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Brief Report   |    
Hippocampal and Anterior Cingulate Activation Deficits in Patients With Geriatric Depression
Jose M. de Asis, M.D.; Emily Stern, M.D.; George S. Alexopoulos, M.D.; Hong Pan, Ph.D.; Wilfred Van Gorp, Ph.D.; Hilary Blumberg, M.D.; Balu Kalayam, M.D.; David Eidelberg, M.D.; Dimitris Kiosses, Ph.D.; David A. Silbersweig, M.D.
Am J Psychiatry 2001;158:1321-1323. doi:10.1176/appi.ajp.158.8.1321
Abstract

OBJECTIVE: The authors assessed frontotemporal function in patients with geriatric depression, a debilitating and increasingly prevalent disorder that has not been examined with brain activation paradigms. METHOD: Six depressed elderly patients and five healthy comparison subjects underwent high-sensitivity [15O]H2O positron emission tomography scans during a paced word generation task and a resting condition. RESULTS: Bilateral activation deficits were noted in the dorsal anterior cingulate gyrus and hippocampus of the depressed geriatric patients relative to the comparison subjects. Patients had memory deficits that correlated with lower hippocampal activity during both rest and activation. CONCLUSIONS: These initial findings suggest that hippocampal and dorsal anterior cingulate hypoactivation may constitute contributing neural substrates of geriatric depression. They also suggest that hippocampal dysfunction is related to the memory dysfunction characteristic of this disorder.

Abstract Teaser
Figures in this Article

Memory and executive functions are frequently impaired in depressed elderly patients (1). These cognitive impairments influence the course of geriatric depression (2, 3) and may be associated with its pathogenesis (1).

Resting neuroimaging studies of younger depressed patients have shown left-sided or bilateral hypoactivity in the dorsolateral, inferior, and medial frontal regions as well as the temporal limbic regions, particularly the amygdala (47). Resting state hypoactivity in the medial prefrontal cortex has been correlated with cognitive impairment (8). Blunted left cingulate activation has been observed in younger depressed patients performing a response interference task (9).

Geriatric depression often occurs in the context of age-related brain changes that contribute to its pathogenesis (10). Therefore, findings in younger adults may not necessarily generalize to the elderly. Functional neuroimaging studies in geriatric depression have reported lower levels of global blood flow, orbitofrontal and inferior temporal regional blood flow decreased (11, 12), and abnormalities in posterior association cortices (13). These valuable findings were noted only under resting conditions and yielded limited information on the integrity of neural systems that serve executive functions and memory.

On the basis of clinical findings from elderly depressive subjects and neuroimaging findings from younger adults, we used positron emission tomography (PET) during an activation paradigm (involving a word generation task) in addition to resting state measurements to test the hypothesis that prefrontal and mesial temporal brain malfunction exists in patients with geriatric depression.

The patient group consisted of six right-handed older subjects (four men and two women; mean age=70.7 years, range=59–82) with DSM-IV major depression, a 24-item Hamilton Depression Rating Scale (14) score greater than 30, and a Mini-Mental State Examination score greater than 24 (nondemented). The comparison group consisted of five right-handed subjects (three men and two women; mean age=67.6 years, range=62–78). Two patients were drug-free, while one patient each was taking bupropion, venlafaxine, lithium, and risperidone. Exclusion criteria were comorbid axis I diagnosis and axis III diagnosis of medical or neurologic conditions. All subjects signed informed consent.

Mattis Dementia Rating Scale data were obtained from five of six patients and four of five comparison subjects. Differences between patients and comparison groups on neuropsychological subtest scores were assessed with one-tailed t tests. A repeated measure one-way analysis of variance was performed to assess the correlation in patients between specific subtest scores and adjusted regional cerebral blood flow (rCBF) during the rest condition as well as the correlation between subtest scores and activation changes in adjusted rCBF for the brain regions with significant between-group activation differences.

A GE Advance PET scanner in three-dimensional mode with interplane septa retracted was used. A high sensitivity [15O]H2O (8 mCi) slow bolus rCBF imaging technique (15) was employed. Cognitive tasks were performed for 60 seconds, starting 10 seconds before the rise in brain time-activity curve. A 90-second acquisition time was used, which reflects the pattern of brain activity during radiotracer deposition. Each subject had 12 scans in one session, four scans in each of the three conditions. The activation condition was a word generation task in response to a computerized auditory presentation of letters at a rate of one every 5 seconds. The control condition required the subjects to repeat letters presented in the same manner as the activation condition. The third condition was a rest condition. The order of scans was counterbalanced within subjects to counteract time and order effects. The scans were performed with eyes closed, lights dimmed, and low levels of ambient noise. Response latency and accuracy were recorded on digital audio tape.

Image analysis with statistical parametric mapping (SPM 96) (16) was performed on a Sun SPARC Ultra 2 workstation (Sun Microsystems, Mountain View, Calif.). After realignment of images, stereotactic transformation to Talairach space, and smoothing with a 15-mm gaussian filter, group and condition effects were estimated with multiple linear regression according to the general linear model at each voxel, with global flow considered as a potential confounding variable. A contrast was defined to identify areas of relatively lower rCBF in geriatric depressed patients versus comparison subjects, in the activation versus control state, and a z test was performed with 114 residual degrees of freedom over 255 resolution elements. A correlation analysis was also performed to assess the relationship between resting and activation rCBF measures and neuropsychological scores. Probability was estimated according to the theory of random fields (16). For the activation contrast, all SPM maxima for which z>2.33 (representing a significance level of p<0.01, one-tailed, uncorrected) are reported.

Available neuropsychological data (Mattis Dementia Rating Scale scores) from five of the patients and four of the comparison subjects showed that the patients performed significantly worse on the subtests of memory (one-tailed t test, without assumption of equal variance: t=2.92, df=4, p<0.03), initiation/perseveration (t=2.36, df=4, p<0.04), and conceptualization (verbal and nonverbal similarities) (t=2.11, df=5.21, p<0.05). A nonsignificant difference was noted for the attention subtest scores (t=1.95, df=4.52, p<0.06), and no significant difference was noted for scores on the construction subtest (t=0.88, df=4, p<0.21). Reaction time (t=0.52, df=7, p=0.62) and accuracy (t=–1.54, df=7, p<0.22) in scanning task performance in patients did not differ significantly from those of comparison subjects.

For the contrast that demonstrated lower activity in the depressed elderly group relative to the comparison group during activation (versus the control state), significantly lower rCBF (thresholded at p<0.01, uncorrected) was noted in frontotemporal regions: left anterior cingulate gyrus (x, y, z=–16, 0, 40) (z=3.23, p<0.001), right anterior cingulate gyrus (14, –2, 40) (z=3.43, p<0.001), left hippocampus (–32, –30, –10) (z=2.73, p<0.01), right hippocampus (34, –32, –4) (z=2.93, p<0.01), left insula (–34, –4, 18) (z=3.67, p<0.001), and the right inferior temporal gyrus (Brodmann’s area 20; 66, –1, –28) (z=3.86, p<0.001) (F1). Inspection of mean adjusted rCBF levels in the cingulate and hippocampal regions indicated a double dissociation, with increasing activity in comparison subjects and decreasing activity in patients.

For patients, considering the hippocampal and anterior cingulate maxima listed above, significant correlations were noted only between memory scores and left hippocampal resting adjusted rCBF (r=0.94, df=3, p<0.05), right hippocampal resting rCBF (r=0.91, df=3, p<0.05), and left hippocampal activation rCBF change (r=0.80, df=3, p<0.05).

These data provide preliminary evidence that geriatric depression is associated with bilateral cingulate and hippocampal hypoactivity upon challenge with a word generation task. Given the neurobehavioral functions ascribed to these regions, it is plausible that hypoactivity of the dorsal cingulate is associated with executive and psychomotor symptoms (17) often prominent in geriatric depression, while bilateral hippocampal hypoactivity is associated with memory impairment (18) commonly observed in geriatric depression. The patients studied did indeed have memory and initiation/perseveration deficits relative to the comparison subjects. The available memory and initiation/perseveration data from the patients studied help to make additional, more specific statements concerning possible associations between the aforementioned neural and neuropsychological findings. In particular, they implicate resting and activation hippocampal dysfunction (especially on the left) in patients’ memory impairment.

These preliminary findings are limited by the relatively small study group size and potential medication effects in four of the patient subjects. However, the within-subject medication effects were reduced by having the subjects perform the activation and control tasks under identical pharmacological conditions, and the effect across subjects was reduced by partialing out subject-specific effects and by the fact that medicated patients were not all receiving the same class of medication. Hippocampal atrophy has been noted in recurrent major depression (19). While such structural changes may relate to the current findings, it is notable that the mean adjusted rCBF levels at the hippocampal maxima were as high or higher in patients than they were in comparison subjects. Nevertheless, further studies of larger numbers of unmedicated subjects, with hippocampal volume measures, will be important to assess the generalizability of these findings.

Presented in part at the 54th annual meeting of the Society of Biological Psychiatry, Washington, D.C., May 13–16, 1999, and the fifth International Conference on Human Brain Mapping, Düsseldorf, Germany, June 22–26, 1999. Received Oct. 25, 1999; revisions received Nov. 1, 2000, and Feb. 7, 2001; accepted Feb. 19, 2001. From the Department of Psychiatry, Weill Medical College of Cornell University; and the Department of Neurology, North Shore University Hospital, Manhassett, N.Y. Address reprint requests to Dr. Silbersweig, Functional Neuroimaging Laboratory, Department of Psychiatry, Box 140, Weill Medical College of Cornell University, 525 East 68th St., New York, N.Y. 10021; dasilber@med.cornell.edu (e-mail). Supported by the New York Community Trust’s DeWitt-Wallace fund; NIMH grants MH-42819, MH-51842, MH-49762, and MH-19132; and the Sanchez Foundation. The authors thank the subjects for their participation and Drs. Vijay Dhawan and Abdelfatihe Belakhlef and the North Shore University Hospital PET team for technical assistance.

 
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Figure 1.

Bilateral Hippocampal and Anterior Cingulate Activation Deficits in Patients With Geriatric Depression Relative to Comparison Subjects During a Word Generation Taska

aPET statistical maps, superimposed on a structural T1-weighted MRI template, show significant differences in the hippocampus (z>2.33, df=114, p<0.01) and anterior cingulate gyrus (z>3.10, df=114, p<0.001).

Cummings JL: The neuroanatomy of depression. J Clin Psychiatry 1993; 54(suppl):14-20
 
Kalayam B, Alexopoulos GS: Prefrontal dysfunction and treatment response in geriatric depression. Arch Gen Psychiatry  1999; 56:713-718
[PubMed]
[CrossRef]
 
Alexopoulos GS, Meyers BS, Young RC, Kalayam B, Kakuma T, Gabrielle M, Sirey JA, Hull: Executive dysfunction and long-term outcomes of geriatric depression. Arch Gen Psychiatry  2000; 57:285-290
[PubMed]
[CrossRef]
 
Bench CJ, Friston KJ, Brown RG, Scott LC, Frackowiak RS, Dolan RJ: The anatomy of melancholia—focal abnormalities of cerebral blood flow in major depression. Psychol Med  1992; 22:607-615
[PubMed]
[CrossRef]
 
Drevets WC, Price JL, Simpson JR Jr, Todd RD, Reich T, Vannier M, Raichle ME: Subgenual prefrontal cortex abnormalities in mood disorders. Nature  1997; 386:824-827
[PubMed]
[CrossRef]
 
Drevets WC, Videen TO, Price JL, Preskorn SH, Carmichael ST, Raichle ME: A functional anatomical study of unipolar depression. Neuroscience 1992; 12:3628-  3641
 
Mayberg HS, Lewis PJ, Regenold W, Wagner HN Jr: Paralimbic hypoperfusion in unipolar depression. J Nucl Med  1994; 35:929-934
[PubMed]
 
Bench CJ, Friston KJ, Brown RG, Frackowiak RS, Dolan RJ: Regional cerebral blood flow in depression measured by positron emission tomography: the relationship with clinical dimensions. Psychol Med  1993; 23:579-590
[PubMed]
[CrossRef]
 
George MS, Ketter TA, Parekh PI, Rosinsky N, Ring HA, Pazzaglia PJ, Marangell LB, Callahan AM, Post RM: Blunted left cingulate activation in mood disorder subjects during a response interference task (the Stroop). J Neuropsychiatry Clin Neurosci  1997; 9:55-63
[PubMed]
 
Lebowitz BD, Pearson JL, Schneider LS, Reynolds CF, Alexopoulos GS, Bruce ML, Conwell Y, Katz IR, Meyers BS, Morrison MF, Mossey MF, Niederehe G, Parmelee P: Diagnosis and treatment of depression in late life: consensus statement update. JAMA 1997; 278:1186-  1190
 
Lesser IM, Mena I, Boone KB, Miller BL, Mehringer CM, Wohl M: Reduction of cerebral blood flow in older depressed patients. Arch Gen Psychiatry  1994; 51:677-686
[PubMed]
 
Kumar A, Newberg A, Alavi A, Berlin J, Smith R, Reivich M: Regional cerebral glucose metabolism in late-life depression and Alzheimer disease: a preliminary positron emission tomography study. Proc Natl Acad Sci USA 1993; 90:7019-  7023
 
Sackeim HA, Prohovnik I, Moeller JR, Brown RP, Apter S, Prudic J, Devanand DP, Mukherjee S: Regional cerebral blood flow in mood disorders, I: comparison of major depressives and normal controls at rest. Arch Gen Psychiatry  1990; 47:60-70
[PubMed]
 
Hamilton M: A rating scale for depression. J Neurol Neurosurg Psychiatry  1960; 23:56-62
[PubMed]
[CrossRef]
 
Silbersweig DA, Stern E, Frith CD, Cahill C, Schnorr L, Grootoonk S, Spinks T, Clark J, Frackowiak R, Jones T: Detection of thirty-second cognitive activations in single subjects with positron emission tomography: a new low-dose H2(15)O regional cerebral blood flow three-dimensional imaging technique. J Cereb Blood Flow Metab  1993; 13:617-629
[PubMed]
[CrossRef]
 
Friston KJ, Holmes AP, Worsley KJ, Poline JP, Frith CD, Frackowiak RSJ: Statistical parametric maps in functional imaging: a general linear approach. Hum Brain Mapp  1995; 2:189-210
 
Devinsky O, Morrell MJ, Vogt BA: Contributions of anterior cingulate cortex to behaviour. Brain  1995; 118:279-306
[PubMed]
[CrossRef]
 
Squire LR: Memory systems. C R Acad Sci III  1998; 321:153-156
[PubMed]
 
Sheline YI, Wang PW, Gado MH, Csernansky JG, Vannier MW: Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci USA 1996; 93:3908-  3913
 

Figure 1.

Bilateral Hippocampal and Anterior Cingulate Activation Deficits in Patients With Geriatric Depression Relative to Comparison Subjects During a Word Generation Taska

aPET statistical maps, superimposed on a structural T1-weighted MRI template, show significant differences in the hippocampus (z>2.33, df=114, p<0.01) and anterior cingulate gyrus (z>3.10, df=114, p<0.001).

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References

Cummings JL: The neuroanatomy of depression. J Clin Psychiatry 1993; 54(suppl):14-20
 
Kalayam B, Alexopoulos GS: Prefrontal dysfunction and treatment response in geriatric depression. Arch Gen Psychiatry  1999; 56:713-718
[PubMed]
[CrossRef]
 
Alexopoulos GS, Meyers BS, Young RC, Kalayam B, Kakuma T, Gabrielle M, Sirey JA, Hull: Executive dysfunction and long-term outcomes of geriatric depression. Arch Gen Psychiatry  2000; 57:285-290
[PubMed]
[CrossRef]
 
Bench CJ, Friston KJ, Brown RG, Scott LC, Frackowiak RS, Dolan RJ: The anatomy of melancholia—focal abnormalities of cerebral blood flow in major depression. Psychol Med  1992; 22:607-615
[PubMed]
[CrossRef]
 
Drevets WC, Price JL, Simpson JR Jr, Todd RD, Reich T, Vannier M, Raichle ME: Subgenual prefrontal cortex abnormalities in mood disorders. Nature  1997; 386:824-827
[PubMed]
[CrossRef]
 
Drevets WC, Videen TO, Price JL, Preskorn SH, Carmichael ST, Raichle ME: A functional anatomical study of unipolar depression. Neuroscience 1992; 12:3628-  3641
 
Mayberg HS, Lewis PJ, Regenold W, Wagner HN Jr: Paralimbic hypoperfusion in unipolar depression. J Nucl Med  1994; 35:929-934
[PubMed]
 
Bench CJ, Friston KJ, Brown RG, Frackowiak RS, Dolan RJ: Regional cerebral blood flow in depression measured by positron emission tomography: the relationship with clinical dimensions. Psychol Med  1993; 23:579-590
[PubMed]
[CrossRef]
 
George MS, Ketter TA, Parekh PI, Rosinsky N, Ring HA, Pazzaglia PJ, Marangell LB, Callahan AM, Post RM: Blunted left cingulate activation in mood disorder subjects during a response interference task (the Stroop). J Neuropsychiatry Clin Neurosci  1997; 9:55-63
[PubMed]
 
Lebowitz BD, Pearson JL, Schneider LS, Reynolds CF, Alexopoulos GS, Bruce ML, Conwell Y, Katz IR, Meyers BS, Morrison MF, Mossey MF, Niederehe G, Parmelee P: Diagnosis and treatment of depression in late life: consensus statement update. JAMA 1997; 278:1186-  1190
 
Lesser IM, Mena I, Boone KB, Miller BL, Mehringer CM, Wohl M: Reduction of cerebral blood flow in older depressed patients. Arch Gen Psychiatry  1994; 51:677-686
[PubMed]
 
Kumar A, Newberg A, Alavi A, Berlin J, Smith R, Reivich M: Regional cerebral glucose metabolism in late-life depression and Alzheimer disease: a preliminary positron emission tomography study. Proc Natl Acad Sci USA 1993; 90:7019-  7023
 
Sackeim HA, Prohovnik I, Moeller JR, Brown RP, Apter S, Prudic J, Devanand DP, Mukherjee S: Regional cerebral blood flow in mood disorders, I: comparison of major depressives and normal controls at rest. Arch Gen Psychiatry  1990; 47:60-70
[PubMed]
 
Hamilton M: A rating scale for depression. J Neurol Neurosurg Psychiatry  1960; 23:56-62
[PubMed]
[CrossRef]
 
Silbersweig DA, Stern E, Frith CD, Cahill C, Schnorr L, Grootoonk S, Spinks T, Clark J, Frackowiak R, Jones T: Detection of thirty-second cognitive activations in single subjects with positron emission tomography: a new low-dose H2(15)O regional cerebral blood flow three-dimensional imaging technique. J Cereb Blood Flow Metab  1993; 13:617-629
[PubMed]
[CrossRef]
 
Friston KJ, Holmes AP, Worsley KJ, Poline JP, Frith CD, Frackowiak RSJ: Statistical parametric maps in functional imaging: a general linear approach. Hum Brain Mapp  1995; 2:189-210
 
Devinsky O, Morrell MJ, Vogt BA: Contributions of anterior cingulate cortex to behaviour. Brain  1995; 118:279-306
[PubMed]
[CrossRef]
 
Squire LR: Memory systems. C R Acad Sci III  1998; 321:153-156
[PubMed]
 
Sheline YI, Wang PW, Gado MH, Csernansky JG, Vannier MW: Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci USA 1996; 93:3908-  3913
 
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