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Abnormal Flash Visual Evoked Response in Melancholia: A Replication Study Russell G. Vasile, Frank H. Duffy, Gloria McAnulty, John J. Mooney, Kerry Bloomingdale, and Joseph J. Schildkraut
Grand mean flash visual evoked responses (FVER) were measured in two new groups of depressed patients with melancholia to replicate findir.~ of an abnormal FVER in a previously reported pilot study (Vasile et a11989). These different, independently collected groups of melancholic patients demonstrated a statistically significant negative deviation of the FVER 224-300 msec poststimulus maximal in the midl~ne centroparietal region when compared with appropriate normative age-matched control groups ( n = 56 in each group). We utilized the identical computer-based quantified neurophysiological technique with mapping to analyze the data in all three melancholic patient groups--the pilot group (n = 9) with mean age 73.1 years, an older replication group (n = 14) with mean age 75.5 years, and a younger replication group (n = 15) with mean age 63.8 years. We also studied a group of depressed patients without melancholia (n = 11) with mean age 65.2 years, and found a similar, but less pronounced, alteration of the FVER. Lastly, we studied a group of nondepressed neuropsychiatric patients (n = 10) with mean age 61.9 years and found no abnormality of the FVER. Our data suggest that a gradient of FVER abnormality exists in depressed patients, most prominent, but not limited to elderly melancholic patients.
In~oduction In a previous pilot study of nine elderly, medically healthy patients with DSM-III diagnoses of major depression with melancholia, we reported an alteration of the flash visual evoked response (FVER). Differences were seen symmetrically in the midparietal and occipital regions in the 150-300 msec poststimulus latency range (Vasile et al 1989). Given the small size of our original population of melancholics and the large number of variables tested, we stated that our pilot publication was a "hypothesis generating" study and required us to "test our hypothesis" by replicating our findings on an independently derived, larger population. In this article, we report results of a replication study on a new population of depressed patients with melancholia using quantifiecl electrcenceph alography (qEEG) with topographic mapping.
Address reprint requests to Dr. Russell G. Vasile, Deaconess Medicine, 333 Longwood Avenue, Suite 450, Boston, MA 02115. Received February 4, 1991; revised September 1O, 1991. Presented at the American Psychiatric Association New Research Meetings, May 1989 in San Francisco, CA. © 1992 :~ocietyof Biological Psychiatry
0006-3223/92/$05.00
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Previous investigators have reported abnormalities of the visual evoked response in affective illness. Shagass et al (1980) found lower amplitudes of the VER in psychotic depre.ssives as compared with controls and neurotic depressives. Perris (1975) also found lower VER amplitudes in depressives arid found a negative relationship between FVER amplitude and severity of depression. A recent study util;.zing a quantified EEG technique with mapping detected no FVER abnormality in dep~'essed patients (Guidi et al 1989). The differing findings may reflect the variability of the depressed patient populations studied, as well as differences in analytic methodology. To further explore the nature and causes of the FVER abnormality in melancholia, we also studied depressed patients without melancholia and neuropsychiatric patients without depression. Furthermore, the melancholic patients were broken into two age groups to explore the interaction between age and melancholia on the FVER.
Methods
Subjects Twenty-nine newly studied elderly patients hospitalized with DSM-III diagnoses of major depression with melancholia participated in the current investigation in which an attempt was made to replicate findings of an abnormal FVER observed in a previously reported pilot study of nine patients (group 1) (Vasile et al 1989). This replication sample was divided into two groups based on age. The older group consisted of 15 patients ranging in age from 70 to 81 years, mean age _ SD 75.5 "4- 2.7 years (group 2). Tile younger melancholic group consisted of 14 patients ranging in age fi'om 59 to 68 years, mean age _ SD 63.8 _.+ 2.6 years (group 3). Dividing the replication melancholia groups into these two age ranges enabled us to assess what effect, if any, more advanced age would have on the FVER in melancholia, in the older melancholia replication group, 14 of the 15 were medicated with one or more psychoactive drugs (5 on low dose benzodiazepines only, 5 on antidepressants and low dose benzodiazepines, 2 on antidepressants and neuroleptics, I on neuroleptic and low dose benzodiazepines, and I on diphenhydramine). In the younger melancholic replication group all 14 were medicated (6 on low dose benzodiazepines only, 5 on antidepressants, 1 on chloral hydrate only, 1 on diphenhydramine only, and 1 on neuroleptic only). Our previously reported pilot melancholia group consisted of nine medically healthy patients with a mean age __. SD of 73.1 -46.0 years. Seven of the 9 patients were medicated (5 on low dose benzodiazepines alone, 1 on lithium, and 1 on tricyclic antidepressant). Here we also present data on two newly studied additional patient groups. The first was a group of 11 patients with major depression without melancholia ranging in age from 59 to 73 years, mean age _ SD 65.2 __. 5.1 years (group 4). In this depressed nonmelancholic replication group, 10 of 11 patients were on one or more psychoactive drugs (3 on low dose benzodiazepines only, 5 on antidepressants and low dose benzodiazepine, 1 on diphenhydramine only, and 1 on neuroleptic and low dose benzodiazepine). Although depressed, these patients did not exhibit the spec;ac neurovegetative features of affective disturbance sufficient to meet the DSM-III-R criteria for melancholia, a subelassification of major depressive disorder; hence, their depression was phenomenologically different from that ~f the melancholic patients. Inclusion of this group enabled us to explore whether our finding was specific to melancholia or could also be found in patients with nonmelancholic depression.
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Table 1. Subject and Control Populations Mean age _+ SD (yrs)
Group
No. subjects
Age range
Pilot study melancholics Replication-older melancholics Replication-younger melancholics Depressed nonmelancholics Neuropsychiatric patients, nondepressed Older normal controls Younger normal controls
9 15
73. ! +- 6.0 75.5 __ 2.7
65-85 70-81
14
63.8 _ 2.6
59-68
11 10
65.2 _+ 5.1 61.9 -+ 11.0
59-73 60-83
56 56
73.4 -+ 2.7 64.2 _ 2.7
70-79 60-69
Lastly, in this investigation we present data on a group of 10 negiy studied neuropsychiatric patients without depression who ranged in age from 60 to 83 years, mean age -+ SD 61.9 -+ 11 years (group 5). This group consisted of patients with schizophrenia (n - 3), panic disorder (n -- 2), seizures (n - 2), behavior disorder (n - 2), and sleep oisorder (n = 1). Nine of 10 neuropsychiatric nondepressed patients were on medications, including neuroleptics, anticonvulsants, and antianxiety agents, but not antidepressants. This group was utilized to assess whether similar FVER abnormalities would be found in elderly neuropsychiatric patients in whom the diagnosis of depression, with or without melancholia, was excluded (Table 1). Thus, in this investigation we present data on a total of 50 entirely new patients not previously studied or reported. These include all patients in group 2 (replication--older melancholics; n - 15); group 3 (replicationmyounger melancholics, n - 14); group 4 (depressed nonmelancholics, n - 11); and group 5 (neuropsychiatric patients, not depressed, n - 10). We compared our patient groups to an older control group, mean age +- SD 73.4 _+ 2.8 years and a younger control group, mean age - S D 64.2 _.+ 2.7 years. These two age-matched control groups each consisted of 56 nondepressed, unmedicated, medically well subjects. Previously studied normal male controls were members of the normative aging study at the Boston Veterans Administration Outpatient Clinic; female controls were community volunteers. All control subjects were screened to exclude medical, psychiatric, metabolic, or neurologic illness and were closely matched for age and gender to the patient population. Control subjects were on no medication at the time of study (Duffy et al 1984). In the pilot melancholic group, the two replication melancholic groups, and in the depressed nonmelancholic group, the preponderance of patients were women; there were 6 women and 3 men in the melancholia pilot study, 13 women and 2 men in the older, and 12 women and 2 men in the younger melancholic replication groups. I'he depressed nonmelancholic group was composed of 11 women and 3 men. To evaluate the potential relevance of gender difference on the FVER, we separately compared the 28 men with the 28 women within each of the two normal control groups. Diagnosis of depression and melancholia was based on DSM-IH-R criteria with the consensus of four staff psychiatrists, including each patient's attending psychiatrist. All depressed and melanclholic patients were ambulatory and free of significant medical illness. Diagnosis of the neuropsychiatric nondepressed patient group was based on the opinion of each patient's attending psychiatrist or neurologist.
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Neurophysiological Testing All subjects, includiho previously studied controls, were evaluated at Children's Hospital, Boston, MA using quantified EEG with mapping, a computer-based technique for the topographic display and quantitative analysis of scalp-derived neurophysiological data. Data were recorded from 20 scalp electrodes (referenced to linked ears) and four artifact elect'odes placed so as to maximize detection of vertical eye movement (VEM) and blink, horizontal eye movement (HEM), and temporal and occipital muscle activity (EMG). Flash stimuli used to form the FVER were delivered from a Grass model PS-22 photic stimulator at intensity level 8 placed 30 cm directly in front of the subjects closed but undilated eyes. Such supramaximal stimulation largely eliminates pupil size as a key variable (Skala and Holman 1984). For general clinical screening purposes, many qEEG laboratories rely as much on the FVER as they do on the pattern reversal visual evoked response (PRVER) (Duffy 1982; John et al 1988). Although the PRVER is of established clinical use for conditions such as Parkinson~s disease, cortical blindness, and demyelinating disease (Cracco et al 1986), its topographic distribution across the scalp is seen to be largely limited to the occiput when many electrode~ are used. In contrast, the FVER can be readily derived from many regions and may delineate abnormalities at a distance from the occiput (Duffy 1982). In this study only the FVER was consistently utilized across all subjects/patients. During recording, a classic EEG was performed to assure the fully alert state and to assist in the minimization of artifact. Data from artifact free periods were subjected to a simple, but individually adjustable, over-voltage rejection algorithm; signal averaging was performed using a Masscomp 5500 computer with Nicolet software. Grass EEG amplifiers were set to pass 1-300 Hz. Prior to digitization, all signals were low pass flit. d at 90 Hz with a 24 dB per octave Butterworth filter to avoid aliasing. Signals were sampled at 256 Hz resulting in 128 points for 512 mse¢ before and after time of stimulation. The prestimulus or baseline period allowed e0aablishment of baseline zero voltage and also provided an indicator of adequacy of sign,d-to-,~oise ratio. At the time of signal averaging, a continuous plot of signal-to-noise ratio versus number of trials was provided for each subject and averaging of these long latency FVERs was continued until such time as the signal-to-noise ratio versus trials asymptoted, indicating no further signal value to the acquisition of additional trials. Over this population, 250-400 trials per subject were required to asymptote. FVERs were aligned for averaging by a trial marker stored on one tape channel digitized with an accuracy of less than 0.5 msec, well within the limits of our 4 msec sampling rate. Equal 512 msec prestimulus and poststimulus epochs were formed. Alertness and attention were controlled by frequent interruption and interrogation while monitoring the EEG for signs of drowsiness (Santamaria and Chiappa 1987). Sets of 20 FVERs were transformed by the same computer into a corresponding series of topographic maps (Duffy 1989). To delineate regional differences of FVER between groups, the significance probability mapping (SPM) technique was used to search 40 msec epochs of regional between-group difference (Duffy et al 1981). Each of the clinical groups was compared with the most age-appropriate normative control group. Additionally, the control groups were compared to one another. Regions delineated by a t value above a certain criterion t-level (t = 2) were designated as regions of interest (ROI). Between-group t-tests were performed on all four artifact channels, as well as for the 20 scalp electrodes. When an SPM demonstrated between-group differences above a t of 2.00, the t values for the adjacent artifact channels were also examined. If they were
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also above criterion level, the SPM was considered to be possibly contaminated by groupspecific artifact an~ was eliminated from consideration. The same room, ambient illumination, stimula~6r, stimulation instruments, and alert state were utilized for all patient and control groups.
Results Results are shown in Figures 1-8. For each figure the particular comparison is indicated by the top label. Two grand mean FVER waveforms from the PZ (midline parietal) electrode are shown, one depicting a study population and the other the corresponding age-matched control group. For the original and new melancholic to control comparisons the significant results were limited to the 224-260 and 264-300 msec epochs, which are delineated for clarity by thick black lines on all figures. Spatial extent of between-group difference can be s~en by the eight t-statistic SPM shown below. Each t-SgM is a schematic map of the head with nose above, left ear to the left, etc. Black signifies no significant difference; the ROI, shown in white, is defined as a region of significance above the indicated threshold probability level (i.e., p < 0.05, p < 0.02, p < 0.01). The results demonstrate that the regional difference delineated in the pilot melancholic group is replicated for both the age 60--69 and 70-79 new melancholic groups. The data comparing the grand mean parietal FVER of these three different, independently co]llected melancholic populations demonstrates a consistent negative deviation from control group normative FVER data 224-300 msec poststimulus, maximal in the midline centroparietal region. The older replication melancholic group (Figure 2) at 224-71"60msec poststimulus shows a posterior occipital and centroparietal difference from cor~trols at the p < 0.01 level of significance. At the 264-300 msec epoch, the FVER of the older melancholic group again achieves a p < 0.01 level of significance; the spa,~ial distribution of the finding appears somewhat more centroparietal than in the original pilot study (Figure 1). The younger replication melancholic group (Figure 3) shows the I-NER abnormality most prominently at 264-300 msec poststimulus with a parietal-to-posterior occipital distribution. At 224-260 msec poststimulus the finding of abnormal FVER is limited to a centroparietal distribution, achieving a p < 0.02 level of significance. The FVER abnormality seen in the older melancholic replication group is nearly as pronounced in the younger melancholic replication group (Figure 3). The depressed nonmelancholic patient group (Figure 4) exhibits less significant ?,~'oup difference reaching the p < 0.05 levd for both the 224-260 msec and 264-300 msec epochs and, extending minimally to the right posterior region, at the p < 0.02 level during the 264-300 msec epoch. However, the eye artifact electrodes also shc,~ed significant group difference for 224-.260 msec, suggesting that these differences in FVER in the frontal region are artifactual. The failure of what appears to be a large difference between the means of the two groups (Figure 4) to reach statistical significance can be attributable to a large FVER variance within the depressed nonmelancholic population. The origins of this variance arc unclear and are to be addressed by future study of additional patients. Findings were virtually nonexistent in the nondepressed neuropsychiatric patient group (Figure 5). Finally, the younger and older control groups demonstrated no FVER findings when compared with each other (Figure 6). Thus, the original finding appears mainly specific to melancholia and cannot be easily explained by age effect alone, by depression without melancholia, or by general neuropsychiatric illness in the elderly. Moreover, it
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Figures I-8. For each figure depicting the group mean FVER, the particular group compared with normative age-matched controls is indicated by the figure heading. Figure 6 compares the two normative control groups, which differed in age by I0 years. Figures 7 and 8 depict male/female comparisons of the control groups. The T-spm, beneath the co,-responding mean FVER graph, is a schematic map of the head with nose above, left ear to the left, etc. Black signifies no significant difference; white signifies significance above a threshold probability (clip) level indicated by p < 0.05, p < 0.02, p < 0.01. Hence, spatial extent of between-group difference can be seen. Thick black lines on the group mean FVER graph delineates the 224-260 and 264-300 msec epochs, the epochs poststimulus which revealed significant differences between the comparison groups.
Abnormal FVER in Melancholia
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1992;31:325-336
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BIOL PSYCHIATRY 1992;31:325-336
R.G. Vasile et al
seems unlikely that the somewhat different proportions of men and women in the melancholic and control groups could explain the FVER change as no FVER gender difference could be demonstrated within either the 60-69 or the 70-79-year-old control populations (Figures 7-8). Discussion In our previous pilot study, FVER group difference between melancholic patients and controls was reported from the medial parietal region, maximal at PZ for a 40 msec epoch starting at 216 msec. These findings on the pilot melancholics established the hypotheses to be tested by the replication study: (1) FVER difference in time between controls and melancholic patients would be most prominent or restricted to the 224-300 poststimulus latency epoch; (2) FVER difference over the scalp (in space) would involve the centralparietal-occipital region, centered about or always involving PZ but frequently involving adjacent electrodes; (3) Such differences would not be found in nondepressed patients. To test these hypotheses, we conducted the identical analyses on two new independently collected groups of elderly depressed patients with melancholia, one group older than the other. To further explore specificity, we also studied depressed patients without melancholia and neuropsychiatric patients without depression. In the current investigation, we reanalyzed the data from our initial pilot study of nine elderly melancholics now utilizing a large~ control group (n = 56 versus n = 29). As we expected,, the results from the reanalysis of the initial pilot study group were virtually identical to those previously reported. (In the current replication study, we chose the midline parietal PZ electrode for FVER waveform display as regions of statistical significance almost always involved this electrode (see white areas in figure display). Other electrodes, including occipital, central, and ialeral parietal electrodes, were most often within these regions and showed similar changes. In the original pilot study article we showed the midline occipital OZ electrodederive: FVER for display as was the convention in FVER studies.) A large region of between-group difference (Figure 1) was evident, centered about the medial parietal electrode (PZ). From the temporal perspective, group difference was found in two sequential 40-reset epochs, 224-260 msec and 264-300 msec. Group grand mean FVER data from the two newly studied melancholic groups were compared to similar FVER data gathered from age-appropriate nondepressed control subjects. The melancholic FVER demonstrated consistent reduction of positive amplitudes limited to the 224-300 msec latency epoch, maximal in the midline centroparietal region centered about PZ (Figures 2 and 3). Thus, the findings of our initial pilot study (Figure I) are broadly confirmed. Moreover, similarly compared to control data, the FVER of the depressed but nonmelancholic group showed less robust and topographically different abnormalities (Figure 4). However, further studies will be required to definitively determine whether the FVER abnormality in depression lies on a continuum with melancholia at one extreme or whether melancholia constitutes a separable and distinct subpopulation with respect to these FVER abnormalities. Although detailed psychometric testing was not performed, all melanci~olic patients were hospitalized, indicating severity of their depression. Some patients were off medication or only on low dose benzodiazepines in the context of an intensive reevaluation of treatment refractory depression. Although the melancholic populations demonstrated a higher number of women than the control population, there was no evidence to support gender difference within the control populations (Figures 7 and 8). Thus, asymmetries of gender distribution seem
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unlikely to explain our findings. Only a larger study could examine the possibility of an unexpected gender by melancholia interaction effect. As our depressed patients were severely ill, we could not study them in the absence of medication. The older and younger melancholic groups and the nonme|ancholic depressed group exhibited a similar profile of medication usage, with most patients on either low dose benzodiazepines (5 of 15 in tile older melancholic group, 6 of 14 in the younger melancholic group, and 3 of 11 in the nonmelancholic depressed group) or tricyclic antidepressants (5 of 15 in the older melancholic group, 5 of 14 in the younger melancholic group, and 5 of 11 in the depressed nonmelancholic group). It seems unlikely, therefore, that medication effect alone could explain the FVER differences between our melancholic and nonmelancholic depressed patient groups. Further, all four completely unmedicated patients--two in the pilot melancholic group, one in the older melancholic replication group, and one in the depressed nonmelancholic group---also individually demonstrated the same abnormal FVER findings. A pharmacological effect on our findings cannot be completely excluded, however, as benzodiazepines may produce a FVER amplitude reduction (Bond and Lader 1973) and imipramine an amplitude increase (Endo et al 1983). Differences in level of consciousness and auention have also been scrutinized as relevant factors to FVER waveshape morphology and latency shifts, particularly in dementia where such patients may become drowsy more easily than normal subjects unless precautions are taken (Huisman 1987). Level of consciousness and attention were carefully controlled in our study with continuous monitoring of each patient's mental state and EEG background activity. In the current study, FVER data were collected only when patients were fully awake and alert. Thus, it is unlikely that our finding can be simply explained by group-specific state difference. As the long latency FVER may show considerable variation in waveshape morphology among individuals, it could be argued that our findings might represent capitalization upon random group difference. Our experience with the FVER and long latency-evoked response in general argue that, to the contrary, group grand mean VER tend to replicate a~td do not show random between-group difference. To be noted is similar group grand mean FVER morphology for the 60-69 and 70-79-year-old control groups and the ~bsence of any statistically significant between-group difference (Figure 6). Note also the consistent absence of gender difference within the two different control groups (Figures 7-8). The consistency of our FVER finding in three different melancholic populations makes any random (or chance) effect most unlikely. Recent studies utilizing the FVER in depression have yielded varying results. Accentuation of PI00, P200, and NI40 FVER waveforms in young (mean age 32 years) melancholic patients has been reported (Khanna et al 1989). Conversely, attenuation of the FVER in psychomotor retarded depressed patients has been described (Knott and Lapierre 1987). A study utilizing a quantified EEG methodology, however, failed to find any difference in FVER between 10 depressed patients and 10 normal controls (Guidi et al 1989). Earlier studies have described both a diminution of VER amplitude in more severely depressed patients (Penis 1975; Shagass et al 1980) and an augmentation (Vasconetto et al 1971). The conflicting findings in these investigations may reflect variability of the depressed patient populations studied, as well as difference in methodology ancL/or measurement. Other studies have focused on alterations in the VER following treatment of the underlying depressive disorder. A recent investigation found decreased latency ~nd increased amplitude of the PRVER in both positive (Pl, P3) and negative (N 1) components
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in depressed patients that reverted to normal after 28 days of antidepressant treatment (Chakroun 1988). Diminished interhemispheric variability and augmentation of previously attenuated FVER waveforms of depressed patients has also been reported following successful electr~onvu!sive treatments (Perris and Eisemann 1980). A number of lines of investigation suggest that catecholaminergic dysfunction may give rise to abnormalities of the VER (Hadjiconstantinou and Neff 1984). Several studies have suggested a positive correlation between dopamine as well as its precursors and metabolites and the amplitude of the FVER (Gottfries et al 1974; Holder et al 1980; Goodwin et al 1970; He:ary et al 1976; Redmond et al 1975). Other investigations in humans and animals have described a prolongation of latency of the VER associated with dopaminergic deficiency (Bodis-Wollner et al 1982; Onofrj and Bodis-Wollner 1982). Given the longstanding interest in the relationship between catecholamines and depressive disorders (Schildkraut 1965; Schildkraut and Kety 1967), a potential role for the VER in elucidating the pathophysiology of depressive disorders is evident. To further assess the possible neurochemical basis for the abnormal VER in melancholia, we plan to explore relationships between abnormalities of the FVER and measures of catecholamine output and metabolism in unmedicated depressed patients (Schildkraut et al 1978a, 1978b; Schatzberg et al 1989). Such correlational studies between neurophysiological and neurochemical systems promises to further refine a biologically based subclassification of depressive disorders, enabling us to assess whether alteration of the VER is signaling neurotransmitter dysfunction in melancholic patients. In summary, the grand mean FVER data from two newly studied groups of melancholic patients demonstrates a consistent reduction of positive amplitudes over the 224-300 msec latency eDoch, maximal in the midline centroparietal region, replicating the findings from our initial pilot investigation. The nemochemical basis of this finding in melancholia remains to be explored. References Arezzo JA, Peckoff A, Vaughn HG (1975): The sources and intraeranial distribution of auditory evoked potentials in the alert, rhesus monkey. Brain Res 90:57-.-73. Bodis-Wollner I, Yahr MD, Mylin L, Thornton I (1982): Dopaminergic deficiency and delayed visual evoked potentials in humans. Ann Neurol I 1:478-483. Bond AJ. Lader MH (1973): The residual effects of flurazepam. Psychopharmacologia 32:223235. Chakroun H (1988): Effects of selective attention on visual evoked potentials in depressed patients and healthy controls. Acta Psychiatr Belg 88:!38n152. Cracco R (1986): Evoked Potentials. Bodis-Wollner i (ed). Alan R. Liss, New York. Duffy FH ( 1982): Topographic display of evoked potentials: Clinical applications of brain electrical activity mapping (BEAM). Ann NY Acad Sci 388:!83-196. Duffy FH ( 1989): Topographic mapping of brain electrical activity: Clinical applications and issues. in Maurer K (ed), Topographic Brain Mapping of EEG and £voked Potentials. Heidelberg, Germany: Springer-Verlag, pp 19-52. Duffy FH, Barrels PH, Burchfield JL (1981): Significance probability mapping: An aid in the topographic analysis of brain electrical activity. Electroencephalogr Ciin Neurophysiol 51:455462. Duffy FH, Albert MS, McAnulty G, Garvey J (1984): Age-related differences in brain electrical activity of healthy subjects. Ann Neurol 16:430-438. Endo S, Nakayama S, Kuraoka Y, et al (1983): Changes in visual evoked potentials induced by imipramine in patients with endogenous depression. J Nippon Med Sch 50:480-488.
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Goodwin FK, Murphy DL, Brodie HKH, Bunney WE (1970): L-DOPA, catecholamines, and behavior: A clinical and biochemical study in depressed patients. Biol Psychol 2:341-366. Gotffries CG, Pen'is C, Roos BE (1974): Visual averaged evoked responses (AER) and monamine metabolites in cerebrospinal fluid (CSF). Acta Psychiatr Scand (Suppl), 135-141. Guidi M, Scarpino O, Angeleri F (1989): Topographic EEG and flash visual evoked potentials in elderly subjects, depressed patients, and demented patients. Psychiatry Res 29:403-406. Hadjiconstantinou M, Neff NH (1984): Catecholamine systems of retina: A model for studying synaptic mechanisms. Life Sci 35:1135-1147. Henry GM, Buchsbaum M, Murphy DL (1976): Intravenous L-DOPA plus carbidopa in depressed patients: Average evoked response, learning and behavioral changes. Psychosom Med 38:95105. Holder GE, Bartlett JR, Bridges PK, Kantamaneni BD, Curzon G (1980): Correlations between transmitter metabolite concentrations in human ventficular cerebrospinal fluid and pattern visualevoked potentials. Brcin Res 188:582-586. Huisman UW, Posthuma J, Visser SL, Jonker C, de Rijke W (1987): The influence of attention on visual evoked potentials in normal adults and dementias. Clin Neurol Neurosur8 (89)3:151156. John ER, Prichep LS, Fridman J, Easton P (1988): Neurometrics: Computer-assisted differential diagnosis of brain dysfunctions. Science 239:162-169. Khanna S, Mukundan CR, Channabasavanna SM (1989): Middle latency evoked potentials in melancholic depression. Bioi Psychol 25:494-498. Knott VJ, Lapierre YD (1987): Electrophysiologicai and behavioral correlates of psychomotor responsivity in depression. Biol Psychol 22:313-324. Onofrj M, Bodis-Wollner I (1982): Dopaminergic deficiency causes delayed visual evoked potentials in rats. Ann Neurol 11:484-490. Pennis C (1974): Averaged evoked responses (AER) in patients with affective disorders. Acta Psychiatr Scand (Suppl 255), 89-98. Pennis C (1975): EEG techniques in the measurement of the severity of depressive syndromes. Neuropsychobiology I: 16-25. Pennis C, Eisemann M (1980): Further studies of averaged evoked potentials in depressed patients with special reference to possible interhemispheric asymmetries. Adv Biol Psych 4:44-54. Redmond DE Jr, Borge GF, Buchsbaum M, Maas JW (1975): Evoked potential studies of brain catecholamine alterations in monkeys. J Psychiatry Res 12:97-116. Santamaria J, Chiappa K (1987): The EEG of drowsiness in normal adults. J Clin Neurophysiol 44:327-382, Schatzberg AF, Samson JA, Bioomingdale KL, et al (1989): Toward a biochemical classification of depressive disorders X: Urinary catecholamines, their metabolites, and D-type scores in subgroups of depressive disorders. Arch Gen Psychiatry 46:260-268. Schildkraut JJ (1965): Catecholamine hypothesis of affective disorders: A review of supporting evidence. Am J Psychol 122:509-522. Schildkraut JJ, Kety SS (1967): Biogcnic amines and emotion. Science 156:21-30. Schildkraut JJ, Orsulak PJ, LaBrie RA, et al (1978a): Toward a biochemical classification of depressive disorders 1: Application of multivariate discriminant function analysis to data on urinary catechoiamines and metabolites. Arch Gen Psychiatry 35:1436-1439. Schildkraut JJ, Orsulak PJ, Schatzberg AF, et al (1978b): Toward a biochemical classification of depressive disorders II: Differences in urinary excretion of MHPG and other catecholamine metabolites in clinically defined subtypes of depressions. 4rch Gen Psychiatry 35:1427-1433. Shagass C, Roemer RA, Straumanis JJ Jr, Amadeo M (1980): Topography of sensory potentials in depressive disorders. Biol Psychol 15(2):183-207.
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Skala H, Holman J (1984): Effect of pupillary dilatation in flash VER recording. Doc Ophthalmol 63:321-324. Tukey JW (ed) (1987): Exploratory Data Analysis. Reading, MA: Addison-Wesley. Vasconetto C, Floris V, Morocutti C (1971): Visual evoked responses in normal and psychiatric subjects. Electroencephal Clin Neurophysiol 31:77-83. Vasile RG, Duffy FH, McAnulty G, et a! (1989): Abnormal viaual evoked response in melancholia. Biol Psychol 25:785-788.
325
Abnormal Flash Visual Evoked Response in Melancholia: A Replication Study Russell G. Vasile, Frank H. Duffy, Gloria McAnulty, John J. Mooney, Kerry Bloomingdale, and Joseph J. Schildkraut
Grand mean flash visual evoked responses (FVER) were measured in two new groups of depressed patients with melancholia to replicate findir.~ of an abnormal FVER in a previously reported pilot study (Vasile et a11989). These different, independently collected groups of melancholic patients demonstrated a statistically significant negative deviation of the FVER 224-300 msec poststimulus maximal in the midl~ne centroparietal region when compared with appropriate normative age-matched control groups ( n = 56 in each group). We utilized the identical computer-based quantified neurophysiological technique with mapping to analyze the data in all three melancholic patient groups--the pilot group (n = 9) with mean age 73.1 years, an older replication group (n = 14) with mean age 75.5 years, and a younger replication group (n = 15) with mean age 63.8 years. We also studied a group of depressed patients without melancholia (n = 11) with mean age 65.2 years, and found a similar, but less pronounced, alteration of the FVER. Lastly, we studied a group of nondepressed neuropsychiatric patients (n = 10) with mean age 61.9 years and found no abnormality of the FVER. Our data suggest that a gradient of FVER abnormality exists in depressed patients, most prominent, but not limited to elderly melancholic patients.
In~oduction In a previous pilot study of nine elderly, medically healthy patients with DSM-III diagnoses of major depression with melancholia, we reported an alteration of the flash visual evoked response (FVER). Differences were seen symmetrically in the midparietal and occipital regions in the 150-300 msec poststimulus latency range (Vasile et al 1989). Given the small size of our original population of melancholics and the large number of variables tested, we stated that our pilot publication was a "hypothesis generating" study and required us to "test our hypothesis" by replicating our findings on an independently derived, larger population. In this article, we report results of a replication study on a new population of depressed patients with melancholia using quantifiecl electrcenceph alography (qEEG) with topographic mapping.
Address reprint requests to Dr. Russell G. Vasile, Deaconess Medicine, 333 Longwood Avenue, Suite 450, Boston, MA 02115. Received February 4, 1991; revised September 1O, 1991. Presented at the American Psychiatric Association New Research Meetings, May 1989 in San Francisco, CA. © 1992 :~ocietyof Biological Psychiatry
0006-3223/92/$05.00
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Previous investigators have reported abnormalities of the visual evoked response in affective illness. Shagass et al (1980) found lower amplitudes of the VER in psychotic depre.ssives as compared with controls and neurotic depressives. Perris (1975) also found lower VER amplitudes in depressives arid found a negative relationship between FVER amplitude and severity of depression. A recent study util;.zing a quantified EEG technique with mapping detected no FVER abnormality in dep~'essed patients (Guidi et al 1989). The differing findings may reflect the variability of the depressed patient populations studied, as well as differences in analytic methodology. To further explore the nature and causes of the FVER abnormality in melancholia, we also studied depressed patients without melancholia and neuropsychiatric patients without depression. Furthermore, the melancholic patients were broken into two age groups to explore the interaction between age and melancholia on the FVER.
Methods
Subjects Twenty-nine newly studied elderly patients hospitalized with DSM-III diagnoses of major depression with melancholia participated in the current investigation in which an attempt was made to replicate findings of an abnormal FVER observed in a previously reported pilot study of nine patients (group 1) (Vasile et al 1989). This replication sample was divided into two groups based on age. The older group consisted of 15 patients ranging in age from 70 to 81 years, mean age _ SD 75.5 "4- 2.7 years (group 2). Tile younger melancholic group consisted of 14 patients ranging in age fi'om 59 to 68 years, mean age _ SD 63.8 _.+ 2.6 years (group 3). Dividing the replication melancholia groups into these two age ranges enabled us to assess what effect, if any, more advanced age would have on the FVER in melancholia, in the older melancholia replication group, 14 of the 15 were medicated with one or more psychoactive drugs (5 on low dose benzodiazepines only, 5 on antidepressants and low dose benzodiazepines, 2 on antidepressants and neuroleptics, I on neuroleptic and low dose benzodiazepines, and I on diphenhydramine). In the younger melancholic replication group all 14 were medicated (6 on low dose benzodiazepines only, 5 on antidepressants, 1 on chloral hydrate only, 1 on diphenhydramine only, and 1 on neuroleptic only). Our previously reported pilot melancholia group consisted of nine medically healthy patients with a mean age __. SD of 73.1 -46.0 years. Seven of the 9 patients were medicated (5 on low dose benzodiazepines alone, 1 on lithium, and 1 on tricyclic antidepressant). Here we also present data on two newly studied additional patient groups. The first was a group of 11 patients with major depression without melancholia ranging in age from 59 to 73 years, mean age _ SD 65.2 __. 5.1 years (group 4). In this depressed nonmelancholic replication group, 10 of 11 patients were on one or more psychoactive drugs (3 on low dose benzodiazepines only, 5 on antidepressants and low dose benzodiazepine, 1 on diphenhydramine only, and 1 on neuroleptic and low dose benzodiazepine). Although depressed, these patients did not exhibit the spec;ac neurovegetative features of affective disturbance sufficient to meet the DSM-III-R criteria for melancholia, a subelassification of major depressive disorder; hence, their depression was phenomenologically different from that ~f the melancholic patients. Inclusion of this group enabled us to explore whether our finding was specific to melancholia or could also be found in patients with nonmelancholic depression.
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Table 1. Subject and Control Populations Mean age _+ SD (yrs)
Group
No. subjects
Age range
Pilot study melancholics Replication-older melancholics Replication-younger melancholics Depressed nonmelancholics Neuropsychiatric patients, nondepressed Older normal controls Younger normal controls
9 15
73. ! +- 6.0 75.5 __ 2.7
65-85 70-81
14
63.8 _ 2.6
59-68
11 10
65.2 _+ 5.1 61.9 -+ 11.0
59-73 60-83
56 56
73.4 -+ 2.7 64.2 _ 2.7
70-79 60-69
Lastly, in this investigation we present data on a group of 10 negiy studied neuropsychiatric patients without depression who ranged in age from 60 to 83 years, mean age -+ SD 61.9 -+ 11 years (group 5). This group consisted of patients with schizophrenia (n - 3), panic disorder (n -- 2), seizures (n - 2), behavior disorder (n - 2), and sleep oisorder (n = 1). Nine of 10 neuropsychiatric nondepressed patients were on medications, including neuroleptics, anticonvulsants, and antianxiety agents, but not antidepressants. This group was utilized to assess whether similar FVER abnormalities would be found in elderly neuropsychiatric patients in whom the diagnosis of depression, with or without melancholia, was excluded (Table 1). Thus, in this investigation we present data on a total of 50 entirely new patients not previously studied or reported. These include all patients in group 2 (replication--older melancholics; n - 15); group 3 (replicationmyounger melancholics, n - 14); group 4 (depressed nonmelancholics, n - 11); and group 5 (neuropsychiatric patients, not depressed, n - 10). We compared our patient groups to an older control group, mean age +- SD 73.4 _+ 2.8 years and a younger control group, mean age - S D 64.2 _.+ 2.7 years. These two age-matched control groups each consisted of 56 nondepressed, unmedicated, medically well subjects. Previously studied normal male controls were members of the normative aging study at the Boston Veterans Administration Outpatient Clinic; female controls were community volunteers. All control subjects were screened to exclude medical, psychiatric, metabolic, or neurologic illness and were closely matched for age and gender to the patient population. Control subjects were on no medication at the time of study (Duffy et al 1984). In the pilot melancholic group, the two replication melancholic groups, and in the depressed nonmelancholic group, the preponderance of patients were women; there were 6 women and 3 men in the melancholia pilot study, 13 women and 2 men in the older, and 12 women and 2 men in the younger melancholic replication groups. I'he depressed nonmelancholic group was composed of 11 women and 3 men. To evaluate the potential relevance of gender difference on the FVER, we separately compared the 28 men with the 28 women within each of the two normal control groups. Diagnosis of depression and melancholia was based on DSM-IH-R criteria with the consensus of four staff psychiatrists, including each patient's attending psychiatrist. All depressed and melanclholic patients were ambulatory and free of significant medical illness. Diagnosis of the neuropsychiatric nondepressed patient group was based on the opinion of each patient's attending psychiatrist or neurologist.
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Neurophysiological Testing All subjects, includiho previously studied controls, were evaluated at Children's Hospital, Boston, MA using quantified EEG with mapping, a computer-based technique for the topographic display and quantitative analysis of scalp-derived neurophysiological data. Data were recorded from 20 scalp electrodes (referenced to linked ears) and four artifact elect'odes placed so as to maximize detection of vertical eye movement (VEM) and blink, horizontal eye movement (HEM), and temporal and occipital muscle activity (EMG). Flash stimuli used to form the FVER were delivered from a Grass model PS-22 photic stimulator at intensity level 8 placed 30 cm directly in front of the subjects closed but undilated eyes. Such supramaximal stimulation largely eliminates pupil size as a key variable (Skala and Holman 1984). For general clinical screening purposes, many qEEG laboratories rely as much on the FVER as they do on the pattern reversal visual evoked response (PRVER) (Duffy 1982; John et al 1988). Although the PRVER is of established clinical use for conditions such as Parkinson~s disease, cortical blindness, and demyelinating disease (Cracco et al 1986), its topographic distribution across the scalp is seen to be largely limited to the occiput when many electrode~ are used. In contrast, the FVER can be readily derived from many regions and may delineate abnormalities at a distance from the occiput (Duffy 1982). In this study only the FVER was consistently utilized across all subjects/patients. During recording, a classic EEG was performed to assure the fully alert state and to assist in the minimization of artifact. Data from artifact free periods were subjected to a simple, but individually adjustable, over-voltage rejection algorithm; signal averaging was performed using a Masscomp 5500 computer with Nicolet software. Grass EEG amplifiers were set to pass 1-300 Hz. Prior to digitization, all signals were low pass flit. d at 90 Hz with a 24 dB per octave Butterworth filter to avoid aliasing. Signals were sampled at 256 Hz resulting in 128 points for 512 mse¢ before and after time of stimulation. The prestimulus or baseline period allowed e0aablishment of baseline zero voltage and also provided an indicator of adequacy of sign,d-to-,~oise ratio. At the time of signal averaging, a continuous plot of signal-to-noise ratio versus number of trials was provided for each subject and averaging of these long latency FVERs was continued until such time as the signal-to-noise ratio versus trials asymptoted, indicating no further signal value to the acquisition of additional trials. Over this population, 250-400 trials per subject were required to asymptote. FVERs were aligned for averaging by a trial marker stored on one tape channel digitized with an accuracy of less than 0.5 msec, well within the limits of our 4 msec sampling rate. Equal 512 msec prestimulus and poststimulus epochs were formed. Alertness and attention were controlled by frequent interruption and interrogation while monitoring the EEG for signs of drowsiness (Santamaria and Chiappa 1987). Sets of 20 FVERs were transformed by the same computer into a corresponding series of topographic maps (Duffy 1989). To delineate regional differences of FVER between groups, the significance probability mapping (SPM) technique was used to search 40 msec epochs of regional between-group difference (Duffy et al 1981). Each of the clinical groups was compared with the most age-appropriate normative control group. Additionally, the control groups were compared to one another. Regions delineated by a t value above a certain criterion t-level (t = 2) were designated as regions of interest (ROI). Between-group t-tests were performed on all four artifact channels, as well as for the 20 scalp electrodes. When an SPM demonstrated between-group differences above a t of 2.00, the t values for the adjacent artifact channels were also examined. If they were
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also above criterion level, the SPM was considered to be possibly contaminated by groupspecific artifact an~ was eliminated from consideration. The same room, ambient illumination, stimula~6r, stimulation instruments, and alert state were utilized for all patient and control groups.
Results Results are shown in Figures 1-8. For each figure the particular comparison is indicated by the top label. Two grand mean FVER waveforms from the PZ (midline parietal) electrode are shown, one depicting a study population and the other the corresponding age-matched control group. For the original and new melancholic to control comparisons the significant results were limited to the 224-260 and 264-300 msec epochs, which are delineated for clarity by thick black lines on all figures. Spatial extent of between-group difference can be s~en by the eight t-statistic SPM shown below. Each t-SgM is a schematic map of the head with nose above, left ear to the left, etc. Black signifies no significant difference; the ROI, shown in white, is defined as a region of significance above the indicated threshold probability level (i.e., p < 0.05, p < 0.02, p < 0.01). The results demonstrate that the regional difference delineated in the pilot melancholic group is replicated for both the age 60--69 and 70-79 new melancholic groups. The data comparing the grand mean parietal FVER of these three different, independently co]llected melancholic populations demonstrates a consistent negative deviation from control group normative FVER data 224-300 msec poststimulus, maximal in the midline centroparietal region. The older replication melancholic group (Figure 2) at 224-71"60msec poststimulus shows a posterior occipital and centroparietal difference from cor~trols at the p < 0.01 level of significance. At the 264-300 msec epoch, the FVER of the older melancholic group again achieves a p < 0.01 level of significance; the spa,~ial distribution of the finding appears somewhat more centroparietal than in the original pilot study (Figure 1). The younger replication melancholic group (Figure 3) shows the I-NER abnormality most prominently at 264-300 msec poststimulus with a parietal-to-posterior occipital distribution. At 224-260 msec poststimulus the finding of abnormal FVER is limited to a centroparietal distribution, achieving a p < 0.02 level of significance. The FVER abnormality seen in the older melancholic replication group is nearly as pronounced in the younger melancholic replication group (Figure 3). The depressed nonmelancholic patient group (Figure 4) exhibits less significant ?,~'oup difference reaching the p < 0.05 levd for both the 224-260 msec and 264-300 msec epochs and, extending minimally to the right posterior region, at the p < 0.02 level during the 264-300 msec epoch. However, the eye artifact electrodes also shc,~ed significant group difference for 224-.260 msec, suggesting that these differences in FVER in the frontal region are artifactual. The failure of what appears to be a large difference between the means of the two groups (Figure 4) to reach statistical significance can be attributable to a large FVER variance within the depressed nonmelancholic population. The origins of this variance arc unclear and are to be addressed by future study of additional patients. Findings were virtually nonexistent in the nondepressed neuropsychiatric patient group (Figure 5). Finally, the younger and older control groups demonstrated no FVER findings when compared with each other (Figure 6). Thus, the original finding appears mainly specific to melancholia and cannot be easily explained by age effect alone, by depression without melancholia, or by general neuropsychiatric illness in the elderly. Moreover, it
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Figures I-8. For each figure depicting the group mean FVER, the particular group compared with normative age-matched controls is indicated by the figure heading. Figure 6 compares the two normative control groups, which differed in age by I0 years. Figures 7 and 8 depict male/female comparisons of the control groups. The T-spm, beneath the co,-responding mean FVER graph, is a schematic map of the head with nose above, left ear to the left, etc. Black signifies no significant difference; white signifies significance above a threshold probability (clip) level indicated by p < 0.05, p < 0.02, p < 0.01. Hence, spatial extent of between-group difference can be seen. Thick black lines on the group mean FVER graph delineates the 224-260 and 264-300 msec epochs, the epochs poststimulus which revealed significant differences between the comparison groups.
Abnormal FVER in Melancholia
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1992;31:325-336
FIG S: NON-DEPRESSEDNEUROPSYCHIATRICPATIENTS /~
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seems unlikely that the somewhat different proportions of men and women in the melancholic and control groups could explain the FVER change as no FVER gender difference could be demonstrated within either the 60-69 or the 70-79-year-old control populations (Figures 7-8). Discussion In our previous pilot study, FVER group difference between melancholic patients and controls was reported from the medial parietal region, maximal at PZ for a 40 msec epoch starting at 216 msec. These findings on the pilot melancholics established the hypotheses to be tested by the replication study: (1) FVER difference in time between controls and melancholic patients would be most prominent or restricted to the 224-300 poststimulus latency epoch; (2) FVER difference over the scalp (in space) would involve the centralparietal-occipital region, centered about or always involving PZ but frequently involving adjacent electrodes; (3) Such differences would not be found in nondepressed patients. To test these hypotheses, we conducted the identical analyses on two new independently collected groups of elderly depressed patients with melancholia, one group older than the other. To further explore specificity, we also studied depressed patients without melancholia and neuropsychiatric patients without depression. In the current investigation, we reanalyzed the data from our initial pilot study of nine elderly melancholics now utilizing a large~ control group (n = 56 versus n = 29). As we expected,, the results from the reanalysis of the initial pilot study group were virtually identical to those previously reported. (In the current replication study, we chose the midline parietal PZ electrode for FVER waveform display as regions of statistical significance almost always involved this electrode (see white areas in figure display). Other electrodes, including occipital, central, and ialeral parietal electrodes, were most often within these regions and showed similar changes. In the original pilot study article we showed the midline occipital OZ electrodederive: FVER for display as was the convention in FVER studies.) A large region of between-group difference (Figure 1) was evident, centered about the medial parietal electrode (PZ). From the temporal perspective, group difference was found in two sequential 40-reset epochs, 224-260 msec and 264-300 msec. Group grand mean FVER data from the two newly studied melancholic groups were compared to similar FVER data gathered from age-appropriate nondepressed control subjects. The melancholic FVER demonstrated consistent reduction of positive amplitudes limited to the 224-300 msec latency epoch, maximal in the midline centroparietal region centered about PZ (Figures 2 and 3). Thus, the findings of our initial pilot study (Figure I) are broadly confirmed. Moreover, similarly compared to control data, the FVER of the depressed but nonmelancholic group showed less robust and topographically different abnormalities (Figure 4). However, further studies will be required to definitively determine whether the FVER abnormality in depression lies on a continuum with melancholia at one extreme or whether melancholia constitutes a separable and distinct subpopulation with respect to these FVER abnormalities. Although detailed psychometric testing was not performed, all melanci~olic patients were hospitalized, indicating severity of their depression. Some patients were off medication or only on low dose benzodiazepines in the context of an intensive reevaluation of treatment refractory depression. Although the melancholic populations demonstrated a higher number of women than the control population, there was no evidence to support gender difference within the control populations (Figures 7 and 8). Thus, asymmetries of gender distribution seem
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unlikely to explain our findings. Only a larger study could examine the possibility of an unexpected gender by melancholia interaction effect. As our depressed patients were severely ill, we could not study them in the absence of medication. The older and younger melancholic groups and the nonme|ancholic depressed group exhibited a similar profile of medication usage, with most patients on either low dose benzodiazepines (5 of 15 in tile older melancholic group, 6 of 14 in the younger melancholic group, and 3 of 11 in the nonmelancholic depressed group) or tricyclic antidepressants (5 of 15 in the older melancholic group, 5 of 14 in the younger melancholic group, and 5 of 11 in the depressed nonmelancholic group). It seems unlikely, therefore, that medication effect alone could explain the FVER differences between our melancholic and nonmelancholic depressed patient groups. Further, all four completely unmedicated patients--two in the pilot melancholic group, one in the older melancholic replication group, and one in the depressed nonmelancholic group---also individually demonstrated the same abnormal FVER findings. A pharmacological effect on our findings cannot be completely excluded, however, as benzodiazepines may produce a FVER amplitude reduction (Bond and Lader 1973) and imipramine an amplitude increase (Endo et al 1983). Differences in level of consciousness and auention have also been scrutinized as relevant factors to FVER waveshape morphology and latency shifts, particularly in dementia where such patients may become drowsy more easily than normal subjects unless precautions are taken (Huisman 1987). Level of consciousness and attention were carefully controlled in our study with continuous monitoring of each patient's mental state and EEG background activity. In the current study, FVER data were collected only when patients were fully awake and alert. Thus, it is unlikely that our finding can be simply explained by group-specific state difference. As the long latency FVER may show considerable variation in waveshape morphology among individuals, it could be argued that our findings might represent capitalization upon random group difference. Our experience with the FVER and long latency-evoked response in general argue that, to the contrary, group grand mean VER tend to replicate a~td do not show random between-group difference. To be noted is similar group grand mean FVER morphology for the 60-69 and 70-79-year-old control groups and the ~bsence of any statistically significant between-group difference (Figure 6). Note also the consistent absence of gender difference within the two different control groups (Figures 7-8). The consistency of our FVER finding in three different melancholic populations makes any random (or chance) effect most unlikely. Recent studies utilizing the FVER in depression have yielded varying results. Accentuation of PI00, P200, and NI40 FVER waveforms in young (mean age 32 years) melancholic patients has been reported (Khanna et al 1989). Conversely, attenuation of the FVER in psychomotor retarded depressed patients has been described (Knott and Lapierre 1987). A study utilizing a quantified EEG methodology, however, failed to find any difference in FVER between 10 depressed patients and 10 normal controls (Guidi et al 1989). Earlier studies have described both a diminution of VER amplitude in more severely depressed patients (Penis 1975; Shagass et al 1980) and an augmentation (Vasconetto et al 1971). The conflicting findings in these investigations may reflect variability of the depressed patient populations studied, as well as difference in methodology ancL/or measurement. Other studies have focused on alterations in the VER following treatment of the underlying depressive disorder. A recent investigation found decreased latency ~nd increased amplitude of the PRVER in both positive (Pl, P3) and negative (N 1) components
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in depressed patients that reverted to normal after 28 days of antidepressant treatment (Chakroun 1988). Diminished interhemispheric variability and augmentation of previously attenuated FVER waveforms of depressed patients has also been reported following successful electr~onvu!sive treatments (Perris and Eisemann 1980). A number of lines of investigation suggest that catecholaminergic dysfunction may give rise to abnormalities of the VER (Hadjiconstantinou and Neff 1984). Several studies have suggested a positive correlation between dopamine as well as its precursors and metabolites and the amplitude of the FVER (Gottfries et al 1974; Holder et al 1980; Goodwin et al 1970; He:ary et al 1976; Redmond et al 1975). Other investigations in humans and animals have described a prolongation of latency of the VER associated with dopaminergic deficiency (Bodis-Wollner et al 1982; Onofrj and Bodis-Wollner 1982). Given the longstanding interest in the relationship between catecholamines and depressive disorders (Schildkraut 1965; Schildkraut and Kety 1967), a potential role for the VER in elucidating the pathophysiology of depressive disorders is evident. To further assess the possible neurochemical basis for the abnormal VER in melancholia, we plan to explore relationships between abnormalities of the FVER and measures of catecholamine output and metabolism in unmedicated depressed patients (Schildkraut et al 1978a, 1978b; Schatzberg et al 1989). Such correlational studies between neurophysiological and neurochemical systems promises to further refine a biologically based subclassification of depressive disorders, enabling us to assess whether alteration of the VER is signaling neurotransmitter dysfunction in melancholic patients. In summary, the grand mean FVER data from two newly studied groups of melancholic patients demonstrates a consistent reduction of positive amplitudes over the 224-300 msec latency eDoch, maximal in the midline centroparietal region, replicating the findings from our initial pilot investigation. The nemochemical basis of this finding in melancholia remains to be explored. References Arezzo JA, Peckoff A, Vaughn HG (1975): The sources and intraeranial distribution of auditory evoked potentials in the alert, rhesus monkey. Brain Res 90:57-.-73. Bodis-Wollner I, Yahr MD, Mylin L, Thornton I (1982): Dopaminergic deficiency and delayed visual evoked potentials in humans. Ann Neurol I 1:478-483. Bond AJ. Lader MH (1973): The residual effects of flurazepam. Psychopharmacologia 32:223235. Chakroun H (1988): Effects of selective attention on visual evoked potentials in depressed patients and healthy controls. Acta Psychiatr Belg 88:!38n152. Cracco R (1986): Evoked Potentials. Bodis-Wollner i (ed). Alan R. Liss, New York. Duffy FH ( 1982): Topographic display of evoked potentials: Clinical applications of brain electrical activity mapping (BEAM). Ann NY Acad Sci 388:!83-196. Duffy FH ( 1989): Topographic mapping of brain electrical activity: Clinical applications and issues. in Maurer K (ed), Topographic Brain Mapping of EEG and £voked Potentials. Heidelberg, Germany: Springer-Verlag, pp 19-52. Duffy FH, Barrels PH, Burchfield JL (1981): Significance probability mapping: An aid in the topographic analysis of brain electrical activity. Electroencephalogr Ciin Neurophysiol 51:455462. Duffy FH, Albert MS, McAnulty G, Garvey J (1984): Age-related differences in brain electrical activity of healthy subjects. Ann Neurol 16:430-438. Endo S, Nakayama S, Kuraoka Y, et al (1983): Changes in visual evoked potentials induced by imipramine in patients with endogenous depression. J Nippon Med Sch 50:480-488.
Abnormal FVER in Melancholia
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