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Abstract

OBJECTIVE: Depression is commonly associated with frontal hypometabolic activity accompanied by hypermetabolism in certain limbic regions. It is unclear whether successful antidepressant treatments reverse these abnormalities or create new resting levels of metabolism. The aim of the present study was to assess the effects of successful paroxetine treatment on regional glucose metabolism in patients with major depression. METHOD: Positron emission tomography with [18F]fluorodeoxyglucose was performed on 13 male patients before and after 6 weeks of paroxetine therapy. Resting state scans were also acquired under similar conditions in 24 healthy male subjects for comparison. RESULTS: After successful paroxetine therapy, increased glucose metabolism occurred in dorsolateral, ventrolateral, and medial aspects of the prefrontal cortex (left greater than right), parietal cortex, and dorsal anterior cingulate. Areas of decreased metabolism were noted in both anterior and posterior insular regions (left) as well as right hippocampal and parahippocampal regions. In comparison to metabolism levels in a group of healthy volunteers, the increase in prefrontal metabolic activity represented a normalization of previously reduced metabolic activity, whereas the reduction in pregenual anterior cingulate activity represented a decrease from previously elevated metabolic levels. CONCLUSIONS: These results provide further support for a dysfunction in cortical-limbic circuitry in depression, which is at least partly reversed after successful paroxetine treatment.

Functional imaging studies in depression have consistently demonstrated regional blood flow and metabolic abnormalities. Most (15) but not all (68) investigators have reported a decrease in metabolic activity in the prefrontal cortex in individuals with major depression, particularly in the dorsolateral and medial areas. Regions of decreased metabolism in the inferior parietal and dorsal anterior cingulate as well as in paralimbic regions (anterior insula, inferior orbital, and inferior temporal cortex) have also been identified (9).

In contrast, there is less consensus on the changes in functional brain activity after antidepressant treatment. It is unclear whether antidepressant treatments act to reverse these abnormalities or create new resting levels of metabolism. The balance of evidence appears to support a return to normalcy in some but not all areas. Buchsbaum and colleagues (10) noted a significant correlation between the normalization of previously elevated activity in the anterior cingulate and the reduction in depressive symptoms in responders to sertraline treatment. Increased metabolic activity in left prefrontal, inferior parietal, dorsal anterior, and posterior cingulate areas was also associated with remission during fluoxetine treatment, as was a decrease below baseline metabolism in limbic and paralimbic regions, including the subgenual cingulate, insula, and hippocampus (11). In contrast, Brody and colleagues (12) did not confirm their hypothesis that activity in the dorsolateral prefrontal cortex would increase after paroxetine treatment, although they did report a significantly greater decrease in ventrolateral and orbitofrontal activity in responders than in nonresponders to paroxetine treatment. There are further reports of increased activity in the left prefrontal cortex (1, 13, 14), no change in activity (15), and decreased left prefrontal cortical activity (8) after treatment with disparate antidepressants. Differences in antidepressant agents (e.g., tricyclics or selective serotonin reuptake inhibitors [SSRIs]), concomitant benzodiazepine prescriptions, drug washout criteria, and diagnostic subtypes of depressed subjects, as well as differences in imaging techniques and methods of analysis, may explain these discrepant findings.

To date, no single positron emission tomography (PET) study has utilized methods that control for antidepressant drug type, concomitant medication, and gender. As a result, evidence concerning the functional neuroanatomy of antidepressant effects is derived from a set of studies that employed differing methods. In an effort to address these issues, we used [18F]fluorodeoxyglucose (FDG) PET to examine the neuroanatomical basis of paroxetine treatment in a well-defined homogeneous unipolar population of male patients. On the basis of converging evidence from previous studies, we hypothesized that antidepressant treatment with paroxetine for 6 weeks would be associated with 1) increased activity in both the prefrontal and inferior parietal cortices, as well as in the anterior and posterior cingulate, and 2) decreased activity in the subgenual cingulate and paralimbic regions.

Method

Subjects

Thirteen consecutively screened right-handed male patients (mean age=36.0 years, SD=10) who met DSM-IV criteria for a major depressive episode in the context of major depressive disorder and provided written informed consent to complete PET/FDG studies were examined. Inclusion criteria were a 17-item Hamilton Depression Rating Scale (16) score of >18, a body mass index within 20% of age-adjusted averages, and no recent exposure to antidepressant treatments (3 months for ECT, 8 weeks for fluoxetine, and 4 weeks for all other antidepressant agents).

None of the patients had a concurrent DSM-IV diagnosis, and none was receiving additional psychotropic medication at the time of study. Subjects were also required to be medically stable. However, one subject was receiving the angiotensin-converting enzyme inhibitor ramipril (10 mg/day) for hypertension and was treated with isophane insulin human (10 U b.i.d.).

Twenty-four healthy right-handed male volunteers (mean age=31.7 years, SD=6.7) who provided written informed consent were also recruited as a comparison group. Volunteers were required to meet similar body mass index criteria, to have a score of 5 or less on the Hamilton depression scale, and to have no current or past psychiatric history, including psychotropic drug use or alcohol abuse. The psychiatric status for both groups was determined by using the Structured Clinical Interview for DSM-IV (SCID) (17).

Medication

After single-blind placebo dosing for a mean of 3 days (SD=1) and the first PET scan, paroxetine was administered at a dose of 20 mg/day. Two of the original 15 subjects were excluded at this time because of reductions in Hamilton depression scale scores (to 13 and 11, respectively). After 4 weeks of paroxetine therapy at a dose of 20 mg/day, clinicians had the option of increasing the dose to 40 mg/day. Blood was sampled for plasma paroxetine approximately 5 hours after the first dose of paroxetine and again at the same time after 42 days of treatment. It was analyzed by using high-performance liquid chromatography with mass spectrometric detection methods (18). Paroxetine plasma levels were measured as an index of compliance and are included in Table 1.

PET Procedure

PET scans were conducted at the PET Centre, the Centre for Addiction and Mental Health, University of Toronto. The first scan for depressed patients was conducted before the first dose of paroxetine and 5 hours after placebo ingestion. A second PET/FDG scan was completed after a mean of 42 days (SD=3) of paroxetine therapy at approximately the same time as the first PET scan. All PET sessions began at 8:00 a.m. The images were acquired by using a GEMS-Scanditronix (Uppsala, Sweden) PC 2048b brain PET scanner with 15 slices of 6.5-mm interslice distance and reconstructed in-plane resolution of approximately 8 mm. The images were acquired parallel to the anterior-posterior commissure line. The subjects were fitted with a customized thermoplastic face mask to minimize head movement for the initial scan and for accurate repositioning of the next scan. Five mCi of FDG, synthesized on the day of each scan, were injected in an intravenous bolus. After the injection, each subject remained in a resting state with eyes open in a dimly lit room with low ambient noise for a 45-minute uptake period. Emission data were acquired over a 35-minute period, at approximately 1 million counts per slice, followed by a 10-minute 68germanium transmission scan for subsequent attenuation correction. The same procedure was followed after 6 weeks for the group with major depression and on a single occasion for the comparison group.

Image Analysis

After spatial realignment to minimize anatomical variance between the first and second scans for the depressed patients, the scans were spatially realigned to the Montreal Neurological Institute’s 300 stereotactic template, based on Talairach and Tournoux’s stereotaxic atlas (19), at nine parameters to correct for differences in the whole-brain global mean. The images were Gaussian-filtered to a final in-plane resolution of 8 mm full width at half maximum.

Two separate repeated analysis of covariance (ANCOVA) comparisons were carried out, with age as a covariate, by using the statistical parametric mapping technique, version 1996, developed by Friston et al. (20), to detect differences on a voxel-by-voxel basis 1) within subjects before and after treatment and 2) between depressed subjects and the comparison group before treatment. Brain regions that were identified as having 100 or more contiguous voxels and a cluster level of p<0.05 in within- or between-group comparisons were defined as significant at a threshold of p<0.01. In order to quantify the magnitude of change in relative glucose metabolism in these regions before and after treatment, mean values, standard deviations, and percent change in voxel scores in a priori regions were calculated and are presented in Table 2.

Results

Seven patients received paroxetine, 20 mg/day, throughout the trial, and six received paroxetine, 40 mg/day, for the final 2 weeks of the study. Higher plasma paroxetine levels were detected after 6 weeks of treatment in the 40-mg/day group (mean=82.6 ng/ml, SD=67.1) than in the 20-mg/day group (mean=36.8 ng/ml, SD=28.5). All patients had at least a 50% reduction in Hamilton depression scale scores. The mean Hamilton depression scale score was 22.42 (SD=3.59) before treatment and 6.0 (SD=4.1) after treatment (Table 1).

Changes in Metabolic Rates

Areas of increased metabolism after treatment were seen in the dorsolateral, ventrolateral, and medial prefrontal cortex, parietal cortex, and dorsal anterior cingulate (Figure 1, top), whereas areas of decreased metabolism occurred in both anterior and posterior insular regions (left) as well as right hippocampal and parahippocampal regions (Figure 1, bottom). There were more regions with increased activity in the left hemisphere and more regions on the right displaying decreased activity (Table 2).

Differences Between Patients and Comparison Subjects

At pretreatment, the depressed group demonstrated significantly higher metabolic activity in the right pregenual anterior cingulate (Brodmann’s area 24a: 8, 36, –4) (t=4.60, df=35, p<0.001) and significantly decreased metabolism in the ventral striatum (caudate and putamen: 12, 20, –6) (t=4.94, df=35, p<0.001) than the comparison group. No other regions met the statistical parametric mapping 96 threshold for significance.

Since our a priori hypothesis stated that untreated depressed patients would show hypometabolism in the prefrontal and anterior cingulate and inferior parietal cortices, we conducted a further post hoc analysis. Regions within depressed subjects that had shown increased activity after treatment were selected for direct comparison by using ANCOVA between groups. Mean voxel values of relative glucose metabolism were calculated for comparison subjects to best match the anatomical regions listed in Table 2 for pre- and posttreatment increases or decreases. The three regions within the dorsolateral prefrontal cortex (–28, 40, 0; –38, 14, 38; and –36, 24, 36) described in Table 2 had significantly lower metabolism in untreated patients than in the comparison group (t=6.24, df=12, p<0.001; t=3.26, df=12, p=0.003; t=3.67, df=12, p=0.003, respectively).

Discussion

Successful antidepressant treatment with paroxetine was associated with significant increases in metabolic activity in dorsolateral, ventrolateral, and ventral prefrontal areas, as well as dorsal medial prefrontal, anterior cingulate, and inferior parietal regions. Increases were predominantly but not exclusively on the left side. Significant reductions in glucose metabolism were also noted in both anterior and posterior insular regions, hippocampus, and parahippocampus (right more than left).

These findings support the results of several previous reports involving different antidepressant agents. Tricyclic antidepressant treatment (with concomitant benzodiazepines) was associated with an increase in left-sided prefrontal activity, although medication status at the time of repeat testing was inconsistent in this study (14); increased parietal activity was similarly associated with response to sertraline (10). In contrast to our findings of increased ventrolateral activity after successful treatment with paroxetine, Brody and colleagues (12) reported a significant decrease in ventrolateral and orbitofrontal activity in paroxetine responders compared to nonresponders.

A similar pattern of dorsal frontal, dorsal anterior cingulate, and inferior parietal activation accompanied by reduced ventral, mid, and posterior insula activity as well as reduced hippocampal activity was also reported by Mayberg et al. (21). We also identified increased pregenual anterior cingulate (Brodmann’s area 24a) activity in untreated depressed patients compared to healthy volunteers, replicating findings in reports by Mayberg et al. (11) and Wu et al. (22), who also reported increased baseline activity in responders to sleep deprivation. However, we failed to confirm that a decrease in metabolism below normal in this area is associated with treatment nonresponse (11, 12), since all our patients were treatment responders. Furthermore, anterior cingulate metabolism increased even further with successful treatment, a finding not previously reported.

Functional Considerations

Prefrontal cortex

The role of the prefrontal cortex in depression remains elusive (2325). Patients with lesions of the ventral prefrontal cortex lose the ability to express emotion in combination with thoughts that would ordinarily provoke an emotional response. In contrast, their planning and intellectual working abilities appear to remain intact (26). In depressed subjects, impaired modulation of the left ventral prefrontal cortex has been associated with impairment in the ability to shift emotional and cognitive sets appropriately, such that they maintain a negative thought pattern or mood (24, 27, 28).

Decreased blood flow in the left dorsolateral prefrontal cortex, on the other hand, has been associated with the psychomotor and attentional deficits and executive functioning impairments of depression (2931). Increased, primarily left-sided, prefrontal cortex metabolism after successful treatment with paroxetine may thus be the correlate of improved motor function, negative thinking, and cognitive abilities in our subjects.

Medial prefrontal cortex and cingulate gyrus

In the medial prefrontal cortex, the anterior cingulate cortex plays a critical role in the expression and modulation of emotion (30, 32). The functions of the anterior cingulate differ across its length, and electrical stimulation studies have identified arousal and heightened attention, simple motor movements, and affective changes such as euphoria, sadness, fear, or anguish depending on which portion of the cingulate was stimulated (26, 33, 34). In addition, bilateral cingulate ablation has been associated with akinetic mutism (26), whereas defined lesions within the anterior cingulate have been reported to improve depressive and anxiety symptoms (35). Consistent with these observations are findings of increased anterior cingulate activity in a range of PET activation studies involving attention, memory, response selection, language, and pain perception (34, 3638), which have predominantly focused on Brodmann’s areas 24 and 32.

Recently, Mayberg et al. (11) proposed a model of depression in which the pregenual anterior cingulate (Brodmann’s area 24a) serves as a facilitator of interactions between limbic and frontal brain regions. Overall, we report similar bidirectional findings, although we did not find evidence of altered metabolism in the subgenual cingulate region (Brodmann’s area 25).

Our findings of increased dorsal anterior cingulate metabolism after treatment of depression are in line with those of other studies, which suggest that changes in this region are a state phenomenon and are correlated with improvement of various dimensions of depressive symptom profiles (22, 29, 3941). Our data only partially confirm the role of the pregenual anterior cingulate (Brodmann’s area 24a) as a predictor of treatment response, because all our patients were responders and all showed pretreatment hyperactivity in this region compared to healthy volunteers. However, there was a further increase with treatment and not a decrease below normal, as found by Mayberg et al. (11) and Brody et al. (12).

Paralimbic structures

Reciprocal connections between paralimbic structures and the prefrontal cortex have been postulated (4245) and are supported by our finding of decreased metabolism in these structures after paroxetine treatment. It is of interest that although we report decreased metabolic activity in the insula after treatment, it remained higher than in the comparison group. Mayberg et al. (11), on the other hand, found an increase in metabolism in these regions in fluoxetine nonresponders and a decrease from previously normal patterns in responders, which suggests that suppression or disconnection of paralimbic regions may be necessary for the normalization of those dorsal neocortical areas that are associated with recovery from depression. This hypothesis is of particular interest in light of treatment with SSRIs, because these drugs are known to exert their mechanism of action by means of the raphe nuclei, which have close connections to the hippocampus, amygdala, anterior insula, hypothalamus, and cingulate gyrus as well as to neocortical sites, including the prefrontal cortex and inferior parietal cortex (46, 47).

Parietal cortex

The parietal cortex has strong limbic and paralimbic connections, and it primarily receives input from the pulvinar and lateral posterior nuclei of the thalamus (31, 48, 49). Dolan and colleagues (31) reported significant associations between attention and memory deficits in untreated depressed patients and reduced cerebral blood flow in the inferior parietal region. Hence, evidence of increased activity after response to paroxetine therapy may reflect symptomatic improvement in our population.

Regional Serotonergic Dysfunction and Antidepressants

It is unclear whether abnormalities of metabolism in specific brain regions reflect neurochemical changes. In general, receptor ligand studies tend to show abnormalities in the prefrontal cortex (50, 51). However, at least one neurochemical study (52) has shown a global effect of paroxetine on serotonin 5-HT2 receptor binding potential.

Limitations and Future Directions

There are several limitations to the current study. The fact that our comparison group had only one PET scan is a potential limitation. When Bartlett and colleagues (53) examined the test-retest variability of a measure of regional cerebral glucose metabolism, the average regional changes were no more than 1%. On the other hand, Stapleton and associates (54) reported a higher level of glucose utilization during the first PET scan than during the second in healthy male volunteers, a finding they attributed to anxiety changes in subjects with low trait anxiety. It should be noted, however, that we only compared first scans in the depressed group with our comparison group. We may also have had insufficient power to detect additional group differences since our group size was relatively small. This may have been particularly relevant in the comparison between depressed subjects and healthy volunteers. Because patient and comparison populations were male, any generalizations to female populations were prevented. On the other hand, the use of a single sex population, together with the unexpected uniformity of drug response, contributed to the homogeneity of this population. Further studies examining metabolic changes after 6–12 months of treatment will help to determine whether these changes remain stable in the remitted state.

In summary, treatment with paroxetine resulted in elevated levels of glucose metabolism in several frontal regions, including the dorsolateral prefrontal cortex, medial and ventral areas, anterior cingulate, and inferior parietal cortex. In some but not all cases, there was evidence of reduced metabolism in these areas in untreated depressed subjects compared to that of healthy volunteers. Paroxetine treatment also reduced metabolic activity in several paralimbic regions.

TABLE 1
TABLE 2

Presented in part at the 53rd annual meeting of Biological Psychiatry in Toronto, May 26–29, 1998. Received June 2, 2000; revisions received Sept. 29 and Dec. 26, 2000; accepted Dec. 28, 2000. From the Department of Psychiatry, University of Toronto, Toronto; the Mood and Anxiety Disorders Program, Centre for Addiction and Mental Health; and the PET Centre, Toronto. Address reprint requests to Dr. Kennedy, Mood and Anxiety Disorders Program, Centre for Addiction and Mental Health, Clarke Site, 250 College St., Toronto, Ont. M5T 1R8, Canada; (e-mail). Funded by Boehringer–Ingelheim Canada Limited. Drs. Kennedy and Meyer acknowledge additional support from the Medical Research Council of Canada. The authors thank Shahryar Rafi Tari, Doug Hussey, Nicole Cohen, Beata Eisfeld, Natasha Owen, and the staff of the PET Centre and Depression Clinic.

Figure 1.

Figure 1. Changes in Regional Brain Glucose Metabolism in 13 Depressed Male Patients After 6 Weeks of Paroxetine Therapya

aRed areas represent significant increases in metabolism, blue areas represent significant decreases, and yellow regions represent changes that did not reach statistical significance.

References

1. Baxter LR Jr, Schwartz JM, Phelps ME, Mazziotta JC, Guze BH, Selin CE, Gerner RH, Sumida RM: Reduction of prefrontal cortex glucose metabolism common to three types of depression. Arch Gen Psychiatry 1989; 46:243–250Crossref, MedlineGoogle Scholar

2. 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; 22:607–615Crossref, MedlineGoogle Scholar

3. Biver F, Goldman S, Delvenne V, Luxen A, De Maertelaer V, Hubain P, Mendlewicz J, Lotstra F: Frontal and parietal metabolic disturbances in unipolar depression. Biol Psychiatry 1994; 36:381–388Crossref, MedlineGoogle Scholar

4. Cohen RM, Semple WE, Gross M, Nordahl TE, King AC, Pickar D, Post RM: Evidence for common alterations in cerebral glucose metabolism in major affective disorders and schizophrenia. Neuropsychopharmacology 1989; 2:241–254Crossref, MedlineGoogle Scholar

5. Mayberg HS: Limbic-cortical dysregulation: a proposed model of depression. J Neuropsychiatry Clin Neurosci 1997; 9:471–481Crossref, MedlineGoogle Scholar

6. Kling AS, Metter EJ, Riege WH, Kuhl DE: Comparison of PET measurement of local brain glucose metabolism and CAT measurement of brain atrophy in chronic schizophrenia and depression. Am J Psychiatry 1986; 143:175–180LinkGoogle Scholar

7. Raichle ME, Martin WR, Herscovitch P, Mintun MA, Markham J: Brain blood flow measured with intravenous H2(15)O, II: implementation and validation. J Nucl Med 1983; 24:790–798MedlineGoogle Scholar

8. Drevets WC, Raichle ME: Neuroanatomical circuits in depression: implications for treatment mechanisms. Psychopharmacol Bull 1992; 28:261–274MedlineGoogle Scholar

9. Mayberg HS: Frontal lobe dysfunction in secondary depression. J Neuropsychiatry Clin Neurosci 1994; 6:428–442Crossref, MedlineGoogle Scholar

10. Buchsbaum MS, Wu J, Siegel BV, Hackett E, Trenary M, Abel L, Reynolds C: Effect of sertraline on regional metabolic rate in patients with affective disorder. Biol Psychiatry 1997; 41:15–22Crossref, MedlineGoogle Scholar

11. Mayberg HS, Liotti M, Brannan SK, McGinnis S, Mahurin RK, Jerabek PA, Silva JA, Tekell JL, Martin CC, Lancaster JL, Fox PT: Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. Am J Psychiatry 1999; 156:675–682AbstractGoogle Scholar

12. Brody AL, Saxena S, Silverman DH, Alborzian S, Fairbanks LA, Phelps ME, Huang SC, Wu HM, Maidment K, Baxter LR Jr: Brain metabolic changes in major depressive disorder from pre- to post-treatment with paroxetine. Psychiatry Res 1999; 91:127–139Crossref, MedlineGoogle Scholar

13. Baxter LR Jr, Phelps ME, Mazziotta JC, Schwartz JM, Gerner RH, Selin CE, Sumida RM: Cerebral metabolic rates for glucose in mood disorders: studies with positron emission tomography and fluorodeoxyglucose F18. Arch Gen Psychiatry 1985; 42:441–447Crossref, MedlineGoogle Scholar

14. Martinot JL, Hardy P, Feline A, Huret JD, Mazoyer B, Attar-Levy D, Pappata S, Syrota A: Left prefrontal glucose hypometabolism in the depressed state: a confirmation. Am J Psychiatry 1990; 147:1313–1317Google Scholar

15. Hurwitz TA, Clark C, Murphy E, Klonoff H, Martin WR, Pate BD: Regional cerebral glucose metabolism in major depressive disorder. Can J Psychiatry 1990; 35:684–688Crossref, MedlineGoogle Scholar

16. Hamilton M: A rating scale for depression. J Neurol Neurosurg Psychiatry 1960; 23:56–62Crossref, MedlineGoogle Scholar

17. First MB, Spitzer RL, Gibbon M, Williams JBW: Structured Clinical Interview for DSM-IV Axis I Disorders (SCID). New York, New York State Psychiatric Institute, Biometrics Research, 1995Google Scholar

18. Agro A, Korts D, Evans K, Kennedy S, Houle S, Vaccarrino FJ, Knott V, Gilbert S: The Effects of Chronic and Acute Dosing of Paroxetine on Regional Brain Metabolism and Quantified QEEG: An Exploratory Study (511.4): Internal Technical Report U98-3119, XII of XVI. Burlington, Ont, Canada, Boehringer–Ingelheim Canada, 1998, pp 1–88Google Scholar

19. Talairach J, Tournoux P: Co-Planar Stereotaxic Atlas of the Human Brain. New York, Thieme Medical, 1988Google Scholar

20. Friston KJ, Frith CD, Liddle PF, Frackowiak RS: Comparing functional (PET) images: the assessment of significant change. J Cereb Blood Flow Metab 1991; 11:690–699Crossref, MedlineGoogle Scholar

21. Mayberg HS, Brannan SK, Tekell JL, Silva JA, Mahurin RK, McGinnis S, Jerabek PA: Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response. Biol Psychiatry 2000; 48:830–843Crossref, MedlineGoogle Scholar

22. Wu JC, Gillin JC, Buchsbaum MS, Hershey T, Johnson JC, Bunney WE Jr: Effect of sleep deprivation on brain metabolism of depressed patients. Am J Psychiatry 1992; 149:538–543LinkGoogle Scholar

23. Drevets WC, Videen TO, Price JL, Preskorn SH, Carmichael ST, Raichle ME: A functional anatomical study of unipolar depression. J Neurosci 1992; 12:3628–3641Google Scholar

24. Quintana J, Fuster JM, Yajeya J: Effects of cooling parietal cortex on prefrontal units in delay tasks. Brain Res 1989; 503:100–110Crossref, MedlineGoogle Scholar

25. Levin BE, Llabre MM, Reisman S, Weiner WJ, Sanchez-Ramos J, Singer C, Brown MC: Visuospatial impairment in Parkinson’s disease. Neurology 1991; 41:365–369Crossref, MedlineGoogle Scholar

26. Damasio AR, Van Hoesen GW: Emotional disturbances associated with focal lesions of the limbic frontal lobe, in Neuropsychology of Human Emotion. Edited by Heilman KM, Satz P. New York, Guilford, 1983, pp 85–110Google Scholar

27. Goldman-Rakic PS: Motor control function of the prefrontal cortex. Ciba Found Symp 1987; 132:187–200MedlineGoogle Scholar

28. Iversen SD, Mishkin M: Perseverative interference in monkeys following selective lesions of the inferior prefrontal convexity. Exp Brain Res 1970; 11:376–386Crossref, MedlineGoogle Scholar

29. 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; 47:60–70Crossref, MedlineGoogle Scholar

30. MacLean P: Some psychiatric implications of physiological studies on frontotemporal portion of limbic system (visceral brain). Electroencephalogr Clin Neurophysiol 1952; 4:407–418Crossref, MedlineGoogle Scholar

31. Dolan RJ, Bench CJ, Liddle PF, Friston KJ, Frith CD, Grasby PM, Frackowiak RS: Dorsolateral prefrontal cortex dysfunction in the major psychoses; symptom or disease specificity? J Neurol Neurosurg Psychiatry 1993; 56:1290–1294Google Scholar

32. Papez JW: A proposed mechanism of emotion, 1937. J Neuropsychiatry Clin Neurosci 1995; 7:103–112Crossref, MedlineGoogle Scholar

33. Talairach J, Bancaud J, Szikla G, Bonis A, Geier S, Vedrenne C: [New approach to the neurosurgery of epilepsy: stereotaxic methodology and therapeutic results, 1: introduction and history.] Neurochirurgie 1974; 20:1–240 (French)MedlineGoogle Scholar

34. Laitinen LV: Emotional responses to subcortical electrical stimulation in psychiatric patients. Clin Neurol Neurosurg 1979; 81:148–157Crossref, MedlineGoogle Scholar

35. Ballantine HT Jr, Bouckoms AJ, Thomas EK, Giriunas IE: Treatment of psychiatric illness by stereotactic cingulotomy. Biol Psychiatry 1987; 22:807–819Crossref, MedlineGoogle Scholar

36. Petersen SE, Fox PT, Posner MI, Mintun M, Raichle ME: Positron emission tomographic studies of the cortical anatomy of single-word processing. Nature 1988; 331:585–589Crossref, MedlineGoogle Scholar

37. Corbetta M, Miezin FM, Dobmeyer S, Shulman GL, Petersen SE: Attentional modulation of neural processing of shape, color, and velocity in humans. Science 1990; 248:1556–1559Google Scholar

38. 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; 23:579–590Crossref, MedlineGoogle Scholar

39. Bench CJ, Frackowiak RS, Dolan RJ: Changes in regional cerebral blood flow on recovery from depression. Psychol Med 1995; 25:247–261Crossref, MedlineGoogle Scholar

40. Ebert D, Ebmeier KP: The role of the cingulate gyrus in depression: from functional anatomy to neurochemistry. Biol Psychiatry 1996; 39:1044–1050Google Scholar

41. Volk SA, Kaendler SH, Hertel A, Maul FD, Manoocheri R, Weber R, Georgi K, Pflug B, Hor G: Can response to partial sleep deprivation in depressed patients be predicted by regional changes of cerebral blood flow? Psychiatry Res 1997; 75:67–74Google Scholar

42. Porrino LJ, Crane AM, Goldman-Rakic PS: Direct and indirect pathways from the amygdala to the frontal lobe in rhesus monkeys. J Comp Neurol 1981; 198:121–136Crossref, MedlineGoogle Scholar

43. Vogt BA, Nimchinsky EA, Vogt LJ, Hof PR: Human cingulate cortex: surface features, flat maps, and cytoarchitecture. J Comp Neurol 1995; 359:490–506Crossref, MedlineGoogle Scholar

44. Carmichael ST, Price JL: Architectonic subdivision of the orbital and medial prefrontal cortex in the macaque monkey. J Comp Neurol 1994; 346:366–402Crossref, MedlineGoogle Scholar

45. Morecraft RJ, Geula C, Mesulam MM: Architecture of connectivity within a cingulo-fronto-parietal neurocognitive network for directed attention. Arch Neurol 1993; 50:279–284Crossref, MedlineGoogle Scholar

46. Hervas I, Bel N, Fernandez AG, Palacios JM, Artigas F: In vivo control of 5-hydroxytryptamine release by terminal autoreceptors in rat brain areas differentially innervated by the dorsal and median raphe nuclei. Naunyn Schmiedebergs Arch Pharmacol 1998; 358:315–322Crossref, MedlineGoogle Scholar

47. Davidson C, Stamford JA: The effect of paroxetine on 5-HT efflux in the rat dorsal raphe nucleus is potentiated by both 5-HT1A and 5-HT1B/D receptor antagonists. Neurosci Lett 1995; 188:41–44Crossref, MedlineGoogle Scholar

48. Goldman-Rakic PS: Development of cortical circuitry and cognitive function. Child Dev 1987; 58:601–622Crossref, MedlineGoogle Scholar

49. Trojanowski JQ, Jacobson S: Areal and laminar distribution of some pulvinar cortical efferents in rhesus monkey. J Comp Neurol 1976; 169:371–392Crossref, MedlineGoogle Scholar

50. Rajkowska G: Postmortem studies in mood disorders indicate altered numbers of neurons and glial cells. Biol Psychiatry 2000; 48:766–777Crossref, MedlineGoogle Scholar

51. Arango V, Ernsberger P, Marzuk PM, Chen JS, Tierney H, Stanley M, Reis DJ, Mann JJ: Autoradiographic demonstration of increased serotonin 5-HT2 and beta-adrenergic receptor binding sites in the brain of suicide victims. Arch Gen Psychiatry 1990; 47:1038–1047Google Scholar

52. Meyer JH, Kapur S, Eisfeld B, Brown GM, Houle S, DaSilva J, Wilson AA, Rafi-Tari S, Mayberg HS, Kennedy SH: The effect of paroxetine on 5-HT2A receptors in depression: an [18F]setoperone PET imaging study. Am J Psychiatry 2001; 158:78–85LinkGoogle Scholar

53. Bartlett EJ, Brodie JD, Wolf AP, Christman DR, Laska E, Meissner M: Reproducibility of cerebral glucose metabolic measurements in resting human subjects. J Cereb Blood Flow Metab 1988; 8:502–512Crossref, MedlineGoogle Scholar

54. Stapleton JM, Morgan MJ, Liu X, Yung BC, Phillips RL, Wong DF, Shaya EK, Dannals RF, London ED: Cerebral glucose utilization is reduced in second test session. J Cereb Blood Flow Metab 1997; 17:704–712Crossref, MedlineGoogle Scholar