Neurotoxicity of Alcoholism: Its

Effect on Cognitive Function

Neurotoxicity of Alcoholism: Its

Effect on Cognitive Function

RSA Education Lecture SeriesJune, 2006

Lecturer: Sara Jo Nixon, Ph.DSection Editor: Marlene Oscar-Berman,

Ph.D.

RSA Education Lecture SeriesJune, 2006

Lecturer: Sara Jo Nixon, Ph.DSection Editor: Marlene Oscar-Berman,

Ph.D.

What is the prevalence of neurocognitive

impairments associated with long-term chronic

alcoholism?

Prevalence of Alcoholic Individuals with and without Cognitive Impairments

(~20 Million Nationwide)

10% (2 million)with severe impairments:

(i) Alcohol-Induced Persisting Amnestic Disorder [Korsakoff’s syndrome], or(ii) Alcohol-Induced Persisting Dementia.

Mild to moderate impairments remain after 3 weeks of abstinence.

Approx. 10-30% (2-3 million)

Persisting Mild NeurocognitiveDisorder Associated with Alcohol Abuse or Alcoholism (with continued deficits despite 1 year of abstinence).

Modified from Grant & Adams, 1996

Intermediate-Duration Mild Neurocognitive Disorder Associated with Alcohol Abuse and Alcoholism (improvement after several months of abstinence).

No impairments detectable after 2-3 weeks of abstinence.

Approx. 70-90% (6-8 million)

Do not meet DSM-IV criteriafor amnesia or dementia.

90% (18 million)

Approx. 50% (9 million)

Approx. 50% (9 million)

Why are the outcomes so different?

B. Neuropsychiatric Risk Factors:Pre-abuse FAS/FAESystemic illnesses and general healthHead injuryPsychiatric comorbidityUse of other drugs

D. Alcohol History:Amount per occasionDuration of abusive drinkingPattern over lifetimeRecent amount/durationLength of abstinence

BrainStructure &Function

NeuropsychologicalPerformance

C. SES &Education

F. Motivation & Expectancies

A. Age Gender Family History Temperament

E. TestCharacteristics& Subject Sample

Digit SymbolDigit Symbol

Evert & Oscar-Berman, AHRW 1995Evert & Oscar-Berman, AHRW 1995

ObjectAssemblyObjectAssembly

Block DesignBlock Design

WAIS-RSubtestsWAIS-RSubtests

Performance of alcoholic and nonalcoholic men and women in tests of four types of neuropsychological

functioning.

Performance of alcoholic and nonalcoholic men and women in tests of four types of neuropsychological

functioning.

Verbal Skills Visual-SpatialPerformance

Verbal Memory Set-Shifting Flexibility

0

45

50

55

Mean Performance Index

Nixon, 1994 AHRW, adapted from Glenn et al., 1993

Alcoholism and Brain Dysfunction

• Problem solving• Attention• Short-term memory• Visuospatial ability• Balance and postural stability

-1.5-1.5

-1-1

-0.5-0.5

00

Age-C

orr

ect

ed Z

-Sco

reA

ge-C

orr

ect

ed Z

-Sco

re

ExecutiveExecutive STM &STM & UpperUpper DeclarativeDeclarative Visuo-Visuo- BalanceBalance

Alcoholics (n=49)Alcoholics (n=49)

Controls (n=61)Controls (n=61)

ProductionProduction LimbLimb MemoryMemory spatialspatial

Sullivan et al., ACER Sullivan et al., ACER 20002000

Characteristic Behaviors of Alcoholics

• impaired judgment• blunted affect • poor insight• social withdrawal• reduced motivation• distractibility• cognitive rigidity• inattention• perseveration

ExecutiveFunctions

FRONTAL LOBE DYSFUNCTIONFRONTAL LOBE DYSFUNCTION

Characteristic Behaviors of Alcoholics

PARIETAL LOBE DYSFUNCTIONPARIETAL LOBE DYSFUNCTION

• poor sense of direction• impaired constructional ability• impaired spatial placement• impaired drawing ability

VisuospatialAbilities

Characteristic Behaviors of Alcoholics

CEREBELLAR DYSFUNCTIONCEREBELLAR DYSFUNCTION

• impaired timing• impaired tracking• impaired balance• impaired gait• increased falls

MotorControl

Theoretical/Empirical Neuropsychological Assessments:

Theoretical/Empirical Neuropsychological Assessments:

• Mild, diffuse generalized brain dysfunction:

• Continuing discussion of aging sensitivity and differential sensitivity of specific brain areas/functions

• Characterized by considerable heterogeneity:• 50-85% of those affected• Highly sensitive laboratory tests

• Ecologically relevant tests show similar outcome

• impersonal problem-solving• interpersonal problem-solving

• Mild, diffuse generalized brain dysfunction:• Continuing discussion of aging sensitivity and differential sensitivity of specific brain areas/functions

• Characterized by considerable heterogeneity:• 50-85% of those affected• Highly sensitive laboratory tests

• Ecologically relevant tests show similar outcome

• impersonal problem-solving• interpersonal problem-solving

Oscar-Berman, 1987Parsons & Nixon, 1993

Neurocognitive Tests:Neurocognitive Tests:

• Use techniques from cognitive psychology and behavioral/cognitive neuroscience. • Shifting the focus from a localization approach to a process approach, e.g., attentional processes, executive function as outcome of system processes.

• Use techniques from cognitive psychology and behavioral/cognitive neuroscience. • Shifting the focus from a localization approach to a process approach, e.g., attentional processes, executive function as outcome of system processes.

Other Processing ApproachesCognitive Efficiency:

Speed/Accuracy Trade-offs

Other Processing ApproachesCognitive Efficiency:

Speed/Accuracy Trade-offs

0.85

0.90

0.95

1.00

1.05

1.10

1.15

LM VPA BMCST Sternberg

AlcoholicsControls

LM=Little Men VPA=Visual-Perceptual Analysis BMCST=Bexley-Maudsley Category Sorting TestLM=Little Men VPA=Visual-Perceptual Analysis BMCST=Bexley-Maudsley Category Sorting Test

Glenn & Parsons, 1991Glenn & Parsons, 1991

Overall EfficiencyOverall Efficiency

0.39(0.12)

0.41(0.12)

0.33(0.10) 0.30

(0.10)0.30

(0.09)

.20

.25

.30

.35

.40

.45

Overall E Ratio

Overall E Ratio

Similarly shaded barsdenote NS differences. Similarly shaded barsdenote NS differences.

CNTRCNTRLL

Etoh/PotEtoh/Pot Etoh/AllEtoh/All EtohEtoh Etoh/StimEtoh/Stim

n = (65) (12) (41) (43) (28)

Nixon et al., ACER 1998

Summary: Cognitive/Behavioral EffectsSummary: Cognitive/Behavioral Effects

• Widespread Deficits: by function and/or area

• Often Subclinical Levels: statistically significantly inferior to community comparison groups

• Observable via either neuropsychological or neurocognitive techniques

• Not associated with withdrawal processes

• Equivalent impairments for males/females (?)

• Widespread Deficits: by function and/or area

• Often Subclinical Levels: statistically significantly inferior to community comparison groups

• Observable via either neuropsychological or neurocognitive techniques

• Not associated with withdrawal processes

• Equivalent impairments for males/females (?)

Electrophysiology:Event-Related Potential Components

Electrophysiology:Event-Related Potential Components

N1,Nd:Nd amplitude reflecting selection of relevant

channelP3:

P3b - more typically studied- task relevant stimulus in awareness

P3a - rare, deviant or novel stimuli in repetitive unattended train of stimuliN2(MMN):

Latency index stimulus evaluation timeAmplitude related to degree of stimulus devianceMMN - produced in response to an attended deviant

N1,Nd:Nd amplitude reflecting selection of relevant

channelP3:

P3b - more typically studied- task relevant stimulus in awareness

P3a - rare, deviant or novel stimuli in repetitive unattended train of stimuliN2(MMN):

Latency index stimulus evaluation timeAmplitude related to degree of stimulus devianceMMN - produced in response to an attended deviant

Average event-related potential (ERP) wave recorded in response to a target stimulus (blue line) and nontarget stimulus (red line). Target stimuli are those that require the subject to respond in some way.

Average event-related potential (ERP) wave recorded in response to a target stimulus (blue line) and nontarget stimulus (red line). Target stimuli are those that require the subject to respond in some way.

Porjesz & Begleiter, AHRW 1995

Illustration of N400Illustration of N400

crycry

drinkdrink

eateat

0 400 msec

5V

Bentin, 1989Bentin, 1989

The pizza was too hot toThe pizza was too hot to

N400N400

T3: Temporal 3 (left hemisphere)

T4: Temporal 4 (right hemisphere)

AlcoholicsControls

Nixon et al., 2002Nixon et al., 2002

Summary: NeurophysiologicalAlcohol Related AberrationsSummary: NeurophysiologicalAlcohol Related Aberrations

• Early components associated with attentional processes

• Later components associated with stimulus evaluation, target identification

• Components associated with semantic processing

• Early components associated with attentional processes

• Later components associated with stimulus evaluation, target identification

• Components associated with semantic processing

Cortical Gray Matter Volumes

AlcoholicAlcoholic ControlControl

57 yr old men57 yr old men

Lifetime consumption of alcohol 1866 kg 60 kg (~600 gal) (~20 gal)

Lifetime consumption of alcohol 1866 kg 60 kg (~600 gal) (~20 gal)

Prefrontal

Prefrontal

Frontal Frontal AntAnt PostPost

Parietal-OccipitalParietal-OccipitalTemporalTemporal

-2

-1

0

1

OOllddeerr AAllccoohhoolliiccss ((NN==2299))

YYoouunnggeerr AAllccoohhoolliiccss ((NN==3333))

controls

Z-score

Z-score

AntAnt PostPost

Pfefferbaum et al., 1997

Group Differences: Group Differences: Match to Center Match to Center vsvs. Rest. Rest

Areas 9, 10, 45, Areas 9, 10, 45, 4646

rightrightleftleft

Areas 45, 47Areas 45, 47

rightright

Controls > AlcoholicsControls > Alcoholics

Alcoholics > ControlsAlcoholics > Controls

p=.05p=.05

p<.001p<.001

p<.001p<.001

Pfefferbaum et al., NeuroImage 2001Pfefferbaum et al., NeuroImage 2001

Recovery of function: When and Where?

Neuropsychological Recoveryin Alcoholic WomenNeuropsychological Recoveryin Alcoholic Women

Fabian & Parsons, 1983Fabian & Parsons, 1983

Efficiency Over Time*

*Time 1 includes only those who were in Time 2 (excludes Etoh/Pot due to low n). Group main effect p = .006; Time main effect p = .006.

No significant group * time effort

Nixon et al., unpublished data

Neurophysiological Recovery Neurophysiological Recovery

• Different aspects associated with differential recovery:

• Current data suggest no/limited changes in certain components:

• Raises issues about preexisting alterations in neurophysiology and role in risk:

• Different aspects associated with differential recovery:

• Current data suggest no/limited changes in certain components:

• Raises issues about preexisting alterations in neurophysiology and role in risk:

Mean differences in regional brain metabolism in 10 alcoholic subjects between 8-15 days and 31-60 days after alcohol withdrawal.Mean differences in regional brain metabolism in 10 alcoholic subjects between 8-15 days and 31-60 days after alcohol withdrawal.

Volkow et al., 1994Volkow et al., 1994

Neurofunctional RecoveryNeurofunctional Recovery

Symptom Severity (GSI)

Abstinence (Years) DeSoto, O’Donnell & DeSoto, 1989

Family History: Role in Cognitive FunctionFamily History: Role in Cognitive Function

VariableVariable

Halstead Impairment Index 0.51(.27)0.53(.27)

Tactual Performance Test 47.3(10.9)45.6(9.2) (Time/block T-score)

Tactual Performance Test 47.0(11.9)47.4(9.3) (Memory T-score)

Tactual Performance Test 47.7(10.1)50.0(7.9) (Errors T-score)

Speech-Sounds Perception Test 39.8(9.9)42.2(8.9) (Errors T-score)

Seashore Rhythm Test 50.0(13.1) 53.6(8.9) (Correct T-score)

Halsted Category Test 40.4(10.6) 42.1(10.1) (Errors T-score) Finger Tapping 44.5(12.4) 46.8(17.1) (Dominant T-score)

Halstead Impairment Index 0.51(.27)0.53(.27)

Tactual Performance Test 47.3(10.9)45.6(9.2) (Time/block T-score)

Tactual Performance Test 47.0(11.9)47.4(9.3) (Memory T-score)

Tactual Performance Test 47.7(10.1)50.0(7.9) (Errors T-score)

Speech-Sounds Perception Test 39.8(9.9)42.2(8.9) (Errors T-score)

Seashore Rhythm Test 50.0(13.1) 53.6(8.9) (Correct T-score)

Halsted Category Test 40.4(10.6) 42.1(10.1) (Errors T-score) Finger Tapping 44.5(12.4) 46.8(17.1) (Dominant T-score)

FH +FH +GroupGroup

Means (SD) of neuropsychological test performances for Family History Positive alcoholic subjects and Family History Negative alcoholic subjects.

Means (SD) of neuropsychological test performances for Family History Positive alcoholic subjects and Family History Negative alcoholic subjects.

FH - FH -

Adams et al., 1998Adams et al., 1998

(n = 27)(n = 27)

(n = 21)(n = 21)

Behavioral Disorders Confounds

Behavioral Disorders ConfoundsRegression Analyses:

Behavioral Disorders, Sex, Group, & Cognitive Efficiency

Regression Analyses: Behavioral Disorders, Sex, Group, & Cognitive

EfficiencyRegression SetRegression Set

Utah-total, child, or adult*GroupSex

CBDC-totalGroupSex

CBDC subscales†

ADD, CD, LD

Utah-total, child, or adult*GroupSex

CBDC-totalGroupSex

CBDC subscales†

ADD, CD, LD

Cognitive EfficiencyCognitive Efficiency

nsF(1,170) = 9.73, p = 0.002

ns

F(1,158) = 11.08, p = 0.001 ns

nsF(1,157) = 9.05, p = 0.001

nsF(1,170) = 9.73, p = 0.002

ns

F(1,158) = 11.08, p = 0.001 ns

nsF(1,157) = 9.05, p = 0.001

*None of the Utah scores contributed significantly to the regression. †Of the CBDC subscales, LD contributed significantly, although it entered the equation after Group.

*None of the Utah scores contributed significantly to the regression. †Of the CBDC subscales, LD contributed significantly, although it entered the equation after Group.

Nixon et al., 1995

Overall SummaryOverall Summary• Observable long-term cognitive deficits

• Differential recovery• Verbal earliest• Frontal lobe/executive function• Abstracting perhaps last• Correlation between performance and underlying physiological processes; further study

• Number of factors which must be clarified and considered• Gender: Is there a differential sensitivity?• FH: Associated with both neurocognitive and behavioral risk for “deficits”• Pre-existing behavioral disorders

• Observable long-term cognitive deficits

• Differential recovery• Verbal earliest• Frontal lobe/executive function• Abstracting perhaps last• Correlation between performance and underlying physiological processes; further study

• Number of factors which must be clarified and considered• Gender: Is there a differential sensitivity?• FH: Associated with both neurocognitive and behavioral risk for “deficits”• Pre-existing behavioral disorders