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Smaller orbital frontal cortex volumes associated with functional disability in depressed elders
Smaller Orbital Frontal Cortex Volumes Associated with Functional Disability in Depressed Elders Warren D. Taylor, David C. Steffens, Douglas R. McQuoid, Martha E. Payne, Shwu-Hua Lee, Te-Jen Lai, and K. Ranga Rama Krishnan Background: Depression is associated with significant functional impairment. Recent evidence has linked the orbital frontal cortex (OFC) with depression. We examined the relationship between OFC volumes in older subjects and impairment in the basic (BADL) and instrumental (IADL) activities of daily living. Methods: The sample consisted of 81 subjects aged 60 years or older; 41 were depressed subjects and 40 healthy control subjects. In a structured interview, subjects reported their medical history and ability to perform both BADL and IADL. Subjects then had a brain magnetic resonance imaging (MRI) scan; the OFC was manually traced bilaterally using neuroanatomical landmarks. Logistic regression was used to examine the effect of OFC volume on BADL and IADL while controlling for the effects of total brain volume, subject status, medical comorbidity, and demographic factors. Results: Smaller OFC volumes, along with greater cognitive impairment as measured by the Mini-Mental State Examination, were significantly associated with BADL impairment. Smaller OFC volumes and being depressed were significantly associated with IADL impairment. Conclusions: Smaller OFC volumes are independently associated with functional impairment, supporting its role in depression. Further studies are needed to determine how smaller OFC volumes are related to other MRI abnormalities associated with depression and functional impairment. Biol Psychiatry 2003;53:144 –149 © 2003 Society of Biological Psychiatry Key Words: Depression, disability, geriatrics, orbital frontal cortex, prefrontal cortex
Introduction
I
t is well established that depression in the elderly is associated with significant functional impairment (Armenian et al 1998; Bruce et al 1994; Lenze et al 2001; Sato et al 1999). Disability is typically categorized as either
impairment in basic activities of daily living (BADL), such as using the toilet, bathing, or dressing, or impairment in instrumental activities of daily living (IADL), such as shopping, preparing meals, or managing finances. Clinical studies in older subjects usually find depressionassociated impairment in both of these domains (Alexopoulos et al 1996; Bruce et al 1994; Femia et al 2001; Steffens et al 1999), which may improve with antidepressant therapy (Chemerinski et al 2001; Oslin et al 2000). How are depression and functional disability related? This is a complex relationship that becomes more complicated when one considers that cognitive dysfunction may be seen in late-life depression. One common deficit is an impaired response to negative feedback (Elliott et al 1996, 1997, 1998; Steffens et al 2001), a finding described as a “catastrophic response to perceived failure” (Beats et al 1996). This finding has been considered to be an important link between cognitive and emotional processes (Elliott et al 1997). Output pathways from the medial orbital frontal cortex (OFC) to the striatum are thought to be critically involved in stimulus reinforcement (Bechara et al 1999, 2000). Impairment of this circuit may contribute to impaired response to negative feedback (Elliott et al 1996, 1997, 1998). If this pathway is associated with depression and disability, difficulties with ADLs could lead to frustration, decreased effort, and increased disability. Recent evidence has further implicated the medial OFC in late-life depression (Ebert and Ebmeier 1996). Smaller OFC volumes (Bremner et al 2002; Lai et al 2000), decreased OFC neuronal density (Rajkowska et al 1999), and greater OFC lesion severity (MacFall et al 2001) are associated with depression. If impairment of OFC circuits is truly involved in impaired responses to negative feedback and depression, it should also be associated with greater functional impairment. We hypothesized that smaller OFC volumes would be associated with greater BADL and IADL impairment.
Methods and Materials From the Department of Psychiatry and Behavioral Medicine at Duke University Medical Center, Durham, North Carolina. Address reprint requests to Warren D. Taylor, M.D., Duke University Medical Center, Department of Psychiatry, DUMC 3903, Durham NC 27710. Received April 12, 2002; revised June 12, 2002; accepted June 20, 2002.
© 2003 Society of Biological Psychiatry
Sample All subjects were participants in the National Institute of Mental Health–sponsored Duke University Mental Health Clinical Re0006-3223/03/$30.00 doi:10.1016/S0006-3223(02)01490-7
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search Center (MHCRC) for the Study of Depression in Later Life. Participation was restricted to subjects aged 60 years or older with a diagnosis of major depressive disorder. Exclusion criteria included 1) another major psychiatric illness; 2) current or past alcohol or drug dependence; 3) primary neurologic illness, including dementia; 4) medications or medical illness that may affect cognitive function; 5) physical disability that precludes cognitive testing; and 6) metal in the body that precludes magnetic resonance imaging (MRI). The Duke University Institutional Review Board (IRB) approved this study. The purpose of the MHCRC and its procedures were explained to each participant, and those who provided written informed consent were enrolled. Control subjects were age-matched and recruited from a listing of over 1900 community-dwelling elders from the Aging Center Subject Registry at Duke University; these individuals have expressed a willingness to participate in Duke Aging Center Research. Eligible control subjects had a nonfocal neurologic examination, no self-report of neurologic or depressive illness, and no evidence of a depression diagnosis based on the Diagnostic Interview Schedule (DIS; Robins et al 1981) portion of the Duke Depression Evaluation Schedule (DDES; Landerman et al 1989). The study’s purpose and procedures were explained; those providing written informed consent were enrolled.
Assessment Procedures At baseline, a study geriatric psychiatrist administered a standardized clinical assessment to each subject. This assessment included the Montgomery-Asberg Depression Rating Scale (Montgomery and Asberg 1979) and the Clinical Global Impression scale (Guy 1976). Cognitive status was measured with the Mini-Mental State Examination (MMSE; Folstein et al 1975). The Cumulative Illness Rating Scale (CIRS; Linn et al 1988), modified for geriatric populations (Miller et al 1992), assessed the burden of comorbid medical illnesses. A trained interviewer administered the DDES, which assesses depression with the DIS, as well as cognitive status, physical health, and social support.
Baseline Cognitive Screen Subjects were excluded if they had dementia or if a study geriatric psychiatrist suspected dementia at baseline. The majority of subjects had MMSE scores above 24; some severely depressed individuals had scores below 25. These subjects were followed through an acute 12-week treatment phase; if the scores remained below 25, they were not included in this study and were not followed longitudinally.
Measures DEPENDENT VARIABLES. The DDES includes 16 selfreported items assessing two domains of physical function. Seven items, modified from previous studies (Branch et al 1984; Katz et al 1970; Nagi 1976), address BADL self-maintenance skills: the ability to eat, dress, groom, ambulate, bathe, use the toilet, and bend to pick up an object from the floor. Nine items also modified from prior studies (Rosow and Breslau 1966)
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assess IADL performance: getting around the neighborhood, shopping for necessities, preparing meals, cleaning house, doing yardwork, keeping track of money, walking one fourth of a mile, walking up and down a flight of stairs, and caring for children. The wording of all items followed a consistent pattern (“Can you . . .”), with a standardized three-option answer format (“yes” [coded 0], “with difficulty” [coded 1], or “no” [coded 2]). Higher scores were thus indicative of greater impairment. Composite measures were constructed for each domain by summing the scores within that domain, a previous strategy used (Steffens et al 1999). The potential composite variable ranges were 0 –14 for the BADL summary variable and 0 –18 for the IADL summary variable. NON-MRI INDEPENDENT VARIABLES. The independent variables included in this analysis were age, gender, race, status as depressed or control subject, cognitive status as measured by the MMSE, and comorbid medical burden as measured by the CIRS total score.
MRI Variables MRI ACQUISITION. All subjects were screened for the presence of cardiac pacemakers, neurostimulators, metallic implants, metal in the orbit, aneurysm clips, or any other condition for which MRI was contraindicated. Subjects were imaged with a 1.5-Tesla whole-body MRI system (Signa, GE Medical Systems, Milwaukee, WI) using the standard head (volumetric) radiofrequency coil. Padding was used to immobilize the head without causing discomfort. The scanner alignment light was used to adjust the head tilt and rotation so that the axial plane lights passed across the cantho-meatal line and the sagittal lights were aligned with the center of the nose. A rapid sagittal localizer scan was acquired to confirm the alignment. A dual-echo, fast spin-echo acquisition was obtained in the axial plane for morphometry of cerebral structures. The pulse sequence parameters were repetition time ⫽ 4000 msec, echo time ⫽ 30, 135 msec, 32 KHz (⫾ 16 KHz) full imaging bandwidth, echo train length ⫽ 16, a 256 ⫻ 256 matrix, 3-mm section thickness, one excitation and a 20-cm field of view. The images were acquired in two separate acquisitions, with a 3-mm gap between sections for each acquisition. The second acquisition was offset by 3 mm from the first so that the resulting data set consisted of contiguous sections. MRI PROCESSING. Images were archived as normal procedure on magneto-optical disks in the MRI center and transferred to the Duke Neuropsychiatric Imaging Research Laboratory (NIRL) for processing on SUN workstations. Volume measurements used a NIRL-modified version of MrX Software, which was created by GE Corporate Research and Development (Schenectady, NY) and originally modified by Brigham and Women’s Hospital (Boston, MA) for image segmentation. The basic segmentation protocol is a supervised, semi-automated method that has been described previously (Byrum et al 1996; Kikinis et al 1992). Once the brain was segmented into tissue types and the nonbrain tissue stripped away through a masking procedure, total hemispheric gray and white matter volumes were calculated. The total left and right gray and white matter was defined as total brain volume.
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Next, specific regions of interest (ROIs) were assessed using tracing and connectivity functions. The medial OFC was traced bilaterally, and a mask was created and applied to the segmented brain. The neuroanatomic borders of the OFC used for this study have been previously described (Lai et al 2000). The final step was to run a summarizing program that calculated the volume within the specific OFC ROI defined by the analyst. All technicians received extensive training by experienced volumetric analysts. Reliability was established by repeated measurements on multiple MRI scans before raters were approved to process study data. Intraclass correlation coefficients were as follows: total brain ⫽ .998, left medial orbitofrontal cortex ⫽ .9, and right medial orbitofrontal cortex ⫽ .9.
Analytic Strategy For bivariate analyses, we first constructed dichotomous variables for BADL and IADL that compared groups with any impairment with groups without any impairment. These analyses included the calculation of t statistics for continuous variables and 2 statistics for dichotomous variables. The composite measures of BADL and IADL skills were further analyzed as dichotomous variables in multivariate logistic regression analyses. To obtain the simplest model, one variable was removed at a time by backward selection, based on the size of the p value. As a variable was removed, the model was refitted with the remaining variables before removing another variable (Harrell 2000). In some cases, specific variables (such as OFC volume) were forwarded to the more parsimonious model based on clinical significance.
Results The initial sample consisted of 41 depressed and 41 age-matched control subjects. One control subject was excluded because of a lack of BADL or IADL scores, leaving a total of 40 control subjects. There were significantly more women in the control group than in the depressed group, and the depressed group had a significantly lower MMSE score. There was also a trend for the control group to be older. These variables are summarized in Table 1. A total of 71 individuals reported no difficulties with BADL, whereas 10 individuals reported at least one BADL impairment. For IADL, 54 subjects had no IADL impairment, whereas 26 had at least one IADL impairment. All subjects had BADL scores; one was missing an IADL score. BADL scores ranged from 0 to 5 in depressed subjects; control subjects all had BADL scores of 0. IADL scores ranged from 0 to 15 in depressed subjects, and from 0 to 2 in control subjects. In each scale, 0 indicates no impairment, and increasing values indicate progressive impairment. Impairment was defined as having any score above 0 for either BADL or IADL. All individuals with BADL impairment were depressed subjects; when compared with
Table 1. Demographic Information: Depressed and Control Subjects Depressed Subjects (n ⫽ 41) Gender Female Male Race Caucasian Other Age Mini-Mental Score CIRS Score
Control Subjects (n ⫽ 40)
21 (51.22) 20 (48.78)
33 (82.50) 7 (17.50)
34 (82.93) 7 (17.07) 68.73 (6.98) 28.17 (2.097) 3.93 (3.028)
36 (90.00) 4 (10.00) 71.42 (6.07) 29.05 (1.037) 2.80 (2.534)
p Value .0028a
.353a .068b .020b .735b
Data for gender and race are expressed as n(%); all other data presented as mean (SD). CIRS, Cumulative Illness Rating Scale. a p value for 2 test. b p value for t test.
subjects without BADL impairment, they were also more likely to be African American, have lower baseline MMSE scores, and have smaller total brain and OFC volumes. There were no significant differences in age, gender, or CIRS score (see Table 2). When compared with subjects without IADL impairment, those with IADL impairment were more likely to be depressed subjects, have greater CIRS scores, and smaller OFC volumes. There was also a trend toward smaller total brain volumes, although this did not reach statistical significance. There were no significant differences between the groups in regard to age, gender, race, or MMSE score (see Table 2). Table 3 presents the results for the logistic regression models for BADL and IADL. Initial models (listed as model 1) included demographic variables, subject status, and total brain and OFC volumes. More parsimonious models (listed as model 2) then examined OFC volume while excluding nonsignificant variables from the initial model. In an exploratory model (not shown), total brain volume was carried forward to the parsimonious models, despite the fact that it was not significant in the initial models. In this model, total OFC volume was not significantly associated with IADL impairment (odds ratio [OR] ⫽ 1.062, confidence interval [CI] ⫽ .829-1.36) but remained significantly associated with BADL impairment (OR ⫽ 2.831, CI ⫽ 1.235-6.490). For the final models (Table 3), total OFC volume was significantly associated with BADL and IADL impairment after controlling for other variables. For BADL, lower MMSE score continued to be significantly associated with impairment. For IADL, status as a depressed subject continued to be significantly associated with impairment. We tested other models (not shown) examining left and right hemispheric OFC volumes. Total brain hemispheric volume continued to be statistically insignificant on the
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Table 2. Demographic, Clinical, and Magnetic Resonance Imaging Characteristics of the Sample Based on Presence of Any Impairment in Basic Activities of Daily Living (BADL) or Instrumental Activities of Daily Living (IADL)
Variable Age (Mean) Gender (% Female) Race (% Caucasian) Status (% Depressed Subject) MMSE Score (Mean) CIRS Score (Mean) Left Brain Volume Right Brain Volume Total Brain Volume Left OFC Volume (Mean) Right OFC Volume (Mean) Total OFC Volume (Mean)
No BADL Impairment (n ⫽ 71)
Any BADL Impairment (n ⫽ 10)
69.94 (6.41) 64.79 91.55 43.66 28.87 (1.25) 3.20 (2.83) 446.79 (56.01) 447.7 (55.84) 1024.90 (125.43) 6.54 (1.42) 6.94 (1.57) 13.48 (2.68)
70.90 (8.50) 80 50 100 26.70 (3.02) 4.60 (2.72) 398.41 (38.43) 403.61 (40.04) 930.75 (92.25) 4.84 (1.31) 5.43 (1.09) 10.27 (2.15)
p Valuea
No IADL Impairment (n ⫽ 54)
Any IADL Impairment (n ⫽ 26)
p Valuea
.6728 .4829 .0032b .001b .0498b .144 .010b .0185b .0251b .0006b .0042b .005b
69.80 (6.54) 64.81 88.89 35.19 28.91 (1.09) 2.74 (2.44) 449.86 (52.23) 450.58 (52.35) 1032.2 (118.63) 6.63 (1.41) 7.07 (1.56) 13.70 (2.61)
70.81 (6.99) 69.23 80.77 80.77 28.19 (2.28) 4.31 (2.77) 425.51 (59.96) 428.48 (59.15) 981.57 (130.53) 5.72 (1.56) 6.13 (1.51) 11.85 (2.93)
.5282 .6956 .3242 .0001b .1393 .0118b .067 .094 .0876 .011b .0127b .0055b
All data in parentheses are SD. All brain and OFC volumes measured in mL. MMSE, Mini Mental State Examination; CIRS, Cumulative Illness Rating Scale; OFC, orbital frontal cortex. a t test for continuous variables; 2 test for dichotomous variables. b Significant at ␣ ⫽ .05.
initial models. In the parsimonious models, MMSE score and depressed subject status continued to be significantly associated with respective BADL and IADL impairment. The left OFC volume was further associated with both BADL (OR ⫽ 6.062, CI ⫽ 1.877-19.572) and IADL impairment (OR ⫽ 1.495, CI ⫽ 1.027-2.178), whereas the right OFC volume was only significantly associated with BADL impairment (OR ⫽ 2.625, CI ⫽ 1.234-6.079).
Discussion We observed that medial orbitofrontal gyri volume was associated with impairment in both BADL and IADL, independent of the effects of age, gender, depression, and medical illness burden. Moreover, this finding appears to be independent of total brain volume. Although other investigators have examined the effect of MRI hyperintensities on functional status (Cahn et al 1996; Samuelsson et al 1996; Steffens et al 2002), to our knowledge this is
the first study to associate ADL impairment with smaller regional frontal volumes. As demonstrated in previous studies (Armenian et al 1998; Bruce et al 1994; Lenze et al 2001; Sato et al 1999), we also found an association between depression and functional disability. Given that this is a cross-sectional study, we must only cautiously make conclusions about causality. Hypothetically, OFC volume reductions represent impairment in OFC function, which then contributes to increased disability; an alternate hypothesis to our findings is that increased disability and OFC volume reductions develop from a mutual cause. When compared with healthy control subjects, depressed elders exhibit smaller OFC volumes (Bremner et al 2002; Lai et al 2000), reduced glial density and smaller neuronal sizes (Rajkowska et al 1999), and greater OFC lesion severity (MacFall et al 2001). These findings may potentially be representative of more global neurodegenerative or cerebrovascular processes that result in disability through other mechanisms. Our finding that
Table 3. Logistic Regression Models for Basic Activities of Daily Living (BADL) and Instrumental Activities of Daily Living (IADL), Odds Ratio with 95% Confidence Intervals and Indication of Level of Significance Variable Age Gender Subject Status Race MMSE Score CIRS Score Total Brain Volume Total OFC Volume
BADL Model 1 1.090 (.884 –1.343) .518 (.031– 8.543) .001 (.001–999.99)a 2.610 (.659 –10.330) 1.712 (.991–2.958) 1.011 (.715–1.428) 1.000 (.986 –1.014) 1.724 (.661– 4.499)
BADL Model 2
1.816 (1.202–2.742)b
2.529 (1.302– 4.912)b
IADL Model 1 .957 (.868 –1.056) .454 (.090 –2.298) .075 (.015–.365)b .743 (.323–1.707) 1.149 (.767–1.722) .806 (.626 –1.040) 1.003 (.996 –1.010) 1.088 (.838 –1.413)
Data are presented as odds ratio (95% confidence interval). Total brain and OFC volumes measured in mL. MMSE, Mini Mental State Examination; CIRS, Cumulative Illness Rating Scale; OFC, medial orbital frontal cortex. a All those with BADL impairment were depressed subjects. b Significant at ␣ ⫽ .05.
IADL Model 2
.149 (.047–.472)b
1.244 (1.014 –1.525)b
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total brain volume was not associated with disability speaks against this possibility. How then could impairment in OFC function contribute to disability? One possibility is that the OFC predisposes individuals to depression, which is itself associated with disability. Another possibility is that the OFC may be independently associated with both depression and disability. The medial OFC is involved in stimulus reinforcement and emotion modulation. Damage to the OFC impairs the learning and reversal of stimulus–reinforcement associations (Rolls 2000); in other words, it prevents the correction of previous behavioral responses, even when the responses are no longer appropriate. Clinically, this may appear as an impaired response to negative feedback (Elliott et al 1996, 1997, 1998). Hypothetically an ADL failure may result in a strong negative emotional response that causes frustration and discourages the patient from further effort, thus contributing toward greater functional impairment. There are some limitations to our study. The dependent BADL and IADL variables were obtained from subject self-report; in depressed subjects, these results may not represent true impairment, as depression may influence the perception of functional impairment. Another limitation is our method of screening for dementia. We excluded subjects who failed to have a MMSE score of 24 or greater following acute antidepressant therapy. Although the majority of the sample had baseline scores well over this value, we cannot definitively state that we did not include subjects with early dementia. The small number of subjects with BADL impairment is further limitation. Although we found a robust relationship between smaller OFC volumes and BADL impairment, this association must be viewed cautiously. We also found that a higher proportion of African Americans exhibited BADL impairment, although race was not a significant predictor of disability in the final models. Although this may be a spurious finding given the small number of subjects, other possible explanations exist, such as reporting differences or problems with access to medical care. Financial resources may also be important, as at least one group has found that income is an independent predictor of disability (Palmore and Burchett 1997). The small sample size may also have influenced differences in the demographics between our depressed and control groups. There were significantly more women in the control than in the depressed group; this difference probably does not significantly influence the study, as gender was not associated with disability in later models. Depressed subjects also exhibited a significantly lower MMSE score than control subjects. This may have influenced our findings regarding BADL impairment, as lower MMSE was associated with BADL impairment, and all
individuals with BADL impairment were in the depressed group. Although this is a confounder, the statistically significant MMSE difference between the two groups (28 for depressed subjects, 29 for control subjects) is not generally considered clinically significant. This study demonstrates that smaller OFC volumes are associated with greater BADL and IADL impairment. Longitudinal studies will be needed to help determine causal relationships. Other studies will also be needed to examine how OFC volume abnormalities and MRI hyperintensities may differentially affect disability. Such research will help clarify the complex relationship between depression, disability, and MRI findings. Supported by National Institute of Mental Health Grants P50 MH60451 and R01 MH54846. The authors thank Chris Byrum, M.D., Ph.D. and James MacFall, Ph.D. for their assistance in designing the MR imaging protocol and help with the image processing procedures. We also thank Denise L. Fetzer, M.A. for laboratory assistance.
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Introduction
I
t is well established that depression in the elderly is associated with significant functional impairment (Armenian et al 1998; Bruce et al 1994; Lenze et al 2001; Sato et al 1999). Disability is typically categorized as either
impairment in basic activities of daily living (BADL), such as using the toilet, bathing, or dressing, or impairment in instrumental activities of daily living (IADL), such as shopping, preparing meals, or managing finances. Clinical studies in older subjects usually find depressionassociated impairment in both of these domains (Alexopoulos et al 1996; Bruce et al 1994; Femia et al 2001; Steffens et al 1999), which may improve with antidepressant therapy (Chemerinski et al 2001; Oslin et al 2000). How are depression and functional disability related? This is a complex relationship that becomes more complicated when one considers that cognitive dysfunction may be seen in late-life depression. One common deficit is an impaired response to negative feedback (Elliott et al 1996, 1997, 1998; Steffens et al 2001), a finding described as a “catastrophic response to perceived failure” (Beats et al 1996). This finding has been considered to be an important link between cognitive and emotional processes (Elliott et al 1997). Output pathways from the medial orbital frontal cortex (OFC) to the striatum are thought to be critically involved in stimulus reinforcement (Bechara et al 1999, 2000). Impairment of this circuit may contribute to impaired response to negative feedback (Elliott et al 1996, 1997, 1998). If this pathway is associated with depression and disability, difficulties with ADLs could lead to frustration, decreased effort, and increased disability. Recent evidence has further implicated the medial OFC in late-life depression (Ebert and Ebmeier 1996). Smaller OFC volumes (Bremner et al 2002; Lai et al 2000), decreased OFC neuronal density (Rajkowska et al 1999), and greater OFC lesion severity (MacFall et al 2001) are associated with depression. If impairment of OFC circuits is truly involved in impaired responses to negative feedback and depression, it should also be associated with greater functional impairment. We hypothesized that smaller OFC volumes would be associated with greater BADL and IADL impairment.
Methods and Materials From the Department of Psychiatry and Behavioral Medicine at Duke University Medical Center, Durham, North Carolina. Address reprint requests to Warren D. Taylor, M.D., Duke University Medical Center, Department of Psychiatry, DUMC 3903, Durham NC 27710. Received April 12, 2002; revised June 12, 2002; accepted June 20, 2002.
© 2003 Society of Biological Psychiatry
Sample All subjects were participants in the National Institute of Mental Health–sponsored Duke University Mental Health Clinical Re0006-3223/03/$30.00 doi:10.1016/S0006-3223(02)01490-7
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search Center (MHCRC) for the Study of Depression in Later Life. Participation was restricted to subjects aged 60 years or older with a diagnosis of major depressive disorder. Exclusion criteria included 1) another major psychiatric illness; 2) current or past alcohol or drug dependence; 3) primary neurologic illness, including dementia; 4) medications or medical illness that may affect cognitive function; 5) physical disability that precludes cognitive testing; and 6) metal in the body that precludes magnetic resonance imaging (MRI). The Duke University Institutional Review Board (IRB) approved this study. The purpose of the MHCRC and its procedures were explained to each participant, and those who provided written informed consent were enrolled. Control subjects were age-matched and recruited from a listing of over 1900 community-dwelling elders from the Aging Center Subject Registry at Duke University; these individuals have expressed a willingness to participate in Duke Aging Center Research. Eligible control subjects had a nonfocal neurologic examination, no self-report of neurologic or depressive illness, and no evidence of a depression diagnosis based on the Diagnostic Interview Schedule (DIS; Robins et al 1981) portion of the Duke Depression Evaluation Schedule (DDES; Landerman et al 1989). The study’s purpose and procedures were explained; those providing written informed consent were enrolled.
Assessment Procedures At baseline, a study geriatric psychiatrist administered a standardized clinical assessment to each subject. This assessment included the Montgomery-Asberg Depression Rating Scale (Montgomery and Asberg 1979) and the Clinical Global Impression scale (Guy 1976). Cognitive status was measured with the Mini-Mental State Examination (MMSE; Folstein et al 1975). The Cumulative Illness Rating Scale (CIRS; Linn et al 1988), modified for geriatric populations (Miller et al 1992), assessed the burden of comorbid medical illnesses. A trained interviewer administered the DDES, which assesses depression with the DIS, as well as cognitive status, physical health, and social support.
Baseline Cognitive Screen Subjects were excluded if they had dementia or if a study geriatric psychiatrist suspected dementia at baseline. The majority of subjects had MMSE scores above 24; some severely depressed individuals had scores below 25. These subjects were followed through an acute 12-week treatment phase; if the scores remained below 25, they were not included in this study and were not followed longitudinally.
Measures DEPENDENT VARIABLES. The DDES includes 16 selfreported items assessing two domains of physical function. Seven items, modified from previous studies (Branch et al 1984; Katz et al 1970; Nagi 1976), address BADL self-maintenance skills: the ability to eat, dress, groom, ambulate, bathe, use the toilet, and bend to pick up an object from the floor. Nine items also modified from prior studies (Rosow and Breslau 1966)
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assess IADL performance: getting around the neighborhood, shopping for necessities, preparing meals, cleaning house, doing yardwork, keeping track of money, walking one fourth of a mile, walking up and down a flight of stairs, and caring for children. The wording of all items followed a consistent pattern (“Can you . . .”), with a standardized three-option answer format (“yes” [coded 0], “with difficulty” [coded 1], or “no” [coded 2]). Higher scores were thus indicative of greater impairment. Composite measures were constructed for each domain by summing the scores within that domain, a previous strategy used (Steffens et al 1999). The potential composite variable ranges were 0 –14 for the BADL summary variable and 0 –18 for the IADL summary variable. NON-MRI INDEPENDENT VARIABLES. The independent variables included in this analysis were age, gender, race, status as depressed or control subject, cognitive status as measured by the MMSE, and comorbid medical burden as measured by the CIRS total score.
MRI Variables MRI ACQUISITION. All subjects were screened for the presence of cardiac pacemakers, neurostimulators, metallic implants, metal in the orbit, aneurysm clips, or any other condition for which MRI was contraindicated. Subjects were imaged with a 1.5-Tesla whole-body MRI system (Signa, GE Medical Systems, Milwaukee, WI) using the standard head (volumetric) radiofrequency coil. Padding was used to immobilize the head without causing discomfort. The scanner alignment light was used to adjust the head tilt and rotation so that the axial plane lights passed across the cantho-meatal line and the sagittal lights were aligned with the center of the nose. A rapid sagittal localizer scan was acquired to confirm the alignment. A dual-echo, fast spin-echo acquisition was obtained in the axial plane for morphometry of cerebral structures. The pulse sequence parameters were repetition time ⫽ 4000 msec, echo time ⫽ 30, 135 msec, 32 KHz (⫾ 16 KHz) full imaging bandwidth, echo train length ⫽ 16, a 256 ⫻ 256 matrix, 3-mm section thickness, one excitation and a 20-cm field of view. The images were acquired in two separate acquisitions, with a 3-mm gap between sections for each acquisition. The second acquisition was offset by 3 mm from the first so that the resulting data set consisted of contiguous sections. MRI PROCESSING. Images were archived as normal procedure on magneto-optical disks in the MRI center and transferred to the Duke Neuropsychiatric Imaging Research Laboratory (NIRL) for processing on SUN workstations. Volume measurements used a NIRL-modified version of MrX Software, which was created by GE Corporate Research and Development (Schenectady, NY) and originally modified by Brigham and Women’s Hospital (Boston, MA) for image segmentation. The basic segmentation protocol is a supervised, semi-automated method that has been described previously (Byrum et al 1996; Kikinis et al 1992). Once the brain was segmented into tissue types and the nonbrain tissue stripped away through a masking procedure, total hemispheric gray and white matter volumes were calculated. The total left and right gray and white matter was defined as total brain volume.
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Next, specific regions of interest (ROIs) were assessed using tracing and connectivity functions. The medial OFC was traced bilaterally, and a mask was created and applied to the segmented brain. The neuroanatomic borders of the OFC used for this study have been previously described (Lai et al 2000). The final step was to run a summarizing program that calculated the volume within the specific OFC ROI defined by the analyst. All technicians received extensive training by experienced volumetric analysts. Reliability was established by repeated measurements on multiple MRI scans before raters were approved to process study data. Intraclass correlation coefficients were as follows: total brain ⫽ .998, left medial orbitofrontal cortex ⫽ .9, and right medial orbitofrontal cortex ⫽ .9.
Analytic Strategy For bivariate analyses, we first constructed dichotomous variables for BADL and IADL that compared groups with any impairment with groups without any impairment. These analyses included the calculation of t statistics for continuous variables and 2 statistics for dichotomous variables. The composite measures of BADL and IADL skills were further analyzed as dichotomous variables in multivariate logistic regression analyses. To obtain the simplest model, one variable was removed at a time by backward selection, based on the size of the p value. As a variable was removed, the model was refitted with the remaining variables before removing another variable (Harrell 2000). In some cases, specific variables (such as OFC volume) were forwarded to the more parsimonious model based on clinical significance.
Results The initial sample consisted of 41 depressed and 41 age-matched control subjects. One control subject was excluded because of a lack of BADL or IADL scores, leaving a total of 40 control subjects. There were significantly more women in the control group than in the depressed group, and the depressed group had a significantly lower MMSE score. There was also a trend for the control group to be older. These variables are summarized in Table 1. A total of 71 individuals reported no difficulties with BADL, whereas 10 individuals reported at least one BADL impairment. For IADL, 54 subjects had no IADL impairment, whereas 26 had at least one IADL impairment. All subjects had BADL scores; one was missing an IADL score. BADL scores ranged from 0 to 5 in depressed subjects; control subjects all had BADL scores of 0. IADL scores ranged from 0 to 15 in depressed subjects, and from 0 to 2 in control subjects. In each scale, 0 indicates no impairment, and increasing values indicate progressive impairment. Impairment was defined as having any score above 0 for either BADL or IADL. All individuals with BADL impairment were depressed subjects; when compared with
Table 1. Demographic Information: Depressed and Control Subjects Depressed Subjects (n ⫽ 41) Gender Female Male Race Caucasian Other Age Mini-Mental Score CIRS Score
Control Subjects (n ⫽ 40)
21 (51.22) 20 (48.78)
33 (82.50) 7 (17.50)
34 (82.93) 7 (17.07) 68.73 (6.98) 28.17 (2.097) 3.93 (3.028)
36 (90.00) 4 (10.00) 71.42 (6.07) 29.05 (1.037) 2.80 (2.534)
p Value .0028a
.353a .068b .020b .735b
Data for gender and race are expressed as n(%); all other data presented as mean (SD). CIRS, Cumulative Illness Rating Scale. a p value for 2 test. b p value for t test.
subjects without BADL impairment, they were also more likely to be African American, have lower baseline MMSE scores, and have smaller total brain and OFC volumes. There were no significant differences in age, gender, or CIRS score (see Table 2). When compared with subjects without IADL impairment, those with IADL impairment were more likely to be depressed subjects, have greater CIRS scores, and smaller OFC volumes. There was also a trend toward smaller total brain volumes, although this did not reach statistical significance. There were no significant differences between the groups in regard to age, gender, race, or MMSE score (see Table 2). Table 3 presents the results for the logistic regression models for BADL and IADL. Initial models (listed as model 1) included demographic variables, subject status, and total brain and OFC volumes. More parsimonious models (listed as model 2) then examined OFC volume while excluding nonsignificant variables from the initial model. In an exploratory model (not shown), total brain volume was carried forward to the parsimonious models, despite the fact that it was not significant in the initial models. In this model, total OFC volume was not significantly associated with IADL impairment (odds ratio [OR] ⫽ 1.062, confidence interval [CI] ⫽ .829-1.36) but remained significantly associated with BADL impairment (OR ⫽ 2.831, CI ⫽ 1.235-6.490). For the final models (Table 3), total OFC volume was significantly associated with BADL and IADL impairment after controlling for other variables. For BADL, lower MMSE score continued to be significantly associated with impairment. For IADL, status as a depressed subject continued to be significantly associated with impairment. We tested other models (not shown) examining left and right hemispheric OFC volumes. Total brain hemispheric volume continued to be statistically insignificant on the
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Table 2. Demographic, Clinical, and Magnetic Resonance Imaging Characteristics of the Sample Based on Presence of Any Impairment in Basic Activities of Daily Living (BADL) or Instrumental Activities of Daily Living (IADL)
Variable Age (Mean) Gender (% Female) Race (% Caucasian) Status (% Depressed Subject) MMSE Score (Mean) CIRS Score (Mean) Left Brain Volume Right Brain Volume Total Brain Volume Left OFC Volume (Mean) Right OFC Volume (Mean) Total OFC Volume (Mean)
No BADL Impairment (n ⫽ 71)
Any BADL Impairment (n ⫽ 10)
69.94 (6.41) 64.79 91.55 43.66 28.87 (1.25) 3.20 (2.83) 446.79 (56.01) 447.7 (55.84) 1024.90 (125.43) 6.54 (1.42) 6.94 (1.57) 13.48 (2.68)
70.90 (8.50) 80 50 100 26.70 (3.02) 4.60 (2.72) 398.41 (38.43) 403.61 (40.04) 930.75 (92.25) 4.84 (1.31) 5.43 (1.09) 10.27 (2.15)
p Valuea
No IADL Impairment (n ⫽ 54)
Any IADL Impairment (n ⫽ 26)
p Valuea
.6728 .4829 .0032b .001b .0498b .144 .010b .0185b .0251b .0006b .0042b .005b
69.80 (6.54) 64.81 88.89 35.19 28.91 (1.09) 2.74 (2.44) 449.86 (52.23) 450.58 (52.35) 1032.2 (118.63) 6.63 (1.41) 7.07 (1.56) 13.70 (2.61)
70.81 (6.99) 69.23 80.77 80.77 28.19 (2.28) 4.31 (2.77) 425.51 (59.96) 428.48 (59.15) 981.57 (130.53) 5.72 (1.56) 6.13 (1.51) 11.85 (2.93)
.5282 .6956 .3242 .0001b .1393 .0118b .067 .094 .0876 .011b .0127b .0055b
All data in parentheses are SD. All brain and OFC volumes measured in mL. MMSE, Mini Mental State Examination; CIRS, Cumulative Illness Rating Scale; OFC, orbital frontal cortex. a t test for continuous variables; 2 test for dichotomous variables. b Significant at ␣ ⫽ .05.
initial models. In the parsimonious models, MMSE score and depressed subject status continued to be significantly associated with respective BADL and IADL impairment. The left OFC volume was further associated with both BADL (OR ⫽ 6.062, CI ⫽ 1.877-19.572) and IADL impairment (OR ⫽ 1.495, CI ⫽ 1.027-2.178), whereas the right OFC volume was only significantly associated with BADL impairment (OR ⫽ 2.625, CI ⫽ 1.234-6.079).
Discussion We observed that medial orbitofrontal gyri volume was associated with impairment in both BADL and IADL, independent of the effects of age, gender, depression, and medical illness burden. Moreover, this finding appears to be independent of total brain volume. Although other investigators have examined the effect of MRI hyperintensities on functional status (Cahn et al 1996; Samuelsson et al 1996; Steffens et al 2002), to our knowledge this is
the first study to associate ADL impairment with smaller regional frontal volumes. As demonstrated in previous studies (Armenian et al 1998; Bruce et al 1994; Lenze et al 2001; Sato et al 1999), we also found an association between depression and functional disability. Given that this is a cross-sectional study, we must only cautiously make conclusions about causality. Hypothetically, OFC volume reductions represent impairment in OFC function, which then contributes to increased disability; an alternate hypothesis to our findings is that increased disability and OFC volume reductions develop from a mutual cause. When compared with healthy control subjects, depressed elders exhibit smaller OFC volumes (Bremner et al 2002; Lai et al 2000), reduced glial density and smaller neuronal sizes (Rajkowska et al 1999), and greater OFC lesion severity (MacFall et al 2001). These findings may potentially be representative of more global neurodegenerative or cerebrovascular processes that result in disability through other mechanisms. Our finding that
Table 3. Logistic Regression Models for Basic Activities of Daily Living (BADL) and Instrumental Activities of Daily Living (IADL), Odds Ratio with 95% Confidence Intervals and Indication of Level of Significance Variable Age Gender Subject Status Race MMSE Score CIRS Score Total Brain Volume Total OFC Volume
BADL Model 1 1.090 (.884 –1.343) .518 (.031– 8.543) .001 (.001–999.99)a 2.610 (.659 –10.330) 1.712 (.991–2.958) 1.011 (.715–1.428) 1.000 (.986 –1.014) 1.724 (.661– 4.499)
BADL Model 2
1.816 (1.202–2.742)b
2.529 (1.302– 4.912)b
IADL Model 1 .957 (.868 –1.056) .454 (.090 –2.298) .075 (.015–.365)b .743 (.323–1.707) 1.149 (.767–1.722) .806 (.626 –1.040) 1.003 (.996 –1.010) 1.088 (.838 –1.413)
Data are presented as odds ratio (95% confidence interval). Total brain and OFC volumes measured in mL. MMSE, Mini Mental State Examination; CIRS, Cumulative Illness Rating Scale; OFC, medial orbital frontal cortex. a All those with BADL impairment were depressed subjects. b Significant at ␣ ⫽ .05.
IADL Model 2
.149 (.047–.472)b
1.244 (1.014 –1.525)b
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total brain volume was not associated with disability speaks against this possibility. How then could impairment in OFC function contribute to disability? One possibility is that the OFC predisposes individuals to depression, which is itself associated with disability. Another possibility is that the OFC may be independently associated with both depression and disability. The medial OFC is involved in stimulus reinforcement and emotion modulation. Damage to the OFC impairs the learning and reversal of stimulus–reinforcement associations (Rolls 2000); in other words, it prevents the correction of previous behavioral responses, even when the responses are no longer appropriate. Clinically, this may appear as an impaired response to negative feedback (Elliott et al 1996, 1997, 1998). Hypothetically an ADL failure may result in a strong negative emotional response that causes frustration and discourages the patient from further effort, thus contributing toward greater functional impairment. There are some limitations to our study. The dependent BADL and IADL variables were obtained from subject self-report; in depressed subjects, these results may not represent true impairment, as depression may influence the perception of functional impairment. Another limitation is our method of screening for dementia. We excluded subjects who failed to have a MMSE score of 24 or greater following acute antidepressant therapy. Although the majority of the sample had baseline scores well over this value, we cannot definitively state that we did not include subjects with early dementia. The small number of subjects with BADL impairment is further limitation. Although we found a robust relationship between smaller OFC volumes and BADL impairment, this association must be viewed cautiously. We also found that a higher proportion of African Americans exhibited BADL impairment, although race was not a significant predictor of disability in the final models. Although this may be a spurious finding given the small number of subjects, other possible explanations exist, such as reporting differences or problems with access to medical care. Financial resources may also be important, as at least one group has found that income is an independent predictor of disability (Palmore and Burchett 1997). The small sample size may also have influenced differences in the demographics between our depressed and control groups. There were significantly more women in the control than in the depressed group; this difference probably does not significantly influence the study, as gender was not associated with disability in later models. Depressed subjects also exhibited a significantly lower MMSE score than control subjects. This may have influenced our findings regarding BADL impairment, as lower MMSE was associated with BADL impairment, and all
individuals with BADL impairment were in the depressed group. Although this is a confounder, the statistically significant MMSE difference between the two groups (28 for depressed subjects, 29 for control subjects) is not generally considered clinically significant. This study demonstrates that smaller OFC volumes are associated with greater BADL and IADL impairment. Longitudinal studies will be needed to help determine causal relationships. Other studies will also be needed to examine how OFC volume abnormalities and MRI hyperintensities may differentially affect disability. Such research will help clarify the complex relationship between depression, disability, and MRI findings. Supported by National Institute of Mental Health Grants P50 MH60451 and R01 MH54846. The authors thank Chris Byrum, M.D., Ph.D. and James MacFall, Ph.D. for their assistance in designing the MR imaging protocol and help with the image processing procedures. We also thank Denise L. Fetzer, M.A. for laboratory assistance.
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