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Changes in the visual evoked potential to pattern reversal with lithium medication
538
Electroencephalograph)' and clinical Neurophysiologv, 1983,55:538-545
Elsevier ScientificPublishers Ireland, Ltd.
CHANGES IN T H E VISUAL EVOKED P O T E N T I A L T O PATTERN REVERSAL W I T H L I T H I U M MEDICATION P.B.C. FENWICK and ROBYN ROBERTSON 1 Institute of Psychiatry, St. Thomas' Hospital and Maudsley Hospital, London SEI 7EH (England)
(Accepted for publication: December 13, 1982)
Lithium has been used increasingly in the treatment of affective illnesses ever since Cade (1949) described 10 manic patients who responded dramatically to the treatment. Numerous papers have been published on the effects of lithium, both on the EEG and on the evoked potential (EP): Gartside et al. 1966; Mayfield and Brown 1966; Heninger 1969; Johnson 1969; Platman and Fieve 1969; Heninger and Demers 1971; ltil and Akpinar 1971; Small et al. 1972; Dimitrakoudi and Jenner 1975; Spring 1979. Small et al. in 1971 studied the effect of lithium carbonate on the somatosensory, auditory and flash visual evoked potentials (VEPs) in a group of patients. They point out that very little change was seen with lithium medication. Buchsbaum et al. (1971) reported that there was an increase in the somatosensory and auditory EPs with lithium medication, but that the flash VEPs either did not change or were reduced at high flash intensities. Heninger (1978) studied somatosensory, auditory and flash VEPs and found that the early components of the somatosensory EPs showed a marked and significan! enhancement, reflecting a change due to lithium in the positivity of the primary sensory cortex itself. The middle components of the auditory EPs were enhanced, although no changes were seen in the later components. No changes were found with a flash stimulus. It is not clear why there should be consistently negative reports of the effect of lithium on the flash VEPs and why the visual system should respond differently from the auditory and
i Now at VancouverGeneral Hospital.
somatosensory systems. However, the visual system handles flash information differently from pattern reversal information (Cobb et al. 1967). The VEP to flash stimuli also has a wider variance than the EP to pattern stimulation. It may be that it is the wide variance which is hiding any change in amplitude. In view of these negative findings for the visual system, it was decided to use pattern reversal rather than a flash stimulus. Our prediction was that the visual system would then behave as both the somatosensory and the auditory systems. Furthermore, it was felt that additional information could be gained by using fractional pattern displacement. Fenwick and Turner (1977) and ParryJones and Fenwick (1979) have already shown that the VEP to fractional pattern displacement, ¼, I, 3, and full, is both linearly and proportionally related to the stimulus displacement. A subsequent study by Fenwick et al. (1981) had shown that the amplitude of the N65-P95 wave and P95-Nt25 wave in children aged 6-11 developed differently. This developmental difference suggested that fractional pattern displacement and an analysis of the two amplitudes could give some insight into the changes which we predicted would occur with lithium.
Method
Patients were referred to the study voluntarily from the Department of Psychiatry at St. Thomas' Hospital. After psychiatric interview and diagnosis, ll patients entered the study, but only 7 completed it. Three patients suffered from manic depression and 4 from depression. These 7 pa-
0013-4649/83/0000-0000/$03.00 © 1983 ElsevierScientificPublishers Ireland, Ltd.
P A T T E R N VEP C H A N G E S W I T H L I T H I U M
tients attended on 3 occasions. The first (control) was before lithium, the second (Tl) 1 week after starting lithium, and the third (T2) 1 month later. VEP and a routine E E G were measured at each recording session. After the last 2 sessions the patient's serum lithium concentration was measured. At the end of each session the patients completed the Crown Crisp Inventory, and the technician and patient also completed a semantic differential form. These semantic differentials rated on a 7-point scale the dimensions of concentration, alertness, movement, anxiety, mood, speed of thinking, whether the procedure was enjoyable, and how clearly the pattern could be seen. These questions allowed both a subjective and objective change in the patient's behaviour to be measured. The Crown Crisp Index enabled any changes in the patient's symptoms during the study to be assessed. The VEP was recorded from one channel; the active electrode was placed 5 cm above the inion in the midline referred to the vertex. LF cut 3 dB down at 0.5 Hz, H F cut 3 dB down at 350 Hz. The response to full pattern reversal was recorded from both eyes together, and from each eye singly. The response to fractional pattern displacement was recorded from both eyes. The order of the 6 conditions, full, 3, ~, ], R and L eye, was randomized between patients and within patients between sessions. The pattern reversal screen subtended an angle at the retina of 15°24 min, the check 42 min; the luminance of the white checks was 1500 ( c d / m 2) and the black squares 120 ( c d / m 2). The pattern reversal was by means of a mirror and the rate was approximately 1/sec, with 128 pattern reversals summed into each average (Fenwick and Turner 1977). The E E G was amplified by a Devices EEG amplifier, and averaged using the Data Lab.'s 4000 microprocessor (300 /~sec per sample). The routine E E G with hyperventilation and photic stimulation was recorded using Ag/AgC1 electrodes with the 10/20 International electrode placement. All the EEG recordings showed the changes already described with lithium medication and none were otherwise abnormal. The patients' medication on the day of the control trial was not altered throughout the study. Lithium was introduced 1 week before the second record-
539
ing session and the dosage adjusted, so that a therapeutic serum concentration was maintained for the treatment period. A control group of 7 normal subjects matched for age had two recording sessions similar to those of the patient group, the first (control) when they joined the study, and the second (T2) 5 weeks after the first. This normal group was then compared with the control and final sessions for the patient group. The design of the experiment, with a test session 1 week after the starting of lithium and 1 month after that, allowed both the acute and chronic effects of lithium treatment to be studied.
Results
Of the II patients who entered the study, 7 completed it. One withdrew because of intolerance to lithium and severe headaches; one moved away; two others did not attend the final session. The mean age of both the patient and the control groups was 35 years with a standard deviation of 10.2 years. The visual acuity for both the patient and control groups was better than 6/9ths.
Questionnaire results The Crown Crisp Index results are shown in Table I. The patients were rated as abnormal on all scales at the start of the study and, even after 5 weeks on lithium, they remained abnormal on all scales except for hysteria. Table I also shows that, for the normal group, no scale is in the abnormal range, and there are significant differences between the normals and the patients on all scales except the somatic and hysteria scales. Thus the normal group is asymptomatic, while the patient group is clearly abnormal.
Semantic differential The results of the most relevant questions in the semantic differential are given in Table II. The patients rated their concentration as worse, their alertness as less, their anxiety as greater, and their mood as sadder than the control group. However, the tests show very little change in concentration in either the patient or the control group. Both groups rated themselves as less alert on the final
540
P.B.C. F E N W I C K , R. R O B E R T S O N
TABLE I M e a n scores on the C r o w n Crisp Index for the patient and n o r m a l groups.
Patients
Anxiety Phobic Obsessions Somatic Depression ltysteria
Normals
Control
Final session
t test P
9.8 7.0 10.0 7.5 9.7 7.3
9 7 9 8 7 6
N.S. N.S. N.S. N.S. N.S. N.S.
4 3 9 2 8 2
session. There was little change in anxiety or mood in either group, although the patients felt slightly less depressed towards the end of the study.
t test P normals vs. patients 2.8 2.2 4.3 3.1 2.7 3.7
0.01 0.02 0.02 N.S. 0.01 N.S.
eye, L eye, and both eyes together, t tests were calculated for the control and T 2 amplitudes between the patient group and the normal control group. There were no significant differences in amplitude between the groups for the control session, but there was a significant increase in amplitudes in the patient group for the final (T 2) session ( P < 0.05). Table IV gives the results in a similar way for the P95-N~25 wave. Again the control condition shows no significant difference between the patient and normal groups, while, for tile T2 condition, there is again a significant increase in amplitude of the patient group ( P <0.01). It is of interest to note that, for this wave, the highest
Evoked potential results Fullpattern displacement.
Two amplitudes, the N65-P95 and Pgs-N~25 peak-to-peak measurement, and one latency measurement, the Pgs, were taken. The measurements were taken from the points of greatest amplitude on the wave. The EP wave forms recorded were no different from those already reported in the literature and are not illustrated here. Table III gives the amplitudes of the full pattern displacement for the N65-P95 w a v e for the R
T A B L E II M e a n and s t a n d a r d error scores for the patient and control groups for each item on the semantic differential. Dimension
Patient group Control
Concentration bad I --, 7 good Alertness sleepy 1 - , 7 a w a k e Anxiety relaxed 1 ---, 7 anx. Mood h a p p y 1 ~ 7 sad
N o r m a l group T~
T2
Control
1' 2
Mean
S.E.
Mean
S.E.
Mean
S.E.
Mean
S.E.
Mean
S.E.
4
0.5
4.7
0.7
4.6
0.6
6.3
0.5
5.9
0.8
4.1
0.8
4.1
0.9
2.9
0.9
6.1
0.7
5.4
0.8
3.4
0.9
2.6
0.6
3.3
0.8
0.6
0.3
0.6
0.4
4
0.9
3.3
0.7
3.7
0.6
1.1
0.7
1.4
0.7
P A T T E R N VEP C H A N G E S W I T H L I T H I U M
541
T A B L E Ill A m p l i t u d e s of the N65-Pg~ waves to full p a t t e r n d i s p l a c e m e n t for the right and left eye singularly a n d for b o t h eyes together. For each c o n d i t i o n the p a t i e n t and control g r o u p s are shown. The significant differences between the a m p l i t u d e s of the n o r m a l and p a t i e n t groups, using a t test, are shown. R i g h t eye
Normal Patient Patient Patient Normal
control control test 1 test 2 test 2
Left eye
Mean
S.E.
6.6 8.8 10.9 11 6.3
0.7 2.2 2.1 1.4 0.9
MEAN
t tests
N.S. t = 2.7 Sig. < 0.05
AMPLITUDES A N D
Both eyes
Mean
S.E.
6.5 8.5 10.7 11.1 6.6
1.5 2.5 1.75 1.7 0.8
STANDARD ERRORS
t tests
N.S. t = 2.5 Sig. < 0.05
OF
THE
FOR THE N65 P95 WAVE
Mean
S.E.
7 10 10.9 13.1 6.6
1.0 2.7 2.6 2.7 0.95
t tests
N.S. t = 2.8 Sig. < 0.05
MEAN
T
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PATTERN
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Fig. 1. The m e a n a m p l i t u d e a n d s t a n d a r d error of the m e a n are s h o w n for the Nrs-P95 wave for the control a n d p a t i e n t groups. The g r a p h s for the control c o n d i t i o n before lithium and the n o r m a l g r o u p show no significant differences using a t test. For the final session 5 weeks after starting lithium treatment, the full p a t t e r n d i s p l a c e m e n t shows a significant difference between the groups, * P < 0.05. The m e a n regression lines for the 3 patient trials show an increase in the slope for the last trial. The straight lines are the linear regression.
542
P.B.C. F E N W I C K , R. R O B E R T S O N
T A B L E IV A m p l i t u d e s of the P95-N125 waves to full pattern d i s p l a c e m e n t for the right and left eye singularly a n d for both eyes together. For each c o n d i t i o n the p a t i e n t a n d control g r o u p s are shown. The significant differences between the a m p l i t u d e s of the n o r m a l a n d p a t i e n t groups, using a t test, are shown. R i g h t eye
Normal Patient Patient Patient Normal
control control test 1 test 2 test 2
Left eye
Mean
S.E.
5.6 9.9 12.6 10.3 5.5
0.7 2.3 1.8 1.4 0.8
MEAN
t tests
N.S. t = 2.8 Sig. < 0.05
AMPLITUDES
AND
Both eyes
Mean
S.E.
7.5 10.2 12.6 10.8 7.0
0.8 2.5 1.6 1.5 0.9
STANDARD ERRORS
FOR THE P 9 5 - N I 2 5
t tests
N.S.
t = 2.7 Sig. < 0.05
OF
THE
Mean
S.E.
7.7 8.2 11.7 10.8 6.7
1.9 2.1 1.8 1.2 0.4
t tests
N.S.
t = 3.6 Sig. < 0.01
MEAN
WAVE
Patient Test I
12, m - -
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10
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9
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T Patmnt
Test 2
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ig
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PATTERN
DISPLACEMENT
Fig. 2. The m e a n a m p l i t u d e a n d s t a n d a r d error of the m e a n is s h o w n for the Pgs-N125 wave for the control and patient groups. The straight line is the linear regression. There are no significant differences between the control c o n d i t i o n s using a t test. For the final session 5 weeks after starting lithium treatment, the full ~ and ~4 p a t t e r n d i s p l a c e m e n t s show a significant difference, using a t test. T h e half is nearly significant a n d would have been if more subjects h a d been used. It can be seen that, for the p a t i e n t trials, all the regression lines r e m a i n a p p r o x i m a t e l y parallel to each other, but that the highest m e a n level was reached after the first week of lithium t r e a t m e n t and not after 5 weeks, as was found for the N6s-P95 wave.
PATTERN VEP CHANGES WITH LITHIUM
543
amplitude is reached 1 week after the introduction of lithium, and not in the final session as it was for the N65-P95 wave, although this difference does not reach significance.
Fractional pattern
displacement
TABLE V P values for an F test comparison between the normals and the patients for the full and fractional pattern displacement for both waves and for the control and final sessions.
amplitudes.
Fig. 1 shows the amplitude of the N65-P95 wave for the fractional and full pattern displacements with both eyes open for the normal control and the patient group for the first or control session. The regression lines run almost parallel to each other and there are no significant differences on any pattern displacement between the groups. The results after 5 weeks of lithium treatment are also shown in Fig. 1. The only significant difference ( P < 0.05) is for the full pattern displacement, as already described. Fig. 1 shows the regression lines for both control and patient groups. For the patient group, the slope for the final session is clearly increased compared to the previous two trials (4.2, control; 10.2, final). Tests between the slopes of the patient and the normal control groups for the control trial and the final assessment were not significantly different. Fig. 2 shows the fractional pattern displacement results of the P95-Nt25 wave in a similar way to that used for the N65-P95 wave. Again there are no differences between the amplitudes for the control and patient groups for any displacement. After treatment of the patient group for 5 weeks with lithium, changes in amplitude do occur and these can be seen in the figure. The ¼ ( P <0.05), ¼ ( P < 0.05), and the full ( P < 0.01) displacements are now significantly different for patient and normal T 2, and the 1 would have been had more subjects been used. Fig. 2 shows the regression lines for the P95-N125 wave and all 3 test sessions of the patient group. It is clear that there is very little difference in slope between them, but what does change is the y intercept, rising as high as 9.1 ~V after 1 week of lithium treatment.
Variance results The variance of both the N65-P95 and P95-N125 amplitudes was calculated for each pattern displacement and compared using an F test between the patient and control groups. The results are shown in Table V. Significant differences were
Full 4
2' 4
Control session
Final session
N65-P95
P95-NI25
N65-P95
P95-Nt2s
< 0.05 < 0.05 < 0.05 < 0.05
0.05 0.05 N.S. 0.05
< 0.05 N.S. < 0.05 < 0.05
< 0.05 N.S. N.S. < 0.05
found for both amplitudes and at each pattern displacement, except for the ½ for the control test. There were fewer differences in the test two comparisons.
Latency and serum lithium results No significant differences in latency for the P95 wave were seen between control and patient groups. The serum lithium levels were as follows: T l mean 0.57 mmol/1 and for T 2 0.66 mmol/1 there was no significant difference between the two sessions, t = 1.26, P = N.S.
Discussion The results of this study confirm the hypothesis that lithium treatment will produce an increase in amplitude of the pattern VEP. The mean amplitude increase for the full pattern response for the N65-P95 wave is 5 #V, an increase of 62%. For the P95-N~25 wave, the increase is 2.8 ~V or 28%. The figure for the early wave of 62% agrees well with that of Heninger (1978) for the increase in the early component of the SEP of 50%. However, he did not publish the figures for the later component, so the rise of the second wave cannot be compared. Small et al. (1971) reported a relationship between mood and EP amplitudes and latencies, but this was not seen in the present study. The Crown Crisp Index showed only a minor and inconsistent change in the depression scores, while the subjective ratings on the semantic differential showed that, on the whole, the patients felt only slightly less depressed at the time of the final
544 session. The increase in amplitude was not simply a result of the patient attending, as the semantic differential result on the dimension of concentration did not change appreciably for the treatment sessions. The results of the fractional pattern displacement are also of interest. For the N65-P95 wave the response to lithium is different in the acute and chronic phase. In the acute phase, the results of the first treatment session show that the slope of the regression line across pattern displacements is not altered while it is the general level of the line which is raised (an increased y intercept). The wave behaves quite differently in the chronic phase (5 weeks after starting lithium) when the y intercept is decreased, but the slope shows a marked increase. For the P95-NI25 wave effects of both the acute and chronic phase are the same with a raised y intercept and no change in slope, but this effect is greater in the acute phase of treatment. However, there is no significant difference between trials, probably due to the small number of patients used. The fact that there is no significant difference between the slopes of the regression lines within sessions suggests that lithium treatment does not affect the generation of the two waves differently, although more subjects are required to confirm this. A further study is also needed to see the effect of smaller pattern displacements than ¼, and to see whether or not the linearity of the response to small pattern amplitudes still holds.
Summary Previous reports in the literature have suggested that lithium medication does not affect the VEP to flash stimulation. It was predicted that this would not be true for pattern reversal stimulation. Seven patients had their pattern evoked potential measured using a 42' check to fractional pattern displacement of ¼, ½, ~ and full square. The VEP was measured before, 1 week after and 5 weeks after the commencement of lithium medication. The results show that there is a significant increase in
P.B.C. FENWICK, R. ROBERTSON both the N65-P95 and P95-NI25 amplitudes when the 'before lithium' sessions are compared to 'after lithium.' Seven normal subjects matched for the age and sex of the patient group were tested twice, once as a 'control' and a further 5 weeks after this. No significant differences were found in the "control' sessions between patient and normal groups although a significant difference in both the N65-P95 and P95-Nj25 amplitude after the treatment of the patient group with lithium was found.
R~sum~
Modifications des potentiels bvoquks visuels au changement de pattern lors du traitement par le lithium De pr6c6dentes donn6es de la littbrature ont sugg6r6 que le traitement par le lithium n'affecte pas le PEV ~t la stimulation par flash. On a pr6dit que ce ne serait pas vrai pour la stimulation par renversement de pattern. Chez 7 patients on a mesur6 le potentiel 6voqu6 par le pattern en utilisant un carr6 de 42' avec des d6placements du pattern de 1/4, 1/2, 3 / 4 et la totalit6 du carr6. Le PEV 6tait mesur6 avant le commencement du traitement au lithium, puis une semaine et 5 semaines apr6s. Les r6sultats montrent une augmentation significative des amplitudes N65-P95 et P95N125 quand on compare les s6ances 'avant lithium' et 'apr6s lithium'. Sept sujets normaux, assortis quant ~ l'glge et aux sexe au groupe de patients, furent testbs 2 lois, une premi6re en tant que 't6moins', puis 5 semaines plus tard. On n'a pas trouv6 de diff6rences significatives entre les s6ances 't6moins' des groupes de patients et des sujets normaux, malgr6 la diff6rence significative pour les amplitudes N65-P95 et P95-N125 apr6s le traitement par le lithium du groupe des patients. The authors would like to thank Mrs. Audrey Wyer for her kind help in the preparation of the manuscript, and Miss Norma West, Mrs. Joan Adams, Mrs. Jacintha Hennessey and Ms Sonja Stone for all the help they gave on the organizational aspects of the study.
PATTERN VEP CHANGES WITH LITHIUM
References Buchsbaum, M., Goodwin, F. and Murphy, D. AER in affective disorders. Amer. J. Psychiat., 1971, 128: 19-25. Cade, J.F.J. Lithium salts in the treatment of psychotic excitement. Med. J. Aust., 1949, 36: 349-352. Cobb, W.A., Ettlinger, G. and Morton, ll.B. Visual evoked potentials in binocular rivalry. Electroenceph. clin. Neurophysiol., 1967, Suppl. 26: 100-104. Crown, S. and Crisp, A.H. Manual of the Crown Crisp Experiential lndex. Hodder and Stoughton, London, 1979. Dimitrakoudi, M. and Jenner, F.A. Electroencephalographic effects of lithium. In: F.N. Johnson (Ed.), Lithium Research and Therapy. Academic Press, New York, 1975: 507-518. Fenwick, P. and Turner, C. Relationship between amplitude of pattern displacement and visual evoked potentials. Electroenceph, clin. Neurophysiol., 1977, 43: 74-78. Fenwick, P., Hennessey, J. and Brown, D. The visual evoked response to pattern reversal in 'normal' 6-11-year-old children. Electroenceph. clin. Neurophysiol., 1981, 51: 49 62. Gartside, I.B., Lippold, C.J. and Meldrum, B.S. The evoked cortical somatosensory response in normal men and its modification by oral lithium carbonate. Electroenceph. clin. Neurophysiol., 1966, 20: 382-390. Heninger, G.R. Lithium effects on cerebral cortical function in manic depressive patients. Electroenceph. clin. Neurophysiol., 1969, 27: 670.
545 Heninger, G.R. Lithium carbonate and brain function. Arch. gen. Psychiat., 1978, 35: 228-233. Heninger, G.R. and Demers, R.G. Lithium effects on the EEG and somatosensory response in relation to sodium metabolism. Electroenceph. clin. Neurophysiol., 1971, 21 : 289-290. Itil, T.M. and Akpinar, S. Lithium effect on the human electroencephalogram. Clin. Electroenceph., 1971, 2: 89-102. Johnson, G. Lithium and the EEG: an analysis of behavioural, biochemical and electrographic changes. Electroenceph. clin. Neurophysiol., 1969, 27: 656(P). Mayfield, D. and Brown, R.G. The clinical laboratory and electroencephalographic effects of lithium. J. psychiat. Res., 1966, 4: 207-219. Parry-Jones, N.O. and Fenwick, P. Coloured pattern displacement and VEP amplitude. Electroenceph. clin. Neurophysiol., 1979, 46: 49-57. Platman, S.R. and Fieve, R R . The effect of lithium carbonate on the electroencephalogram of patients with effective disorders. Brit. J. Psychiat., 1969, 115: 1185-1188. Small, J.G., Small, I.F. and Perez, H.C. EEG, evoked potential and contingent negative variations with lithium in manic depressive disease. Biol. Psychiat., 1971, 3: 47-58. Small, J.G., Milstein, V. and Perez, H.C. EEG and neurophysiological studies of lithium in normal volunteers. Biol. Psychiat., 1972, 5: 65-76. Spring, G.K. EEG observations in confirming neurotoxicity. Amer. J. Psychiat., 1979, 136: 1099-1100.
Electroencephalograph)' and clinical Neurophysiologv, 1983,55:538-545
Elsevier ScientificPublishers Ireland, Ltd.
CHANGES IN T H E VISUAL EVOKED P O T E N T I A L T O PATTERN REVERSAL W I T H L I T H I U M MEDICATION P.B.C. FENWICK and ROBYN ROBERTSON 1 Institute of Psychiatry, St. Thomas' Hospital and Maudsley Hospital, London SEI 7EH (England)
(Accepted for publication: December 13, 1982)
Lithium has been used increasingly in the treatment of affective illnesses ever since Cade (1949) described 10 manic patients who responded dramatically to the treatment. Numerous papers have been published on the effects of lithium, both on the EEG and on the evoked potential (EP): Gartside et al. 1966; Mayfield and Brown 1966; Heninger 1969; Johnson 1969; Platman and Fieve 1969; Heninger and Demers 1971; ltil and Akpinar 1971; Small et al. 1972; Dimitrakoudi and Jenner 1975; Spring 1979. Small et al. in 1971 studied the effect of lithium carbonate on the somatosensory, auditory and flash visual evoked potentials (VEPs) in a group of patients. They point out that very little change was seen with lithium medication. Buchsbaum et al. (1971) reported that there was an increase in the somatosensory and auditory EPs with lithium medication, but that the flash VEPs either did not change or were reduced at high flash intensities. Heninger (1978) studied somatosensory, auditory and flash VEPs and found that the early components of the somatosensory EPs showed a marked and significan! enhancement, reflecting a change due to lithium in the positivity of the primary sensory cortex itself. The middle components of the auditory EPs were enhanced, although no changes were seen in the later components. No changes were found with a flash stimulus. It is not clear why there should be consistently negative reports of the effect of lithium on the flash VEPs and why the visual system should respond differently from the auditory and
i Now at VancouverGeneral Hospital.
somatosensory systems. However, the visual system handles flash information differently from pattern reversal information (Cobb et al. 1967). The VEP to flash stimuli also has a wider variance than the EP to pattern stimulation. It may be that it is the wide variance which is hiding any change in amplitude. In view of these negative findings for the visual system, it was decided to use pattern reversal rather than a flash stimulus. Our prediction was that the visual system would then behave as both the somatosensory and the auditory systems. Furthermore, it was felt that additional information could be gained by using fractional pattern displacement. Fenwick and Turner (1977) and ParryJones and Fenwick (1979) have already shown that the VEP to fractional pattern displacement, ¼, I, 3, and full, is both linearly and proportionally related to the stimulus displacement. A subsequent study by Fenwick et al. (1981) had shown that the amplitude of the N65-P95 wave and P95-Nt25 wave in children aged 6-11 developed differently. This developmental difference suggested that fractional pattern displacement and an analysis of the two amplitudes could give some insight into the changes which we predicted would occur with lithium.
Method
Patients were referred to the study voluntarily from the Department of Psychiatry at St. Thomas' Hospital. After psychiatric interview and diagnosis, ll patients entered the study, but only 7 completed it. Three patients suffered from manic depression and 4 from depression. These 7 pa-
0013-4649/83/0000-0000/$03.00 © 1983 ElsevierScientificPublishers Ireland, Ltd.
P A T T E R N VEP C H A N G E S W I T H L I T H I U M
tients attended on 3 occasions. The first (control) was before lithium, the second (Tl) 1 week after starting lithium, and the third (T2) 1 month later. VEP and a routine E E G were measured at each recording session. After the last 2 sessions the patient's serum lithium concentration was measured. At the end of each session the patients completed the Crown Crisp Inventory, and the technician and patient also completed a semantic differential form. These semantic differentials rated on a 7-point scale the dimensions of concentration, alertness, movement, anxiety, mood, speed of thinking, whether the procedure was enjoyable, and how clearly the pattern could be seen. These questions allowed both a subjective and objective change in the patient's behaviour to be measured. The Crown Crisp Index enabled any changes in the patient's symptoms during the study to be assessed. The VEP was recorded from one channel; the active electrode was placed 5 cm above the inion in the midline referred to the vertex. LF cut 3 dB down at 0.5 Hz, H F cut 3 dB down at 350 Hz. The response to full pattern reversal was recorded from both eyes together, and from each eye singly. The response to fractional pattern displacement was recorded from both eyes. The order of the 6 conditions, full, 3, ~, ], R and L eye, was randomized between patients and within patients between sessions. The pattern reversal screen subtended an angle at the retina of 15°24 min, the check 42 min; the luminance of the white checks was 1500 ( c d / m 2) and the black squares 120 ( c d / m 2). The pattern reversal was by means of a mirror and the rate was approximately 1/sec, with 128 pattern reversals summed into each average (Fenwick and Turner 1977). The E E G was amplified by a Devices EEG amplifier, and averaged using the Data Lab.'s 4000 microprocessor (300 /~sec per sample). The routine E E G with hyperventilation and photic stimulation was recorded using Ag/AgC1 electrodes with the 10/20 International electrode placement. All the EEG recordings showed the changes already described with lithium medication and none were otherwise abnormal. The patients' medication on the day of the control trial was not altered throughout the study. Lithium was introduced 1 week before the second record-
539
ing session and the dosage adjusted, so that a therapeutic serum concentration was maintained for the treatment period. A control group of 7 normal subjects matched for age had two recording sessions similar to those of the patient group, the first (control) when they joined the study, and the second (T2) 5 weeks after the first. This normal group was then compared with the control and final sessions for the patient group. The design of the experiment, with a test session 1 week after the starting of lithium and 1 month after that, allowed both the acute and chronic effects of lithium treatment to be studied.
Results
Of the II patients who entered the study, 7 completed it. One withdrew because of intolerance to lithium and severe headaches; one moved away; two others did not attend the final session. The mean age of both the patient and the control groups was 35 years with a standard deviation of 10.2 years. The visual acuity for both the patient and control groups was better than 6/9ths.
Questionnaire results The Crown Crisp Index results are shown in Table I. The patients were rated as abnormal on all scales at the start of the study and, even after 5 weeks on lithium, they remained abnormal on all scales except for hysteria. Table I also shows that, for the normal group, no scale is in the abnormal range, and there are significant differences between the normals and the patients on all scales except the somatic and hysteria scales. Thus the normal group is asymptomatic, while the patient group is clearly abnormal.
Semantic differential The results of the most relevant questions in the semantic differential are given in Table II. The patients rated their concentration as worse, their alertness as less, their anxiety as greater, and their mood as sadder than the control group. However, the tests show very little change in concentration in either the patient or the control group. Both groups rated themselves as less alert on the final
540
P.B.C. F E N W I C K , R. R O B E R T S O N
TABLE I M e a n scores on the C r o w n Crisp Index for the patient and n o r m a l groups.
Patients
Anxiety Phobic Obsessions Somatic Depression ltysteria
Normals
Control
Final session
t test P
9.8 7.0 10.0 7.5 9.7 7.3
9 7 9 8 7 6
N.S. N.S. N.S. N.S. N.S. N.S.
4 3 9 2 8 2
session. There was little change in anxiety or mood in either group, although the patients felt slightly less depressed towards the end of the study.
t test P normals vs. patients 2.8 2.2 4.3 3.1 2.7 3.7
0.01 0.02 0.02 N.S. 0.01 N.S.
eye, L eye, and both eyes together, t tests were calculated for the control and T 2 amplitudes between the patient group and the normal control group. There were no significant differences in amplitude between the groups for the control session, but there was a significant increase in amplitudes in the patient group for the final (T 2) session ( P < 0.05). Table IV gives the results in a similar way for the P95-N~25 wave. Again the control condition shows no significant difference between the patient and normal groups, while, for tile T2 condition, there is again a significant increase in amplitude of the patient group ( P <0.01). It is of interest to note that, for this wave, the highest
Evoked potential results Fullpattern displacement.
Two amplitudes, the N65-P95 and Pgs-N~25 peak-to-peak measurement, and one latency measurement, the Pgs, were taken. The measurements were taken from the points of greatest amplitude on the wave. The EP wave forms recorded were no different from those already reported in the literature and are not illustrated here. Table III gives the amplitudes of the full pattern displacement for the N65-P95 w a v e for the R
T A B L E II M e a n and s t a n d a r d error scores for the patient and control groups for each item on the semantic differential. Dimension
Patient group Control
Concentration bad I --, 7 good Alertness sleepy 1 - , 7 a w a k e Anxiety relaxed 1 ---, 7 anx. Mood h a p p y 1 ~ 7 sad
N o r m a l group T~
T2
Control
1' 2
Mean
S.E.
Mean
S.E.
Mean
S.E.
Mean
S.E.
Mean
S.E.
4
0.5
4.7
0.7
4.6
0.6
6.3
0.5
5.9
0.8
4.1
0.8
4.1
0.9
2.9
0.9
6.1
0.7
5.4
0.8
3.4
0.9
2.6
0.6
3.3
0.8
0.6
0.3
0.6
0.4
4
0.9
3.3
0.7
3.7
0.6
1.1
0.7
1.4
0.7
P A T T E R N VEP C H A N G E S W I T H L I T H I U M
541
T A B L E Ill A m p l i t u d e s of the N65-Pg~ waves to full p a t t e r n d i s p l a c e m e n t for the right and left eye singularly a n d for b o t h eyes together. For each c o n d i t i o n the p a t i e n t and control g r o u p s are shown. The significant differences between the a m p l i t u d e s of the n o r m a l and p a t i e n t groups, using a t test, are shown. R i g h t eye
Normal Patient Patient Patient Normal
control control test 1 test 2 test 2
Left eye
Mean
S.E.
6.6 8.8 10.9 11 6.3
0.7 2.2 2.1 1.4 0.9
MEAN
t tests
N.S. t = 2.7 Sig. < 0.05
AMPLITUDES A N D
Both eyes
Mean
S.E.
6.5 8.5 10.7 11.1 6.6
1.5 2.5 1.75 1.7 0.8
STANDARD ERRORS
t tests
N.S. t = 2.5 Sig. < 0.05
OF
THE
FOR THE N65 P95 WAVE
Mean
S.E.
7 10 10.9 13.1 6.6
1.0 2.7 2.6 2.7 0.95
t tests
N.S. t = 2.8 Sig. < 0.05
MEAN
T
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Nor real Control
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Patient Control
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Test 2
Patient
Test 2
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PATTERN
DISPLACEMENT
Fig. 1. The m e a n a m p l i t u d e a n d s t a n d a r d error of the m e a n are s h o w n for the Nrs-P95 wave for the control a n d p a t i e n t groups. The g r a p h s for the control c o n d i t i o n before lithium and the n o r m a l g r o u p show no significant differences using a t test. For the final session 5 weeks after starting lithium treatment, the full p a t t e r n d i s p l a c e m e n t shows a significant difference between the groups, * P < 0.05. The m e a n regression lines for the 3 patient trials show an increase in the slope for the last trial. The straight lines are the linear regression.
542
P.B.C. F E N W I C K , R. R O B E R T S O N
T A B L E IV A m p l i t u d e s of the P95-N125 waves to full pattern d i s p l a c e m e n t for the right and left eye singularly a n d for both eyes together. For each c o n d i t i o n the p a t i e n t a n d control g r o u p s are shown. The significant differences between the a m p l i t u d e s of the n o r m a l a n d p a t i e n t groups, using a t test, are shown. R i g h t eye
Normal Patient Patient Patient Normal
control control test 1 test 2 test 2
Left eye
Mean
S.E.
5.6 9.9 12.6 10.3 5.5
0.7 2.3 1.8 1.4 0.8
MEAN
t tests
N.S. t = 2.8 Sig. < 0.05
AMPLITUDES
AND
Both eyes
Mean
S.E.
7.5 10.2 12.6 10.8 7.0
0.8 2.5 1.6 1.5 0.9
STANDARD ERRORS
FOR THE P 9 5 - N I 2 5
t tests
N.S.
t = 2.7 Sig. < 0.05
OF
THE
Mean
S.E.
7.7 8.2 11.7 10.8 6.7
1.9 2.1 1.8 1.2 0.4
t tests
N.S.
t = 3.6 Sig. < 0.01
MEAN
WAVE
Patient Test I
12, m - -
I1'
---..Normal Control
10
• .......
9
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8
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,
,
I
I
,
TT
*-"
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o
I, ° I
o . . . .
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Patpent Control Norma! Test 2
T Patmnt
Test 2
7 6. 5'
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.
ig
4,
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PATTERN
DISPLACEMENT
Fig. 2. The m e a n a m p l i t u d e a n d s t a n d a r d error of the m e a n is s h o w n for the Pgs-N125 wave for the control and patient groups. The straight line is the linear regression. There are no significant differences between the control c o n d i t i o n s using a t test. For the final session 5 weeks after starting lithium treatment, the full ~ and ~4 p a t t e r n d i s p l a c e m e n t s show a significant difference, using a t test. T h e half is nearly significant a n d would have been if more subjects h a d been used. It can be seen that, for the p a t i e n t trials, all the regression lines r e m a i n a p p r o x i m a t e l y parallel to each other, but that the highest m e a n level was reached after the first week of lithium t r e a t m e n t and not after 5 weeks, as was found for the N6s-P95 wave.
PATTERN VEP CHANGES WITH LITHIUM
543
amplitude is reached 1 week after the introduction of lithium, and not in the final session as it was for the N65-P95 wave, although this difference does not reach significance.
Fractional pattern
displacement
TABLE V P values for an F test comparison between the normals and the patients for the full and fractional pattern displacement for both waves and for the control and final sessions.
amplitudes.
Fig. 1 shows the amplitude of the N65-P95 wave for the fractional and full pattern displacements with both eyes open for the normal control and the patient group for the first or control session. The regression lines run almost parallel to each other and there are no significant differences on any pattern displacement between the groups. The results after 5 weeks of lithium treatment are also shown in Fig. 1. The only significant difference ( P < 0.05) is for the full pattern displacement, as already described. Fig. 1 shows the regression lines for both control and patient groups. For the patient group, the slope for the final session is clearly increased compared to the previous two trials (4.2, control; 10.2, final). Tests between the slopes of the patient and the normal control groups for the control trial and the final assessment were not significantly different. Fig. 2 shows the fractional pattern displacement results of the P95-Nt25 wave in a similar way to that used for the N65-P95 wave. Again there are no differences between the amplitudes for the control and patient groups for any displacement. After treatment of the patient group for 5 weeks with lithium, changes in amplitude do occur and these can be seen in the figure. The ¼ ( P <0.05), ¼ ( P < 0.05), and the full ( P < 0.01) displacements are now significantly different for patient and normal T 2, and the 1 would have been had more subjects been used. Fig. 2 shows the regression lines for the P95-N125 wave and all 3 test sessions of the patient group. It is clear that there is very little difference in slope between them, but what does change is the y intercept, rising as high as 9.1 ~V after 1 week of lithium treatment.
Variance results The variance of both the N65-P95 and P95-N125 amplitudes was calculated for each pattern displacement and compared using an F test between the patient and control groups. The results are shown in Table V. Significant differences were
Full 4
2' 4
Control session
Final session
N65-P95
P95-NI25
N65-P95
P95-Nt2s
< 0.05 < 0.05 < 0.05 < 0.05
0.05 0.05 N.S. 0.05
< 0.05 N.S. < 0.05 < 0.05
< 0.05 N.S. N.S. < 0.05
found for both amplitudes and at each pattern displacement, except for the ½ for the control test. There were fewer differences in the test two comparisons.
Latency and serum lithium results No significant differences in latency for the P95 wave were seen between control and patient groups. The serum lithium levels were as follows: T l mean 0.57 mmol/1 and for T 2 0.66 mmol/1 there was no significant difference between the two sessions, t = 1.26, P = N.S.
Discussion The results of this study confirm the hypothesis that lithium treatment will produce an increase in amplitude of the pattern VEP. The mean amplitude increase for the full pattern response for the N65-P95 wave is 5 #V, an increase of 62%. For the P95-N~25 wave, the increase is 2.8 ~V or 28%. The figure for the early wave of 62% agrees well with that of Heninger (1978) for the increase in the early component of the SEP of 50%. However, he did not publish the figures for the later component, so the rise of the second wave cannot be compared. Small et al. (1971) reported a relationship between mood and EP amplitudes and latencies, but this was not seen in the present study. The Crown Crisp Index showed only a minor and inconsistent change in the depression scores, while the subjective ratings on the semantic differential showed that, on the whole, the patients felt only slightly less depressed at the time of the final
544 session. The increase in amplitude was not simply a result of the patient attending, as the semantic differential result on the dimension of concentration did not change appreciably for the treatment sessions. The results of the fractional pattern displacement are also of interest. For the N65-P95 wave the response to lithium is different in the acute and chronic phase. In the acute phase, the results of the first treatment session show that the slope of the regression line across pattern displacements is not altered while it is the general level of the line which is raised (an increased y intercept). The wave behaves quite differently in the chronic phase (5 weeks after starting lithium) when the y intercept is decreased, but the slope shows a marked increase. For the P95-NI25 wave effects of both the acute and chronic phase are the same with a raised y intercept and no change in slope, but this effect is greater in the acute phase of treatment. However, there is no significant difference between trials, probably due to the small number of patients used. The fact that there is no significant difference between the slopes of the regression lines within sessions suggests that lithium treatment does not affect the generation of the two waves differently, although more subjects are required to confirm this. A further study is also needed to see the effect of smaller pattern displacements than ¼, and to see whether or not the linearity of the response to small pattern amplitudes still holds.
Summary Previous reports in the literature have suggested that lithium medication does not affect the VEP to flash stimulation. It was predicted that this would not be true for pattern reversal stimulation. Seven patients had their pattern evoked potential measured using a 42' check to fractional pattern displacement of ¼, ½, ~ and full square. The VEP was measured before, 1 week after and 5 weeks after the commencement of lithium medication. The results show that there is a significant increase in
P.B.C. FENWICK, R. ROBERTSON both the N65-P95 and P95-NI25 amplitudes when the 'before lithium' sessions are compared to 'after lithium.' Seven normal subjects matched for the age and sex of the patient group were tested twice, once as a 'control' and a further 5 weeks after this. No significant differences were found in the "control' sessions between patient and normal groups although a significant difference in both the N65-P95 and P95-Nj25 amplitude after the treatment of the patient group with lithium was found.
R~sum~
Modifications des potentiels bvoquks visuels au changement de pattern lors du traitement par le lithium De pr6c6dentes donn6es de la littbrature ont sugg6r6 que le traitement par le lithium n'affecte pas le PEV ~t la stimulation par flash. On a pr6dit que ce ne serait pas vrai pour la stimulation par renversement de pattern. Chez 7 patients on a mesur6 le potentiel 6voqu6 par le pattern en utilisant un carr6 de 42' avec des d6placements du pattern de 1/4, 1/2, 3 / 4 et la totalit6 du carr6. Le PEV 6tait mesur6 avant le commencement du traitement au lithium, puis une semaine et 5 semaines apr6s. Les r6sultats montrent une augmentation significative des amplitudes N65-P95 et P95N125 quand on compare les s6ances 'avant lithium' et 'apr6s lithium'. Sept sujets normaux, assortis quant ~ l'glge et aux sexe au groupe de patients, furent testbs 2 lois, une premi6re en tant que 't6moins', puis 5 semaines plus tard. On n'a pas trouv6 de diff6rences significatives entre les s6ances 't6moins' des groupes de patients et des sujets normaux, malgr6 la diff6rence significative pour les amplitudes N65-P95 et P95-N125 apr6s le traitement par le lithium du groupe des patients. The authors would like to thank Mrs. Audrey Wyer for her kind help in the preparation of the manuscript, and Miss Norma West, Mrs. Joan Adams, Mrs. Jacintha Hennessey and Ms Sonja Stone for all the help they gave on the organizational aspects of the study.
PATTERN VEP CHANGES WITH LITHIUM
References Buchsbaum, M., Goodwin, F. and Murphy, D. AER in affective disorders. Amer. J. Psychiat., 1971, 128: 19-25. Cade, J.F.J. Lithium salts in the treatment of psychotic excitement. Med. J. Aust., 1949, 36: 349-352. Cobb, W.A., Ettlinger, G. and Morton, ll.B. Visual evoked potentials in binocular rivalry. Electroenceph. clin. Neurophysiol., 1967, Suppl. 26: 100-104. Crown, S. and Crisp, A.H. Manual of the Crown Crisp Experiential lndex. Hodder and Stoughton, London, 1979. Dimitrakoudi, M. and Jenner, F.A. Electroencephalographic effects of lithium. In: F.N. Johnson (Ed.), Lithium Research and Therapy. Academic Press, New York, 1975: 507-518. Fenwick, P. and Turner, C. Relationship between amplitude of pattern displacement and visual evoked potentials. Electroenceph, clin. Neurophysiol., 1977, 43: 74-78. Fenwick, P., Hennessey, J. and Brown, D. The visual evoked response to pattern reversal in 'normal' 6-11-year-old children. Electroenceph. clin. Neurophysiol., 1981, 51: 49 62. Gartside, I.B., Lippold, C.J. and Meldrum, B.S. The evoked cortical somatosensory response in normal men and its modification by oral lithium carbonate. Electroenceph. clin. Neurophysiol., 1966, 20: 382-390. Heninger, G.R. Lithium effects on cerebral cortical function in manic depressive patients. Electroenceph. clin. Neurophysiol., 1969, 27: 670.
545 Heninger, G.R. Lithium carbonate and brain function. Arch. gen. Psychiat., 1978, 35: 228-233. Heninger, G.R. and Demers, R.G. Lithium effects on the EEG and somatosensory response in relation to sodium metabolism. Electroenceph. clin. Neurophysiol., 1971, 21 : 289-290. Itil, T.M. and Akpinar, S. Lithium effect on the human electroencephalogram. Clin. Electroenceph., 1971, 2: 89-102. Johnson, G. Lithium and the EEG: an analysis of behavioural, biochemical and electrographic changes. Electroenceph. clin. Neurophysiol., 1969, 27: 656(P). Mayfield, D. and Brown, R.G. The clinical laboratory and electroencephalographic effects of lithium. J. psychiat. Res., 1966, 4: 207-219. Parry-Jones, N.O. and Fenwick, P. Coloured pattern displacement and VEP amplitude. Electroenceph. clin. Neurophysiol., 1979, 46: 49-57. Platman, S.R. and Fieve, R R . The effect of lithium carbonate on the electroencephalogram of patients with effective disorders. Brit. J. Psychiat., 1969, 115: 1185-1188. Small, J.G., Small, I.F. and Perez, H.C. EEG, evoked potential and contingent negative variations with lithium in manic depressive disease. Biol. Psychiat., 1971, 3: 47-58. Small, J.G., Milstein, V. and Perez, H.C. EEG and neurophysiological studies of lithium in normal volunteers. Biol. Psychiat., 1972, 5: 65-76. Spring, G.K. EEG observations in confirming neurotoxicity. Amer. J. Psychiat., 1979, 136: 1099-1100.