all of which are connected to the OFC (16,24). Thus, heightened OFC activity may make individuals with OCD particularly efficient at recognizing conditioned aversive reinforcers and more vulnerable to anticipatory anxiety or distress (25). Since the OFC is involved in maintaining representations of the reinforcement value of stimuli in working memory, the inability of patients with this disorder to inhibit intrusive thoughts and images may be interpreted as reflective of a hyperactive working memory (26). The correlations between Y-BOCS score and white matter anisotropy of the CC rostrum that we observed suggest that white matter abnormalities in the orbitofrontal region are implicated in OCD symptom severity.
Szeszko et al (27) reported their use of DT imaging in patients with OCD. They compared, voxel by voxel, the imaging data in 15 patients with OCD and 15 healthy volunteers and observed substantially lower FA bilaterally in three areas of the anterior cingulated gyrus white matter in the patients with OCD. In our study, however, we chose an ROI analysis method aimed at identifying microstructural white matter abnormalities of the CC. The cingulum was not clearly defined in the transverse T2-weighted imaging planes, so we could not evaluate it. The contrasting findings of these two DT imaging studies may be due to differences in characteristics, such as age, sex, handedness, race, total Y-BOCS score, and/or HDRS score, between the patient groups. Furthermore, important group differences in the white matter integrity in other brain regions implicated in the pathophysiology of OCD, including the orbitofrontal lobe and striatal regions, were not observed in the Szeszko et al study (27).
We observed abnormal white matter FA in the CC rostrum of the patients with OCD. However, there were no significant differences in DM between the groups. FA and DM can be studied independently. FA is a measure of the directionality of diffusion. On the other hand, DM is a measure of the average diffusion in all directions and thus is more sensitive to fiber density than to fiber orientation and organization (28). Although microstructural changes can be roughly estimated by using FA or DM, both parameters are indispensable for yielding more pertinent information about morphologic changes in the brain. DT measures can be influenced by many factors, such as dense packing of axons, relative permeability of the membrane to water, internal axonal structure, tissue water content or degree of myelination, and/or the pathophysiology underlying the reduced white matter anisotropy. Although the pathophysiology underlying the reduced white matter anisotropy in the CC rostrum in patients with OCD has not been confirmed, more than one process may be responsible for the FA reduction.
Our study had limitations. A relatively small number of patients and control subjects were examined. There were also a few methodologic concerns. Because of the difficulty in placing ROIs in subcortical regions with no remarkable landmarks, microstructural abnormalities of the white matter tracts connecting the OFC to the rostrum were not directly examined. The Functool software applies thresholding to apparent diffusion coefficient maps that may substantially affect mean ROI data. Thus, the potential effects of medication on DT measures could not be examined. Also, since the source diffusion-weighted images had an in-plane spatial resolution of only 1.9 x 1.9 mm and a thickness of 4 mm, the noise introduced during the conversion of these images to FA maps could have limited the spatial resolution even further. We also cannot exclude the possibility that potential partial volume averaging effects influence DT measurements, especially in such a small subdivision of the CC as the rostrum, whose volume may differ between groups. However, for all subjects, the superoinferior thickness of the rostrum measured in the sagittal plane was 5–9 mm, greater than the 4-mm image section thickness. Furthermore, we cannot exclude the possibility that the head motion resulting from anxiety related to being inside the magnet differed between groups. Therefore, we checked the raw echo-planar images for head motion and verified that the patients with OCD and the control subjects had kept equally still.
In conclusion, our study results support the widely held view that the orbital prefrontal region is involved in the pathophysiology of OCD. It is important that the results also indicate that the OFC influences symptom severity in patients with OCD. Future studies with larger numbers of drug-naïve patients and more complex methods, such as tract tracing for direct examination of the targeted white matter, may help to elucidate the contribution of microstructural white matter changes in the orbitofrontal region to the pathophysiology and outcomes of OCD.
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ADVANCE IN KNOWLEDGE
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- In patients with obsessive-compulsive disorder (OCD), we observed abnormal white matter anisotropy in the rostrum of the corpus callosum (CC) and an inverse relationship between white matter anisotropy in the CC rostrum and severity of OCD symptoms.
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IMPLICATION FOR PATIENT CARE
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- Diffusion-tensor imaging performed in addition to Yale-Brown obsessive-compulsive scale scoring may help to predict the severity of OCD symptoms.
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ACKNOWLEDGMENTS
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We are grateful to the MR imaging group at Kansai Medical University for valuable assistance.
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FOOTNOTES
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Abbreviations: CC = corpus callosum • DM = mean diffusivity • DT = diffusion tensor • FA = fractional anisotropy • HDRS = Hamilton Depression Rating Scale • OCD = obsessive-compulsive disorder • OFC = orbitofrontal cortex • ROI = region of interest • STIR = short inversion time inversion recovery • Y-BOCS = Yale-Brown Obsessive-Compulsive Scale
Author contributions: Guarantors of integrity of entire study, Y.S., K.N.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, Y.S., K.N., G.O., H.K., K.I.; clinical studies, Y.S., K.N., G.O., K.T., T.S., C.U., H.K., K.I.; statistical analysis, Y.S., K.N., G.O.; and manuscript editing, all authors
Authors stated no financial relationship to disclose.
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ABSTRACT
INTRODUCTION
