Abnormal Eeg Patterns in Treatment-Resistant ...

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/n,ern J. Neurosrienc.e, 2001, Vol. 109, pp. 47-59

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ABNORMAL EEG PATTERNS IN TREATMENT-RESISTANT SCHIZOPHRENIC PATIENTS * JULIETA RAMOS".~,LUIS F. CERDAN~, MIGUEL A. GUEVARA", CLAUDIA AMEZCUA" and ARACELI SANZa "Instituto de Neurociencias de la Universidad de Guadalajara, 'Centro Comunitario de Salud Mental No. I ., Jalisco, Instituto Mexicano del Seguro Social (Received I 7 January 2001)

This study was conducted in order to compare the EEG patterns of schizophrenics who do not respond to typical neuroleptics with those who do respond under typical neuroleptic medication and a group of controls. Absolute (AP) and relative power (RP), and inter- and intrahemispheric correlations were calculated. Nonresistant schizophrenics showed lower delta RP, higher alpha1 AP and RP and higher correlation between prefrontal areas than the resistant ones and controls. Resistant schizophrenics showed lower alpha2 RP, lower betal and beta2 in temporal but higher beta2 AP and RP in occipital derivations, and higher intrahemispheric correlation between Fp2 and F4 and lower between F8 and T4 than the nonresistant and controls. The resistants also showed a higher antero-posterior betal and beta2 index than the controls. We concluded that the EEG pattern showed by the nonresistants may be associated with their good neuroleptic response that was not present in the resistant schizophrenics. Keywords: EEG; Schizophrenia; Neuroleptic-resistance; Power; Correlation

Discrepant results in relation to EEG abnormalities in schizophrenia have been reported. One reason for these discrepancies is the kind of medical treatment the patients receive. In this context, in an attempt to *This research was supported by CONACyT 4214P-H9608. +Addressfor correspondence: Ray0 261 1, Col. Jardines Del Bosque, Guadalajara, Jal., 44520, Mexico, e-mail: jramos(iudgserv.cencar.udg.mx 41


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avoid the effects of medication, some authors have overcome investigations with unmedicated patients and first-episode patients that have never been medicated. These studies have demonstrated higher delta, theta and low alpha power (Clementz et al., 1994). Omori et al. (1995) also found more fast theta and slow alpha waves as well as less fast alpha waves in schizophrenics than in the normal controls, but failed to find higher delta and slow theta activity. EEG coherence is another measure that has shown abnormalities in schizophrenics. Some authors have reported higher coherence in unmedicated schizophrenics than in normal subjects (Nagase et al., 1992; Wada et d., 1998) while other have found the opposite (Flor-Henry and Koles, 1987). Sponheim et al. (1994) did not find differences in EEG between the first-episode and chronic medicated schizophrenics which suggests that EEG abnormalities are independent of the medication and the duration of the disorder, however, other authors have reported that neuroleptics indeed modify EEG activity (Galderisi et af., 1990; Kemali et al., 1992; Schellenberg et al., 1992). Kernah et al. (1992) observed that after the haloperidol treatment there was a decrease of delta relative power and an increase of theta2, beta1 and beta2 relative power, and after 28 days an increase of alpha1 and a decrease of fast beta relative power. Regarding clinical response, Schellenberg et al. (1992) found that the increase observed in alpha, after haldol decanoate treatment, was related to a decrease in clinical symptomathology and Czobor and Volavka (1993) reported the same relation with haloperidol. Besides the effect of medication other variables can contribute to the controversial results in EEG abnormalities in schizophrenia, such as the samplc conformation regarding the illnesses heterogeneity, and individual charactcristics. One of the evolutive subtypes of schizophrenia is constituted by those patients who do not respond to medication with typical neuroleptics. The objective of the present study was to investigate whether these patients who do not respond to typical neuroleptics will show a different pattern of EEG activity versus those who do respond under typical neuroleptic medication. Bartlett et al. (1998) have in fact demonstrated different brain metabolic responses to haloperidol among neuroleptic responders,

EEG PATTERNS IN SCHIZOPHRENIA

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nonresponders and normal subjects, therefore, it would be plausible to find EEG differences between responders and nonresponders, under a typical neuroleptic treatment, since EEG is another noninvasive tool to study the brain functions.

METHODS


Subjects The sample was formed by 10 neuroleptic-resistant (RE), 10 nonresistant schizophrenics in remission stage (NR) recruited from the Guadalajara Mental Health Center of the Mexican Social Security Institute (IMSS) and 10 normal control volunteers (CO). All subjects were right-handed males. The CO and NR were matched with each RE patient by age and educational level (at least 9 years). CO were screened by a psychiatrist to ensure the absence of personal or family psychiatric history. The exclusion criteria included substance abuse and/or evidence of neurological diseases. All patients fulfilled the criteria for paranoid schizophrenia according to medical history information, the international criteria of the DSM-IV (American Psychiatric Association DSM-IV, 1995) and International Classification of Mental Diseases (ICD-10) (World Health Organization, 1992). Patients were classified as neuroleptoresistant if they met the Keefe, Mohs and Silverman (1990) and Brenner and Merlo (1 995) criteria for resistant schizophrenia. Neuroleptoresistant patients have shown permanent psychopathological symptoms for more than 2 years. The RE and NR groups were also paired by the kind of treatment with typical neuroleptics (haloperidol and fluphenazine decanoate, and biperiden for Parkinsonian symptoms), and by the duration of the illness since the first episode. Patients who did not follow medical treatment were excluded. An informed consent to participate in the study was obtained from the subjects. There were no significant differences in the educational level, illness duration or number of hospitalizations among groups. Details of psychopathological and neuropsychological characteristics of the subjects are described elsewhere (Cerd6n et al., in preparation).

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PROCEDURE


EEG Recording The EEG was recorded in one session between 16:30 and 18:30hrs. Subjects were seated on a comfortable arm-chair and instructed to minimize blinking and moving eyes either in the opened or closed-eyes conditions. Resting EECs were recorded at Fpl, Fp2, F3, F4, F7, F8, T3, T4, C3, C4,01, and 0 2 derivations with linked ears as reference according to the International lOj20 System. Electrode impedance was kept below 10KOhms. The EEG recordings were carried out on a 14 channel Grass polygraph 8Plus (filters 1 - 35 Hz). In addition, the electro-oculogram (EOG) was recorded by the electrodes at both outer canthuses in order to eliminate EEC epochs contaminated with eye movement artifacts. EEG signals were captured by a PC computer through an analog to digital converter. Samples without eye movements, drowsiness, muscle activity or other artifacts were selected by visual inspection. Fifty five samples of 1 second duration (256 samples at the rate of 256Hz) were analyzed through a Fast Fourier Transformation in order to obtain absolute power (AP) and afterwards relative power (RP) for delta (1 to 3.5 Hz), theta1 (4 to 5.5 Hz), theta2 (6 to 7.5 Hz), alpha1 (8 to 9.5 Hz), alpha2 (10 to 12.5 Hz), beta1 (13 to 17.5 Hz) and beta2 (18 to 25 Hz) frequency bands. Inter and intrahemispheric correlation values (Pearson’s product moment correlation coefficients) were also calculated for each band. Power values were log transformed (John et al., 1980) and correlation values were transformed to Fisher’s 2 scores to ensure normalized distribution (Guilford and Fruchter, 1984). Afterwards, an additional measure was taken, an index of anteroposterior gradient by subtracting frontal from occipital (01-F3 and 02-F4) alpha and beta log transformed values of AP and RP.

Statistical Analyses EEG differences between groups were analyzed using mixed design analyses of variance (ANOVAs). Three-way ANOVAs of groups, by derivations by hemispheres were performed on each frequency band


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for absolute and relative power. For testing interhemispheric correlation, ANOVAs of groups by pairs of electrodes were performed. For intrahemisphreric correlation groups by conditions (opened and closed eyes) by hemispheres ANOVAs were performed, one for each pair of derivations. Antero-posterior index was tested by groups by hemispheres ANOVAs. Subsequent Tukey’s tests were used for pairwise comparisons. Significant level was set at p < .05.

RESULTS Absolute (AP) and Relative Power (RP)

De/ta RP in open and closed eyes conditions was significantly different between groups (F(2,130) = 4.39, p = .02 y Fc2,130) = 5.54, p = .01). NR had lower delta RP than CO and RE. Alfa2 Relative Power

Eyes open

OO /

18

16 14

12

10 T

8

r~

T

6 4

2 0

PF

SF

IF

CE

TE

oc

FIGURE 1 Means and standard errors of alpha2 relative power for the three groups: normal controls (CO),nonresistant (NR) and neuroleptic-resistant (RE) schizophrenics. Mean effect for derivations is present, means of Fpl and Fp2 (PF), F3 and F4 (SF), F7 and F8 (IF), C3 and C4 (CE), T3 and T4 (TE) and 01 and 0 2 (OC) derivations.

Beta2 Relative Power Eyes Open

YO

18 16 14

-

12 -


10 -

Yo l2

Eyes Closed

1

PF

SF

IF

CE

TE

oc

FIGURE 2 Means and standard errors of beta2 relative power for the three groups: normal controls (CO), nonresistant (NR) and neuroleptic-resistant (RE) schizophrenics. Mean effect for derivations is present, means of Fpl and Fp2 (PF), F3 and F4 (SF), F7 and F8 (IF), C3 and C4 (CE), T3 and T4 (TE) and 01 and 0 2 (OC) derivations.



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Theta1 and Theta2 No significant differences were found among groups for AP nor for RP, but both groups of patients showed a trend of having a higher thetal and theta2 than CO. Alpha1 ANOVAs gave significant differences among groups for AP with eyes closed (F(2,130)= 3.74, p = .03) and for RP with both eyes ~ ~ ) p = .01) and closed (F(2,~30) = 5.06, p = .01). NR open ( F ( ~ , =I 4.79, showed higher alphal AP and RP than RE. The greater differences were found in the occipital area with eyes closed. Alpha2 For RP a group by derivations by hemispheres interaction = 2.30, p = .01). RE showed was observed with eyes opened (F(lo,130) lower alpha2 than N R in T3, T4 and F8 and lower than CO and N R in prefrontal regions (Fig. 1). Beta1 A significant group by derivation interaction was observed in RP with eyes opened. RE had lower betal than CO and N R in temporal zones. Beta2 Group effect was significant with eyes open in AP (F(lO,l30) = 2.5, p = ,009) and in RP a group by derivation interaction was significant both with eyes open (F(l0,130)= 2.75, p = .04) and closed (F(10,130)= 2.71, p = .005). RE had lower beta2 in temporals in relation to CO and NR and higher beta2 in occipital regions than CO with eyes open and than NR with eyes closed (Fig. 2). Interhemispheric Correlation

2 1.8

T

0.6

0.2

delta

thetal

theta2

alphal

alpha2

betal

beta2

FIGURE 3 Means and standard error of interhemispheric prefrontal correlation (FplFp2) with eyes closed, for each group: normal controls (CO), non-resistant (NR) and neuroleptic-resistant (RE) schizophrenics.

Antero - Posterior Index Absolute Power

'I

Log

co


0.5

-0.5

NR

0 5-

I

0

I

I

-05'

'1

05

RE

-

0

FIGURE 4 Antero-posterior index obtained by subtracting fronlal from occipital ( 0 1 F3 and 02-F4) absolute power with eyes opened for each group: normal controls (CO), nonresistant (NR) and neuroleptic-resistant (RE) schizophrenics, for the left (LH) and the right (RH) hemispheres.


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Interhemispheric Correlation


Groups by derivations interactions were significant for delta (F(l0,iyj)= 2.49; p = .009), alphal (FOo,130) = 2.30; p = .Ol); and alpha2 (F(Io,i30, =2 . 2 7 ,= ~ .01) with eyes open, and for theta2 (F(jo,iyj) = 2.14; p = .02), alphal (F(io,i30 = ,2.32; p = .01) and alpha2 (F(,O,i30) = 1.94; p = .04) with eyes closed. Interhemispheric correlation (rTER) was higher in NR than in CO between prefrontal derivations (Fpl-Fp2), except for delta with eyes open, where RE had higher rTER than CO (Fig. 3). Intrahemispheric Correlation A significant interaction of groups by conditions by hemisphere was found in the intrahemispheric correlation (rTRA) for delta (F(28,34)= 1.96, p = .003) and alphal (F(28,364)= 1.65, p=.O2). RE showed a higher rTRA between Fp2 and F4 than CO and NR and a lower rTRA, between F8 and T4, with eyes opened in delta. In alphal band, RE showed lower correlation between Fp2 and F4 than NR and CO, and between Fp2 and 0 2 than CO. N R had lower rTRA between Fp2 and F8 than CO and RE. Antero-Posterior Index ANOVAs showed significant differences between groups for beta 1 (F(2,26 = )4.97, p = .01) AP with eyes opened and; a groups by hemispheres interaction for alphal (F(2,26) = 7.15, p = .004) and beta1 (F(2,26) = 5.72, p = .02); and for beta2 RP (F(2,26) = 3.2, p = .05) with eyes closed. In every case RE showed a greater index than CO. For alphal RP also N R had a greater index than CO in the right hemisphere (Fig. 4).

(F(2,26) = 3.47, p = .04) and beta2

DISCUSSION The present results indicate that resistant schizophrenics compared to nonresistant ones show indeed a different pattern of EEG activity. Our results agreed with other studies which have reported that medicated patients showed lower delta activity than unmedicated ones


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(John et al., 1994) and those which have described a reduction of delta after haloperidol medication (Galderisi et al., 1990; Kemali et al., 1992) and its correlation with a decrease in the general symptom severity (Czobor and Volavka, 1993). Therefore, the lower delta RP in NR, observed in this study, could be associated with their good response to the neuroleptic treatment that was not present in RE. An increment of the beta rhythm has also been seen in nonmedicated schizophrenics especially in posterior derivations, and has been interpreted as evidence of cortical excitability in acute untreated schizophrenics (Miyauchi et al., 1990). However, the haloperidol treatment is able to cause a reduction of fast beta band according to other authors (Czobor and Volavka, 1993; Galderisi et al., 1990). In our data, NR did not show differences in comparison to CO, but RE did show higher beta2 AP with eyes opened compared to NR and CO in occipital regions and the opposite in the temporal derivations. The increase of betal and beta2 in occipital regions was also reflected in the antero-posterior index which indicated that RE had higher betal and beta2 AP, and beta2 RP in occipital lis. frontal derivations in comparison to CO and NR, especially in the left hemisphere. These differences point out an abnormal distribution pattern regarding that normal subjects showed, as was expected, higher alphal and alpha2 AP in occipital regions than in frontal ones. On the contrary, RE had higher alpha but also higher betal and beta2 AP in occipital regions. On the other hand, the lower beta2 values observed in RE in temporal zones could be related to the several morphological and physiological abnormalities described in the temporal lobes of schizophrenics (see review by Lawrie and Abukmeil, 1998). In fact this RE group had a smaller temporal lobe size than CO and N R revealed by Computerized Tomography (unpublished data). Regarding the alpha band, there is controversy. In some studies an increase of slow alpha and a decrease of fast alpha has been found in unmedicated schizophrenics related with normal controls (Omori et al., 1995) and Kemali et al. (1992) described a decrease of alpha2 RP with a concomitant increase of the slow alpha RP but not in a significant level. Our results agreed with those of Galderisi et al., (1990) because we also found higher absolute and relative alphal values in NR than in RE that would indicate again, a good response to neuroleptics, and



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alpha2 RP also showed higher values in this group. The increase in alpha power has been found associated with a decrease in the level of psychophathology (Czobor and Volavka, 1993; Schellenberg et al., 1992). The increased interhemispheric correlation, between frontal derivations, found in this study, may be interpreted as a less functional specialization of the cerebral hemispheres in NR patients, possibly as a consequence of the effects of medication that allows them to make a functional reorganization, to compensate somehow for their deficits. Although the RE group showed a similar trend of higher rTER, it did not reach a significant value. Other authors have also reported higher interhemispheric coherence in unmedicated schizophrenics (Nagase et al., 1992). Merrin, Floyd and Fein (1989) found that the higher interhemispheric coherence in unmedicated schizophrenics than affective patients and normal controls in unmedicated schizophrenics was unchanged after the neuroleptic treatment. These authors have suggested that the increased EEG coherence reflects abnormal patterns of cortical organization rather than a transient state related to an acute clinical disturbance. Intrahemisphreric correlation abnormalities were found in the right hemisphere: rTRA in the delta band, between Fp2 and F4 was increased in the RE group in comparison to CO and NR while the opposite was seen between F8 and T4 derivations. FlorHenry and Koles (1984) reported a greater reduction of right side (but not left side) intrahemispheric coherence (8 - 13 Hz) in schizophrenics compared to normals, depressed and manic patients. In addition, John et af., (1994) have also described an increase of interhemispheric coherence in anterior regions but a decrease of intrahemispheric coupling between anterior and posterior regions. These authors point out that this suggest a poor access of sensorial information to regions concerned with evaluation of sensations especially in nonmedicated patients. The diminution of the right hemisphere fronto-temporal correlation found here, may be related to the alteration in the inhibitory functions of the orbitofrontal cortex over the limbic system described in schizophrenia, which plays an important role in the regulation of emotions. In conclusion, based on the experiments performed with firstepisode and unmedicated schizophrenics, mentioned above, it appears that an abnormal EEG pattern is already present in schizophrenics

J. RAMOS


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before any pharmacological treatment which consists of higher delta and beta, and lower alpha. Some authors have also reported higher theta. A good treatment response with typical neuroleptics may be related to a decrease in delta and beta and an increase of the slow alpha band. The present results would indicate that the NR group had an EEG pattern, probably associated with a good neuroleptic response that was not present in the RE group of patients. This would imply that RE have lower flexibility of their brain functioning and/or they require employment of another kind of neuroleptics, atypical neuroleptics such as clozapine, olanzapine, risperidone, etc., that have a different pharmacological profile. With the results obtained in this study we can not elucidate whether the differences found between RE and NR patients represent a differential characteristic EEG pattern or differences in their brain capability to respond to typical neuroleptic treatments. There are only very few data available about this particular neurolepticresistant group of schizophrenics, so further studies are needed to study these alterations in their brain functioning. References American Psychiatric Association DSM-IV (1995) Diagnostic and Sfatistical Manual of Merzntal Disordevs. (Spanish version: Pichot, P., Lopez-lbor, J. and Miyar, M. Eds., Barcelona: Masson). Bartlett, E. J., Brodie, J. D., Simkowitz, P., Schlosser, R., Dewey, S. L. & Lindenmayer, J. P. (1998) Effect of haloperidol challenge on regional brain metabolism in neuroleptic-responsive and nonresponsive schizophrenic patients. American Journal ojPsychiatry, 155, 337-343. Brenner, H. D. & Merlo, M . C. G. (1995) Definition of therapy resistant schizophrenia, and its assesment. European Psychiatry, 10, 11 18. Clementz, B. A,, Sponheim, S. R., Lacono, W . G. & Beiser, M . (1994) Resting EEG in first-episode schizophrenia patients, bipolar psychosis patients, and their firstdegree relatives. Psychophysiology, 31, 486 - 494. Czobor, P. & Volavka, J. (1 993) Quantitative electroencephalogram examination of effects of risperidone in schizophrenic patients. Journal of Clinical Psychophtzrmac o ~ o g J liqsj, , 332-342. Flor-Henrv. ,. P. & Koles. Z. J. (1984) Statistical auantitative EEG studies of depression, mania, schizophrenia and normals. Biological Psychology, 19, 257-279. Galderisi, S., Mucci, A,, Di Gregorio, M . R., Bucci, P., Maj, M. & Kemali, D. (1990) C-EEG brain mapping in DSM-Ill schizophrenics after acute and chronic haloperidol treatment. European NeuropsychopharmacoLogy,1 , I5 I 154. Guilford, J. P. & Fruchter, B. (1984) Estadistica aplicuda a l a Psicologia y a la Educacibn Mi.xico: McGraw Hill. John, E. R., Ahn, H., Prichep, L., Trepetin, M., Brown, D. & Kaye, H. (1980) Developmental equations for the EEG. Scicnce, 210, 1255- 1258. -

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John, E. R., Prichep, L. S., Alper, K. R., Mas, F. G., Cancro, R., Easton, P. et a/. (1994) Quantitative electrophysiological characteristics and subtyping of schizophrenia. Biological Psychiatry, 36, 801 -826. Keefe, R., Mohs, R. & Silverman, 1. M. (1990) Characteristics of kraepelinian schizophrenia and their relation to premorbid social functioning. In: Angrist, B. 0. and Schulz, C. H. (Eds.) The neuroleptic nonresponsive patient: characterization and treatment. Washington, D.C.: American Psychiatric Press. Kemali, D., Galderisi, S., Maj, M., Mucci, A., Di Gegorio, M. & Bucci, P. (1992) Computerized EEG topography findings in schizophrenic patients before and after haloperidol treatment. International Journal of Psychophysiology, 13, 283 - 290. Lawrie, S. M. & Abukmeil, S. S. (1998) Brain abnormality in Schizophrenia: A systematic and quantitative review of volumetric magnetic resonance: imaging studies. British Journal of Psychiatry, 172, 1 18---120. Merrin, E. L., Floyd, T. C. & Fein, G. (1989) EEG coherence in unmedicated schizophrenic patients. Biological Psychiazry, 25, 60- 66. Miyauchi, T., Tanaka, K., Hagimoto, H., Miura, T., Kishimoto, H. & Matsushita, M. (1 990) Computerized EEG in schizophrenic patients. Biological Psychiatry, 28, 488 -494. Nagase, Y., Okubo, Y., Matsuura, M., Kojima, T. & Toru, M. (1992) EEG coherence in unmedicated schizophrenic patients: topographical study of predominantly never medicated cases. Biological Psychiatry, 32, 1028 1034. Omori, M., Koshino, Y . , Murata, T., Murata, I., Nishio, M., Sakamoto, K. eta/. (1995) Quantitative EEG in never-treated schizophrenic patients. Biological Psychiatry, 38, 303 - 309. Schellenberg, R., Schwarz, A., Knorr, W. & Haufe, C. (1992) EEG-brain mapping. A method to optimize therapy in schizophrenics using absolute power and center frequency values. Schizophrenic Research, 8, 21 29. Sponheim, S. R., Clementz, B. A., Iacono, W. G . & Beiser, M. (1994) Resting EEG in first-episode and chronic schizophrenia. Psychophysiology, 31, 37 -43. Wada, Y., Nanbu, Y., Kikuchi, M., Koshino, Y. & Hashimoto, T. (1998) Aberrant functional organization in schizophrenia: analysis of EEG coherence during rest and photic stimulation in drug-naive patients. Neuropsychobiology, 38, 263 -269. World Health Organization (WHO) (1992) International Cluss$cation of Mental Diseases (ICD-10). (Spanish version: Madrid: Meditor). -

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