Although early intervention from the beginning of a psychotic episode is essential for a better prognosis, biomarkers predictive of symptomatic and functional improvement in early psychotic disorders are lacking. This study aimed to investigate whether the spectral power of resting-state electroencephalography (EEG) can be used as a predictive marker of the 1-year prognosis in patients with first-episode psychosis (FEP).
Twenty-four patients with FEP and matched healthy control (HC) subjects were examined with resting-state EEG at baseline. The symptomatic severity and functional status of FEP patients were assessed at baseline and reassessed after 1 year of usual treatment. Repeated measures analysis of variance was conducted to compare EEG spectral powers across the groups. Multiple regression analysis revealed EEG spectral powers predictive of symptomatic and functional improvement in FEP patients at the 1-year follow-up.
Delta band power in the frontal and posterior regions was significantly higher in patients with FEP than in HCs. Higher delta band power in the posterior region predicted later improvement of positive symptoms and general functional status. Lower delta band power in the frontal region predicted improvement of negative symptoms and general functioning after 1 year.
These results suggest that increased delta absolute power is observed from the beginning of psychotic disorders. Furthermore, decreased delta power in the frontal region and increased delta power in the posterior region might be used as a predictive marker of a better prognosis of FEP, which would aid early intervention in clinical practice.
The prognosis of first-episode psychosis (FEP) is highly heterogeneous, ranging from sustained recovery to multiple recurrences and treatment resistance [
To date, efforts to predict the prognosis of FEP using clinical characteristics have not been successful enough [
In this context, resting-state electroencephalography (EEG) can be a new brain biomarker for predicting the prognosis of FEP because EEG is a direct measure of electrical activities in the brain that are fundamental to neuronal communication. Furthermore, EEG has advantages for clinical application in that it is generally more applicable and less costly than brain imaging or ERP analysis. Quantitative analysis of resting-state EEG can provide the precise power of each EEG frequency to support the findings of their qualitative counterparts [
In the current study, we aimed to investigate whether resting-state EEG spectral powers can predict symptomatic or functional improvement in patients with FEP after 1 year of usual treatment. In line with previous studies, we hypothesized that patients with FEP would show increased theta, delta, and beta frequency power and decreased alpha frequency power compared to healthy control (HC) subjects. We also expected that the altered frequency band power found in FEP patients could be a new biomarker to predict symptomatic or functional improvement during the 1-year follow-up period.
In total, 24 patients with FEP and 24 age- and sex-matched HC subjects participated in this resting-state EEG study. FEP patients were enrolled from the inpatient and outpatient clinics of the Department of Neuropsychiatry at Seoul National University Hospital (SNUH). A patient with FEP was defined as a patient who was diagnosed with schizophreniform disorder, schizophrenia, or schizoaffective disorder using the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Axis I Disorders (SCID-I) and whose duration of psychotic illness was no longer than 2 years. The clinical status of patients with FEP was assessed using the Positive and Negative Syndrome Scale (PANSS) and the Global Assessment of Functioning (GAF) at the time of enrollment and reassessed after 1 year of usual treatment [follow-up duration (days), mean 393, standard deviation 32, minimum length 347, maximum length 482]. Medication use at baseline and during the follow-up period as well as the DUP was evaluated based on a thorough review of the medical records. The doses of antipsychotics and benzodiazepines were converted into an olanzapine-equivalent dose [
This study was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of Seoul National University Hospital. Written informed consent was obtained from all of the participants after a full explanation of the study procedure was provided (H-1810-144-983).
Participants were instructed not to drink coffee, tea or any other stimulant beverages and to refrain from cigarette smoking within the 2 hours before the recording session. The participants were seated in a comfortable single chair located in an isolated shield room with their eyes closed. Continuous EEG recordings were acquired for approximately 5 minutes using a Neuroscan 64 Channel SynAmps system equipped with a 64-channel Quick-Cap based on the modified international 10–20 system (Neuroscan, El Paso, TX, USA). Both mastoid sites were used as the reference. The EEG signals were digitized at a sampling rate of 1 kHz and online filtered between direct current (DC) and 100 Hz. Eye movement artifacts were monitored by the vertical and horizontal electrooculogram using electrodes below the left eye and near the outer canthus of the left eye. The impedances of all electrodes were less than 5 kΩ.
We used the EEGLAB toolbox to process the EEG data and to perform spectral analysis [
The demographic and clinical characteristics of subjects were compared using independent samples t-tests for continuous variables and χ2 analysis for categorical data. To examine group differences in absolute spectral powers, repeated measures analysis of variance (ANOVA) was performed with the three grouped regions of electrode sites (frontal, centro-parietal, and posterior) as the within-subjects factor and group (FEP vs. HC) as the between-subjects factor. Because antipsychotic medication and benzodiazepines have been reported to be related to several quantitative electroencephalography (QEEG) frequency powers, the baseline olanzapine-equivalent dose of antipsychotics and lorazepam-equivalent dose of benzodiazepine were used as covariates [
The demographic characteristics of the two groups (FEP and HC) at baseline and the clinical characteristics of the FEP group at baseline and after a 1-year follow-up are presented in
In the multiple regression analysis, improvement in positive symptoms was predicted by higher baseline delta power in the posterior region [β=0.031, 95% confidence interval (CI)=0.002–0.059, p=0.036] and higher baseline PANSS positive symptom subscale scores (β=0.851, 95% CI=0.618–1.083, p<0.001). Lower baseline delta power in the frontal region (β=-0.025, 95% CI=-0.048– -0.003, p=0.028), higher baseline PANSS negative symptom subscale scores (β=0.912, 95% CI=0.609–1.216, p<0.001), and female sex (β=4.643, 95% CI=1.621–7.665, p=0.005) predicted later improvement in negative symptoms. Improvement in general functional status was predicted by decreased baseline delta power in the frontal region (β=-0.073, 95% CI=-0.138– -0.009, p=0.027), increased baseline delta power in the posterior region (β=0.189, 95% CI=0.084–0.294, p=0.001), lower GAF scores at baseline (β=-1.135, 95% CI=-1.604–-0.665, p<0.001), and lower mean daily olanzapine-equivalent doses of antipsychotics used during the 1 year period (β=-0.096, 95% CI=-0.171– -0.021, p=0.015)(
This study aimed to identify biological predictors of 1-year symptomatic and functional improvement in patients with FEP using quantitative analysis of resting-state EEG. We found that delta absolute power at the frontal and posterior regions was significantly increased in patients with FEP compared to HCs. Moreover, the altered power of the delta frequency band was a significant predictor of symptomatic and functional improvement after 1 year of usual treatment in FEP patients. Higher delta power in the posterior region and more severe positive symptoms at baseline predicted later improvement of positive symptoms. Improvement of negative symptoms was associated with lower delta power in the frontal region, higher negative symptoms at baseline, and female sex. In addition, better general functional status after 1 year was predicted by lower delta power in the frontal region, higher delta power in the posterior region, poorer functional status at baseline, and a lower dose of antipsychotic medication used over the 1-year period.
In line with previous studies, we found significantly higher delta power in patients with FEP compared to HCs [
We found that decreased baseline delta power in the frontal region was associated with improvements in negative symptoms and general functioning after 1 year in patients with FEP. This finding is in line with previous studies that showed that increased delta power showed a positive correlation with higher scores on the PANSS negative subscale and was a marker for negative symptoms in patients with psychotic disorder [
Interestingly, in this study, delta power measured in the posterior region predicted improvements in psychotic symptoms and general functional status in an opposite manner relative to delta power measured in the frontal region. That is, increased baseline delta power in the posterior region predicted later improvement of positive symptoms and general functional status. The findings of delta power in the posterior site may be explained by the relationship between the reduced slow wave density and worse positive symptoms in patients with schizophrenia [
Because the response to antipsychotic medications, their adverse effects, and the prognosis of FEP patients varies [
We must acknowledge several limitations of this study. First, the observational period was limited to a relatively short 1-year period to find improvements in negative symptoms or general functional status, which should be augmented by future studies with longer follow-up periods. Second, because all patients except one were medicated at the time of EEG assessment, we could not completely rule out medication effects, which may have biased the results. Although we tried to control for the dose of antipsychotics and benzodiazepines as covariates in the group comparison analyses, cautious interpretation is warranted. Third, EEG was measured only at baseline so that we could not show longitudinal changes in spectral powers in association with symptomatic or functional changes.
This study was the first to investigate whether the spectral power of resting-state EEG can be a predictive biomarker of a 1-year prognosis in FEP patients. Delta frequency power was increased in patients with FEP and predictive of symptomatic and functional improvements. The results of the current study not only suggest that delta frequency power is associated with pathophysiological mechanisms regardless of the duration of illness or medication effect but also elucidate the possibility of delta frequency power as a putative predictor of short-term prognosis from the beginning of a psychotic disorder. Using resting-state EEG, which is cost effective and easily applied in clinical practice, personalized medicine to optimize the intensity of acute and maintenance treatment for FEP patients would be further aided.
This research was supported by the Brain Research Program and the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Science, ICT & Future Planning (Grant no. 2017M3C7A1029610, 2016R1E1A1A02921618, 2019R1C1C1002457).
The authors have no potential conflicts of interest to disclose.
Conceptualization: Rinvil Renaldi, Minah Kim. Data curation: Tak Hyung Lee, Yoo Bin Kwak. Fornal analysis: Rinvil Renaldi, Minah Kim, Tak Hyung Lee. Funding acquisition: Minah Kim, Jun Soo Kwon. Investigation: Rinvil Renaldi, Minah Kim, Tak Hyung Lee, Yoo Bin Kwak, Andi J. Tanra, Jun Soo Kwon. Methodology: Minah Kim, Tak Hyung Lee, Yoo Bin Kwak. Project administration: Rinvil Renaldi, Minah Kim, Andi J. Tanra, Jun Soo Kwon. Resources: Minah Kim, Jun Soo Kwon. Software: Rinvil Renaldi, Minah Kim, Tak Hyung Lee, Yoo Bin Kwak. Supervision: Minah Kim, Andi J. Tanra, Jun Soo Kwon. Validation: Rinvil Renaldi, Minah Kim, Tak Hyung Lee, Yoo Bin Kwak, Andi J. Tanra, Jun Soo Kwon. Visualization: Rinvil Renaldi, Minah Kim, Tak Hyung Lee. Writing—original draft: Rinvil Renaldi, Minah Kim. Writing—review & editing: Andi J. Tanra, Jun Soo Kwon.
Group comparison results. A: Two-dimensional topographic maps of quantitative electroencephalography (QEEG) absolute power of each frequency band across patients with first-episode psychosis (FEP) and healthy control (HC) subjects. The color bar with numbers in the graph indicates QEEG absolute power (µV2). B: Group comparison of QEEG absolute power in delta, theta, alpha, and beta frequencies at the frontal, centroparietal, and posterior sites. The vertical lines indicate standard errors. *indicates that the mean difference is significant at the 0.05 level.
The partial correlations of the symptomatic and functional improvements in patients with first-episode psychosis (FEP) during the 1-year follow-up period with baseline delta absolute power in the frontal or posterior regions adjusted for controlling factors. PANSS: Positive and Negative Syndrome Scale, GAF: Global Assessment of Functioning.
Demographic and clinical characteristics of patients with first-episode psychosis (FEP) at baseline and after 1 year of follow-up and healthy control (HC) subjects
FEP (N=24) |
HC (N=24) |
Statistical analysis |
||||
---|---|---|---|---|---|---|
Mean | SD | Mean | SD | χ2 or t | p | |
Age (years) | 22.4 | 5.1 | 22.8 | 4.2 | -0.337 | 0.738 |
Sex (male/female) | 10/14 | 9/15 | 0.087 | 0.768 | ||
Handedness (right/left) | 22/2 | 22/2 | 0.000 | 1.000 | ||
Education (years) | 13.3 | 2.1 | 14.3 | 1.6 | -1.921 | 0.061 |
IQ | 98.0 | 13.7 | 116.9 | 13.3 | -4.828 | <0.001 |
DUP (months) | 5.7 | 4.0 | - | - | - | - |
PANSS | ||||||
Total scores | 69.1 | 14.0 | 46.8 | 10.1 | 6.238 | <0.001 |
Positive symptoms | 17.3 | 4.6 | 10.2 | 2.6 | 6.923 | <0.001 |
Negative symptoms | 17.3 | 4.6 | 12.8 | 4.1 | 3.743 | 0.001 |
General symptoms | 34.5 | 7.1 | 23.8 | 5.0 | 5.678 | <0.001 |
GAF | 45.3 | 8.7 | 66.9 | 10.6 | -7.742 | <0.001 |
Antipsychotics dose |
10.0 | 8.3 | 21.0 | 47.6 | -1.381 | 0.181 |
an independent t-test or Welch’s t-test was used if the variances were not equal; χ2 analysis or Fisher’s exact test was used for categorical data; a paired samples t-test was used to compare values obtained at baseline and after 1 year in FEP patients,
olanzapine-equivalent dose of antipsychotics,
the mean difference is significant at the 0.005 level.
SD: standard deviation, IQ: intelligence quotient, DUP: duration of untreated psychosis, PANSS: Positive and Negative Syndrome Scale, GAF: Global Assessment of Functioning
Means and standard deviations (SDs) of electroencephalography (EEG) absolute spectral power in the frontal, centro-parietal, and posterior regions in patients with first-episode psychosis (FEP) and healthy control (HC) subjects
FEP (N=24) |
HC (N=24) |
Statistical analysis |
||||
---|---|---|---|---|---|---|
Mean | SD | Mean | SD | F | p | |
Delta frequency | ||||||
Frontal region | 93.5 | 69.8 | 68.4 | 33.6 | 7.586 | 0.009 |
Centro-parietal region | 72.1 | 28.8 | 65.4 | 32.5 | 1.427 | 0.239 |
Posterior region | 47.2 | 37.5 | 34.6 | 24.3 | 7.915 | 0.007 |
Theta frequency | ||||||
Frontal region | 62.7 | 26.0 | 68.8 | 52.1 | 0.013 | 0.908 |
Centro-parietal region | 67.9 | 29.7 | 65.5 | 43.6 | 0.220 | 0.642 |
Posterior region | 33.4 | 19.0 | 31.0 | 24.1 | 2.326 | 0.134 |
Alpha frequency | ||||||
Frontal region | 240.6 | 114.0 | 247.6 | 136.0 | 0.066 | 0.799 |
Centro-parietal region | 185.0 | 123.9 | 171.7 | 131.2 | 0.130 | 0.720 |
Posterior region | 185.0 | 123.9 | 171.7 | 131.2 | 2.762 | 0.104 |
Beta frequency | ||||||
Frontal region | 46.5 | 22.4 | 47.8 | 55.8 | 0.003 | 0.954 |
Centro-parietal region | 53.9 | 28.2 | 44.6 | 20.7 | 0.868 | 0.357 |
Posterior region | 38.3 | 18.6 | 33.4 | 22.4 | 2.636 | 0.112 |
analysis of variance with olanzapine-equivalent dose of antipsychotics and lorazepam-equivalent dose of benzodiazepine at baseline as covariates,
the mean difference is significant at the 0.05 level
Results of multiple regression analysis with the backward selection method to predict symptomatic and functional improvement in patients with first-episode psychosis (FEP)
Outcome variables | Significant predictors | R2 | Beta | Standardized beta | p | 95% CI |
|
---|---|---|---|---|---|---|---|
Lower | Upper | ||||||
Improvement in PANSS positive symptom subscale score | Delta power in the posterior region | 0.813 | 0.031 | 0.229 | 0.036 | 0.002 | 0.059 |
Baseline PANSS positive symptom subscale score | 0.851 | 0.778 | <0.001 | 0.618 | 1.083 | ||
Improvement in PANSS negative symptom subscale score | Delta power in the frontal region | 0.754 | -0.025 | -0.302 | 0.028 | -0.048 | -0.003 |
Baseline PANSS negative symptom subscale score | 0.912 | 0.716 | <0.001 | 0.609 | 1.216 | ||
Sex | 4.643 | 0.397 | 0.005 | 1.621 | 7.665 | ||
Improvement in GAF | Delta power in the frontal region | 0.709 | -0.073 | -0.376 | 0.027 | -0.138 | -0.009 |
Delta power in the posterior region | 0.189 | 0.519 | 0.001 | 0.084 | 0.294 | ||
Baseline GAF score | -1.135 | 0.224 | <0.001 | -1.604 | -0.665 | ||
Antipsychotic dose |
-0.096 | -0.335 | 0.015 | -0.171 | -0.021 |
mean daily olanzapine-equivalent dose of antipsychotics.
PANSS: Positive and Negative Syndrome Scale, GAF: Global Assessment of Functioning