CHANGES IN P300 LATENCY DURING THE EARLY WITHDRAWAL PERIOD IN CHRONIC ALCOHOL-DEPENDENT PATIENTS: TWO CASE REPORTS

Atsushi Sekine*, Yoshitsugu Niiyama1, Masato Abe and Tetsuo Shimizu

Department of Psychiatry, Akita University School of Medicine, Akita and
1 Akita University, College of Allied Medical Science, Akita, Japan

Received 19 September 2001; in revised form 4 December 2001; accepted 18 December 2001


    ABSTRACT
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Aims: The present study focused on changes in P300 of the event-related potential (ERP) in two patients with alcohol dependence recorded throughout their alcohol withdrawal period. Results: As a result of this investigation, the peak latency of P300 in each patient was significantly shorter 2 or 3 days after abstinence from alcohol, when marked neurological manifestations appeared, compared to that of the control obtained from 8 to 10 days after cessation of drinking. Conclusions: It seems reasonable to conclude that the shortening of P300 latency reflects the enhancement of brain activity during the early withdrawal period and that an investigation of changes in P300 would be helpful to clarify the nature of neural activity in the brain associated with alcohol withdrawal.


    INTRODUCTION
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The event-related potential (ERP) has been applied as a psychological marker of various cognitive functions to examine psychiatric and neurological disorders. In particular, P300 potential of the ERP has been used widely, due to the ease of its observation in a simple discriminative task. There is widespread evidence of the reduction of amplitude and increased latency of P300 (Pfefferbaum et al., 1979Go, 1991Go; Patterson et al., 1987Go; Steinhauer et al., 1987Go; Cadaveira et al., 1991Go; Begleiter and Porjesz, 1999Go) in chronic alcoholics. Several recent reports have noted that peak latency of P300 shortens rather than lengthens during alcohol withdrawal (Patterson et al., 1987Go; Romani and Cosi, 1989Go; Parsons et al., 1990Go). However, very few attempts have been made to clarify the phase of the withdrawal period in which such changes in ERP appear, or how ERP alters over the course of the withdrawal period. We therefore recorded ERP over time during alcohol withdrawal and evaluated the changes in P300. Prior to the study, a full explanation was given regarding the purpose and experimental details of the study, and consent was obtained from each patient for a series of recordings.


    SUBJECTS AND METHODS
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Case report
Case 1. A 40-year-old male started drinking alcohol when he was 16 years old. From the age of 20 years, he was drinking 1.44 l of Japanese sake, equivalent to 160 g of alcohol, every day. In 1990, at the age of 38 years, he was admitted for the first time to our Department of Psychiatry with complaints of malaise, loss of appetite and decreasing body weight. Three days after ceasing drinking, delirium tremens associated with excitation occurred. The symptoms of delirium tremens improved over the course of a day. Following discharge from hospital, he continued to drink every day. When he was 39 years, the patient was again admitted to the Department of Internal Medicine for treatment of acute pancreatitis. Three days after ceasing drinking, visual hallucinations appeared, but no concomitant excitation was observed. In January 1992, he was admitted to our Department of Psychiatry for the second time, because of psychiatric problems related to alcohol consumption. The patient was lucid upon admission, but complained of anxiety and fretfulness. Exhaled air had an obvious alcoholic odour. The patient displayed diaphoresis and coarse tremor of the fingers. Biochemical examinations at the time of admission revealed mild liver dysfunction. Diazepam (15 mg/ day) had been taken in three doses per day for 2 months prior to admission, and was maintained during hospitalization. Two days after ceasing drinking, the patient displayed no symptoms of excitation or hallucination, although feelings of anxiety and irritation were aggravated. These psychiatric symptoms resolved on the fourth day after cessation of alcohol consumption, although there was no treatment other than the continued administration of diazepam. ERP findings in the present study were obtained from repeated electroencephalogram (EEG) recordings at the time of the patient’s second admission.

Case 2. This was a 57-year-old man, who formed a drinking habit during his teens. Since March 1990, aged 48 years, he has been drinking 1.26 l of Japanese sake, equal to 140 g of alcohol, every day. The patient commonly complained of visual hallucinations, reporting that ‘birds are flying’, ‘I see a flower garden’, etc. In August 1992, he was admitted to our Department of Psychiatry complaining of autonomic nervous symptoms, such as palpitation, in addition to insomnia, anxiety and fretfulness. Following discharge from hospital, the patient continued to drink, and in August 1997, he was admitted for the second time. Two days after ceasing drinking, hyperacusia, coarse tremor of the fingers and extreme perspiration were displayed, but resolved on day 4. The patient was admitted to hospital for the third and fourth times in January and December 1999, respectively, after continuing to drink. He was lucid at the time of the latest admission but displayed diaphoresis and coarse tremor of the fingers. Diazepam (15 mg/day) had been taken in three doses per day for one and a half months prior to admission and was maintained following admission. Two days after ceasing drinking, feelings of anxiety and irritation, finger tremor, and autonomic nervous symptoms became aggravated. Furthermore, hyperaesthesia and hallucinatory symptoms were displayed, with the patient making statements such as ‘What I see in front of my eyes is now coming into my eyes’, ‘I hear birds crying’, etc. These psychiatric symptoms resolved on the fifth day following cessation of drinking, although there was no treatment, other than the continued administration of diazepam. ERP findings in the present study were obtained from repeated EEG recordings at the time of the patient’s fourth admission.

ERP recording procedure
Ag/AgCl electrodes were used to record EEG activity. They were placed at 21 sites of the 10–20 electrode system including Fpz (midpoint between Fp1 and Fp2) and Oz (midpoint between O1 and O2). Linked ear electrodes were used for reference. To record ERP, two kinds of brief tone (2000 and 1000 Hz), each with a duration of 100 ms, were generated by an automatic stimulator, and were presented to the patients through an earphone at the intensity of 60 dB (normal hearing level). The 1000 Hz (frequent) tone was presented at 80% incidence and the 2000 Hz (rare) tone at 20%. The presentation order of tones was randomized. The inter-stimulus interval was also randomized within the range of 1.0–3.0 s (mean 2.0 s).

The patient was placed in a reclining position on a bed in an electrically shielded and sound-attenuated laboratory, and was exposed to the sound stimulation. The patient was told to respond to the rare stimuli (target) by pressing a button attached to the palm of his right hand with his thumb (oddball paradigm). The button-press response was converted to an electrical signal that was monitored and recorded with other data on an FM data recorder. The EEG was recorded twice daily (at 10:00 and 17:00) for 5 days, from day 1 (the first day following the cessation) to day 5, and once a day (at 10:00) for 3 days, from day 8 to day 10. ERPs were obtained from six blocks of EEG containing 30-target stimulations respectively recorded in the same period. Amplitudes of N100, P200 and N200 were sometimes so low that identification of these components was difficult. Moreover they showed poor reproducibility for each block during the same period, and were therefore excluded from the present analysis. The amplitude and latency of P300 was measured at Pz on the scalp. The amplitude of P300 varied substantially between blocks of the same period; however, the latencies of P300 obtained from blocks of the same period were relatively stable. Therefore only P300 latency was evaluated in the present study as an index of brain activity during alcohol withdrawal. For statistical analysis of changes in P300 latency, one-factor analysis of variance was used to compare results obtained from the withdrawal period with control results from day 8 to day 10. Statistical significance was set at the P < 0.05 level.


    RESULTS
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Figure 1Go shows changes over time in P300 latency in Cases 1 and 2 during the alcohol withdrawal periods. As shown in Case 1, the peak latency of P300 on the afternoon of day 3 was significantly shorter than that of the control (P < 0.05). Furthermore, the peak latency of P300 recorded on the morning of day 4 showed a shorter tendency, although there was no statistically significant difference. The period when peak latency of P300 was significantly shorter coincided with that when neurological manifestations developed in the first admission. As shown in Case 2, the peak latency of P300 was significantly shorter on the morning of day 2 compared to the control value (P < 0.05), whereas that of P300 was significantly longer on the afternoon of day 1, compared to the control. Although there was no statistically significant difference, the peak latency of P300 showed a shorter tendency on the afternoon of day 3. The period when peak latency of P300 was significantly shorter coincided with that when neurological manifestations developed in both the second and the fourth admissions.



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Fig. 1. P300 latency (in ms) registered in each patient during the first days of abstinence from alcohol consumption. For each patient, each value has been compared to the mean of those obtained on day 8 to day 10 (control). Values are means ± SD of P300 latency obtained in each period. *P < 0.05.

 
The evaluation of erroneous answer ratio and reaction time in the press-button response to target stimulation in case 1 revealed no significant differences at any stage of the withdrawal period. The ratio of erroneous answers on the morning of day 2 (error answer ratio = 7.2%) was significantly higher (P < 0.001) in case 2 compared with that of the control days (error answer ratio = 1.3%). Although a tendency for prolongation was observed, the reaction time on the morning of day 2 (364.45 ± 103.50 ms) did not show any significant difference from the control days (347.30 ± 69.05 ms).


    DISCUSSION
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The physiological mechanism of delirium tremens during the alcohol withdrawal period has been attributed to rebound excitability occurring in extensive regions of the central nervous system (CNS). Long-term and severe alcohol consumption exerts a suppressive effect on the CNS, and the abrupt elimination of this effect could logically result in rebound excitability (Tachibana et al., 1975Go). However, there are very few physiological methods to confirm such an interpretation. We believe that ERP may represent a useful index to estimate neuronal activity in the brain. However, during withdrawal from alcohol, various neurological manifestations often appear, and it is difficult to obtain cooperation from patients for recording and thus observe changes in ERP at this time. For this reason, there have been no reports describing changes in ERP over time during alcohol withdrawal. We were able to evaluate changes in P300 during the alcohol withdrawal period and found that the peak latency of P300 was significantly shorter during the early withdrawal period. Specifically, we hypothesized that the shortening of P300 latency may reflect enhanced excitation of neural activity in the brain during alcohol withdrawal. In Case 2, when P300 latency was significantly shorter compared with the control value, the erroneous answer ratio was significantly higher. This result also suggests that excessive excitability during alcohol withdrawal may inhibit adequate information processing in the brain. Given the above, we concluded that neural activity in brain is excessively enhanced during the early withdrawal period in alcohol-dependent patients. Further research using ERP in larger numbers of patients would help to clarify the nature of neural activity in the brain associated with alcohol withdrawal.


    FOOTNOTES
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
* Author to whom correspondence should be addressed at: Department of Psychiatry, Akita University School of Medicine, 1-1-1 Hondo, Akita-city, Akita 010-8543, Japan. Back


    REFERENCES
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Begleiter, H. and Porjesz, B. (1999) What is inherited in the predisposition toward alcoholism? A proposed model. Alcoholism: Clinical and Experimental Research 23, 1125–1135.[ISI][Medline]

Cadaveira, F., Grau, C., Roso, M. and Sanchez-Touret, M. (1991) Multimodality exploration of event-related potentials in chronic alcoholics. Alcoholism: Clinical and Experimental Research 15, 607–611.[ISI][Medline]

Parsons, O. A., Sinha, R. and Williams, H. L. (1990) Relationships between neuropsychological test performance and event-related potentials in alcoholic and nonalcoholic samples. Alcoholism: Clinical and Experimental Research 14, 746–755.[ISI][Medline]

Patterson, B. W., Williams, H. L., McLean, G. A., Smith, L. T. and Schaeffer, K. W. (1987) Alcoholism and family history of alcoholism: effects on visual and auditory event-related potentials. Alcohol 4, 265–274.[ISI][Medline]

Pfefferbaum, A., Horvath, T. B., Roth, W. T. and Kopell, B. S. (1979) Event-related potential changes in chronic alcoholics. Electroencephalography and Clinical Neurophysiology 47, 637–647.[ISI][Medline]

Pfefferbaum, A., Ford, J. M., White, P. M. and Mathalon, D. (1991) Event-related potentials in alcoholic men: P3 amplitude reflects family history but not alcohol consumption. Alcoholism: Clinical and Experimental Research 15, 839–850.[ISI][Medline]

Romani, A. and Cosi, V. (1989) Event-related potentials in chronic alcoholics during withdrawal and abstinence. Neurophysiologie Clinique 19, 373–384.[Medline]

Steinhauer, S. R., Hill, S. Y. and Zubin, J. (1987) Event-related potentials in alcoholics and their first-degree relatives. Alcohol 4, 307–314.[ISI][Medline]

Tachibana, M., Tanaka, K., Hishikawa, Y. and Kaneko, Z. (1975) A sleep study of acute psychotic states due to alcohol and meprobamate addiction. Advances in Sleep Research 2, 177–205.





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