In this study, we compared the relative and absolute spectral power patterns across frequency bands between AWS patients in the acute period (within 48 hours after AWS) and age- and sex-matched healthy controls. In addition, we investigated whether spectral characteristics from early standard EEG are helpful for predicting and identifying patients at risk of developing DTs. The main findings of the current study were as follows: 1) Clinical and alcohol-related variables were comparable between AWS patients with or without DTs. 2) In QEEG analysis, AWS patients demonstrated higher relative delta, theta, and all range of beta power than did the healthy control group, whereas alpha power was lower in the AWS group. The spectral differences between the groups were predominant in the frontal area (except alpha-2 power, which was lower in almost all brain areas). 3) The absolute and relative spectral analysis showed that the high-frequency beta band power, specifically beta-3 (20–30 Hz), was lower in patients with than in patients without DTs. These differences were recorded with a certain topographic dominance in the left frontal cortical areas. Additionally, in terms of the spectral power ratios, patients with DTs had higher TAR than those without DTs in the central area.
Our observation of increased beta power and decreased alpha power in alcohol-withdrawal patients, as compared to healthy controls, was consistent with previous findings of EEG abnormalities in the alcohol-withdrawal state. Most previous studies investigating alcohol-dependence showed EEG abnormalities, such as generalized reduction of alpha rhythm and increased power in the delta, theta, and beta activities14. Compared with these previous results, our results expand the understanding of association between alcohol use and EEG characteristics, considering that alcohol-withdrawal syndromes are a part of alcohol-dependence. Rebound hyperexcitability, driven by abrupt cessation from chronic alcohol exposure, might affect neuroelectric activity in the central nervous system. Changes in the glutamate/GABA balance occurs during alcohol-withdrawal periods15. In addition, increased beta power might reflect increasing cortical hyperexcitability after seizure as well as an alcohol-withdrawal state, resulting from an imbalance between excitatory and inhibitory neurons. This speculation is supported by the mechanisms for the generation of beta oscillations, which involves the balance between networks of excitatory pyramidal cells (AMPAergic) and inhibitory interneurons (GABAergic)16. The cumulative neurophysiological effects of alcohol consumption on the brain might be suggestive of our findings. Increased absolute power in the beta frequency range of 12.5–20 Hz has been observed in alcohol-dependence, over all brain locations, but prominently in the central brain region, in a previous study17. Another study showed alcohol-dependence was positively correlated with absolute high beta and gamma power (20–40 Hz) in the left fronto-central-parietal leads on EEG18.
Alpha power has been reported to be linked with cortical arousal level and cognitive and memory performance19,20. In particular, the slow alpha frequency (8–10 Hz; alpha-1) is related to attentional demands, whereas the fast alpha frequency (10–12 Hz; alpha-2) mediates semantic memory and stimulus-related aspects21. The frontal cortex (particularly the left inferior frontal gyrus), plays a role in supporting cognitive functions that are not only specific to language, as it has many afferent and efferent connections to all other neocortical regions (i.e., the parietal, temporal, and occipital regions, as well as to the cingulate, limbic, and basal ganglia structures22. The prefrontal cortex is thus the only cortical area interacting with all four sensory modalities received from olfactory sensation20. Alcoholism may particularly affect frontal cognitive function. In various brain imaging studies, chronic alcohol intake results in reduction of regional cerebral blood flow impairment, affecting the function of cerebral tissue in the medial frontal region, decreasing tissue metabolic rates, and affecting neurophysiology 21,23. Alcohol-dependence was associated with reduced absolute power and lower voltage of the alpha frequency in our study, which might reflect alcohol-related attentional, stimulus-reactive, and cognitive dysfunctions, as compared to in healthy controls, which was consistent with previous results about alcohol-dependence and electric deflection in the post-seizure state 24,25. Taken together, the differential dominance in the frontal area between the AWS patients and the healthy control group can be explained by a strong connection of alcoholism to frontal lobe pathology and the post-seizure state 23.
Studies on QEEG analysis in DTs, particularly in the alcohol-withdrawal state, remain scarce. Our study highlighted that specific EEG characteristics could be a significant predictor of DTs, based on a direct comparison of EEG data obtained in the acute period post-AWS. We found that the AWS group without DTs had higher absolute and relative power in the beta-3 range than did the AWS group with DTs. Although we did not perform cognitive assessment, cognitive deterioration associated with DTs could also be an explanation for the lower beta power in the AWS patients with DTs, given that lower beta power has negative effects on memory processing, such as episodic memory encoding and retrieval 26. Patients with alcohol-dependence with DTs had worse intellectual functioning, which was clearly observed in terms of attention and productive visual-motor coordination as compared to such patients without DTs 27.
Findings regarding beta activity related to cognitive activity have been less consistent. However, the beta-3 frequency, ranging from 20 to 30 Hz, has specifically been associated with cognitive processes, such as semantic speech retrieval 28, prosodic aspects 29, and working memory 30. It has been proposed that high-frequency band power, not only beta-3, but also gamma activity, is an indicator of cognitive activity and that coherent oscillations in this frequency range allow the binding of distant brain regions that are necessary to allow cognitive experience31. Visual or auditory stimulation and cognitive activities suppress brainwaves while increasing the power of the high-frequency beta and gamma bands32. Hence, the decreased high beta (specifically beta-3) power in the DT group may reflect cognitive dysfunction that precedes the development of DTs. This suggests that beta-3 power could be used as a predictive factor for the development of DTs during alcohol withdrawal. Interestingly, the difference in beta power between patients with and without DTs was prominent in the left hemisphere. While the reasons for asymmetry of EEG spectral power remain unclear, our finding may be in line with studies indicating that the mirrored reduction of left and right asymmetry might depend on the specific cognitive domain, such as verbal (left) and visuospatial (right) functions25, 26. The frontal lobe, particularly the left frontal gyrus, is involved in functions such as creative thinking, planning of future actions, decision-making, artistic expression, aspects of emotional behaviour, and spatial working memory22. It has been reported that an increased high beta frequency band (22‒30 Hz) induced by an epileptic drug (levetiracetam) was correlated with better neuropsychological measures in patients with epilepsy33. Enhancing activities of the neuronal networks in the prefrontal cortex and left hippocampus also correlates with an increased beta-3 band.
Another index used to explore the difference in EEG characteristics for predicting alcohol-withdrawal delirium is the frequency band ratio. Our results showed an increased TAR in the central area in patients who developed DTs. The reverse metric of the TAR, the alpha/theta ratio (ATR), has been used as a marker of functional connectivity and performance enhancement, and is used to discriminate individuals with probable Alzheimer’s disease from healthy older controls. Increased frontal-midline theta is related to learning in a task and during performance of an attention-demanding procedure. The theta frequency has been associated with long-range functional interactions in working memory. The TAR is known to change with age and cognitive ability, even in healthy individuals. One study reported that the relationship between cognitive ability and the TAR was age-dependent, and that cognitive performance at the CZ midline location predicted the TAR34. Another study showed that the TAR was increased relative to controls in older adults with amnesic mild cognitive impairment35. Alpha/theta neurofeedback training has also been shown to have clinical benefits in the treatment of alcoholism and addiction 36,37. An increased TAR in patients with AWS, specifically in those who progressed to DTs, might indicate addiction and preceding cognitive impairment, which was previously found to be associated with Alzheimer’s disease29.
The current study had several limitations. First, the study sample was small, and there might have been a selection bias, since this study was performed at a single center. Unexpectedly, most of the subjects who were initially enrolled were subsequently excluded because of structural brain lesions on neuroimaging, to avoid interference on EEG. Most of our subjects had brain lesions in cerebral cortex because alcohol intoxication is one of the strongest predictors of traumatic brain injury and a greater vascular burden 38. Second, all subjects were male, implying that it may be difficult to generalize this finding to females. Third, we did not perform a neuropsychiatric test to identify delirium. Further studies using neuropsychiatric scores and QEEG findings (for example, cognitive deviation to the left and right cortical function or changes in degree between groups). However, this study had several strengths. This study was performed according to a strict protocol, under well-controlled circumstances and time-lines. Furthermore, no previous report has used QEEG to predict alcohol-related DTs, particularly after AWS, which is the severe state of alcohol-withdrawal.