AlcoholicAlcoholic BrainBrain

Wajana Khemawichanurt,MD

Autopsy evaluations suggest that up to 78% of individuals with diagnosed alcoholism demonstrate some degree of brain pathology Approximately 10 % of alcoholic patients meet the criteria for dementia or amnestic disorder

Research has indicated that cognitive rehabilitation is important in recovery of brain-behavior functioning Some studies have indicated that patients with more impair cognitive functioning are more likely to relapse

EFFECTS OF SHORT-TERM EFFECTS OF SHORT-TERM ALCOHOL CONSUMPTIONALCOHOL CONSUMPTION Altering the balance

between inhibitory and excitatory neurotransmission Increasing inhibitory neurotransmission Decreasing excitatory neurotransmission

Alcohol Increases Inhibitory Alcohol Increases Inhibitory NeurotransmissionNeurotransmission

The main inhibitory neurotransmitter in the brain is gamma-aminobutyric acid (GABA) Acting through a receptor subtype called GABAA Increase the function of glycine receptors (Glycine is the major inhibitory neurotransmitter in the spinal cord and brain stem )

Increase inhibitory neurotransmission by increasing the activity of inhibitory neuromodulators, such as adenosine

Alcohol Decrease Excitatory

Neurotransmission The major excitatory neurotransmitters in the brain are the aspartate and glutamate, whichact through both NMDA receptors

Short-term exposure to alcohol appears to inhibit both NMDA and non-NMDA receptor activity

LONG-TERM ALCOHOL CONSUMPTION

The brain attempts to restore equilibrium after long term alcohol ingestion

Decrease in GABAA functionmay result from a decrease inreceptor levels or a change in the protein composition of the receptor, leading to decreased sensitivity to neurotransmission

Glutamate receptors appear to adapt to the inhibitory effects of alcohol by increasing their excitatory activity A compensatory decrease in adenosine activityfollowing long-term alcohol exposure

Alcohol Withdrawal Alcohol Withdrawal SyndromeSyndrome

The hyperactivity of neural adaptive mechanisms no longer balanced by the inhibitory effects of alcohol

GABA’s role in withdrawal is related to decreased inhibitory function Increased NMDA receptor activity significantly increases the amount of calcium that enters nerve cells

The GABAA and NMDA receptor systems together could be responsible for a significant portion of the alcohol withdrawal syndrome

Investigating Alcohol’s Effects on Memory

A phenomenon called long-term potentiation (LTP) appears to be fundamental for memory formation LTP is a sudden but lasting : increase in the overall level of excitatory neurotransmission in the hippocampus, a brain region involved in memory

LTP seems to require activation of glutamate receptors and inhibition of GABAA receptors Short-term alcohol exposure inhibits glutamate receptor function and stimulates GABAA receptor function in the hippocampusDecreased LTP in the hippocampus

The neurotransmitter systems linked to the reinforcing effects of alcohol are dopamine, endogenous opiates (i.e., morphine like neurotransmitters), GABA, serotonin, and glutamate acting at the NMDA receptor

Alcohol has been shown to activate dopamine systems in certain areas of the brain (i.e., the limbic system) through an interaction with glutamate receptors

Hypotheses Emphasizing Hypotheses Emphasizing the Vulnerability the Vulnerability of Brain Regions of Brain Regions 

Entire brain Entire brain : Vulnerable to cerebral atrophy

Limbic system, thalamus, Limbic system, thalamus, and hypothalamus and hypothalamus : Vulnerable to alcohol–induced persisting amnesic disorder (also known as Wernicke–Korsakoff syndrome)

Frontal lobe systems Frontal lobe systems : More vulnerable to the effects of alcoholism than other brain regions/systems.Right hemisphere Right hemisphere : More vulnerable to the effects of alcoholism than the left hemisphere Neurotransmitter systems Neurotransmitter systems : Several neurotransmitter systems are vulnerable to effects of alcoholism e.g., gamma–aminobutyric acid [GABA], glutamate, dopamine, acetylcholine, and serotonin systems

Neuroimaging technique Neuroimaging technique findingfinding

CT and MRI – cerebral atrophy in recent detoxified patients PET studies – overall decrease glucose metabolism in the frontal cortex Autopsy studies – significant change in the frontal cortex and hippocampus

Shrinkage: CerebrumShrinkage: Cerebrum

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Non-alcoholic Alcoholic

Shrinkage: CerebellumShrinkage: Cerebellum

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Healthy Control Alcoholic

Neurocognitive Neurocognitive consequences of alcohol consequences of alcohol

abuse abuse Brain damage of varying severity : mild moderate damage is common

Alcohol use damage the cerebral hemisphere , frontal lobe and causes generalized brain dysfunction

Onset of neurocognitive symptoms and cerebral atrophy may appear before liver damage or other overt medical signs of alcohol dependence

Treatment outcome may be compromised by neurocognitive deficits

Cognitive decline may result in serious by irreversible neurological impairment

Drinkers recalled 10% less verbal and nonverbal information than controls Decreases on attention and information processing, along with deficits in language competence and academic achievement

Deficits in executive functioning, specifically in future planning

Impair in abstract reasoning strategies, and generation of new solutions to problems

Brain electrical activity measured as event–related potentials (ERPs) in response to target stimuli (which require the subject to respond in some way) and nontarget stimuli (to be ignored by the subject).

Seven areas of impairment Seven areas of impairment inin

executive functioningexecutive functioning1. Problems of starting – decreased spontaneity and initiation : delay before patients response to question 2. Difficulties in making mental or behavioral shifts – rigidity or perseveration on a single idea or single action

3. Difficulties with attention4. Problems in stopping – impulsivity and decreased affect regulation5. Problem with social awareness – inability to appreciate the impact f behavior on others

6. Deficient self-awareness and insight – defective self criticism7. A concrete attitude – loss of perspective

Four major factors that Four major factors that contribute to alcohol contribute to alcohol

related cognitive related cognitive dysfunctiondysfunction1. Direct toxin effect of

alcohol on CNS – impact on neurotransmitters eg. Serotonin , dopamine glutamate2. Compromised nutrition – thiamine deficiency

3. Alcohol induced damage to the liver 4. Cranio-cerebral trauma (research has indicated that -5070% of TBI patients have been using alcohol )

Common neurologicaland psychological symptoms of alcohol intoxication

• Slurred speech

• Ataxia

• Nystagmus• Changeable mood

• Impair memory

• Attention deficits

Alcohol Alcohol IntoxicationIntoxication

Alcohol drinking markedly reduces brain metabolism

Alcohol Withdrawal Alcohol Withdrawal

Neuropsychological functioning significant impaired immediately after cessation of alcohol

After 2 weeks of abstinence most patient improve on test of memory ,intellectual functioning , visual motor skill

Studies have shown that alcoholics under age 40 years old exhibit gradual improvement over 3-4 weeks .older adults recovery more slowly

Alcohol-induced persisting Alcohol-induced persisting amnestic disorderamnestic disorder

< Wernicke-Korsakoff’s < Wernicke-Korsakoff’s Syndrome >Syndrome > Wernicke-Korsakoff

syndrome is caused by lack of thiamine(vitamin B1)

The syndrome is made up of two separate, but related disorders : Wernicke’s encephalopathy (WE) and Korsakoff’s amnestic syndrome (KS)

WE usually occurs before KS develops

Wernicke’s Encephalopathy Wernicke’s Encephalopathy

• Neurologicl symptoms of Wernicke’s encephalopathy include ataxia , clouding of consciousness, nystagmus and other vision dysfuncton < occulomotor dysfunction >

• Degenerative changes in the brain (atrophy of the mamillary bodies , enlargement of the third ventricle or aqueduct and possibly degeneration of the cerebellar vermis)

FLAIR sequence in axial and sagital planes shows signs of Wernicke’s encephalopathy. Increased signal around the third ventricle and medially in both thalami (thick arrow). Also increased signal around the aqueduct of the midbrain (narrow arrow) and in the tectal plate (<). Mamillary bodies are smaller than normal (>).

Brain Regions Affected Brain Regions Affected by by

Thiamine DeficiencyThiamine Deficiency• Thalamus-major relay for (sensory and motor input)• Mamillary Body-helps processes memories• Cerebellum-movement coordination•Peripheral Nerves-transmission of nerve impulses

Korsakoff’s amnestic syndrome (KS)Korsakoff’s amnestic syndrome (KS)

• The symptoms of Korsakoff’s syndrome include : loss of memory<particularly short term memory>, loss of spontaneity and initiative , confabulation

• Undamaged parts of the brain that deal with memory, awareness and understanding can compensate for the damaged areas and lost abilities

Recovery of memory function among patient with KS ranged from complete (21%), to significant (25%), slight (28%) or none (26%)

The majority were left with a chronic gait disturbance (62%)

Nystagmus improved more slowly and in 60% it was permanent

Alcohol-induced persisting Alcohol-induced persisting dementiadementia

< Alcoholic dementia> < Alcoholic dementia> Gradual progressive decline in cognitive functioning Symptoms of frontal lobe impairment – decreased interest , poor personal hygine , poor judgment , poor attention and recent memory and flattened affect

Associated with chronic alcohol abuse for approximately 15-20 years duration Neurological studies autopsy,CAT scans and MRI – enlarged cerebral ventricles, frontal cortical atrophy<reduction in both amount of tissue and size of cells>

Estimated that as many as 25% of elderly alcoholic patients have alcohol-induced Dementia

Neuroimaging and neuropathological evidence show prominent white matter loss (most notable in the prefrontal cortex, corpus callosum, and cerebellum)

Neuronal loss in the superior frontal association cortex, hypothalamus, and cerebellum

Surface rendered brains (top) and rendered ventricular system (bottom, green) of a 59-year-old healthy man (A and C) and a 53-year-old man with WKS (B and D).

Sullivan E V , and Pfefferbaum A Alcohol and Alcoholism 2009;44:155-165

© The Author 2008. Published by Oxford University Press on behalf of the Medical Council on Alcohol. All rights reserved

Hepatic encephalopathy and Hepatic encephalopathy and cirrhosis of the liver cirrhosis of the liver

Cirrhosis lead to portal systemic encephalopathy<PSE> associated with attentional deficits , memory loss , incoordination and confusion

Some cognitive deficits improve after liver transplant But memory impairment remain

Individual with cirrhosis from alcohol use perform worse on test of short term memory , eye tracking and eye-hand coordination than individual with cirrhosis from other factors

Neurocognitive Neurocognitive functioning recoveryfunctioning recovery

Post-detox functioning of chronic alcoholics show deterioration of cognitive functioning for at least several weeks Typical several month after detox have problem in memory , abstract reasoning and visuospatial functions

Studies of abstinence from 13 month to 3 years – nonverbal learning and memory recovery more slowly than verbal memory

Neurocognitive functioning recovery in abstinence patients appear to be gradual over period of years

Attentional deficits may be evidence for long period of time : 2 years or more Significantly better scores on tests of working memory, visuospatial abilities, and gait and balance with abstinence from alcohol

Volume RecoveryVolume Recovery

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During Treatment 2 Years Later

AmphetaminesAmphetamines

High doses of amphetamine and methamphetamine alters dopaminergic neurons that innervate the striatum (caudate-putamen )

The areas of the brain that suffered the greatest loss were associated with emotion and rewards (the limbic system) and memory (the hippocampus)

Structural brain Structural brain abnormalities related abnormalities related

with methamphetaminewith methamphetamine

Smaller volumes of the temporal lobe, but not of the frontal lobe  Abnormalities in the cortex, hippocampus, white matter, and ventricles 

The methamphetamine abusers had less gray matter in the cingulate, limbic, and paralimbic cortices. The abusers displayed white-matter hypertrophy and smaller hippocampal volumes Hippocampal deficits that were postulated to contribute to impaired memory performance

 Neuronal deficits and or toxicities might lead to the white-matter hypertrophy Low glucose metabolism in anterior cingulate

Cognitive flexibility Cognitive flexibility : in abstinence methamphetamine users has been shown to be associated with decreased frontal white matter metabolism

Inhibitory Control Inhibitory Control : Lack ofinhibition including the suppression of emotional, cognitive and behavioral responses

The Profile of Cognitive The Profile of Cognitive Deficits AssociatedDeficits Associated

with Amphetamine and with Amphetamine and Opiate DependenceOpiate Dependence

Sustained attention

Strategic Planning

Decision-Making

Memory and Learning

Cognitive training modules have already shown effectiveness in a variety of clinical groups, including patients with schizophrenia(Bell et al. 2005; Hogarty et al. 2004; Kosten et al. 2006;Wykes et al. 2003), traumatic brain injury (Sarajuuri et al.2005), and chronic drug users (Czuchry and Dansereau2003a; FalsStewart and Lucente 1994b).

Neurocognitive Training and Remediation

Thank you.