EEG Power Spectra Differentiate Positive and Negative Subgroups in Neuroleptic-Naive Schizophrenia Patients

Twenty-eight consecutively recruited patients fulfilling the DSM-IV criteria for schizophrenia or schizophreniform disorder 26 were selected for the study from among those who attended the outpatient department the National Institute of Mental Health and Neurosciences (NIMHANS), in Bangalore, India. The diagnosis of schizophrenia was arrived at using criteria from the DSM-IV based on the consensus of a research psychiatrist who conducted a semistructured interview and a trained research assistant who used the Mini International Neuropsychiatric Interview (MINI) Plus. 27 The inclusion criteria were: age between 17 and 45 years; age of onset of illness more than or equal to 17 years; duration from onset less than or equal to 3 years; right-handedness (as assessed by modified Annett’s inventory 28 ) and an Mini-Mental State Examination (MMSE) score of ≥21. The exclusion criteria were: other DSM-IV axis I disorders (as ascertained by administration of MINI-Plus); previous exposure to psychotropic drugs; significant suicidal or homicidal risk or other disruptive behavior which warranted immediate interventions; history of ECT within the previous 6 months; history of institutionalization, defined as continuous hospital stay for more than 6 months and prominent catatonic features.

Twenty-five randomly selected healthy participants, between the ages of 17 and 45 years old served as the comparison group. These participants, predominantly constituted by hospital staff and bystanders of hospitalized patients, were interviewed by an experienced psychiatrist and ascertained to have no present or past neuropsychiatric disorders; in addition, there was no history of psychotic disorders in their first degree relatives.

Both groups of participants were ascertained to have no unstable medical or neurological conditions, history of significant head injury or substance dependence (excluding tobacco) meeting DSM-IV criteria. Written informed consent was obtained from all the subjects after complete description of the study to the subjects and their significant relatives. The study was approved by the ethical review board of NIMHANS.

Both neuroleptic-naive, recent-onset schizophrenia (NRS) patients and healthy comparison subjects were asked to avoid alcoholic beverages for at least 3 days prior to the EEG recording as well as to avoid use of nicotine for at least 3 hours prior to the recording. In the case of patients, all of whom were hospitalized and accompanied by a close relative (as is the case with all patients in our setting), abstinence from the above substances was ensured under supervision by the accompanying relative as well as the nurse-in-charge. However, for both patients and comparison subjects, we did not carry out a urine drug screen prior to the EEG recording. Further, no specific instructions regarding caffeine consumption prior to EEG recording was given. The EEGs were recorded between 3 p.m. and 6 p.m.

The participants were seated in a comfortable reclining chair with a head rest in a dimly lit, sound-attenuated, and electrically shielded room. They were given a half hour to acclimatize with the conditions. The EEG Electro-cap was fixed and electro-conducting gel was applied for all the electrodes. Three minutes of EEG was acquired while the subjects were seated with their eyes closed in an alert, quiet, and relaxed state. The participants were instructed to minimize blinking and roving movements of their eyes.

The EEG recording was performed with a 32-channel bioamplifier system (band pass filter: 0.5–30 Hz) of the Nihon-Kohden type using the EEG-SYS software. 29 The amplifiers were calibrated with a 50 μV sin wave in the 4–8 Hz frequency band, generated by the Nihon-Kohden signal generator. The EEG was recorded from 30 cephalic locations (FP1, FP2, AF3, AF4, F5, F3, F1, Fz, F2, F4, F6, T1, FCz, T2, T3, C5, C3, C1, Cz, C2, C4, C6, T4, T5, P3, Pz, P4, T6, O1, O2) positioned according to the 10/20 International System ( Figure 1 ). Eye movements were monitored using electrodes placed 1/2 inch lateral to the outer canthi of both eyes and connected to the horizontal oculogram channel, as well as with electrodes positioned 1/2 inch above and 1/2 inch below both eyes and connected to the vertical oculogram channel. The electronically linked averaged ear-lobe signal ([A1 + A2]/2) was used as the reference signal. The impedance of all electrodes was kept below 5 kilo ohms. A ground electrode was placed 3 cm anterior to Fz. The signals were digitized at a rate of 256 Hz and converted into ASCII format for further processing and analysis.

Baseline correction of the digital EEG signal was achieved using an autoregressive filter with coefficient 0.97. The 50 Hz and other high frequency noises were removed using a bidirectional 150-order Finite Impulse Response (FIR) digital filter with a bandwidth of 0.5–30 Hz (time constant: 0.3 second). Epochs contaminated by artifacts due to eye movements, eye blinking, drowsiness, muscle tension, sweat, or technical errors were excluded offline by careful visual inspection of the record by a researcher who was blind to the group status of the subjects. Prior to this, interrater reliability of artifact rejection was established. An average artifact-free EEG length of 75.43±26.05 seconds and 72.88±35.59 seconds was obtained in the comparison group and schizophrenia group, respectively. It has been shown by previous research that reliable EEG power values in all frequency bands could be obtained in both schizophrenia patients and healthy comparison subjects from a minimum of 32 seconds of artifact-free data. 30 For each participant, the artifact-free EEG signals were then subjected to Fast Fourier Transformation 1 by averaging over each 2-second epoch using a Hanning window to obtain the spectral power in the following nonoverlapping frequency bands: delta: 0.5 Hz–4.0 Hz; theta: 4.5 Hz–8.0 Hz; alpha1: 8.5 Hz–10 Hz; alpha2: 10.5 Hz–12.5 Hz; beta1: 13.0 Hz–17.5 Hz; beta2: 18.0 Hz–21.0 Hz; beta3: 21.5 Hz–30.0 Hz. These band widths were defined in accordance to the factor solution of Herrmann et al., 31 generated from resting eyes closed EEG. Both absolute and relative power (absolute power/total power) in all the bandwidths were computed, following which the weighted relative power for each band 32 at each electrode position was computed by multiplying (i.e., weighting) the relative power value of a given band and site by the number of artifact-free 2-second epochs of EEG available within each 180-second eyes closed EEG record of every subject. The relative power was used for statistical analysis considering that NRS patients had significantly higher total power compared to healthy comparison subjects ( Table 1 ). EEG signal processing and computation of power values were carried out using MATLAB, version 5.3.1. 33

The symptoms in schizophrenia patients were assessed using the Scale for the Assessment of Negative Symptoms (SANS) 34 and the Scale for the Assessment of Positive Symptoms (SAPS). 35 The psychopathology ratings for all the patients were carried out by one psychiatrist who had sufficient training and experience in administering the scales. The schizophrenia patient sample was subgrouped based on their SANS and SAPS scores into “positive” and “negative” according to the guidelines suggested by Andreasen et al. 36 Briefly, those subgrouped as positive schizophrenia had at least one of the following present to a marked degree (rating of ≥4 on SAPS): (1) hallucinations; (2) delusions; (3) formal thought disorder; or (4) bizarre behavior. Additionally, none of the following SANS items were present to a marked degree (rating of ≥4): (a) alogia; (b) affective flattening; (c) avolition-apathy; (d) anhedonia-asociality; or (e) attentional impairment. On the other hand, in those subgrouped as “negative” schizophrenia, at least two of the SANS items mentioned as (a)-(e) above were present to a marked degree, while none of the SAPS items mentioned as (1)-(4) above were present to a marked degree. The mixed subgroup (n=9) which included those patients who did not meet criteria for either positive or negative schizophrenia or who met criteria for both were excluded from subgroup analysis. Further, the psychopathological dimension scores were calculated from the total scores of SANS and SAPS subitems as follows: psychosis = delusions + hallucinations; negative = affective blunting + alogia + avolition + anhedonia; disorganization = formal thought disorder + bizarre behavior + inappropriate affect. 37 A more detailed description of the pattern of psychopathological dimensions observed in neuroleptic-naive, recent-onset schizophrenia patients from India is given elsewhere. 38

Normal distribution of the weighted relative spectral power values was assessed using Shapiro-Wilks test of normality. Since most of the power values were non-normally distributed, nonparametric statistical tests (Mann-Whitney U test and Kruskal-Wallis test) were used initially to make group and subgroup (Bonferroni corrected) comparisons of delta, theta, alpha1, alpha2, beta, and total power at individual electrode locations for purposes of graphical representation of power values in the individual bands.

The F values and significance levels for the group main effect using repeated measures ANCOVA are summarized in Table 1 . Neuroleptic-naive, recent-onset schizophrenia (NRS) patients had significantly higher total and delta power and lower theta, as well as a trend toward lower alpha2 relative to healthy comparison subjects, as analyzed using repeated measures ANCOVA with group and gender entered as fixed factors and age as covariate in the model containing seven regions, each comprising four channels as mentioned earlier. Beta power showed no differences between NRS and healthy comparison subjects. On performing subsequent univariate ANCOVA ( Table 3 ), NRS patients showed higher delta power and lower alpha2 power in the left and right frontal regions as well as lower theta power in all seven regions. There were no regional differences noted between NRS and healthy comparison subjects in alpha1 power.

The F values and significance levels for the main effect of symptom subgroups using repeated measures ANCOVA are given in Table 1 . There were significant differences between the subgroups in total, delta, theta, and alpha1 power. Univariate ANCOVA ( Table 3 ) showed significantly higher delta power in the left and right frontal, right temporal and left parieto-occipital regions in the negative symptom subgroup relative to healthy comparison subjects. Theta power was lower in the left and right frontal, central, and left temporal regions in the positive symptom subgroup and lower in both positive symptom and negative symptom subgroups in the right temporal and left parieto-occipital regions, relative to healthy comparison subjects. The positive symptom subgroup had higher alpha1 power in all the regions relative to both healthy comparison subjects and negative symptom subgroups. There were no regional differences in alpha2 power across the subgroups.

Spectral power maps generated using the mean relative weighted power values at the 30 locations in the four spectral bands (delta, theta, alpha1, and alpha2) which showed significant differences between groups/subgroups are shown in the (a) panels of Figure 1, Figure 2, Figure 3, and Figure 4 . These maps were plotted using the “griddata (v4)” method on MATLAB version 5.3.1. Power values in the delta, theta, and alpha2 in the NRS patients and healthy comparison subject groups, and symptom subgroups, as well as in the alpha1 band in the subgroups, at electrode locations where significant group/subgroup differences were noted using Mann-Whitney U test or Kruskal-Wallis test, are represented graphically in in the (b) and (c) panels of Figure 1, Figure 2, Figure 3, and Figure 4 .