Auditory laterality in depression: Relation to circadian patterns and EEG sleep

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Auditory Laterality in Depression: Relation to Circadian Patterns and EEG Sleep Paul Berger-Gross, Gerard E. Bruder, Frederic Quitkin, and Raymond Goetz

Unmedicated endogenous (ED) and nonendogenous depressed (ND) patients were tested in the morning and evening on a dichotic click detection task and a dichotic consonantvowel (CV) discrimination task. The ED and ND groups showed a morning to evening shift in lateral asymmetry for detecting dichotic clicks, which was opposite in direction to that previously seen for normal subjects. In contrast, there was no morning to evening shift in asymmetry for dichotic CV discrimination. Lateral asymmetry for dichotic click detection was significantly correlated with EEG sleep characteristics (sleep latency, REM period latency, REM time) and ratings of diurnal variation on the Hamilton Depression Scale. A reversal of the normal lateral asymmetry in the morning was associated with lengthened sleep latencies and with clinical ratings of diurnal variation.

Introduction A number of studies using measures of lateralized cerebral function (e.g., neuropsychological tests, dichotic listening, lateral eye movements, skin conductance, the electroencephalogram (EEG)) have reported evidence that generally favors the hypothesis of fight hemisphere involvement in depressive disorders (Flor-Henry 1976; Gruzelier and Venables 1974; Myslobodsky and Horesh 1978; Tucker 1981; Fromm and Schopflocher 1984). Three studies using dichotic listening techniques in which nonverbal stimuli (clicks or musical chords) were presented at approximately the same time to the two ears found that fight-handed depressed patients did not show the left ear (fight hemisphere) advantage seen for fight-handed normal controls (Yozawitz et al. 1979; Bruder et al. 1981; Johnson and Crockett 1982). We used a task that involved the detection of dichotic click stimuli at threshold intensity levels. Normal subjects needed less intensity to detect dichotic click stimuli when the left ear click preceded the fight ear click by 60 msec as compared with the opposite order of presentation. Both affective psychotic patients in one study (Yozawitz

From the New York State Psychiatric Institute and Dcpartu~nt of Psychiatry, Columbia UniversityCollege of Physicians and Surgeons, New York, NY. Support~ by National Instituteof Mental Health Grants MH36295 ~ d MI130906. Address reprint requests to: Paul Berger-Gross,Depalln~nt of Neurology, Box 118, DownstateMedical Center, 450 Clarkson Ave., Brooklyn, NY 1! 203. Received July 2, 1984; revised December 3, 1984.

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et al. 1979) and bipolar depressed patients in a second study (Bruder et al. 1981) showed the reverse of this normal lateral asymmetry, i.e., a right ear lead advantage. The purpose of this study was to test patients in the morning and evening as a first step in evaluating the hypothesis that this abnormal pattern of perceptual asymmetry in depressed patients is related to a shift in circadian rhythm. This hypothesis had its origins in two prior findings. First, normal subjects have been found to display circadian and ultradian fluctuations of sensory and cognitive performance (Froberg 1977; Rogers and Vilkin 1978; Klein and Armitage 1979). A recent study (Berger-Gross and Bruder 1984) tested normal subjects in the morning and evening on the dichotic click detection task. They showed the expected left ear lead advantage in the morning but not in the evening, which was interpreted in terms of a daily rhythm that diminishes fight hemispheric activation in the evening. Second, there axe reports linking psychobiological and clinical aspects of depression to circadian rhythm disturbances (Kripke et al. 1978; Wehr et al. 1979, 1980). The present study tested unmedicated depressed patients in the morning and evening on a verbal and nonverbal task. The use of both verbal and nonverbal dichotic listening tasks was designed to contrast predominantly left hemisphere (verbal) versus right hemisphere (nonverbal) processing. In this way, differential morning to evening changes as a function of tasks differing in hemispheric lateralization might provide clearer inferences with respect to the source of these changes. The verbal task used dichotically presented consonant-vowel (CV) syllables, which have been found to yield a right ear (left hemisphere) advantage in normal right-handed subjects (Berlin et al. 1973; Speaks et al. 1982). The nonverbal task provided measures of dichotic and monotic click detection, which are the same ones used in our prior studies (Yozawitz et al. 1979; Bruder et al. 1981; Berger-Gross and Bruder 1984). The patients in this study were divided into subgroups of endogenous (ED) and nonendogenous depressed (ND) patients, defined on the basis of Research Diagnostic Criteria (RDC) (Spitzer et al. 1978). It was anticipated that ED patients, particularly those who clinically display diurnal variation of mood, might be more likely to show a disturbance of circadian patterns when compared with ND patients. The availability of EEG sleep data on a subsample of depressed patients in this study also made it possible to correlate the dichotic laterality effects for these patients with their sleep characteristics (e.g., sleep latency, REM latency, and REM time). There are several reasons why this was of interest. First, sleep-wake cycles and EEG sleep characteristics are known to be altered in depressed patients (Kupfer et al. 1978; Akiskal et al. 1982; Feinberg et al. 1982; Reynolds et al. 1982). Second, it has been argued that the altered sleep findings in depressed patients result from a disturbance of circadian rhythm of arousal (Schulz et al. 1979). Third, it has been suggested that sleep-wake cycles and oscillations of sleep stages are related to neuropsychological functioning (Klein and Armitage 1979; Broughton 1982), and one study reported finding a relationship between EEG sleep measures and neuropsychological dysfunction in depressed patients (Shipley et al. 1981).

Methods

Subjects Depressed patients were tested about 7-14 days after admission to either an inpatient or outpatient research unit at New York State Psychiatric Institute. They received no anti-

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depressant or antipsychotic medication during this initial period. The drug washout period was thereby a minimum of 7 days, although for most patients it was l0 or more days. A total of 26 depressed patients with no history of neurological problems participated in this study. These patients were divided into two subgroups on the basis of diagnoses provided by psychiatrists on the research units. The ED subgroup consisted of 16 patients who met DSM-III criteria for major affective disorder and who also met RDC for endogenous major depressive disorder. The ND subgroup was more heterogeneous, consisting of 10 patients who met DSM-III criteria for major affective disorder (n = 5), atypical affective disorder (n -- 3), or other specific affective disorder (n = 2). Although all patients were tested during a depressive episode, four ED patients had bipolar (BP) disorders (two BPI and two BPII), and two ND patients had bipolar disorders (one BPI and one BPII). The characteristics of the patients in the ED and ND subgroups are summarized in Table 1. The ED and ND groups did not differ significantly in age, sex, education level, or handedness. The patients were all right-handed, as indicated by their positive laterality quotient (LQ) on the Edinburgh Handedness Inventory (Oldfield 1971). Hamilton Depression Scale ratings provided by psychiatrists in the research units indicated that the ED patients were more severely depressed than the ND patients---t (18) = 4.13, two-tailed p < 0.001. Not all patients were tested on both the verbal and nonverbal tasks, as some patients were not available for the amount of time necessary to complete both tasks in either the morning or evening session. There were three ED patients and one ND patient who were not tested on the click detection task, and two ED patients and one ND patient were not tested on the CV syllable task. The loss of these patients from the ED and ND samples did not alter the subject characteristics given in Table 1 for the total samples.

Procedure Each patient was tested during a morning session (between 8:00 and 11:30 AM) and an evening session (between 4:00 and 7:30 PM). The order of the sessions was counterbalanced across the total sample of patients such that alternate patients were tested initially either in the morning or evening.

Dichotic and Monotic Click Thresholds. The threshold intensity needed to detect dichotic and monotic click stimuli was measured using a three-interval forced-choice task (Bruder et al. 1981). A click stimulus was presented during one of three sequential flashes of light, and the subject indicated in which interval the stimulus occurred by pressing one of three response buttons. The lowest intensity needed by the subject to attain 67% accuracy in this task was estimated using a block up-and-down staircase procedure. The advantage of this task is that it yields precise threshold estimates that are independent of the subject's decision criterion. The threshold intensity needed to detect a single monotic click in each ear was initially measured in a brief session in which the "block up-and-down staircases" for the two ears were alternated randomly within the session. These threshold measures were used to equate the clicks in the dichotic condition for any difference in threshold intensity between the two ears. Next, measures of the thresholds for two dichotic conditions and two monotic single click conditions were obtained in the same session. In one dichotic condition, a click was presented first to the right ear, followed, after a delay of 60 msec, by a click

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Table 1. Characteristics of Patients Endogenous Males (n) Females (n)

Nonendogenous

7 9

6 4

36.3 10.2

34.1 10.4

14.9 2.2

15.4 1.6

83.8 15.8

91.8 10.6

Age (years) Mean so

Education (years) Mean SD

Handedness (laterality quotient) Mean st)

Hamilton Depression Scale scores Mean SD

27.2 7.5

14.2 5.8

to the left ear. In the other dichotic condition, the left ear click preceded the right ear click by 60 msec. The two monotic conditions were single clicks presented to either the fight or left ear alone. The separate "block up-and-down staircases" for these four conditions were begun at the threshold intensity for each ear and were alternated randomly with the restriction that in every six blocks there be two blocks for each dichotic condition and one block for each monotic condition. Intensity was manipulated in 1 dB steps using stepping rules for maintaining 67% detection accuracy. The median of the intensity levels revisited during the session for each staircase provided a threshold measure for each condition. Other details concerning the staircase procedures, apparatus, and calibration of click intensity in peak equivalent SPL are given elsewhere (Bruder et al. 1981). Dichotic CV Task. A tape recording of the CV discrimination task was provided by the Kresge Hearing Research Laboratory. It consists of randomly paired stop-consonant-vowels (ba, da, ga, ka, pa, ta). Each subject received 16 monaural trials (to check accuracy of CV identification for each ear), 14 dichotic practice trials, and 90 dichotic test trials. Dichotic trials consisted of presenting simultaneously a different CV syllable to each ear. The subject reported the two syllables presented using a multiple-choice answer sheet. The answer sheet contained a random ordering of the six possible CV syllables for each trial. The subject was instructed to cross off the two syllables that were heard on each trial and to guess where necessary. Other procedural details and the scoring of accuracy were the same as described by Berlin et al. (1973). The percentage of trials on which the subject correctly reported only the right or left ear syllable (single correct tfials) was scored separately from trials on which the syllables in both ears were correctly reported (double correct trials). The tape recording was presented to subjects by a stereo tape deck (Tandberg, 3500X) and circumaural earphones (Sharpe HA-10, MKH). A 1000-Hz reference tone at the beginning of the tape was used in calibrating the output of each earphone with a half-

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inch Bruel and Kjaer microphone. The tape was presented at a comfortable level of 67 dB SPL.

EEG Sleep. Nine ED and two ND patients were also studied by the Sleep Unit at New York State Psychiatric Institute. The EEG sleep was measured during the same week as the dichotic listening tests, and, in most cases, the dichotic listening tests were given on days in which the patients slept in the Sleep Unit. Polysonmographic recordings of sleep EEGs were made using standard procedures previously described by Puig-Antich et al. (1982). Sleep records were scored using the Rechtschaffen and Kales (1968) method. Patients were studied on two or three consecutive nights, and their EEG sleep data for these nights were computed for a series of variables that are routinely assessed in this Sleep Unit. The variables used for this study were sleep latency, total sleep time, REM period latency, REM period length, percent REM, and total REM. The definitions of these sleep variables are given elsewhere (Puig-Antich et al. 1982). Results

Dichotic Click Thresholds The mean threshold intensities (in decibels) for the ED and ND subgroups in the morning and evening sessions are plotted in Figure 1 as a function of the order in which the dichotic clicks were presented to the two ears. A 2 (ear order) x 2 (time of day) x 2 (diagnostic subgroup) ANOVA indicated that there was no significant difference in dichotic click thresholds either across the morning versus evening sessions or across the ED versus ND subgroups. Only the interaction between the ear order of dichotic clicks and time of day was significant, F,,2o) = 10.55, p = 0.004. This indicates that the threshold asymmetry for the right-left (RL) and left-fight (LR) order of dichotic clicks differed for the morning versus evening sessions. As can be seen in Figure 1, the morning to evening shift in threshold asymmetry was the same for the ED and ND subgroups. In the morning, both groups needed less intensity to detect dichotic click stimuli when the right ear click preceded the left ear click (RL) compared to the opposite order of clicks (LR). In the evening, however, the groups showed the reverse direction of threshold asymmetry, i.e., the threshold intensity was lower for the LR condition than for the RL condition.

.......

Morning Evening

27-

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26

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Figure 1. Mean threshold intensities as a function of right-left (RL) versus left-right (LR) order of dichotic clicks in the morning and evening sessions for 13 ED patients and 9 ND patients.

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Monotic Click Thresholds A 2 (ear) x 2 (time of day) x 2 (diagnostic subgroup) ANOVA indicated that the threshold intensity needed to detect a single monotic click did not differ significantly across the morning versus evening sessions or across the El) versus ND subgroups. Only the interaction among ear, time of day, and diagnostic subgroup proved to be significant, F(l,2o) = 5.54, p = 0.029. The nature of this three-way interaction can be seen in Figure 2, which shows the mean threshold intensities for monotic click stimuli. In the morning, the ED group needed more intensity to detect a click in the left ear compared with the fight ear--t(12) = 2.68, two-tailed p = 0.02. In the evening, however, this threshold asymmetry decreased and was no longer statistically significant. In contrast, the ND group showed no significant threshold asymmetry for monotic click stimuli in either the morning or evening.

Dichotic CV Discrimination Table 2 presents the percentages of trials on which ED and ND patients correctly reported CV syllables in the fight ear only, left ear only, or both ears. The difference in percentage of single correct trials for the fight and left ears provides a measure of ear advantage. The ED and ND groups showed essentially the same fight ear advantage for CV discfimination in both the morning and evening sessions. A 2 (ear) x 2 (time of day) x 2 (diagnostic subgroup) ANOVA indicated that only the main effect of ear was significant, F
EEG Sleep Measures Correlation coefficients were computed between the sleep variables and laterality scores for the morning and evening session. In computing these correlations, the sleep data were averaged across two or, in a few cases, three nights so as to reduce the number of correlation coefficients. ~ Although the remaining analyses still involved a large number of correlations, more were significant than would be expected by chance alone (×2 = 6.60, p = 0.02). A consistent pattern of correlations existed between EEG sleep variables and dicbotic threshold asymmetry in the morning session. The threshold asymmetry for detecting dichotic clicks in the morning was significantly correlated with sleep latency (r = 0.71, p = 0.015). Figure 3 (bottom) shows that an advantage for detecting the RL dichotic condition (i.e., the reverse of the normal direction of threshold asymmetry) was associated with lengthened sleep latency, i.e., more than 1 st) above the mean for normal adults (mean = 26.7 _-_ 15.7 min) tested in the Sleep Unit (Quitkin et al. in press). A similar relationship (top of Figure 3) was also observed between dichotic threshold asymmetry in the morning and REM period latency (r = 0.74, p = 0.009). Here, however, the patients with the abnormal RL advantage generally displayed REM period latencies in the normal range, i.e., greater than the 55-60 rain value usually used as the cut-off value for REM latency. Also, dichotic threshold asymmetry in the morning was negatively correlated with both total REM (r = - 0.71, p = 0.015) and percent REM (r = - 0.65,

IWhen we examined the correlations separately for the sleep data obtained on the first and second nights, the results were essentially the same as reported for the average across nights.

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Morning Evening

ED

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Figure 2. Mean threshold intensities for right versus left ear monotic click stimuli in the morning and evening sessions for 13 ED patients and 9 ND patients.

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~r p = 0.031). This indicates that the abnormal RL advantage was associated with less REM time. Dichotic threshold asymmetries in the evening did not correlate significantly with the sleep variables, nor did the morning or evening laterality scores for dichotic CV discrimination or monotic click detection correlate with any of the sleep variables.

HamiltonDepressionScaleScores The laterality scores for the morning and evening session did not correlate significantly with the Hamilton Depression Scale scores for the patients. However, correlations between ratings for items on this scale and dichotic asymmetry scores did reveal a significant correlation of interest. The threshold asymmetry for detecting dichotic clicks in the morning was significantly correlated with ratings on the diurnal variation item of the Hamilton Depression Scale (r = 0.49, p = 0.044). Thus, an abnormal reversal of threshold asymmetry (i.e., an RL advantage in the morning) was associated with diurnal variation of symptoms.

Discussion

DichoticThresholdAsymmetry Morning to evening shifts in lateral asymmetry for detecting dichotic click stimuli were found for endogenous (ED) and nonendogenous depressed (ND) patients. The direction of the morning to evening shift for depressed patients was different from that previously Table 2. Percentage Correct CV Discrimination Endogenous (n = 14)

Nonendogenous (n = 9)

38.2 23.3 28.6

40.5 23.5 30.1

37.9 21.9 28.0

39.0 24.0 25.7

Morning Right ear Left ear Both

Evening Right ear Left ear Both

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Figure 3. Scattergrams relating dichotic threshold asymmetry (differences in threshold intensity for RL and LR conditions) in the morning to REM period latencies (top) and sleep latencies (bottom)for 11 depressed patients.

observed for normal subjects who were tested using exactly the same methods (BergerGross and Bruder, 1984). Depressed patients showed a right ear lead (left hemisphere) advantage in the morning and a left ear lead (right hemisphere) advantage in the evening, which was opposite to the direction of the morning to evening shift for normal subjects. Our theoretical interpretation of the morning to evening changes in dichotic threshold asymmetry is based on three assumptions. (1) We assume that the normal advantage for detecting the left ear leading condition during the day is related to a right hemisphere advantage for hemispheric activation. It has previously been suggested that cerebral activation or arousal is mediated primarily by a mechanism centered in the right hemisphere (Heilman and Van Den Abell 1979; Jutai 1984). As a result, stimuli in the left hemispace may be more effective for yielding bilateral cerebral activation compared with stimuli in the right hemispace (Heilman and Van Den Abell 1979; Bowers and Heiiman 1980; Prohovnik 1980). (2) We assume that the disappearance of the advantage for detecting the left ear lead condition in the evening for normal subjects is due to a daily rhythm that diminishes right hemispheric activation (Berger-Gross and Binder 1984). This daily rhythm is normally associated with heightened cerebral arousal during the day but diminished arousal during the evening. (3) We assume that the opposite direction of morning to evening shift in dichotic threshold asymmetry for depressed patients is related to a difference in their daily rhythm of cerebral arousal. A disturbance of the circadian rhythm of arousal has been hypothesized to explain EEG sleep abnormalities in depression and may be one of several biological rhythms that are not synchronized in the normal fashion with day-evening cycles (Kripke et al. 1978; Schulz et al. 1979; Wehr et al. 1980). Prior studies have found a reversal of the normal direction of dichotic threshold asymmetry for depressed patients tested once during the day (Yozawitz et al. 1979; Bruder et al. 1981). Three findings of the present study support the hypothesis that this abnormal pattern of perceptual asymmetry is related to a shift in circadian rhythm. First, the dichotic

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threshold asymmetry for ED and ND patients was dependent on time of day. Second, support for the circadian hypothesis was found in correlations between dichotic threshold asymmetry and EEG sleep in depressed patients. A reversal of the normal direction of threshold asymmetry in the morning was associated with abnormally long sleep latency. Although REM period latency, total REM, and percent REM were also correlated with dichotic threshold asymmetry, patients with reversed asymmetry generally had REM measures in the normal range. Shipley et al. (1981) similarly examined the correlation between neuropsychological test performance and EEG sleep in depressed patients. Although their tests did not provide information concerning the locus of dysfunction, a high level of impairment on neuropsychological tests was associated with prolonged sleep latency but not with REM abnormality. Third, additional evidence for the circadian hypothesis was evident in the significant correlation between dichotic threshold asymmetry in the morning and ratings of diurnal variation on the Hamilton Depression Scale. Namely, an abnormal reversal of threshold asymmetry was associated with diurnal variation in the symptoms of depressed patients. Although a two-point examination (morning versus evening) over the 24-hr cycle can hardly provide definitive evidence for this circadian hypothesis, it should give impetus for more fine-grained examinations of the issue. Moreover, future studies would do well to examine circadian variation in depressed patients not only on behavioral laterality measures, but also on more direct measures of cerebral activation or arousal, e.g., cortical event-related potentials or regional cerebral blood flow.

Monotic Threshold Asymmetry ED patients showed a threshold asymmetry for detecting monotic click stimuli that was not seen for ND patients in this study or normal subjects in our prior study (Berger-Gross and Bruder 1984). Also, this monotic threshold asymmetry was related to time of day. ED patients displayed significantly poorer left ear as compared to right ear sensitivity in the morning but not in the evening. Although we have previously reported evidence of reduced sensitivity for monotic click detection in affective psychotic patients, there was no evidence in those studies that this was a lateralized effect (Bruder et al. 1980). However, the patients in those studies were more heterogeneous in their diagnostic characteristics, and they were medicated at the time of testing. In a study of the effects of electroconvulsive therapy (ECT), unmedicated depressed patients in a pre-ECT phase also showed significantly poorer left ear, as compared with right ear, sensitivity for monotic click detection (Epstein et al. 1983). Most of the patients in the EC~ study were severely depressed and had an endogenous major depressive disorder. The threshold asymmetry for monotic click stimuli exhibited by the ED patients raises the question whether or not this effect was related to their abnormal threshold asymmetry for dichotic click stimuli. There is no evidence that this was the case. The monotic click thresholds for each ear and ear asymmetry scores did not correlate significantly with dichotic threshold asymmetry scores for either El) or ND patients in the morning or evening session. It should also be noted that the ED and ND patients displayed the same morning to evening changes in threshold asymmetry for dichotic click stimuli (Figure 1), and yet, these groups differed in their findings for monotic click stimuli (Figure 2). Although this could mean that threshold asymmetry measures for monotic and dichotic click stimuli may tap different aspects of hemispheric function, further research is mw.ded to clarify this issue.

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Dichotic C V Discrimination Although laterality effects for the nonverbal detection task changed as a function of time of day, discrimination of CV syllables did not. Neither the depressed patients in this study nor the normal subjects in our prior study (Berger-Gross and Bruder 1984) gave any evidence of a morning to evening change in the right ear advantage for CV discrimination. In interpreting the difference in morning to evening findings for the CV discrimination and click detection tasks, one question is whether or not a difference in the difficulty level of these tasks could account for the different findings. This is not a likely explanation as, in fact, there was no sizeable difference in overall accuracy levels across these tasks. 2 Our interpretation of the morning to evening change in threshold asymmetry for dichotic clicks assumes that this change reflects a daily rhythm of right hemispheric activation or arousal. In contrast, the left hemispheric processes that are dominant for the discrimination of CV syllables appear to be static with respect to circadian alterations in cerebral arousal. Conclusion Depressed patients tested during the day do not display the normal left ear lead (right hemisphere) advantage for detecting dichotic click stimuli. Our timings provide initial evidence that this abnormal pattern of perceptual asymmetry is linked to circadian rhythm and EEG sleep disturbances that characterize depressive disorders. It is hypothesized that a shift in a daily rhythm of right hemisphere activation or arousal in depressed patients could account for the altered lateral asymmetry for dichotic click detection. Many individuals at New York Stall PsychiatricInstitutehelped makethis researchpossible. We thank Samuel Sutton for his helpful comments on this paper; Jonathan Stewart, Patrick McC-rath, and Wilma Harrison for providing diagnoses and clinical ratings of patients; Joaquim Puig-Antich for providing EEG sleep data; and Malvin Janal for assisting with statistical analyses.

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