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Background: Chronic alcoholism is accompanied by "frontal" neuropsychological deficits that include an inability to maintain focus of attention. This might be associated with pronounced involuntary attention shifting to task-irrelevant stimulus changes and, thereafter, an impaired reorienting to the relevant task. The neural abnormalities that underlie such deficits in alcoholics were explored with event-related potential (ERP) components that disclosed different phases of detection and orienting to stimulus changes., Methods: Twenty consecutive abstinent male alcoholics (DSM-IV) and 20 age-matched male controls (healthy social drinkers) were instructed to discriminate equiprobable 100 and 200 msec tones in a reaction-time task (RT) and to ignore occasional, either slight (7%) or wide (70%), frequency changes (hypothesized to increase RT) during an ERP measurement., Results: In the alcoholics, we found pronounced distractibility, evidenced by a RT lag (p < 0.01) caused by deviants, that correlated (Spearman p = 0.5) with a significantly enhanced (p < 0.01) amplitude of mismatch negativity (MMN) to deviants. Significantly increased RT lag for trials subsequent to deviants (slight p < 0.001, wide p < 0.05) in the alcoholics suggested impaired reorienting to the relevant task. The MMN enhancement also predicted poorer hit rates in the alcoholics (Spearman p = 0.6-0.7). Both the MMN enhancement and pronounced distractibility correlated (Spearman p = 0.4) with an early onset of alcoholism., Conclusions: Attentional deficits in the abstinent alcoholics were indicated by the increased distractibility by irrelevant sound changes. The MMN enhancement suggested that this reflects impaired neural inhibition of involuntary attention shifting, being most pronounced in early-onset alcoholics.

Fifteen alcoholics diagnosed according to DSM-III-R, who were detoxified for at least 2 weeks and showed no clinical withdrawal signs, were investigated with 16 channel EEG mapping during resting, manumotor and music perception conditions, and were compared with 13 control persons. Single photon emission computed tomography (SPECT) using hexa-methyl-propilene-amine-oxime (HMPAO) labeled with 99m-technetium (99mTc) as tracer was performed separately (in patients only) and submitted to semiquantitative region of interest (ROI) analysis in 2 slices, 6 and 10 cm above canthomeatal line, respectively. Resting EEG showed increased power values in fast beta frequency band for the detoxified alcoholics. On cortical stimulation, patients showed signs of pathological EEG reactivity. Correlations of EEG parameters to cerebral blood flow (CBF) values (patients only) yielded coefficients around zero for all frequency bands (signs of uncoupling). All findings point to organic brain dysfunctions in these patients which extend beyond the period of withdrawal.

Recent studies have suggested an important kindling-like exacerbation of ethanol withdrawal symptoms after repeated cycles of ethanol intoxication and withdrawal. Few studies, however, have evaluated the effect of multiple episodes of intoxication and withdrawal on spontaneous EEG activity after cessation of ethanol intake. In this study, electrographic activity in cortical and subcortical structures male Sprague-Dawley rats was examined after multiple cycles of ethanol intoxication and withdrawal. After surgical implantation of electrodes, animals received repeated cycles of chronic ethanol exposure in vapor inhalation chambers for 10 or 20 days, with 4-day withdrawal periods between each. Upon removal from the inhalation chamber, spontaneous EEG activity was recorded intermittently for 72 hr. These data were then examined for the presence of spikes and sharp waves. Results indicate that the levels of spike and sharp wave activity observed vary with both length of ethanol exposure and with the number of withdrawal cycles, and that these effects varied with neuronal site. Changes in spike and sharp wave activity were first observed within hippocampal areas, with other subcortical and cortical sites showing increased activity after additional ethanol exposure or additional cycles of intoxication and withdrawal. Hippocampal areas CA1 and CA3 differed significantly from one another in their response to chronic ethanol exposure, with area CA1 most affected by changes in amount of ethanol exposure and are CA3 most affected by number of withdrawal cycles. These results indicate an increased severity of the ethanol withdrawal syndrome after repeated ethanol withdrawal episodes and suggest differential, site-specific changes in neuronal excitability.

Withdrawal Seizure-Prone (WSP) and -Resistant (WSR) mice, which were selectively bred for severe (WSP) or mild (WSR) handling-induced convulsions (HICs) following chronic ethanol inhalation, were found to differ in sensitivity to the anticonvulsant effects of the neuroactive steroid 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha,5 alpha-P. 3 alpha,5 alpha-P (5 or 10 mg/kg, ip) significantly increased seizure thresholds to pentylenetetrazol in ethanol-native males of both the WSP and WSR lines. In general, WSP mice were more sensitive than WSR mice to the anticonvulsant effect of 3 alpha,5 alpha-P. Subsequent studies in male WSP mice exposed to ethanol vapor or air for 24 hr demonstrated enhanced sensitivity to the anticonvulsant effect of 3 alpha,5 alpha-P (0.5-20 mg/kg, ip) during ethanol withdrawal. Only the highest dose affected HICs in air-exposed animals, whereas both the two highest doses significantly reduced HICs in ethanol-exposed mice. These results provide the first demonstration that 3 alpha,5 alpha-P attenuates ethanol withdrawal convulsions and indicate enhanced sensitivity to the anticonvulsant effect of 3 alpha,5 alpha-P in animals withdrawing from ethanol dependence.

Prolonged alcohol consumption leads to the development of tolerance to and dependence on ethanol, resulting in a decreased response to the sedative/hypnotic effects of ethanol, and by negative symptomatology following abrupt termination of use. One symptom associated with ethanol withdrawal in humans, as well as laboratory animals, is enhanced susceptibility to seizures. This study investigated the effects of the neurosteroid, 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha-5 alpha-THP), on alterations in seizure sensitivity associated with ethanol withdrawal. 3 alpha-5 alpha-THP is a potent anxiolytic and anticonvulsant agent that acts via selective interactions with GABAA receptors. Extensive evidence suggests that some aspects of ethanol dependence and withdrawal are mediated by alterations in GABAA receptor function. Withdrawal from chronic ethanol exposure elicited dramatic increases in seizure susceptibility in male and female rats. Administration of 3 alpha-5 alpha-THP just before seizure threshold determinations blocked the increased seizure susceptibility induced by ethanol withdrawal. Ethanol-withdrawn animals were protected by 3 alpha-5 alpha-THP at a dose that had no effect on control animal seizure thresholds. Moreover, male and female rats displayed differential responses to the seizure-threshold lowering effects of ethanol withdrawal, as well as the protection by 3 alpha-5 alpha-THP pretreatment. These findings suggest that there are gender differences associated both with ethanol withdrawal as well as the protection by 3 alpha-5 alpha-THP in ethanol-dependent rats.

Ethanol-dependent mice were treated with the 5-HT3 antagonist MDL 72222 after withdrawal from ethanol. Treatment with unit doses (0, 5.6, 10, and 17.0 mg/kg) of MDL 72222 at 0, 4, and 7 hr after withdrawal dose-dependently exacerbated the severity of ethanol withdrawal seizures. Treatment with a single dose (17 mg/kg) of MDL 72222 at 5 hr after withdrawal also exacerbated the severity of ethanol withdrawal seizures. Ethanol naive mice treated with MDL 72222 (56 mg/kg) did not display any seizures. Treatment with another 5-HT3 antagonist, ICS 205-930 (23 and 46 mg/kg), or the 5-HT2 receptor antagonist ketanserin, did not affect ethanol withdrawal seizures. The findings suggest MDL 72222 selectively enhances sensitivity to withdrawal seizures following chronic ethanol exposure.

Alcoholism and epileptic seizures frequently coincide. Two groups can be distinguished clinically and by EEG. In one group (group I), seizures occur only during a period of alcohol withdrawal or partial withdrawal and can only be explained because of alcoholism in the history of the patient. In the other group (group II), seizures occur spontaneously, as well as during alcohol withdrawal, and epileptogenic factors (residual brain damage, former epileptic seizures, and a family history of seizures) probably play an important role in the manifestation of the seizures. Paroxysms or focal abnormalities are rarely seen in group I; in group II, EEG abnormalities are seen approximately as frequently as in other epileptic conditions. Both groups were examined to determine the extent of their EEG abnormalities after 24 h of sleep deprivation. Before and after sleep deprivation, only 4% of 52 chronic alcoholic patients without epileptogenic risk factors had EEG foci. Of the 52, 2% before sleep deprivation and 8% after sleep deprivation had generalized paroxysms. Of 128 chronic alcoholic patients with additional epileptogenic factors, 19% before sleep deprivation and 24% after sleep deprivation had EEG foci, and 17% before and 28% after sleep deprivation had generalized paroxysms. The pathogenesis of epileptic seizures in both groups and the therapeutic consequences are discussed.

Clinically, patients with Delirium Tremens (DT) and acute alcohol hallucinosis (impending DT) appear excited with vivid false perception. Cerebral blood flow and eeg correspondingly point to hyperexcitability in the CNS during these conditions. Clinical trials with barbital treatment in alcohol withdrawal shows that the amount of drug and the drug plasma concentration is the same no matter whether the physical signs of withdrawal are accompanied by hallucinations and clouding of consciousness. The psychotic signs in DT and acute alcoholic hallucinosis develops after many years of alcoholism as does seizures. We hypothesize that physical withdrawal is determined by the degree of physical dependence developed during the most recent drinking period whereas the psychotic signs and seizures are due to a cumulated CNS hyperactivity developed over many years of repeated alcohol intoxication and withdrawal. Changes of electrolyte concentrations in plasma or CSF do not play an important role in the pathogenesis of DT and related clinical states except that changes in calcium and inorganic phosphate metabolism indirectly point to changes in membrane excitability. A new model for a study of rapidly repeated intoxication and withdrawal episodes in rats has shown that repetition of episodes augments the convulsive component of withdrawal whereas the non-convulsive signs are dependent on the most recent episode only. The augmentation of the convulsive component correlates with regional differences in brain glucose consumption. Furthermore, synaptic proteins and acidic phospholipids may be involved in the development of CNS hyperexcitability during alcohol withdrawal. In conclusion both clinical and experimental studies indicate that severe alcohol withdrawal reactions may consist of two components: 1) Physical withdrawal signs determined by recent physical dependence. 2) A long term cumulated CNS hyperexcitability relating to seizures and psychotic signs during withdrawal. This state is elicited by alcohol withdrawal but it represents a cumulated and permanent or long lasting CNS dysfunction in alcoholics. The precise biochemical/pathophysiological mechanisms for the development of the two-component dysfunction still remain to be clarified in detail.

In 48 patients with sequels of chronic alcoholism automatically analysed EEGs were taken twice: (1) some 2 days after cessation of acute delirious or predelirious states; (2) some 18 days later, after clinical recovery. EEG results were supplemented by neuropsychological, biochemical and clinical data. Complementary analyses in the time (Hjorth's descriptors) and frequency (spectral analysis) domains at the first time operationally identified EEG correlates of a hallucinatory syndrome vs. personality deterioration ("depravation'), together with specific effects of drinking habits and withdrawal. The second examination disclosed prognostically different types of EEG reactions to chronic alcoholism.

For 180 patients suffering alcohol-withdrawal induced delirium, electrolytic concentration in the serum of Na, K, Ca, and Mg was determined in the early withdrawal phase, and the electroencephalograms of 95 delirium patients evaluated in respect of local and diffuse changes and epileptic activity, and compared in delirium patients with and without initial seizures. Delirium patients who had initial seizures suffered significantly longer-lasting periods of delirium and significantly more frequent electrolytic changes in the form of hypomagnesemia and hypopotassemia (hypokalemia). There was no significant difference in the EEG changes. A temporary metabolic disorder in the initial phase of the two-phase withdrawal process should be assumed to be the cause of seizures during alcohol withdrawal, and the pathogenetic significance of hypomagnesemia and hypopotassemia should be taken into consideration.

There is evidence that alcohol abuse and withdrawal produces cerebral impairment, some of which may be temporary and some permanent. This impairment has been found to be relatively specific in terms of brain areas affected. Recently our laboratory reported evidence that psychometrically measured impairment was systematically related to the energy in high frequency (beta-2) bands of the EEG. In the present study we attempted to determine the EEG patterns for male alcoholics undergoing withdrawal in comparison to patients who had been stabilized.

In 30 male patients several EEG examinations could be carried out during delirium tremens (d.t.) or shortly thereafter. Most of the patients showed a normal EEG or changes which can be explained with regard to sedation through medication. 1 patient showed generalized paroxysmal spike wave bursts. On account of experimental results, we may assume that a transitory cerebral excitibality change occures in d.t. This pathophysiological basis explains the normal EEGs and paroxysmal bursts during d.t. 4 cases showed passages of pronounced diffuse slow activity during d.t. partly accompanied by thythmic bilateral slow waves. These changes point to a complication of d.t. that occurs because of another disease which results in cerebral functional disturbances as in other organic psychoses.

The EEG has only rarely been considered in discussions on psychosis in alcoholism. The main topic of this paper is the question whether the EEG is capable of revealing elements for elucidating the pathophysiology of some of the psychotic conditions or symptoms occurring in alcoholism. Although EEG abnormalities are a-specific in nature and no particular EEG signs may be consistent with psychosis, some types of EEG patterns are more frequently observed in certain clinical conditions such as delirium tremens and amnestic-confabulatory states. Taking these 'common' EEG-patterns into account, it may be possible to use the EEG as a diagnostic tool in differentiating between clinical psychopathological syndromes. The pathogenetic importance of tissue hypoxidosis for the development of psychosis in alcoholism is discussed.