NUCLEAR NEUROLOGY Hypofrontality and Negative Symptoms in Major Depressive Disorder Igor I. Galynker, Jun Cai, Fukiat Ongseng, Howard Finestone, Eamon Dutta and Dragos Serseni Departments of Psvchiatry and Radiology, Beth Israel Medical Center, Albert Einstein College of Medicine, New York, New York MOD patients has been reported to be either reduced (5,7-9) or The purpose of the current study was to compare regional cerebral not different relative to control values (10,17). Lower values of blood flow (rCBF) in patients with major depressive disorder (MOD) rCBF in MOD patients than in control subjects have been to that of healthy subjects and to examine the relationship between observed in the left cerebral hemisphere (18), left dorsolateral rCBF, depressive symptoms (DS) and negative symptoms (NS) in prefrontal cortex (2,3,12,19), left prefrontal cortex (20), para- these patients. Methods: Eleven psychiatric inpatients with diag nosed (MOD) and 15 normal control subjects were administered the limbic regions (19,21), bilateral temporal regions (20) and scale for the assessment of negative symptoms (SANS) and the anterior parietal regions (9). The most consistent findings modified Hamilton rating scale for depression with items descriptive involved differences in the left prefrontal rCBF. Nevetheless, of NS excluded (HRSD-DS). Each patient underwent a SPECT scan several reports showed no abnormalities or higher values of using ""Tc-HMPAO at rest. Cortical and subcortical regions of rCBF or rCMRglc (10,17,22). interest (ROIs) were symmetrically defined in each hemisphere. The inconsistency in previous research findings could be Cortical-to-cerebellar perfusion ratios were established quantita related to several factors, including demographic consider tively using ADAC software. Results: Subjects in the MOD group ations, e.g., age and gender (23-25), medication status [specif had significantly lower rCBF in the frontal cortex and cinglulate gyrus (MANOVA, p = 0.038) due to differences in dorsolateral prefrontal ically neuroleptic status (26, 27)] and other methodological and cortex bilaterally (right F = 7.69, p = 0.01; left F = 8.41, p = 0.01) statistical considerations (9). Since several reports indicate that in the right orbitofrontal cortex (F = 6.79, p = 0.02) and in the rCBF abnormalities may be symptom-specific and not disease- cingulate gyrus (F = 5.34, p = 0.03). The MOD group also had lower related (12,28), one major factor that can influence rCBF in rCBF in the posterior cortical structures (MANOVA, p = 0.072), MOD is heterogeneity of depressive symptomatology (29). We which was due to decreased perfusion in the right parietal cortex were particularly interested in the role of negative symptoms (F = 7.54, p = 0.01). There were negative correlations between the (NS) in MOD (30-32) and their relationship to rCBF. Athough SANS total score and rCBF in both the left dorsolateral prefrontal cortex (Pearson's correlation coefficient r = .-67, p < 0.05) and the NS such as avolition, amotivation, poverty of speech and left anterior temporal cortex (r = -0.71, p < 0.01) in MOD patients. thought and blunted affect have been recently measured in Additionally, there were positive correlations between HRSD scores MOD, their association with rCBF abnormalities has not been and rCBF in the left anterior temporal (r = 0.71, p < 0.01), left investigated (30). We expected NS to be associated with dorsolateral prefrontal (r = 0.70, p < 0.01), right frontal (r = 0.82, p < hypofrontality in MOD as has been shown for schizophrenia 0.01) and right posterior temporal (r = 0.74, p < 0.01) cortices. (33,34) and Alzheimer's disease (dementia) (35,36). Cerebral blood flow was not correlated with either mini-mental state The purpose of this study was to replicate the findings of examination scores or age. Conclusion: This preliminary study hypofrontality in hospitalized MOD patients and to assess the replicates the finding of hypofrontality in MOD and indicates that relationship between rCBF abnormalities, NS and other symp decreased perfusion is associated specifically with negative symp toms of depression. tom severity. These results support the hypothesis that, in MOD, negative symptoms and symptoms of depression are distinct phe nomena and underscore the importance of negative symptom evaluation in neuroimaging studies of MOD and other disorders. MATERIALS AND METHODS Key Words: technetium-99m-HMPAO SPECT; regional cerebral Subjects blood flow; depression; negative symptoms; dorsolateral prefrontal Subjects included 11 right-handed patients (7 women and 4 men) cortex; temporal cortex hospitalized in the acute adult psychiatric unit and recruited from a J NucíMed 1998; 39:608-612 sample of 23 patients participating in a study of NS in depression (JO). All subjects gave informed consent and underwent complete physical, neurological and psychiatric evaluations and met \Jver the last 15 yr, pathophysiological investigations of DSM-1V criteria for unipolar MOD. All subjects had a complete depression have increasingly made use of functional brain blood count, routine chemistries and thyroid function tests within imaging technologies, specifically, PET and SPECT. Several normal limits with negative RPR results. Exclusion criteria in studies have measured regional cerebral glucose metabolism cluded previous history of head trauma resulting in a loss of (rCMRglc) and regional cerebral blood flow (rCBF) in patients consciousness, history of seizures or alcohol/substance abuse over with major depressive disorder (MOD) relative to control the 6-mo period preceding hospitalization, ongoing medical illness subjects (1-11), patients with different types of depression (12,13) and patients with other affective disorders (14-17). and abnormal thyroid functions and RPR test results. At the time of assessment, all 11 of the MOD subjects were receiving psycho- The studies comparing MOD patients and control subjects tropic medications, specifically antidepressants and benzodiaz- yielded inconsistent results both when patients were studied at rest and under activation conditions (2-11). Global CBF in epines. MOD patients were compared to 15 normal control subjects (6 men and 9 women; 14 right-handed, 1 left-handed) recruited from full-time hospital staff. Exclusion criteria for the control Received Nov. 19, 1996; revision accepted Jul. 3. 1997. For correspondence or reprints contact: Igor I. Galynker, MD, PhD, 6 Karpas, Beth group were the same as for the MOD subjects, but also included Israel Medical Center, 1st Ave. at 16th St., New York, NY 10003. history of psychiatric illness requiring psychotropic medications. 608 THE JOURNALOFNUCLEARMEDICINE•Vol. 39 •No. 4 •April 1998 Testing Procedures TABLE 1 A single rater tested all the MOD subjects and administered the Age, Sex and Medication Regimens of 11 Patients with Major 17-item Hamilton rating scale for depression (HRSD) (37), the Depressive Disorder scale for assessment of negative symptoms (SANS) (38), the positive and negative symptom scale (PANSS) (39), and the mini- Patient no.1234567891011Age(yr)5547414055404847485434SexFMFFMFFMMFFMédicationNoneSertaline mental state examination (MMSE) (40) to them within the first 3 days of their hospitalization. We derived a corrected Hamilton score (HRSD-DS) that excluded items #7, 8 and 13 in an attempt to index mg/dayVenlafaxin50 DS severity independent of negative symptom severity as described diphenylhydramine50150 mg/day, previously (41). Items #7 (work/interest), #8 (psychomotor retarda mg/dayFluoxetine tion) and #13 (energy) were combined in the HRSD-negative symp mg/dayFluoxetine40 mg/dayFluoxetine20 mg/day; lorazepam 3 tom (HRSD-NS) scale (30,41). Psychometric ratings of the control mg/dayFluoxetine20 mg/day, lorazepam 1 subjects were not performed; we assumed that the control subjects mg/dayParoxetine20 mg/day; clonazepam 1 would test in the normal range as was reported previously (30). mg/day;Nortryptilline20 mg/dayVenlafaxine150 Scanning Procedures mg/dayFluoxetine150 The subjects were scanned within 48 hr of psychiatric ratings 20 mg/day; lorazepam 2 mg/day administration (medications unchanged during that time) using a single-head ADAC (ADAC Laboratories, Milpitas, ÇA)SPECT camera with a low-energy, high-resolution collimator (FWHM 7.5 The results of MANOVA analyses of ROI-to-cerebellum mm at 10 cm depth). They received 740 MBq 99mTc-HMPAO rCBF ratios between MDD and control groups are shown in (Ceretec, Amersham, Ltd., UK) intravenously while sitting with Table 3. The multivariate analyses of rCBF in the frontal cortex their eyes open in a dimly lit room. Acquisition began 20-60 min were significant (p = 0.038). Compared to the control subjects, postinjection and lasted 45 min during a 360°rotation of the MDD patients had lower relative perfusion in the right orbito- gamma camera in a 128 X 128 matrix. The data were prefiltered frontal (p < 0.02) and dorsolateral prefrontal cortex (p < 0.01 ) with a Gaussian filter (cutoff frequency 0.42, filter order 18). bilaterally and in the cingulate gyrus 2 (p < 0.05). The multivariate analyses of rCBF in the posterior cortical structures Data Analysis indicated that perfusion differences between MDD patients and Reconstructions were done in the transaxial, coronal and sagittal control subjects approached statistical significance (p = 0.072). planes. The transaxial plane was reconstructed parallel to the Univariate analyses of variance revealed that this finding was canthomeatal line. The SPECT data,