Participation of cAMP/PKA-Mediated Signaling Pathways in Functional Activity of Regeneration-Competent Cells in the Nervous Tissue under Conditions of Ethanol-Induced Neurodegeneration.

We studied the involvement of cAMP/PKA signaling in the realization of the growth potential of neural progenitors and secretion of neurotrophic growth factors by glial elements under conditions of ethanol-induced neurodegeneration in vitro and in vivo. The stimulating role of cAMP and PKA in cell cycle progression of the neural progenitor cells and in production of neurotrophins by the cells in nervous tissue under the optimal conditions to vital activity was demonstrated. Ethanol inverted the role of cAMP/PKA signaling pathways in determination of the proliferation-differentiation status of neural stem cells. Selective blockade of adenylate cyclase or PKA in neural stem cells increased the rate of their division against the background of relative decrease in differentiation rate. In addition, cAMP/PKA signaling does not longer participate in neurotrophin production by glial cells in neurodegeneration. These findings suggest that inhibitors of activity/expression of adenylate cyclase and PKA can be considered as possible drugs with regenerative activity for the treatment of nervous system pathologies provoked by alcohol.

Forgetting the new locations of one's keys: spatial-memory interference in Korsakoff's amnesia.

The present study focused on interference in a group of patients with amnesia due to Korsakoff's syndrome (KS) within the domain of spatial memory. An object-location memory task was used in which participants first learned an array of objects on a computer screen, followed by a reconstruction of the object positions. Next a trial was given in which the same objects were presented only now in different locations. Participants had to place the objects a second time but at the new locations. This was repeated for seven pairs of baseline/interference trials. Both Korsakoff patients and matched controls did worse on the interference trials than on the baseline trials, indicating that it is difficult to relearn new spatial locations for objects that previously were remembered in other locations. When computing relative interference effects (that is the percentage change from baseline in the interference trials), Korsakoff patients were less affected than controls. It is discussed in how far interference depends on the strength of the original memories, which are markedly lower in KS patients.

Rewriting the valuation and salience of alcohol-related stimuli via memory reconsolidation.

The transient period of memory instability that can be triggered when memories are retrieved under certain conditions offers an opportunity to modify the maladaptive memories at the heart of substance use disorders (SUDs). However, very well-learned memories (such as those in excessive drinking and alcohol use disorders) are resistant to destabilisation when retrieved or may not destabilise at all. Memory retrieval and intervention procedures that reliably destabilise and update maladaptive motivational memories may help to improve the long-term treatment of SUDs. In 59 hazardous drinkers, we tested a novel retrieval procedure for destabilising well-learned cue-drinking memory networks that maximises prediction error (PE) via guided expectancy violation during retrieval of these memories. This was compared with a retrieval procedure without PE and no-retrieval controls. We subsequently counterconditioned alcohol cues with disgusting tastes and images in all groups and assessed responding to alcohol stimuli 1 week later. Counterconditioning following PE retrieval produced generalised reductions in oculomotor attentional bias, explicit valuation and outcome expectancies in response to alcohol cues 1 week after intervention, evidence of updating of distributed motivational drinking memory networks. These findings demonstrate that well-learned cue-drinking memories can be destabilised and that learning history need not constrain memory destabilisation if PE is maximised at retrieval. Broad rewriting of diverse aspects of maladaptive memory by counterconditioning is achievable following this procedure. The procedure described may provide a platform for the development of novel memory-modifying interventions for SUDs.

Thalamic abnormalities are a cardinal feature of alcohol-related brain dysfunction.

Two brain networks are particularly affected by the harmful effect of chronic and excessive alcohol consumption: the circuit of Papez and the frontocerebellar circuit, in both of which the thalamus plays a key role. Shrinkage of the thalamus is more severe in alcoholics with Korsakoff's syndrome (KS) than in those without neurological complication (AL). In accordance with the gradient effect of thalamic abnormalities between AL and KS, the pattern of brain dysfunction in the Papez's circuit results in anterograde amnesia in KS and only mild-to-moderate episodic memory disorders in AL. On the opposite, dysfunction of the frontocerebellar circuit results in a similar pattern of working memory and executive deficits in the AL and KS. Several hypotheses, mutually compatible, can be drawn to explain that the severe thalamic shrinkage observed in KS has different consequences in the neuropsychological profile associated with the two brain networks.

[Alcohol induced cognitive deficits]. / Alkohol induzierte kognitive Dysfunktion.

Previous studies could show a complex relationship between alcohol consumption and cognition but also with processes of ageing both social and biological. Acute effects of alcohol during intoxication include clinical signs such as excitation and reduced inhibition, slurred speech, and increased reaction time but also cognitive dysfunction, especially deficits in memory functions. However, these cognitive deficits during alcohol intoxication are reversible while patients with alcohol addiction and chronic alcohol intake show severe impairments of cognitive functions especially deficits in executive functions. Frontal executive impairments in these patients include deficits in problem solving, abstraction, planning, organizing, and working memory.Additionally, gender specific deficits are relevant for the course of the disease and its concomitant health problems with female alcoholics showing a higher vulnerability for cognitive dysfunction and brain atrophy at earlier stages of alcoholism history.

Dynamics of the cognitive procedural learning in alcoholics with Korsakoff's syndrome.

BACKGROUND: While procedures acquired before the development of amnesia are likely to be preserved in alcoholic patients with Korsakoff's syndrome, the ability of Korsakoff patients (KS) to learn new cognitive procedures is called in question. According to the Adaptive Control of Thoughts model, learning a new cognitive procedure requires highly controlled processes in the initial cognitive phase, which may be difficult for KS with episodic and working memory deficits. The goals of the present study were to examine the learning dynamics of KS compared with uncomplicated alcoholic patients (AL) and control subjects (CS) and to determine the contribution of episodic and working memory abilities in cognitive procedural learning performance. METHODS: Fourteen KS, 15 AL, and 15 CS were submitted to 40 trials (4 daily learning sessions) of the Tower of Toronto task (disk-transfer task similar to the tower of Hanoi task) as well as episodic and working memory tasks. RESULTS: The 10 KS who were able to perform the cognitive procedural learning task obtained lower results than both CS and AL. The cognitive phase was longer in the Korsakoff's syndrome group than in the other 2 groups but did not differ between the 3 groups any more when episodic memory abilities were controlled. CONCLUSIONS: Our results indicate that KS have impaired cognitive procedural learning abilities compared with both AL and CS. Episodic memory deficits observed in KS result in a delayed transition from the cognitive learning phase to more advanced learning phases and, as a consequence, in an absence of automation of the procedure within 40 trials.

Regional cerebral blood flow in patients with alcohol-related dementia: a SPECT study.

The purpose of this study was to investigate regional cerebral blood flow (rCBF) changes using 1110 MBq of Tc-99m ECD SPECT in alcohol-related dementia (ARD) patients. Twenty-five patients with ARD and 22 healthy control subjects were included in the study. Mini-Mental Status Examination was applied to the patients and controls. The ARD patients showed drastically reduced rCBF in the frontal cortices, basal ganglia, and thalami. The results indicate that ARD is associated with hypoperfusion in both cortical and subcortical regions. These findings support previous studies suggesting the association with both cortical and subcortical neuropathology in ARD patients.

Judgment and memory performance for emotional stimuli in patients with alcoholic Korsakoff syndrome.

In this study we investigated whether alcoholic Korsakoff patients are impaired in categorizing neutral and emotional stimuli according to their valence and whether memory performance for this material is reduced. In a group of Korsakoff patients and a comparison group two experimental tasks--one containing emotional and neutral pictures and the other containing words-were administered. Results showed that patients had difficulties in affective judgments due to problems in classifying neutral stimuli. Memory for emotional and neutral material was impaired to a similar degree. Thus, the facilitating effect of emotional valence on memory performance is absent in Korsakoff patients.

Chronic cigarette smoking modulates injury and short-term recovery of the medial temporal lobe in alcoholics.

Memory function is largely mediated by the medial temporal lobe (MTL), and its compromise has been observed in alcohol dependence and chronic cigarette smoking. The effects of heavy alcohol consumption and chronic smoking on hippocampal volumes and MTL metabolites and their recovery during abstinence from alcohol have not been assessed. Male alcoholics in treatment (ALC) [13 smokers (sALC) and 11 non-smokers (nsALC)] underwent quantitative magnetic resonance imaging and short-echo proton magnetic resonance spectroscopic imaging at 1 week and 1 month of sobriety. Outcome measures were compared with 14 age-matched, non-smoking light-drinkers and were related to visuospatial learning and memory. Over 1 month of abstinence, N-acetyl-aspartate, a neuronal marker, and membrane-associated choline-containing metabolites normalized in the MTL of nsALC subjects, but remained low in the MTL of sALC subjects. Metabolite concentration changes in both groups were associated with improvements in visuospatial memory. Hippocampal volumes increased in both groups during abstinence, but increasing volumes correlated with visuospatial memory improvements only in nsALC subjects. In summary, chronic cigarette smoking in alcohol-dependent men appears to have adverse effects on MTL metabolite recovery during short-term sobriety. These data may also have implications for other conditions with established MTL involvement and significant smoking co-morbidity, such as schizophrenia-spectrum and mood disorders.

Wernicke-Korsakoff encephalopathy.

Wernicke described the clinical features of three patients, including two alcoholics, suffering from confusion, ataxia and ophthalmoplegia in whom pathologically he found 'polioencephalitis haemorrhagica superioris'. Korsakoff's doctoral thesis related similar findings but expanded the confabulation and amnesic elements, relating them to alcoholism. This paper, which summarises the salient aspects of the syndrome, discusses their work and shows important earlier descriptions by James Jackson, (1822) Samuel Wilks (1868) and Charles Gayet (1875).

Características del electroencefalograma cuantitativo y trastornos cognitivos en pacientes alcohólicos / Quantitative electroencephalography features and cognitive impairment in alcoholic patients

Objetivo. Se diseñó este trabajo para determinar la relación existente entre las características del análisis cuantitativo del electroencefalograma y los estimadores del estado cognitivo en pacientes alcohólicos en abstinencia. Sujetos y métodos. Se estudió a 49 pacientes con el diagnóstico de alcoholismo (DSM-IV) con 10 días de abstinencia así como la correlación existente entre las medidas de banda ancha del análisis cuantitativo del electroencefalograma (qEEG) y las características de los potenciales evocados cognitivos visual y auditivo (P300) y de los resultados de las pruebas de atención y de memoria. Resultados. Los pacientes se clasificaron en dos grupos: el grupo 1, con un aumento global con predominio frontal de los poderes absolutos delta y theta, y el grupo 2, con disminución de los poderes absolutos delta y theta. La latencia de la onda P300 estuvo retardada en los pacientes, principalmente en el grupo 1, pero la ausencia regional de onda P300 fue más frecuente en el grupo 2. Las pruebas de atención y de memoria fueron anormales en los pacientes, principalmente en los del grupo 1. Conclusiones. Aparentemente, los resultados en ambos grupos reflejan diferentes etapas en la evolución del alcoholismo: el primero solamente con disfunción cortical de origen metabólico y el segundo posiblemente con atrofia cortical añadida; también pudieran representar dos tipos de respuesta biológica de sus sistemas nerviosos ante el mismo agente patógeno. Estos resultados sugieren la conveniencia de realizar estudios de seguimiento en este tipo de pacientes que utilicen qEEG, pruebas cognitivas y resonancia magnética cerebral

Aim. To determine the exact relation between the characteristics of quantitative electroencephalogram analyses and the estimators of the cognitive status in alcoholic patients undergoing withdrawal. Subjects and methods. The study examined 49 patients diagnosed with alcoholism (DSM-IV) after 10 days of withdrawal, as well as the correlation between the bandwidth measures from the quantitative electroencephalogram (qEEG) analysis and the characteristics of the visual and auditory cognitive evoked potentials (P300) and from the findings of the attention and memory tests. Results. The patients were divided into two groups: group one, which displayed an overall increase in the delta and theta absolute powers with frontal predominance, and group two, with reduced delta and theta absolute powers. Latency of the P300 wave was delayed in patients, particularly in those in group one, but regional absence of the P300 wave was more frequent in group two. Results of attention and memory tests were abnormal in patients, especially those in group one. Conclusions. The findings in the two groups appear to reflect different stages in the progression of alcoholism: the first only involved cortical dysfunction due to metabolic causes and the second possibly had added cortical atrophy. They might also represent two types of biological response by their nervous systems to the same pathogenic agent. These findings suggest that it is advisable to conduct follow-up studies involving qEEG, cognitive tests and magnetic resonance imaging of the brain in this kind of patient

[Quantitative electroencephalography features and cognitive impairment in alcoholic patients]. / Características del electroencefalograma cuantitativo y trastornos cognitivos en pacientes alcohólicos.

AIM: To determine the exact relation between the characteristics of quantitative electroencephalogram analyses and the estimators of the cognitive status in alcoholic patients undergoing withdrawal. SUBJECTS AND METHODS: The study examined 49 patients diagnosed with alcoholism (DSM-IV) after 10 days of withdrawal, as well as the correlation between the bandwidth measures from the quantitative electroencephalogram (qEEG) analysis and the characteristics of the visual and auditory cognitive evoked potentials (P300) and from the findings of the attention and memory tests. RESULTS: The patients were divided into two groups: group one, which displayed an overall increase in the delta and theta absolute powers with frontal predominance, and group two, with reduced delta and theta absolute powers. Latency of the P300 wave was delayed in patients, particularly in those in group one, but regional absence of the P300 wave was more frequent in group two. Results of attention and memory tests were abnormal in patients, especially those in group one. CONCLUSIONS: The findings in the two groups appear to reflect different stages in the progression of alcoholism: the first only involved cortical dysfunction due to metabolic causes and the second possibly had added cortical atrophy. They might also represent two types of biological response by their nervous systems to the same pathogenic agent. These findings suggest that it is advisable to conduct follow-up studies involving qEEG, cognitive tests and magnetic resonance imaging of the brain in this kind of patient.

Visuoperceptual learning in alcoholic Korsakoff syndrome.

Relative to the characteristically profound deficits of explicit memory, components of implicit memory remain largely intact in patients with alcohol-induced Korsakoff syndrome (KS). Perceptual priming occurs in KS and transfer of learning has been consistently observed on mirror reading, a perceptual reversal task. Although priming also occurs with fragmented pictures, a perceptual closure task, it is unclear whether transfer of learning can occur. This study examined visuoperceptual learning in 4 men with alcoholic KS, 9 recently detoxified alcoholic men (ALC), 21 healthy age-matched normal control men (NC), and 6 young normal control men (YNC). Subjects were tested with the Gollin Incomplete Pictures Test at initial and 1-hour and 1-day retest sessions. Both alcoholic groups (KS, ALC) were impaired in visuoperceptual ability. All subject groups showed visuoperceptual learning. The KS group showed additional learning after continued exposure to the stimuli, despite their nonmnemonic visuospatial deficits and profound explicit memory impairment for the test stimuli. Transfer of learning to similar but new stimuli was not evident in either the KS or young healthy control subjects; learning occurred only for the specific items presented. The persistence of learning beyond the life of the percept, which was independent of declarative features (such as item recall), suggests that perceptual learning and memory reflects an intact cognitive memory process in KS. This process is likely mediated by posterior cortical networks relatively unaffected in KS and that are independent of the hippocampal-diencephalic declarative memory system.

Trace eyeblink conditioning in abstinent alcoholic individuals: effects of complex task demands and prior conditioning.

Chronic misuse of alcohol affects an integrated neural circuit supporting the formation of associative memories acquired during eyeblink classical conditioning (R. McGlinchey-Berroth et al., 1995). The authors of this study investigated single-cue trace conditioning in amnesic and nonamnesic abstinent alcoholic individuals who either were or were not trained in a single-cue delay conditioning task. Overall, untrained alcoholic participants were severely impaired in acquisition, and alcoholic participants previously trained in single-cue delay conditioning performed similarly to untrained control participants. Individual performance in acquisition varied significantly within task but was relatively stable between the trace and delay tasks; there were nonamnesic and amnesic alcoholic participants who acquired responses at a normal rate in both delay and trace conditioning. The similarity of performances in delay and trace conditioning suggests a common source of impairment across both tasks.

Comparisons of Korsakoff and non-Korsakoff alcoholics on neuropsychological tests of prefrontal brain functioning.

BACKGROUND: Evidence suggests that alcoholics exhibit particular deficits in brain systems involving the prefrontal cortex, but few studies have directly compared patients with and without Korsakoff's syndrome on measures of prefrontal integrity. METHODS: Neuropsychological tasks sensitive to dysfunction of frontal brain systems were administered, along with standard tests of memory, intelligence, and visuospatial abilities, to 50 healthy, abstinent, nonamnesic alcoholics, 6 patients with alcohol-induced persisting amnestic disorder (Korsakoff's syndrome), 6 brain-damaged controls with right hemisphere lesions, and 82 healthy nonalcoholic controls. RESULTS: Korsakoff patients were impaired on tests of memory, fluency, cognitive flexibility, and perseveration. Non-Korsakoff alcoholics showed some frontal system deficits as well, but these were mild. Cognitive deficits in non-Korsakoff alcoholics were related to age, duration of abstinence (less than 5 years), duration of abuse (more than 20 years), and amount of alcohol intake. CONCLUSIONS: Abnormalities of frontal system functioning are most apparent in alcoholics with Korsakoff's syndrome. In non-Korsakoff alcoholics, factors contributing to cognitive performance are age, duration of abstinence, duration of alcoholism, and amount of alcohol consumed.

[Alcohol-related amnesia ("blackout") in broader perspective]. / Alkoholové "okénko" v sirsích souvislostech.

Alcohol-related amnesia ("blackout") is a common even in people who are not alcohol dependent. The average duration of simple alcohol-induced amnesia in our alcohol dependent male patients was almost 8 hours (7.96, SD=23.96). Alcohol-induced amnesia is considered to be a risk factor for long-term impairment of cognitive functions, if alcohol abuse continues. On the other hand cognitive functions in alcohol dependent persons who abstain from alcohol often improve remarkably because of reorganisation and restoration of neuronal networks. This process can be enhanced by vitamin B1, appropriate treatment of withdrawal syndrome, memory training, coping with stress and depression (relaxation techniques can be used), balanced life-style, and nootropic drugs. Alcohol-related amnesia often motivates alcohol dependent patients to overcome their problem, especially if it is appropriately used in psychotherapy.

Compromised pontocerebellar and cerebellothalamocortical systems: speculations on their contributions to cognitive and motor impairment in nonamnesic alcoholism.

BACKGROUND: Corticopontocerebellar and cerebellothalamocortical circuits underlie a wide range of neuropsychological processes compromised by alcoholism. The analyses herein tested whether abnormalities of volumes of brain structures forming nodes of these separate feed-forward and feedback systems are selectively related to each other and whether any of these noncortical regions can account for cognitive and motor deficits occurring as sequelae of chronic alcoholism. METHODS: Regional brain measures originated from our prior neuroimaging studies, showing in alcoholics significant volume deficits in the principal structures of interest: cerebellar hemispheres, vermis, pons, and thalamus as well as prefrontal, frontal, and parietal cortex. Neuropsychological functions targeted for analysis-problem solving, visuospatial ability, and static postural stability-showed 0.6 to 1.6 SD deficits in these alcoholic men. RESULTS: In alcoholics, the patterns of correlations were consistent with dissociation of thalamic and pontine circuitry. Pontine and thalamic volumes were not correlated with each other. Pontine volumes correlated with white matter volumes of anterior superior vermis and gray and white matter volumes of the cerebellar hemispheres but not with cortical regional volumes. Thalamic volumes correlated with gray matter volumes of the cerebellar hemispheres, parietal cortex, and inferior posterior vermian lobule, which itself correlated with parietal, prefrontal, and frontal cortical volumes. Controls did not show these correlational patterns. Brain structure-function relationships in alcoholics examined with multiple regression identified anterior vermian but not prefrontal or parietal volume as a unique predictor of balance scores; vermian and thalamic but not prefrontal cortical volumes as predictors of card sorting scores; and cerebellar hemispheric white matter but not parietal cortical volume as a predictor of visuospatial ability. CONCLUSIONS: Each major node of frontocerebellar circuitry shows volume deficits in alcoholics but can be independently compromised. Disruption of these circuits may underlie alcoholism-related neuropsychological deficits, either by abnormalities present in individual nodes or by disconnection via interruption of selective circuitry.

Cognitive estimation and affective judgments in alcoholic Korsakoff patients.

Alcoholic Korsakoff patients have their most marked deficits in memory, but may exhibit problems in further cognitive and behavioral domains, particularly in so-called frontal lobe functions and on the emotional level. Cognitive estimation is among the frontal lobe-associated functions; nevertheless, the underlying processes of estimation and estimation deficits are still unknown. Additionally, though affective judgments were found to be disturbed in Korsakoff patients one can question whether this result is due to a deficiency in emotional processing itself, or whether deteriorated basic processes underlying all kinds of judgment tasks result in affective judgment errors. In this study, possible relations and underlying cognitive processes of affective and nonaffective judgments (cognitive estimates) were analyzed in a large sample of 39 Korsakoff patients. A neuropsychological test battery was administered together with a new test for cognitive estimation consisting of four dimensions ('size,' 'weight,' 'quantity,' and 'time') and an affective judgment task comprising negative, neutral, and positive words. The Korsakoff patients' results showed marked deficits concerning both, cognitive estimation and affective judgments. These deficits were highly intercorrelated and performance in both tasks was related to basic (e.g., information processing speed) and higher cognitive functions (executive functions and memory), suggesting a common basis in cognitive estimation and in affective judgments in Korsakoff syndrome.

Absence of size congruency effects in amnesic patients' recognition: a failure of perceptually based recollection.

This study examined the status of recollection in amnesia when recollection is supported by perceptual rather than conceptual processes. Two experiments investigated the size congruency effect-the advantage in recognition of patterns presented in the same size, rather than in different sizes-at study and test. In Experiment 1, the authors used a remember-know paradigm in nonamnesic individuals and demonstrated that the size congruency effect was due to enhanced recollection. In Experiment 2, the authors examined whether amnesic patients would show a size congruency effect when their overall level of performance was matched to that of controls. Amnesic patients failed to show a size congruency effect. These findings provide evidence for a disproportionate disruption in recollection compared with familiarity in amnesia, even when recollection is supported by perceptual processes.

The ubiquitin-proteasome system and its role in ethanol-induced disorders.

Some of the most fundamental yet important cellular activities such as cell division and gene expression are controlled by short-lived regulatory proteins. The levels of these proteins are controlled by their rates of degradation. Similarly, protein catabolism plays a crucial role in prolonging cellular life by destroying damaged proteins that are potentially cytotoxic. A major player in these catabolic reactions is the ubiquitin-proteasome system, a novel proteolytic system that has become the primary proteolytic pathway in eukaryotic cells. Ubiquitin-mediated proteolysis is now regarded as the major pathway by which most intracellular proteins are destroyed. Equally important, from a toxicological standpoint, is that the ubiquitin-proteasome system is also widely considered to be a cellular defense mechanism, since it is involved in the removal of damaged proteins generated by adduct formation and oxidative stress. This review describes the history and the components of the ubiquitin-proteasome system, its regulation and its role in pathological states, with the major emphasis on ethanol-induced organ injury. The available literature cited here deals mainly with the effects of ethanol consumption on the ubiquitin-proteasome pathway in the liver. However, since this proteolytic system is an essential pathway in all cells it is an attractive experimental model and therapeutic target in extrahepatic organs such as the brain and heart that are also affected by excessive alcohol consumption.