Changes in forebrain function from waking to REM sleep in depression: preliminary analyses [of 18F]FDG PET studies

Psychiatry Research: Neuroimaging Section 91 Ž1999. 59]78

Changes in forebrain function from waking to REM sleep in depression: preliminary analyses of w 18 FxFDG PET studies Eric A. Nofzinger a,c,U , Thomas E. Nichols b,f , Carolyn C. Meltzer e, Julie Price e, Doris A. Steppea,c , Jean M. Miewalda,c , David J. Kupfer a,c Robert Y. Moorea,d,g a

Sleep and Chronobiology Center, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213, USA b Pitt-CMU Center for the Neural Basis of Cognition (CNBC), Uni¨ ersity of Pittsburgh, Pittsburgh, PA 15213, USA c Department of Psychiatry, Uni¨ ersity of Pittsburgh, Pittsburgh, PA 15213, USA d Department of Neuroscience, Uni¨ ersity of Pittsburgh, Pittsburgh, PA 15213, USA e Department of Radiology, Uni¨ ersity of Pittsburgh, Pittsburgh, PA 15213, USA f Department of Statistics, Carnegie Mellon Uni¨ ersity, Pittsburgh, PA, USA g Department of Neurology, Uni¨ ersity of Pittsburgh, Pittsburgh, PA 15213, USA Received 2 April 1999; received in revised form 18 June 1999; accepted 21 June 1999

Abstract Based on recent functional brain imaging studies of healthy human REM sleep, we hypothesized that alterations in REM sleep in mood disorder patients reflect a functional dysregulation within limbic and paralimbic forebrain structures during that sleep state. Six unipolar depressed subjects and eight healthy subjects underwent separate w 18 Fx2-fluoro-2-deoxy-D-glucose Žw 18 FxFDG. PET scans during waking and during their first REM period of sleep. Statistical parametric mapping contrasts were performed to detect changes in relative regional cerebral glucose metabolism ŽrCMRglu. from waking to REM sleep in each group as well as interactions in patterns of change between groups. Clinical and EEG sleep comparisons from an undisturbed night of sleep were also performed. In contrast to healthy control subjects, depressed patients did not show increases in rCMRglu in anterior paralimbic structures in REM sleep compared to waking. Depressed subjects showed greater increases from waking to REM sleep in rCMRglu in the tectal area and a series of left hemispheric areas including sensorimotor cortex, inferior temporal cortex, uncal gyrus-amygdala, and subicular complex than did the control subjects. These observations indicate that changes in limbic and paralimbic function from waking to REM sleep differ significantly from normal in depressed patients. Q 1999 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Positron emission tomography; Cerebral glucose metabolism; Major depressive disorder; REM sleep; Limbic system

U

Corresponding author. Tel.: q1-412-624-2246; fax: q1-412-624-2841. E-mail address: [email protected] ŽE.A. Nofzinger.

0925-4927r99r$ - see front matter Q 1999 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 9 2 5 - 4 9 2 7 Ž 9 9 . 0 0 0 2 5 - 6

60

E.A. Nofzinger et al. r Psychiatry Research: Neuroimaging Section 91 (1999) 59]78

1. Introduction Alterations in rapid eye movement ŽREM. sleep have been reliably observed in patients with mood disorders ŽLauer et al., 1991; Benca et al., 1992; Nofzinger et al., 1993., and these alterations have been linked to clinical features ŽGiles et al., 1989; Vogel et al., 1990; Reynolds et al., 1993; Nofzinger et al., 1994; Lauer et al., 1995; Dew et al., 1996; Thase et al., 1996, 1997.. Pathophysiologic models, devised to explain these alterations, have previously focused on factors which regulate the global states of REM and NREM sleep, largely derived from laboratory observations of brainstem regulation of cortical states of arousal and from human studies describing circadian and homeostatic mechanisms of REMrNREM sleep regulation ŽGillin et al., 1979, 1991; Borbely ´ and Wirz-Justice, 1982; McCarley, 1982; Kupfer and Ehlers, 1989; McCarley et al., 1995.. Recent findings from the laboratory and from functional brain imaging studies of REM sleep in healthy human subjects suggest that alterations in REM sleep in mood disorder patients may reflect alterations at the level of the forebrain limbic and paralimbic regions. Recent human functional brain imaging studies of REM sleep have demonstrated that the forebrain is not active in a general, non-selective manner but, rather, regional specificity exists during this state ŽMaquet et al., 1996; Braun et al., 1997, 1998; Nofzinger et al., 1997.. The most notable increases in either glucose metabolism or blood flow are in anteriorly located limbic and paralimbic structures including the sub- and pregenual anterior cingulate cortex, the amygdala and the insular cortex, an area we designate ‘the anterior paralimbic REM activation axis’. These data suggest that an important function of REM sleep is the integration of neocortical function with basal forebrain-hypothalamic motivational and reward mechanisms. This is in accord with views that alterations in REM sleep in psychiatric disorders such as depression may reflect dysregulation in limbic and paralimbic structures. A ‘REM sleep probe’ in patients with depression, therefore, may assess the functional capacity of brain structures and systems which are involved in this integration.

Within this framework, we performed waking and REM sleep-related w 18 Fx2-fluoro-2-deoxy-Dglucose Žw 18 FxFDG. PET scans, brain magnetic resonance scans for co-registration with the PET images, and 3 nights of EEG sleep studies in both healthy control subjects and depressed patients. The waking to REM sleep comparison for each group was used as a functional probe of limbic and paralimbic structures. Interactions in changes in rCMRglu from waking to REM sleep between healthy and depressed subjects were used as an assessment of an alteration in limbic and paralimbic function related to depression that, presumably, underlies the previously described alterations in EEG measures of REM sleep observed between depressed and healthy subjects.

2. Methods 2.1. Subjects Depressed subjects were required to be between the ages of 30 and 50 Žright-handed only. who met research diagnostic criteria ŽRDC. ŽSpitzer et al., 1978. for major depression on the basis of an interview with either the Schedule for Affective Disorders and Schizophrenia ŽEndicott and Spitzer, 1978. or the SCID ŽSpitzer et al., 1988.. Only endogenous, melancholic wDSM-III-R criteria ŽAPA Committee on Nomenclature and Statistics, 1987.x primary unipolar RDC subtypes were eligible. Patients were required to have a minimum score of 15 on the first 17 items of the Hamilton Rating Scale for Depression ŽHRSD. ŽHamilton, 1960.. Diurnal mood variation was determined by their response to the diurnal mood item a25 on the HRSD. Healthy control subjects were selected to be age-matched within 5 years of individual depressed subjects. They were required to have a score of F 6 on the first 17 items of the HRSD. Data for five of these subjects were included in a previous report describing forebrain function during REM sleep ŽNofzinger et al., 1997.. In the current study, two additional depressed subjects Žboth female, ages 45 and 47. and two additional control subjects Žboth female, ages 42 and 43. were studied, but they did not

E.A. Nofzinger et al. r Psychiatry Research: Neuroimaging Section 91 (1999) 59]78

maintain REM sleep following the injection of the radioisotope for at least 12 min. Consequently, their data were not included in the current report. No clear clinical differences were noted between these subjects and the rest of the subjects included in this report. All subjects were required to be free of medications that could affect mood or sleep for at least a 2-week period of time Ž8 weeks for fluoxetine. prior to EEG sleep and PET studies. Subjects who could not remain drug- or alcohol-free during the study, verified by nightly drug screens, were excluded. Subjects were also excluded if they met RDC for schizophrenia, lifetime history of substance abuse or alcoholism, borderline or antisocial personality disorder, organic affective disorder, schizoaffective disorder, psychotic subtype of major depression or bipolar depression. All subjects completed the Symptom Check List-90-R ŽSCL-90-R. ŽDerogatis, 1977; Cyr et al., 1985.. A medical history, physical examination and laboratory tests were conducted on all subjects at entry into the study and medical exclusion criteria were applied as previously described ŽNofzinger et al., 1998.. Any subject with an ApnearHypopnea Index G 5 on night 1 screening or periodic limb movement index ) 5 was excluded from further study. Additionally, healthy subjects were excluded if they ever met SADS ŽSpitzer, 1978.-RDC ŽSpitzer et al., 1978. for major depression. 2.2. EEG sleep methods EEG sleep studies were performed at a General Clinical Research Center, University of Pittsburgh Medical Center. EEG sleep was monitored on nights 1]3, screening for sleep apnea and periodic limb movements on night 1. Subjects reported to the GCRC at 18.00 h. Bedtime was defined by the mean bedtime over the 7 days preceding sleep studies as determined by review of a 7-day sleep log. On nights 1 and 2, subjects received a normal saline IV via hole-in-the-wall techniques for accommodation to an indwelling IV used on night 3 for bolus injection of the radioisotope. The routine montage Žnights 2 and 3. consisted of a single EEG channel ŽC4rA1-A2.,

61

two EOG channels Žright and left eyes. referenced to linked mastoids, and a sub-mental EMG channel. EEG sleep was scored manually according to the criteria of Rechtschaffen and Kales ŽRechtschaffen and Kales, 1968.. In addition to sleep continuity and sleep architecture measures, the primary REM sleep-dependent variables included: REM sleep time, percent, and latency Žtime between sleep onset and first REM period, any wakefulness occurring during the interval., activity Ža measure of the number of REMs over the night., and density ŽREM activityrREM time.. In addition to manual scoring, records were scored by automated delta and REM wave counts ŽKupfer et al., 1990.. 2.3. PET methods Subjects were assessed by two PET scans: a waking scan performed in the morning following the second night of sleep studies, the other during REM sleep. All PET studies used a maximum of a 4-mCi dose of 18 FDG. The awake comparison 18 FDG rCMRglu paradigm consisted of 20 min of polysomnographically monitored wakefulness in the morning following the second night of EEG sleep studies, subjects lying supine, eyes closed, ears open, with lights dimmed, in the same bedroom used for sleep studies following a 15-min undisturbed accommodation period. Technicians were instructed to arouse subjects if there was polysomnographic evidence that they were drifting off to sleep although, in the current study, no subject did. The REM sleep PET scan occurred on the third night of study. For the REM sleep 18 FDG rCMRglu paradigm, 4 mCi 18 FDG was injected intravenously via an indwelling catheter following the onset of the first REM period Ždefined by the onset of the first REM in conjunction with EMG, EOG and EEG correlates of REM sleep.. For all subjects, injection occurred within seconds of the identification of REM sleep. After 20 min post-injection for both wake and REM sleep conditions, subjects were asked to get up from bed, then they were transported via wheelchair and positioned in the PET scanner for a 30-min emission scan Žbeginning 60 min after

62

E.A. Nofzinger et al. r Psychiatry Research: Neuroimaging Section 91 (1999) 59]78

injection of the 18 FDG., followed by a 15-min rod-windowed transmission scan. As such, the states of the subjects from post-injection time T s 20 min to the end of scanning were identical between the waking and REM sleep PET conditions. The use of a low dose of 18 FDG as well as the use of rod-windowing to reduce contamination of the transmission scan from activity in the patient allowed this convenient timing of the transmission scan. The acquisition protocol included two-dimensional mode in a Siemens 951 PET scanner. An individually molded, thermoplastic headholder Žmarked with laser guidance for repositioning. was made for each subject to minimize head movement and to allow for head positioning for scanning. The head was positioned such that the lowest scanning place Žvisualized by a system of laser lines within the scanner gantry. was parallel to and 1.0 cm above the canthomeatal line. All PET images were reconstructed using standard commercial software as 31 transaxial slices Žeach 3.375 mm thick. with approximately 8 mm full-width half-maximum transaxial resolution. 2.4. MR methods Subjects underwent MR scanning prior to their PET study using a Signa 1.5 Tesla scanner ŽGE Medical Systems, Milwaukee, WI.. The subjects were positioned in a standard head coil and a brief scout sagittal T1-weighted image was obtained. Standard axial T1-weighted ŽTE s 18; TR s 400; NEXs 1; slice thickness s 3 mmrinterleaved; pixel slice s 0.78125 mm; 256 = 256 pixelsrslice . images were acquired. MR data were transferred to the PET facility over an electronic network. The MR data were cropped in preparation for alignment with the PET data. Cropping was performed with ANALYZE software ŽBiomedical Imaging Resource, Mayo Foundation, Rochester, MN, USA. by setting all non-brain voxels to zero intensity. 2.5. Image analysis Alignments and coregistrations were performed using a modification of Roger Woods’ automated

algorithms ŽMinoshima et al., 1993; Woods et al., 1993; Wiseman et al., 1996. for PET to PET alignment and PET to MR cross-modality registration. This 12-parameter affine transformation accounts for rigid body movements Žsix parameters. and three linear stretches Žthree parameters. along three orthogonal axes; these axes can have any orientation Žthree parameters.. Six 5-min PET emission scans were collected. The first scan was centered, and then images 2]6 were registered to this centered image. The six centered, co-registered emission scans were then summed. This summed image was then registered to the subject’s cropped MR study. The cropped MR image was then registered to a lab standard MR image. Equations translating the lab standard MR image into Talairach ŽTalairach and Tournoux, 1988. space had previously been formulated and could subsequently be used in translating the subject’s MR into Talairach space. Finally, the same equations translating the subject’s high resolution MR into Talairach space were subsequently used to translate the summed PET image Žnow translated into the MR space. into Talairach space. These methods made use of the higher resolution MR image in ultimately defining the transformation equations of the lower resolution PET image. These data were then reviewed by the PET Facility staff to ensure adequate registration Žerror - 1 pixel.. 2.6. Statistical analyses Statistical analyses of the images were performed using Statistical Parametric Mapping, 1996 version ŽSPM 96. ŽFriston et al., 1990, 1991.. Following the coregistration and spatial normalization of the PET data described above, the PET data were smoothed Ž10 = 10 = 10 mm. and then processed by typical SPM approach using an ANCOVA to control for global changes. As such, all subsequent reports of glucose metabolism reflect ‘normalized’ data where the mean brain value was arbitrarily set at 50. Given the possibility that the relationship between regional and global cerebral glucose metabolism varied by group Ždepressed vs. control., the effects of global metabolism were adjusted within each group sepa-

E.A. Nofzinger et al. r Psychiatry Research: Neuroimaging Section 91 (1999) 59]78

rately. A two-study, two-condition, study-specific ANCOVA was used followed by post-hoc contrasts for voxels identified as significant in the ANCOVA. Statistical images Ž t-scores converted to Z-scores. were created for contrasts that corresponded to the effects of condition Žwaking vs. REM sleep. within group Ždepressed and control., and to the interaction of condition by group. The interaction identified areas where the differences in rCMRglu between waking and REM sleep significantly differed between groups. Local maxima in the statistical images were identified by their Talairach atlas Ž x, y, z axis. coordinates Žsee Talairach and Tournoux, 1988.. Studies in our lab have found that a threshold of P- 0.001 adequately controls false positives in normal control subjects ŽMann et al., 1996., so the threshold for the SPM images was set at P- 0.001. Additionally, only those structures where the pixel of maximum significance was surrounded by contiguous regions of change were reported as being significant. Given the absence of any prior reports of cerebral glucose metabolism during REM sleep in depression, we viewed the current study as exploratory in nature. Consequently, we did not correct for multiple comparisons. For graphic representations shown in figures, height thresholds were set at P- 0.01. Overall, this resulted in larger confluent regions of changes in rCMRglu in structures identified on the basis of the more stringent P- 0.001 criteria. Any new structures identified by using the P- 0.01 level of significance were not identified as significant since they were not initially identified using the more conservative P- 0.001 level of significance. Anatomic localization of smaller structures was aided by superimposing the statistical image onto each individual’s MR image which had been spatially normalized into the same Talairach coordinates as part of the spatial normalization procedure Ždescribed above.. For structures shown to demonstrate significant interactions, post-hoc analyses were performed on these select regions of interest to determine if the rCMRglu differed between groups in either the waking or the REM sleep states independently. For demographic, clinical, and EEG sleep measures, we used the non-parametric Wilcoxon rank

63

sum test to test group differences for continuous variables and Fisher’s exact test to test group differences for categorical variables. Analyses were done using SAS software from SAS Institute, Inc., in Cary, NC, and Stat Xact-Turbo for Exact Non-parametric Inference from CYTEL Software Corp., in Cambridge, MA, USA.

3. Results 3.1. Clinical and EEG sleep ¨ ariables The healthy control Ž n s 8. and depressed subjects Ž n s 6. were comparable in age, sex, employment status, education, and handedness ŽTable 1.. As selected, the depressed patients had significantly higher scores on the Beck Depression Inventory and the Hamilton Rating Scale Scores for Depression. They also had higher measures of global distress measured by the SCL-90-R Global Severity Index, subjective sleep disturbance measured by the Pittsburgh Sleep Quality Index, and lower overall assessment of functioning. The depressed subjects were predominantly endogenous in type and predominantly in their first episode of depression. All depressed subjects and none of the control subjects reported diurnal variations in mood based on their response to item a25 of the HRSD. All subjects met inclusionrexclusion criteria as noted above. Table 2 shows that the healthy control subjects and the depressed subjects were not significantly different in sleep continuity and general sleep staging on a baseline Žnight 2. night of recording. The depressed subjects did, however, demonstrate several differences from normal subjects on phasic REM sleep measures Žmanual and automated measures of REM density. on the baseline night of recording. On the night of sleep when the FDG was injected at the beginning of the first REM period, the durations of REM sleep, NREM sleep and waking in the subsequent 20-min period prior to arousal were comparable between groups Žsee Fig. 1.. No statistically significant differences in other measures of REM sleep, such as REM latency, were detected on the PET night. For the waking PET study, the depressed and control

E.A. Nofzinger et al. r Psychiatry Research: Neuroimaging Section 91 (1999) 59]78

64

groups received their radioisotope injections at 167 " 75 and 175 " 38 Žmean " S.D.. min, respectively, following awakening from their second night of sleep in the clinical research center Žbetween-group comparison t-value s 0.266, P s 0.79.. 3.2. Relati¨ e regional metabolic rate comparisons 3.2.1. Healthy subjects: REM sleep ¨ s. waking Four regions demonstrated increases in rCMR-

glu from waking to REM sleep: Ž1. the right parahippocampal gyrus Ž Z for maxima s 4.30 at x, y, z coordinates 18, y50, y12.; Ž2. a large region including much of the hypothalamus Ž Z for maxima s 3.52 at x, y, z coordinates s 4, 0, y4.; Ž3. a dorsally arching region beginning inferiorly in the pregenual anterior cingulate cortex and extending into the pregenual anterior cingulate cortex including confluent areas of the medial prelimbic prefrontal cortex Ž Zs for two local maxima s 3.16 and 3.03 for x, y, z coordinates 0,

Table 1 Demographic and clinical descriptors for depressed Ž n s 6. and control Ž n s 8. subjects Controls

Depressed

Statistica

P

37 Ž27]51. ]

35 Ž29]45. 28 Ž21]45.

0.06 ]

] ]

Sex, no. (%) Male Female

2 Ž25.0. 6 Ž75.0.

1 Ž16.7. 5 Ž83.3.

] ]

] ]

Employment status, no. (%) Employed Unemployed

8 Ž100.0. 0 Ž0.0.

5 Ž83.3. 1 Ž16.7.

] ]

] ]

16 Ž16]19.

14 Ž12]20.

Age Ž years . Current median Žmin]max. At onset median Žmin]max.

Education Median years Žmin]max. Endogenous, no. (%) Probable Yes

1.75

]

]

1 Ž16.7. 5 Ž83.3.

] ]

] ]

Recurrent, no. (%) No Yes

] ]

4 Ž66.7. 2 Ž33.3.

] ]

] ]

Pre¨ ious episodes of depression Median no. Žmin]max.

]

0.5 Ž0.0]5.0.

]

]

24.0 Ž14.3]39.0. 23.0 Ž17.0]28.0.

y2.95 y3.31

- 0.005 - 0.001

55 Ž40.00]65. 1.59 Ž0.80]2.32.

2.89 y3.00

- 0.005 - 0.005

9.5 Ž7.0]13.0.

y3.11

- 0.001

Assessments BDI score median Žmin]max. HRSD score median Žmin]max. GAS score median Žmin]max. GSI score median Žmin]max. PSQI score median Žmin]max. a

0.0 Ž0.0]5.6. 0.0 Ž0.0]3.0. 95 Ž90]95. 0.06 Ž0.00]0.26. 2.5 Ž1.0]6.0.

For categorical variables the Fisher Exact Test was used; for all others, the Wilcoxon Standardized Rank Sum Statistic was used.

E.A. Nofzinger et al. r Psychiatry Research: Neuroimaging Section 91 (1999) 59]78

65

Table 2 EEG sleep comparisons: depressed Ž n s 6. vs. healthy control Ž n s 8.

Baseline night Total recording period Žmin. Sleep maintenance Ž%. Sleep latency Žmin. Min awake Total delta counts Total REM counts REM count density REM latency Žmin. REM min REM density Žmanual. Min stage 1 Min stage 2 Min stage 3 Min stage 4 Delta counts ŽNREM period 1. PET assessment night Sleep latency Žmin. Delta counts ŽNREM1. REM latency Žmin. REM min Župtake.

Controls median Žmin]max.

Depressed median Žmin]max.

Wilcoxon Standard Rank Sum Statistic

P

463 Ž397]530. 96.7 Ž91.8]99.3. 9.5 Ž4.0]54.0. 15.5 Ž3.0]38.0. 4283 Ž2584]10363. 621 Ž405]1260. 4.9 Ž3.8]10.7. 58 Ž5.0]99.0. 118 Ž77]142. 0.96 Ž0.75]1.83. 16 Ž4]36. 253 Ž220]285. 25 Ž0]52. 0 Ž0]48. 1181 Ž29]5881.

494 Ž370]541. 92.0 Ž79.3]99.2. 14.0 Ž3.0]53.0. 37.0 Ž3.0]101.0. 3983 Ž3649]8047. 1121 Ž598]1673. 9.5 Ž7.5]12.4. 52.5 Ž41.0]72.0. 126 Ž80]135. 1.55 Ž1.29]1.94. 14 Ž3]38. 243 Ž166]295. 28 Ž4]46. 9 Ž0]66. 1165 Ž526]2134.

y0.58 1.10 y0.97 y1.04 y0.22 y1.94 y2.07 0.84 0.19 y2.33 y0.06 0.45 y0.19 y0.81 0.07

] ] ] ] ] 0.06 0.04 ] ] 0.02 ] ] ] ] ]

17 Ž4]62. 1412 Ž32]4800. 67 Ž4]84. 15 Ž12]20.

14 Ž2]22. 1806 Ž676]3010. 60 Ž36]68. 16 Ž13]20.

0.78 y0.08 0.84 y0.72

] ] ] ]

34, 8 and y4, 20, y12, respectively.; and Ž4. a region over the right insular cortex Ž Z for maxima s 3.11 at x, y, z coordinates 44, y8, 8.. The only area of significant decrease in rCMRglu from waking to REM sleep included a region of the frontal cortex ŽBrodmann’s area 10. Ž Z for maxima s 3.34 at x, y, z coordinates y26, 54, 0.. 3.3. Depressed subjects: REM sleep ¨ s. waking The most significant area ŽTable 3. that showed increases in rCMRglu from waking to REM sleep in the depressed subjects was a structure in the rostral tectal area Žpretectum, superior colliculus and the periaqueductal gray, Fig. 2.. Verification was aided by the presence of cerebrospinal fluid in subarachnoid cisterns dorsal to the tectum. The second area that showed increases in rCMRglu from waking to REM sleep was a large confluent band over both the primary sensory cortex

and the primary motor cortex of the left hemisphere. A third area involved the left amygdala, extending into the uncal gyrus. A fourth area was observed in the hypothalamus and a fifth area in the left subicular complex. Three areas that showed significant decreases in rCMRglu from waking to REM sleep were noted in the depressed subjects ŽFig. 2.. The first was a large bilateral confluent region over the lingual gyrus of the occipital lobe. The second was a region deep to the right hemispheric caudal insular cortex. The third was a region of the right posterior thalamus. 3.3.1. Group interactions: depressed waking to REM sleep comparison ¨ s. healthy control waking to REM sleep comparison In order to determine if the changes in rCMRglu from waking to REM sleep were significantly different between the depressed and healthy com-

66

E.A. Nofzinger et al. r Psychiatry Research: Neuroimaging Section 91 (1999) 59]78

Fig. 1. Minute-by-minute distribution of wake, NREM, and REM sleep across the 20-min w 18 FxFDG uptake period for the REM sleep PET scan in depressed and control subjects.

E.A. Nofzinger et al. r Psychiatry Research: Neuroimaging Section 91 (1999) 59]78

parison subjects, two SPM interaction contrasts were performed. The first contrast ŽTable 4, Fig. 3. showed structures with significantly greater increases in rCMRglu from waking to REM sleep in the depressed group. For several structures, the interaction seemed to be related to a difference in the direction of change in rCMRglu Žeither increases or decreases. from waking to REM sleep between groups. Structures showing this pattern included the left sensorimotor cortex, the left inferior temporal lobe, the left uncal gyrus, the left frontal cortex ŽBrodmann’s area 10., and the left subicular complex. The tectal area also showed an interaction in this contrast. For this structure the interaction appeared to be related to a large highly significant increase in rCMRglu from waking to REM sleep in the depressed subjects and no significant change from waking to REM sleep in the healthy control subjects. A second contrast ŽTable 4, Fig. 3. showing condition by group interactions was performed to define structures that showed significantly more increases in rCMRglu from waking to REM sleep in the healthy control subjects in comparison with the depressed subjects. Three structures reached statistical significance, each of which showed increases in rCMRglu from waking to REM sleep in the healthy subjects but, if anything tended to show decreases in rCMRglu from waking to REM sleep in the depressed group. These structures

67

included the right parahippocampal gyrus, the right insular cortex, and the anterior cingulate cortex. Two coordinates within the anterior cingulate region are reported in Table 4. The first, the region of maximal interaction, corresponds closely with that reported by Mayberg et al. Ž1997. as being abnormal in waking functional brain imaging studies of depression Ž x, y, z s 0, 38, 12.. The second region reported in the subgenual anterior cingulate cortex Ž x, y, z s 0, 24, y8. lies within the larger region and was selected to correspond to the region reported by Drevets et al. Ž1997. to be abnormal in depression based on waking functional brain imaging studies. 3.3.2. Post-hoc region of interest analyses: betweengroup (depressed ¨ s. control) comparisons for waking and REM sleep Following the identification of structures that demonstrated an interaction in the above analyses Žlisted in Table 4., we determined if there were between-group differences Ždepressed vs. control. for these structures in rCMRglu during either the waking or REM sleep condition. In the waking comparison, the left inferior temporal lobe ŽTalairach coordinates x, y, zs y44, y10, y20; Z s 3.00, Ps 0.001. showed decreased rCMRglu in the depressed group. While the between-group difference in rCMRglu for the inferior region of the anterior cingulate, identified by the interaction analysis, did not reach statistical significance,

Table 3 Depressed subjects Ž n s 6.: normalized glucose metabolic rate comparisons between waking and REM sleep Region size for confluent area Žpixels.

Region of maximal difference in confluent area

Acti¨ ations from waking to REM 62 Tectal area 205 L. sensorimotor cortex 625 L. amygdala, uncul gyrus 145 Hypothalamus 64 L. subicular complex Deacti¨ ations from waking to REM 494 Lingual gyrus 83 R. claustrum 75 R. pulvinar

x

y

z

Z for maxima

0 y40 y24 y2 y16

y32 y24 0 y2 y18

0 48 y20 y4 y12

4.63 4.23 4.10 4.10 3.70

- 0.001 - 0.001 - 0.001 - 0.001 - 0.001

y8 26 18

y76 y2 y30

y8 16 4

4.38 3.61 3.52

- 0.001 - 0.001 - 0.001

Coordinates of maxima

P

68 E.A. Nofzinger et al. r Psychiatry Research: Neuroimaging Section 91 (1999) 59]78 Fig. 2. Brain sections at 26 transaxial levels. Highlighted areas in the yellowrred spectra reveal pixels where there was an increase in rCMRglu from waking to REM sleep for depressed subjects at the P - 0.01 level of significance. Highlighted areas in the blue spectra reveal pixels where there was a decrease in rCMRglu from waking to REM sleep for depressed subjects at the P- 0.01 level of significance. Background MR images are from an individual subject. Both the MR images and the statistical images have been normalized into the same Talairach space.

E.A. Nofzinger et al. r Psychiatry Research: Neuroimaging Section 91 (1999) 59]78 69

Fig. 3. Brain sections at 26 transaxial levels. Highlighted areas in the yellowrred spectra reveal pixels where the change in rCMRglu from waking to REM sleep was significantly greater for depressed subjects than for healthy subjects at the P- 0.01 level of significance. Highlighted areas in the blue spectra reveal pixels where the change in rCMRglu from waking to REM sleep was significantly less for depressed subjects than for healthy subjects at the P - 0.01 level of significance. Background MR images are from an individual subject. Both the MR images and the statistical images have been normalized into the same Talairach space.

70

Region size for confluent area Žpixels.

Region of maximal difference in confluent area

Coordinates of maxima

Depressedd

x

y

z

Relative wake

CMRglu REM

Relative wake

CMRglu REM

Contrast 1a 112 12 179 60 20 31 22

L. sensorimotor cortex Tectal area L. inf. temporal lobe L. uncus L. sensorimotor cortex L. frontal L. subicular complex

y40 0 y44 y24 y48 y24 y14

y24 y32 y10 4 y6 50 y16

48 0 y20 y20 20 y4 y16

69.6" 0.8 44.3" 0.9 55.9" 1.0 50.6" 0.9 64.6" 0.6 67.1" 0.8 45.2" 1.4

77.5" 0.8 55.6" 0.9 62.9" 1.0 56.8" 0.9 71.7 " 0.6 69.9" 0.8 53.2" 1.4

76.4" 0.7 49.6" 0.9 63.5" 1.1 52.4" 0.6 67.5" 1.2 71.0" 1.2 49.7" 0.9

18 44 0

y50 y8 38

y12 8 12

70.0" 0.8 74.8" 1.2 67.5" 1.4

67.4" 0.8 69.9" 1.2 62.6" 1.4

0

24

y8

65.0" 1.2

59.2" 1.2

Contrast 2b 134 167 121 c a

R. parahippocampal gyrus R. insular cortex Subgenual and pregenual ant. cingulate Subgenual ant. cingulate

Controld

Z for maxima

P

73.8" 0.7 51.2" 0.9 59.1" 1.1 50.6" 0.6 65.1" 1.2 63.9" 1.2 47.5" 0.9

4.00 3.56 3.54 3.53 3.26 3.18 3.16

- 0.001 - 0.001 - 0.001 - 0.001 0.001 0.001 0.001

62.7" 0.7 69.0" 1.1 63.7" 0.8

71.8" 0.7 76.6" 1.1 69.9" 0.8

4.21 3.52 3.36

- 0.001 - 0.001 - 0.001

59.7" 2.5

67.0" 2.5

]

]

Depressed activation ŽREM-wake. greater than control activation ŽREM-wake.. Control activation ŽREM-wake. greater than depressed activation ŽREM-wake.. c This region was selected a priori as defined in text and fell within the larger subgenual and pregenual region described above. d All values are relative to a mean brain value arbitrarily set at 50. b

E.A. Nofzinger et al. r Psychiatry Research: Neuroimaging Section 91 (1999) 59]78

Table 4 Depressed vs. healthy subject interactions in normalized cerebral glucose metabolic rate ŽCMRglu. activations from waking to REM sleep

E.A. Nofzinger et al. r Psychiatry Research: Neuroimaging Section 91 (1999) 59]78

a large region of the anterior cingulate immediately superior to this area was shown to have reduced rCMRglu in the depressed patients Ž175 contiguous pixels at P- 0.05 level of significance with x, y, z maxima at 6, 38, 28 where Z s 3.67, P- 0.001.. Two structures were noted to have increased rCMRglu in the depressed patients during waking. First was the left amygdala inclusive of the left uncus Ž76 contiguous pixels significant at a P- 0.05 level including a region maxima at x, y, z s y26, y8, y20 where Z s 2.46, Ps 0.007. and second was the right parahippocampal gyrus Ž267 contiguous pixels significant above a P- 0.05 level including a region maxima at x, y, zs 12, y68, y4 where Z s 3.25, Ps 0.001.. In the REM sleep condition, the left sensorimotor cortex had increased rCMRglu in depressed patients in relation to the controls Ž59 contiguous pixels significant above a P- 0.05 level including a region maxima at x, y, z s y48, y8, 20 where Z s 3.95, P- 0.001.. The majority of the entire right gyrus rectus had decreased rCMRglu in the depressed patients in relation to the controls Ž318 contiguous pixels significant above a P- 0.05 level including a region maxima at x, y, zs 12, 38, y12 where Z s 3.63, P- 0.001..

4. Discussion The patterns of change in relative regional cerebral glucose metabolism from waking to REM sleep in healthy control subjects predominantly involve a set of paramedian structures extending from the hypothalamus into basal forebrain, anterior cingulate and medial prefrontal cortex, the anterior paralimbic REM activation axis ŽNofzinger et al., 1997.. In contrast, the primary result of the present study is that depressed subjects show a distinctly different pattern of change in relative regional cerebral glucose metabolism from waking to REM sleep characterized by the following: Ž1. a lack of increase in rCMRglu from waking to REM sleep in the cortical components of the anterior paralimbic REM activation axis, the subgenual and anterior cingulate, and medial prefrontal cortical areas; Ž2. depressed subjects show increases in rCMRglu from waking to REM

71

sleep predominantly in left hemisphere cortical structures including the sensory and motor cortex and inferior and medial temporal lobe; and Ž3. depressed subjects show increases in rCMRglu in the rostral tectum from waking to REM sleep. 4.1. Waking ¨ s. REM sleep comparisons: healthy and depressed subjects The findings in the current study describing the structures showing increases in rCMRglu during REM sleep compared to waking in the healthy subjects are consistent with other reports ŽBuchsbaum et al., 1989; Maquet et al., 1996; Braun et al., 1997, 1998; Nofzinger et al., 1997.. These structures are primarily anterior mesial limbic and paralimbic structures. Anatomically, these structures are transitional between neocortex and hypothalamic and brainstem regions involved in neuroendocrine, autonomic, metabolic and behavioral homeostatic regulatory mechanisms. The functions of these structures include the modulation of emotional and motivational behavior, selective attention, learning and memory and the coordination of hypothalamic function and the autonomic nervous system. The region that showed the most significant degree of change in rCMRglu from waking to REM sleep in the depressed subjects was the tectal area Žpretectum, superior colliculus and periaqueductal gray.. Given the novelty of change in rCMRglu in this structure in this paradigm and the relatively small size of this structure in the context of the spatial resolution of the current PET paradigm, we confirmed its identity by superimposing the low resolution SPM activation image onto the higher resolution MR image for each individual subject in the study. The superior colliculus is densely innervated by cholinergic neurons involved in the generation of REM sleep and is one of the relay stations through which optic afferents affect brainstem reticular neurons. The superior colliculus and pretectal area are known to be important in the generation of saccadic eye movements. The superior colliculus, more generally, is involved in orienting behavior ŽRobinson and Kertzman, 1995; Sprague, 1996.. It receives inputs from a variety of sensory modalities, and

72

E.A. Nofzinger et al. r Psychiatry Research: Neuroimaging Section 91 (1999) 59]78

neurons controlling brain stem circuits mediating orienting eye and head movements are likely to integrate information from different systems ŽPeck, 1996; Wallace and Stein, 1996.. Electrical stimulation of the superior colliculus in rats is associated with orienting behavior including arousal, freezing and escape with increases in arterial blood pressure, heart rate, and respiration ŽSandner et al., 1993; Brandao et al., 1994. } behaviors and physiologic signs also characteristic of the REM sleep state. Similar functions Žorganization of defensive or aversive behavior. have been proposed for the periaqueductal gray ŽBrandao et al., 1994.. The finding of increases in rCMRglu from waking to REM sleep in the tectal area in depressed patients, therefore, is consistent with the notion that REM sleep may involve central structures related not only to saccadic eye movements, but also related to more primitive defensive and aversive response behavior. A recently published study ŽMiller et al., 1998. indicates that the superior colliculus-pretectal region is necessary for light induction of REM sleep in rats. If these data are generalizable to humans, they implicate the optic tectum in REM sleep regulation and, taken together with our data, may indicate a dysregulation in the tectal control of REM sleep in depression. The left sensorimotor cortex also showed an increase in rCMRglu from waking to REM sleep in the depressed group, and motor behavior is often a component of dream imagery. The left amygdala and adjacent uncal gyrus showed increases in rCMRglu from waking to REM sleep in the depressed subjects. In the post-hoc analyses, the amygdala was also shown to have significantly greater rCMRglu during waking for depressed subjects in relation to the healthy control subjects. Involvement of the amygdala during REM sleep has been seen in three prior reports describing blood flow ŽMaquet et al., 1996; Braun et al., 1997. and glucose metabolism ŽNofzinger et al., 1997. in healthy human subjects. Reciprocal connections have been shown to exist between the amygdala and the upper brainstem reticular areas from which REM sleep is generated ŽHopkins and Holstege, 1978; Takeuchi et al., 1982; Moga and Gray, 1985.. It has been pro-

posed ŽSteriade and McCarley, 1990. that the amygdala-induced facilitation of PGO waves of REM sleep may be related to the elicitation of dreaming sensations by electrical stimulation of the amygdala and other limbic structures in man ŽHalgren et al., 1978.. Elicitation of defensive, fear-associated behavior is also seen during electrical stimulation of the amygdala, in many ways similar to electrical stimulation of other components of a generalized arousal system including the tectal area and the hypothalamus. A large area inclusive of the hypothalamus showed increases in rCMRglu from waking to REM sleep in both control and depressed subjects. Increases in rCMRglu in the hypothalamus during a probe selectively designed to activate limbic and paralimbic structures are consistent with models of increased arousal in the limbicrhypothalamicrpituitary axis presumably having a limbic origin ŽKirkegaard et al., 1975; Matussek et al., 1980; Gold et al., 1988; Chrousos and Gold, 1992; Van Cauter, 1994.. The left subicular complex Žsubiculum, presubiculum and parasubiculum. showed increases in rCMRglu from waking to REM sleep in the depressed subjects. The subicular complex is considered a primary output site of the hippocampus with extensive bi-directional connectivity with wide areas of the neocortex as well as primary subcortical limbic structures ŽAmaral and Insausti, 1990.. Decreases in rCMRglu from waking to REM sleep in the depressed subjects were shown in the lingual gyrus, predominantly on the right, a region deep to the right hemispheric caudal insular cortex which most likely corresponds to the claustrum, and a large region over the posterior thalamus, most likely the pulvinar nucleus, regions involved in visual processing ŽGarey, 1990.. The finding that depressed subjects show decreases in rCMRglu from waking to REM sleep in these components of the visual system is of unclear significance. 4.2. Interactions between depressed and healthy subjects: waking ¨ s. REM sleep Three general patterns of interactions between

E.A. Nofzinger et al. r Psychiatry Research: Neuroimaging Section 91 (1999) 59]78

the depressed and healthy groups were noted. The first type included structures that showed significantly greater increases in rCMRglu from waking to REM sleep in the healthy control subjects than in the depressed subjects. These structures included the right parahippocampal gyrus, the right insular cortex, and the anterior cingulate cortex. As noted above, each of these structures is in phylogenetically older paralimbic cortex. The lack of an increase in rCMRglu from waking to REM sleep in the inferior anterior cingulate Žsubgenual and pregenual. cortex in the depressed subjects suggests a blunted responsivity of this structure in depression. Additionally, more superiorly located regions of the anterior cingulate were noted to have decreased rCMRglu in depressed patients during waking. Blunted increases in rCMRglu in the inferior anterior cingulate and decreased baseline rCMRglu in more superior regions suggest a functional pathology in a broad region of the anterior cingulate cortex in depressed patients. The anterior cingulate cortex has been linked to selective attention, response to novel stimulation and motivation, and has been conceptualized as an effector system of limbic structures translating limbic information to hypothalamic and autonomic effector systems. The decreased responsivity of this structure in the depressed subjects, therefore, may relate to deficiencies in reacting to emotionally and motivationally salient information and in translating this information into effective adaptive behavioral strategies. At the clinical level, this may be manifested as a loss of motivation, a loss of reactivity of mood, and feelings of hopelessness and helplessness characteristic of this anergic condition. Further studies in which clinical measures can be correlated with functional brain imaging measures in individual patients are required to substantiate these hypotheses. Prior studies of waking cerebral activity in depressed patients have shown reductions in brain metabolism in the same structures identified in the current study to be functionally hypoactive during REM sleep. Drevets et al. Ž1997. have identified an area of abnormally decreased activity in the prefrontal cortex ventral to the genu of the corpus callosum in both familial bipolar de-

73

pressives and familial unipolar depressives. Additionally, a reduction in cortical volume was detected in this area by magnetic resonance imaging. We did not find an alteration in waking glucose utilization in this area, perhaps related to limited statistical power of the between-group comparison, or perhaps reflecting the difference in patient populations in our study compared to that of Drevets et al. Ž1997.. Mayberg et al. Ž1997. have identified an area in the rostral anterior cingulate cortex where pretreatment activity predicted a subsequent antidepressant response. While their entire group of depressed patients showed baseline hypoactivity in this region compared to healthy control subjects, the responders to treatment had baseline hypermetabolism in this structure and non-responders had baseline hypometabolism. Based on their review of the literature, they concluded that this region of the cingulate cortex may function as a bridge linking dorsal and ventral cingulate pathways necessary for the normal integrative processing of mood, motor, autonomic and cognitive behaviors that are disturbed in mood disorders patients. Wu et al. Ž1992. identified a structure in the anterior cingulate cortex where baseline activity distinguished subsequent response to sleep deprivation in depressed patients. Inspection of their PET images from that report suggests that this region is comparable to that identified by Mayberg in the pregenual anterior cingulate and prefrontal cortex. Baseline hypermetabolism and subsequent decrease in metabolism in this structure following sleep deprivation characterized the responder group. Ebert et al. Ž1991. reported similar findings in the anterior cingulate cortex during sleep deprivation. Non-responders, in contrast, showed lower baseline metabolism in this structure in relation to the responders with no statistically significant change in metabolism following sleep deprivation. In the current study, the inferior portions of the anterior cingulate Žsubgenual and pregenual anterior cingulate and medial prefrontal cortex. showed a statistically significant interaction between the depressed and control subjects in response to the waking to REM sleep imaging paradigm. Healthy subjects, similar to prior PET studies of healthy human REM sleep

74

E.A. Nofzinger et al. r Psychiatry Research: Neuroimaging Section 91 (1999) 59]78

ŽBuchsbaum et al., 1989; Maquet et al., 1996; Nofzinger et al., 1997., showed a significant increase in rCMRglu in this structure from waking to REM sleep, whereas the depressed patients failed to show an increase in rCMRglu from waking to REM sleep. The current study, therefore, demonstrates a functional impairment, a failure to activate in REM sleep, in these structures which previously have been implicated in depressive pathophysiology and in treatment response in patients with mood disorders. The second general pattern of interaction noted between depressed and control subjects was a large significant increase in rCMRglu in the tectal region of the midbrain from waking to REM sleep noted in the depressed subjects which was not seen in the healthy subjects. Among the characteristic EEG sleep features in depressed patients is an increase in the number of rapid eye movements during REM sleep. At the simplest level of interpretation, the increase in rCMRglu from waking to REM sleep in these tectal structures may relate to the increased eye movement activity noted during REM sleep in depressed patients. The third pattern of interaction noted between the depressed and control subjects was a difference in the direction of change in rCMRglu Žeither increases or decreases. from waking to REM sleep between groups. Structures showing this pattern included the left sensorimotor cortex, the left inferior temporal lobe, the left uncal gyrus, the left frontal cortex ŽBrodmann’s area 10., and the left subicular complex. Notably, the left inferior lobe was shown to have reduced rCMRglu in the depressed patients during waking. The inferior temporal lobe has been associated with the latter stages of processing of visual information originating in the occipital cortex. This inferior visual pathway is thought to be associated with the attribution of meaning Žthe ‘what’. to visual information as opposed to adding spatial associations handled by the dorsal stream of visual information processing. These inferior temporal areas are also more linked to anatomical connections with the amygdala than are other areas of the visual pathways, suggesting that this is the area in which images achieve emotional

salience ŽTurner et al., 1980.. Along these lines, it is important to note that the amygdala showed increased rCMRglu in the depressed patients during waking, in addition to a greater increase in rCMRglu from waking to REM sleep than in the controls. The greater increases in rCMRglu in these structures from waking to REM sleep in depressed patients may reflect differences in the processing of emotionally salient material in the depressed brain during REM sleep. 4.3. Limitations Some limits of the study should be recognized and render the findings as preliminary in nature. First, the sample size of the depressed group is small. Only very large effects could be observed that may be idiosyncratic to this depressed group. These findings will require replication in a different group of depressed patients. Second, the results of the current study should be interpreted as reflecting differences in rCMRglu between waking and predominantly REM sleep. However, it should be recognized that in any study utilizing FDG methods, the final emission scan reflects a weighted average of glucose metabolism across all brain states from the time of injection until the time of emission scanning, where the weighting is proportionally greater for the period immediately following injection. In the current study, the final emission scan reflects brain activity during up to three generalized brain states: Ž1. REM sleep; Ž2. NREM sleep Žif present.; and Ž3. wakefulness Žif present. for the initial 20 min followed by 40 min of wakefulness up to the time of the emission scan. In reference to the work of Huang et al. Ž1981., in the current study, the largest effect of NREM sleep contamination for our subjects Žmaximum NREM sleep duration of 8 min beginning at post-injection time 12 min and lasting until 20 min. is a 3% contribution to absolute metabolism Žmean for all subjects is a 2.5% contribution to overall metabolism.. This is true even after taking into account differences in NREM sleep absolute glucose metabolism between depressed and healthy subjects as previously described by Ho et al. Ž1996.. This is related to the predominance of REM sleep in the early high

E.A. Nofzinger et al. r Psychiatry Research: Neuroimaging Section 91 (1999) 59]78

uptake period following injection and the relatively short duration of NREM sleep during a period of significantly lower uptake and metabolism. Since the conditions for subjects are identical for the waking and REM sleep studies following the initial 20-min period of uptake of FDG, the contributions of this period should be canceled out in within-subject comparative analyses of these studies. The primary findings in the current study, therefore, are predominantly related to differences from waking to REM sleep in rCMRglu, although a small contribution from NREM sleep should be recognized to be present as well. The similarity of our control REM sleep findings to the results of two other studies that utilized blood flow measures during REM sleep ŽMaquet et al., 1996; Braun et al., 1997, 1998. and the thematic consistency between our findings and the known neurobiology of REM sleep lead us to believe that our data reflect predominantly the REM period and not the ensuing NREM period. Third, absolute glucose metabolism was not assessed. This would have required blood sampling during sleep, which we felt would compromise the naturalistic design. Prior studies in healthy subjects have shown that absolute glucose metabolism during REM sleep is comparable to that of waking ŽSakai et al., 1980; Gozukirmize et al., 1982; Heiss et al., 1985; Franck et al., 1987; Meyer et al., 1987; Buchsbaum et al., 1989; Maquet and Franck, 1989; Maquet et al., 1990; Madsen et al., 1991a,b. so that, in the healthy subjects, alterations in regional glucose metabolism from waking to REM sleep reflect the change in brain state. No studies in depressed patients have been reported. Fourth, our comparison waking PET image was acquired during a different circadian time point than was the REM study, and all depressed subjects, and none of the control subjects, reported diurnal mood variation. This raises the possibility that the between-group effects on rCMRglu may relate to interactions in diurnal mood variability between groups. Prior studies of healthy subjects in our PET center, however, suggest that structures affected by these circadian variations are not the same as those identified in our interactions. Also, if diurnal variations in mood were to contribute to the current findings,

75

we would expect the findings to be the reverse of what was found, given that the predominant functional brain imaging finding related to depression is a hypofrontality, the condition that we found during the REM sleep state. Our impression, therefore, is that the results are most likely not related to diurnal mood variations in the depressed but not the control samples, although this remains an issue for future studies. Finally, it will be important to study later REM periods to determine whether the observed alterations are specific to the first REM period or are more generalizable. Fifth, one of the healthy subjects studied demonstrated a short REM latency on the baseline and PET nights of study. This is unusual. We do not think, however, that this skewed the findings since the effects observed were of large magnitude suggesting the relative homogeneity of cerebral metabolism in healthy subjects in significant brain regions.

Acknowledgements This research was supported in part by grants from the Theodore and Vada Stanley Foundation, MH01414, MH30915, RR00056, MH49815, MH24652, MH52247, MH37869, and MH00295. The authors thank Mark A. Mintun, M.D., David Townsend, Ph.D., and Chet Mathis, Ph.D., for their advice on PET methodology, the technical staffs of the Sleep and Chronobiology Center, the General Clinical Research Center and the PET Center at the University of Pittsburgh Medical Center for their help in conducting this work, and Lynda Rose for study coordination. We also thank the anonymous reviewers of this work, whose suggestions were included throughout the report. References Amaral, D.G., Insausti, R., 1990. Hippocampal formation. In: Paxinos, G. ŽEd.., The Human Nervous System. Academic Press, Inc., San Diego, pp. 711]756. American Psychiatric Association Committee on Nomenclature and Statistics, 1987. Diagnostic and Statistical Manual of Mental Disorders, 3rd ed. revised. APA, Washington, DC.

76

E.A. Nofzinger et al. r Psychiatry Research: Neuroimaging Section 91 (1999) 59]78

Benca, R.M., Obermeyer, W.H., Thisted, R.A., Gillin, J.C., 1992. Sleep and psychiatric disorders: a meta-analysis. Archives of General Psychiatry 49, 651]668. Borbely, ´ A.A., Wirz-Justice, A., 1982. A two-process model of sleep regulation. II. Implications for depression. Human Neurobiology 1, 205]210. Brandao, M.L., Cardoso, S.H., Melo, L.L., Motta, V., Coimbra, N.C., 1994. Neural substrate of defensive behavior in the midbrain tectum. Neuroscience and Biobehavioral Reviews 18, 339]346. Braun, A.R., Balkin, T.J., Wesenten, N.J., Carson, R.E., Varga, M., Baldwin, P., Selbie, S., Belenky, G., Herscovitch, P., 1997. Regional cerebral blood flow throughout the sleepwake cycle. An H 2 Ž15.O PET study. Brain 120, 1173]1197. Braun, A.R., Balkin, T.J., Wesensten, N.J., Gwadry, F., Carson, R.E., Varga, M., Baldwin, P., Belenky, G., Herscovitch, P., 1998. Dissociated pattern of activity in visual cortices and their projections during human rapid eye movement sleep. Science 279, 91]95. Buchsbaum, M.S., Gillin, J.C., Wu, J., Hazlett, E., Sicotte, N., DuPont, R.M., 1989. Regional cerebral glucose metabolic rate in human sleep assessed by positron emission tomography. Life Sciences 45, 1349]1356. Chrousos, G.P., Gold, P.W., 1992. The concepts of stress and stress system disorders. Journal of the American Medical Association 267, 1244]1252. Cyr, J.J., McKenna-Foley, J.M., Peacock, E., 1985. Factor structure of the SCL-90-R: is there one? Journal of Personality Assessment 49, 571]578. Derogatis, L.R., 1977. SCL-90: Administration, Scoring and Procedure Manual. Johns Hopkins, Baltimore. Dew, M.A., Reynolds, C.F., Buysse, D.J., Houck, P.R., Hoch, C.C., Monk, T.H., Kupfer, D.J., 1996. Electroencephalographic sleep profiles during depression. Effects of episode duration and other clinical and psychosocial factors in older adults. Archives of General Psychiatry 53, 148]156. Drevets, W.C., Price, J.L., Simpson Jr., J.R., Todd, R.D., Reich, T., Vannier, M., Raichle, M.E., 1997. Subgenual prefrontal cortex abnormalities in mood disorders. Nature 386, 824]827. Ebert, D., Feistel, H., Barocka, A., 1991. Effects of sleep deprivation on the limbic system and the frontal lobes in affective disorders: a study with Tc-99m-HMPAO SPECT. Psychiatry Research: Neuroimaging 40, 247]251. Endicott, J., Spitzer, R.L., 1978. A diagnostic interview. The schedule for affective disorders and schizophrenia. Archives of General Psychiatry 35, 837]844. Franck, G., Salmon, E., Poirrier, R., Sadzot, B., Franco, G., 1987. Etude du metabolisme glucidique cerebral regional chez l’homme, au cours de l’eveil et du sommeil, par tomography a emission de positrons. Rev EEG Neurophysiol Clin 17, 71]77. Friston, K.J., Frith, C.D., Liddle, P.F., Dolan, R.J., Lammertsma, A.A., Frackowiak, R.S., 1990. The relationship between global and local changes in PET scans. Journal of Cerebral Blood Flow and Metabolism 10, 458]466. Friston, K.J., Frith, C.D., Liddle, P.F., Frackowiak, R.S., 1991.

Comparing functional ŽPET. images: the assessment of significant change. Journal of Cerebral Blood Flow and Metabolism 11, 690]699. Garey, L.J., 1990. Visual system. In: Paxinos, G. ŽEd.., The Human Nervous System. Academic Press, Inc., San Diego, pp. 945]978. Giles, D.E., Kupfer, D.J., Roffwarg, H.P., Rush, A.J., Biggs, M.M., Etzel, B.A., 1989. Polysmonographic parameters in first-degree relatives of unipolar probands. Psychiatry Research 27, 127]136. Gillin, J.C., Sitaram, N., Duncan, W.C., 1979. Muscarinic supersensitivity: a possible model of the sleep disturbances of primary depression? Psychiatry Research 1, 17]22. Gillin, J.C., Sutton, L., Ruiz, C., Kelsoe, J., DuPont, R.M., Darko, D., Risch, S.C., Golshan, S., Janowsky, D., 1991. The cholinergic rapid eye movement test with arecoline in depression. Archives of General Psychiatry 48, 264]270. Gold, P.W., Goodwin, F.K., Chrousos, G.P., 1988. Clinical and biochemical manifestations of depression. New England Journal of Medicine 319, 413]420. Gozukirmize, E., Meyer, J.S., Okabe, T., Amano, T., Mortel, K., Karacan, I., 1982. Cerebral blood flow during paroxysmal EEG induced by sleep in patients with complex partial seizures. Sleep 5, 329]342. Halgren, E., Walter, R.D., Cherlow, D.G., Crandal, P.H., 1978. Mental phenomena evoked by electrical stimulation of the human hippocampal formation and amygdala. Brain 101, 83]117. Hamilton, M., 1960. A rating scale for depression. Journal of Neurology, Neurosurgery and Psychiatry 23, 56]62. Heiss, W.D., Pawlik, G., Herholz, K., Wagner, R., Wienhard, K., 1985. Regional cerebral glucose metabolism in man during wakefulness, sleep, and dreaming. Brain Research 327, 362]366. Ho, A.P., Gillin, J.C., Buchsbaum, M.S., Wu, J.C., Abel, L., Bunney, W.E., 1996. Brain glucose metabolism during non-rapid eye movement sleep in major depression: a positron emission tomography study. Archives of General Psychiatry 53, 645]652. Hopkins, D.A., Holstege, G., 1978. Amygdaloid projections to the mesencephalon, pons and medulla oblongata in the cat. Experimental Brain Research 32, 529]547. Huang, S.C., Phelps, M.E., Hoffman, E.J., Kuhl, D.E., 1981. Error sensitivity of fluorodeoxyglucose method for measurement of cerebral metabolic rate of glucose. Journal of Cerebral Blood Flow and Metabolism 1, 391]401. Kirkegaard, C., Norlem, N., Lawridsen, U.B., Bjorum, N., Christiansen, C., 1975. Protirelin stimulation test and thyroid function during treatment of depression. Archives of General Psychiatry 32, 1115]1118. Kupfer, D.J., Ehlers, C.L., 1989. Two roads to rapid eye movement latency. Archives of General Psychiatry 46, 945]948. Kupfer, D.J., Frank, E., McEachran, A.B., Grochocinski, V.J., 1990. Delta sleep ratio: a biological correlate of early recurrence in unipolar affective disorder. Archives of General Psychiatry 47, 1100]1105.

E.A. Nofzinger et al. r Psychiatry Research: Neuroimaging Section 91 (1999) 59]78 Lauer, C.J., Riemann, D., Wiegand, M., Berger, M., 1991. From early to late adulthood changes in EEG sleep of depressed patients and healthy volunteers. Biological Psychiatry 29, 979]993. Lauer, C.J., Schreiber, W., Holsboer, F., Krieg, J.C., 1995. In quest of identifying vulnerability markers for psychiatric disorders by all-night polysomnography. Archives of General Psychiatry 52, 145]153. Madsen, P.L., Holm, S., Vorstrup, S., Friberg, L., Lassen, N.A., Wildschiodtz, G., 1991a. Human regional cerebral blood flow during rapid-eye-movement sleep. Journal of Cerebral Blood Flow and Metabolism 11, 502]507. Madsen, P.L., Schmidt, J.F., Wildschiodtz, G., 1991b. Cerebral oxygen metabolism and cerebral blood flow in humans during deep and rapid-eye movement sleep. Journal of Applied Physiology 70, 2597]2601. Mann, J.J., Malone, K.M., Diehl, D.J., Perel, J., Nichols, T.E., Mintun, M.A., 1996. Positron emission tomographic imaging of serotonin activation effects on prefrontal cortex in healthy volunteers. Journal of Cerebral Blood Flow and Metabolism 16, 418]426. Maquet, P., Franck, G., 1989. Cerebral glucose metabolism during the sleep-wake cycle in man as measured by positron emission tomography. In: Horne, J. ŽEd.., Sleep ’88. Gustav Fischer, Stuttgart, New York, pp. 76]78. Maquet, P., Dive, D., Salmon, E., Sadzot, B., Franco, G., Poirrier, R., von Frenckell, R., Franck, G., 1990. Cerebral glucose utilization during sleep-wake cycle in man determined by positron emission tomography and w 18 Fx2-fluoro-2-deoxy-D-glucose method. Brain Research 513, 136]143. Maquet, P., Peters, J.M., Aerts, J., Delfiore, G., Degueldre, C., Luxen, A., Franck, G., 1996. Functional neuroanatomy of human rapid-eye-movement sleep and dreaming. Nature 383, 163]166. Matussek, N., Ackenheil, M., Hippius, H., 1980. Effect of clonidine on growth hormone release in psychiatic patients and controls. Psychiatry Research 2, 25]36. Mayberg, H.S., Brannan, S.K., Mahurin, R.K., Jerabek, P.A., Brickman, J.S., Tekell, J.L., Silva, J.A., McGinnis, S., Glass, T.G., Martin, C.C., Fox, P.T., 1997. Cingulate function in depression } a potential predictor of treatment response. Neuroreport 8, 1057]1061. McCarley, R.W., Greene, R.W., Rainnie, D., Portas, C.M., 1995. Brainstem neuromodulation and REM sleep. Neuroscience 7, 341]354. McCarley, R.W., 1982. REM sleep and depression: common neurobiological control mechanisms. American Journal of Psychiatry 139, 565]570. Meyer, J.S., Ishikawa, Y., Hata, T., Karacan, I., 1987. Cerebral blood flow in normal and abnormal sleep and dreaming. Brain and Cognition 6, 266]294. Miller, A.M., Obermeyer, W.H., Behan, M., Benca, R.M., 1998. The superior colliculus-pretectum mediates the direct effects of light on sleep. Proceedings of the National Academy of Sciences USA 95, 8957]8962. Minoshima, S., Koeppe, R.A., Mintun, M.A., Berger, K.L.,

77

Taylor, S.F., Frey, K.A., 1993. Automated detection of the intercommissural line for stereotactic localization of functional brain. Journal of Nuclear Medicine 34, 322]329. Moga, M.M., Gray, T.S., 1985. Evidence for corticotropin-releasing factor, neurotensin, and somatostatin in the neural pathway from the central nucleus of the amygdala to the parabrachial nucleus. Journal of Comparative Neurology 241, 275]284. Nofzinger, E.A., Buysse, D.J., Reynolds, C.F., Kupfer, D.J., 1993. Sleep disorders related to another mental disorder Žnon-substancerprimary .: a DSM-IV literature review. wReviewx Journal of Clinical Psychiatry 54, 244]255; discussion 256]259. Nofzinger, E.A., Schwartz, R.M., Reynolds, C.F., Thase, M.E., Jennings, J.R., Frank, E., Fasiczka, A.L., Garamoni, G.L., Kupfer, D.J., 1994. Affect intensity and phasic REM sleep in depressed men before and after treatment with cognitive-behavioral therapy. Journal of Consulting and Clinical Psychology 62, 83]91. Nofzinger, E.A., Mintun, M.A., Wiseman, M.B., Kupfer, D.J., Moore, R.Y., 1997. Forebrain activation in REM sleep: an FDG PET study. Brain Research 770, 192]201. Nofzinger, E.A., Mintun, M.A., Price, J., Meltzer, C.C., Townsend, D., Buysse, D.J., Reynolds, C.F., Dachille, M., Matzzie, J., Kupfer, D.J., Moore, R.Y., 1998. A method for the assessment of the functional neuroanatomy of human sleep using FDG PET. Brain Research Protocols 2, 191]198. Peck, C.K., 1996. Visual-auditory integration in cat superior colliculus: implications for neuronal control of the orienting response. Progress in Brain Research 112, 167]177. Rechtschaffen, A., Kales, A., 1968. A Manual of Standardized Terminology, Techniques and Scoring System for Sleep Stages of Human Subjects. NIH Publication 204. US Government Printing Office, Department of Health, Education and Welfare, Washington, DC. Reynolds, C.F., Hoch, C.C., Buysse, D.J., Monk, T.H., Houck, P.R., Kupfer, D.J., 1993. REM sleep in successful, usual, and pathological aging: The Pittsburgh experience 1980]1991. Journal on Sleep Research 2, 203]210. Robinson, D.L., Kertzman, C., 1995. Covert orienting of attention in macaques. III. Contributions of the superior colliculus. Journal of Neurophysiology 74, 713]721. Sakai, F., Meyer, J.S., Karacan, I., Derman, S., Yamamoto, M., 1980. Normal human sleep: regional cerebral hemodynamics. Annals of Neurology 7 Ž5., 471]478. Sandner, G., Oberling, P., Silveira, M.C., Di Scala, G., Rocha, B., Bagri, A., Depoortere, R., 1993. What brain structures are active during emotions? Effects of brain stimulation elicited aversion on c-fos immunoreactivity and behavior. Behavioral Brain Research 58, 9]18. Spitzer, R.L., Endicott, J., Robins, E., 1978. Research diagnostic criteria: rationale and reliability. Archives of General Psychiatry 35, 773]782. Spitzer, R.L., Williams, J.B.W., Gibbon, M., First, M.B., 1988. Structured Clinical Interview for DSM-III-R: Patient Version ŽSCID-P, 6r01r88.. Biometrics Research Department, New York State Psychiatric Institute, New York.

78

E.A. Nofzinger et al. r Psychiatry Research: Neuroimaging Section 91 (1999) 59]78

Spitzer, R.L., 1978. Schedule for Affective Disorders and Schizophrenia-Lifetime Version ŽSADS-L.. New York State Psychiatric Institute, New York. Sprague, J.M., 1996. Visual mechanisms of visual orienting responses. In: Norita, M., Bando, T., Stein, B.E. ŽEds.., Extrageniculostriate Mechanisms Underlying Visually Guided Orientation Behavior. Elsevier, New York, pp. 1]16. Steriade, M., McCarley, R.W., 1990. Brainstem Control of Wakefulness and Sleep. Plenum Press, New York. Takeuchi, Y., McLean, J.H., Hopkins, D.A., 1982. Reciprocal connections between the amygdala and parabrachial nuclei: ultrastructural demonstration by degeneration and axonal transport of horseradish peroxidase in the cat. Brain Research 239, 583]588. Talairach, J., Tournoux, P., 1988. Co-Planar Stereotaxic Atlas of the Human Brain. Thieme, Paris. Thase, M.E., Buysse, D.J., Frank, E., Cherry, C.R., Cornes, C.L., Mallinger, A.G., Kupfer, D.J., 1997. Which depressed patients will respond to interpersonal psychotherapy? The role of abnormal electroencephalographic sleep profiles. American Journal of Psychiatry 154, 502]509. Thase, M.E., Simons, A.D., Reynolds, C.F., 1996. Abnormal electroencephalographic sleep profiles in major depression. Archives of General Psychiatry 53, 99]108. Turner, B.H., Mishkin, M., Knapp, M., 1980. Organization of the amygdalopetal projections from modality-specific corti-

cal association areas in the monkey. Journal of Comparative Neurology 191, 515]543. Van Cauter, E. A meta-analysis of cortisol rhythm abnormalities in depression. Presented at the Fourth Meeting of the Society for Research on Biological Rhythms, 1994. Vogel, G.W., Buffenstein, A., Minter, K., Hennessey, A., 1990. Drug effects on REM sleep and on endogenous depression. Neuroscience and Biobehavioral Reviews 14, 49]63. Wallace, M.T., Stein, B.E., 1996. Sensory organization of the superior colliculus in cat and monkey. In: Norita, M., Bando, T., Stein, B.E. ŽEds.., Extrageniculostriate Mechanisms Underlying Visually Guided Orientation Behavior. Elsevier, New York, pp. 301]312. Wiseman, M.B., Nichols, T.E., Dachille, M.A., Mintun, M.A., 1996. Working towards an automatic and accurate method for PET-MR alignment. Proceedings, Society of Nuclear Medicine, Journal of Nuclear Medicine 37, 224P. Woods, R.P., Mazziotta, J.C., Cherry, S.R., 1993. Automated image registration. In: Uemura, K., Jones, T., Lassen, N.A., Kanno, I. ŽEds.., Quantification of Brain Function. Tracer Kinetics and Image Analysis in Brain PET. Elsevier Science Publishers, Amsterdam, pp. 391]398. Wu, J.C., Gillin, J.C., Buchsbaum, M.S., Hershey, T., Johnson, J.C., Bunney, W.E., 1992. Effect of sleep deprivation on brain metabolism of depressed patients. American Journal of Psychiatry 149, 538]543.