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Some General Tests of Some General Tests of CognitionCognition

• WAIS-RWAIS-R

• Raven Progressive MatricesRaven Progressive Matrices

• Multilingual Aphasia BatteryMultilingual Aphasia Battery

• Mini-mental Status ExamMini-mental Status Exam

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Some Tests of Some Tests of AttentionAttention

• Continuous Performance Continuous Performance TaskTask

• Trails A and BTrails A and B• StroopStroop

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Some Tests of Some Tests of Executive FunctionExecutive Function

• Wisconsin Card Sorting Wisconsin Card Sorting TestTest

• Porteus MazesPorteus Mazes

• Tower of LondonTower of London

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Wisconsin Card Sorting Wisconsin Card Sorting TestTest

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FluencyFluency

• Controlled Oral Word Controlled Oral Word AssociationAssociation

• Category FluencyCategory Fluency

• Letter FluencyLetter Fluency

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Verbal MemoryVerbal Memory

• Logical Memory (Wechsler Logical Memory (Wechsler Memory Scale)Memory Scale)

• Rey Auditory Verbal Rey Auditory Verbal LearningLearning

• Paired Associated LearningPaired Associated Learning

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Visual Visual Reconstructive Reconstructive

MemoryMemory• Rey Osterreith Complex Rey Osterreith Complex

FigureFigure

• Benton Visual Retention Benton Visual Retention TestTest

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NeurophysiologyNeurophysiology

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Advantages of Advantages of Neurophysiological TechniquesNeurophysiological Techniques• NoninvasiveNoninvasive• Acceptable to disturbed patientsAcceptable to disturbed patients• Require very little technical Require very little technical

equipmentequipment• Inexpensive to useInexpensive to use• Good temporal resolutionGood temporal resolution• Can capture brain activity during Can capture brain activity during

very brief periodsvery brief periods

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Neurophysiological Neurophysiological TechniquesTechniques

• Electroencephalography (EEG)Electroencephalography (EEG)

• Brain Electrical Activity Mapping Brain Electrical Activity Mapping (BEAM)(BEAM)

• Event Related Potentials (ERPs)Event Related Potentials (ERPs)

• Smooth Pursuit Eye Movements Smooth Pursuit Eye Movements (SPEM)(SPEM)

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EEG and BEAMEEG and BEAM

• Neither currently has significant Neither currently has significant research application in research application in schizophreniaschizophrenia

• No specific abnormalities found No specific abnormalities found with these toolswith these tools

• EEG may be used clinically to EEG may be used clinically to rule out a neurological or rule out a neurological or medical conditionmedical condition

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Event Related PotentialsEvent Related Potentials

• Involve the study of brain Involve the study of brain electrical activity in response to electrical activity in response to some type of stimulussome type of stimulus

• Can be used to study Can be used to study information processinginformation processing

• Have been useful in the search Have been useful in the search for the mechanisms of for the mechanisms of schizophreniaschizophrenia

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N100N100

• A negative wave occurring at 100 A negative wave occurring at 100 milliseconds after a stimulusmilliseconds after a stimulus

• Thought to be related to Thought to be related to selective attentionselective attention

• Paradigms require that subjects Paradigms require that subjects focus attention (e.g., dichotic focus attention (e.g., dichotic listening, or focussing attention listening, or focussing attention on the right or left ear while on the right or left ear while hearing stimuli in both ears)hearing stimuli in both ears)

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P300P300• A positive wave occurring at 300 A positive wave occurring at 300

millisecondsmilliseconds• Increases in size when subjects are given a Increases in size when subjects are given a

new or unexpected type of stimulusnew or unexpected type of stimulus• Decreased in schizophrenia, as compared Decreased in schizophrenia, as compared

with normal controlswith normal controls• Correlated with a decrease in temporal lobe Correlated with a decrease in temporal lobe

sizesize• Reflects an abnormality in attentional Reflects an abnormality in attentional

resources or the ability to allocate themresources or the ability to allocate them• Improves with treatmentImproves with treatment

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P50P50• Positive wave occurring at 50 Positive wave occurring at 50

millisecondsmilliseconds• Used to study sensory gating (the Used to study sensory gating (the

ability to filter stimuli, or to inhibit ability to filter stimuli, or to inhibit irrelevant information)irrelevant information)

• Abnormal in schizophrenic patients Abnormal in schizophrenic patients and may also be abnormal in first and may also be abnormal in first degree relativesdegree relatives

• A potential endophenotypic “marker”A potential endophenotypic “marker”

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Prepulse InhibitionPrepulse Inhibition• The most widely used P50 paradigmThe most widely used P50 paradigm• Involves delivering a weak sensory Involves delivering a weak sensory

stimulus (the “inhibiting prepulse”) prior stimulus (the “inhibiting prepulse”) prior to a very strong one that would invoke a to a very strong one that would invoke a startle responsestartle response

• P50 reduced in normals after prepulse P50 reduced in normals after prepulse inhibition, but not in patients with inhibition, but not in patients with schizophreniaschizophrenia

• Implies a basic deficit in filtering or Implies a basic deficit in filtering or gating informationgating information

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Smooth Pursuit Eye Smooth Pursuit Eye MovementsMovements

• Evaluates the ability to smoothly Evaluates the ability to smoothly follow a visual targetfollow a visual target

• Abnormalities in schizophrenia Abnormalities in schizophrenia consistently replicatedconsistently replicated

• Abnormalities also observed in first Abnormalities also observed in first degree relativesdegree relatives

• Also a potential “endophenotypic Also a potential “endophenotypic marker”marker”

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Nongenetic Nongenetic FactorsFactorsBirth InjuriesBirth Injuries

Viral InfectionsViral Infections

NutritionNutrition

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The Copenhagen High The Copenhagen High Risk StudyRisk Study

• A prospective longitudinal study of A prospective longitudinal study of individuals at risk for schizophreniaindividuals at risk for schizophrenia

• 207 children of schizophrenic 207 children of schizophrenic mothers and 104 matched low risk mothers and 104 matched low risk normal controls evaluated between normal controls evaluated between 1962 and 19641962 and 1964

• Goal: to determine why some Goal: to determine why some individuals at risk become ill while individuals at risk become ill while others do notothers do not

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Prenatal Injuries and Prenatal Injuries and Obstetrical ComplicationsObstetrical Complications• Intrauterine bleedingIntrauterine bleeding• Eclampsia or pre-eclamsiaEclampsia or pre-eclamsia• Forceps delivery, potentially Forceps delivery, potentially

causing regional injurycausing regional injury• Prolonged labor, producing Prolonged labor, producing

hypoxia or tissue compressionhypoxia or tissue compression• All carefully documented in the All carefully documented in the

Copenhagen High Risk StudyCopenhagen High Risk Study

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Early ResultsEarly Results• Individuals who developed schizophrenia Individuals who developed schizophrenia

had a higher rate of obstetrical had a higher rate of obstetrical complicationscomplications

• High risk individuals with schizotypal High risk individuals with schizotypal disorder had a low rate of complicationsdisorder had a low rate of complications

• Interpretation: schizophrenia is a Interpretation: schizophrenia is a neurologically complicated form of neurologically complicated form of schizotypal disorderschizotypal disorder

• Schizotypal disorder might be a more Schizotypal disorder might be a more direct representation of the genetic direct representation of the genetic phenotype than schizophrenia itselfphenotype than schizophrenia itself

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Additional Information Additional Information Using CT ScanningUsing CT Scanning

• Individuals who developed Individuals who developed schizophrenia had the largest schizophrenia had the largest ventriclesventricles

• Individuals with schizotypal Individuals with schizotypal disorder had the smallest disorder had the smallest ventriclesventricles

• A modest correlation between A modest correlation between ventricular size and level of ventricular size and level of perinatal complicationsperinatal complications

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ImplicationsImplications• Pregnancy and birth complications may Pregnancy and birth complications may

be important contributing factors to the be important contributing factors to the development of schizophreniadevelopment of schizophrenia

• Could be used for primary prevention in Could be used for primary prevention in high risk samples (e.g., close monitoring, high risk samples (e.g., close monitoring, early medication use)early medication use)

• However, such preventive strategies also However, such preventive strategies also raise important ethical considerations, raise important ethical considerations, such as creating anxiety in the mother or such as creating anxiety in the mother or self-fulfilling prophecies in the childself-fulfilling prophecies in the child

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Viral InfectionsViral Infections• A frequently-replicated relationship A frequently-replicated relationship

between season of birth (winter birth) between season of birth (winter birth) and increased rates of schizophreniaand increased rates of schizophrenia

• Also a relationship between birth in Also a relationship between birth in urban areas and increased rates of urban areas and increased rates of schizophreniaschizophrenia

• Both these factors might predispose to Both these factors might predispose to an increased rate of viral infections, an increased rate of viral infections, and in turn to schizophreniaand in turn to schizophrenia

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Direct Studies of Direct Studies of Influenza EpidemicsInfluenza Epidemics

• First empirical report of an First empirical report of an increased rate of schizophrenia increased rate of schizophrenia after the 1957 influenza after the 1957 influenza pandemic in Finland published pandemic in Finland published by a Finnish group in 1988by a Finnish group in 1988

• Subsequently, replications of the Subsequently, replications of the findings have been reported findings have been reported from Japan, England, Ireland, from Japan, England, Ireland, Scotland, Wales, and AustraliaScotland, Wales, and Australia

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ImplicationsImplications• The influenza virus could be a The influenza virus could be a

contributing factor to the contributing factor to the development of schizophreniadevelopment of schizophrenia

• Findings have epidemiological Findings have epidemiological significance, since influenza can significance, since influenza can potentially be prevented through potentially be prevented through vaccinationvaccination

• No evidence for fetal risk in No evidence for fetal risk in connection with the vaccination of connection with the vaccination of pregnant womenpregnant women

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Nutritional FactorsNutritional Factors

• Studies of children born to pregnant Studies of children born to pregnant mothers who survived the “Dutch mothers who survived the “Dutch Hunger Winter” of World War IIHunger Winter” of World War II

• Offspring have an increased risk for Offspring have an increased risk for schizophreniaschizophrenia

• Implicates nutrition as another Implicates nutrition as another potential contributor to the potential contributor to the pathophysiology of schizophreniapathophysiology of schizophrenia

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Working ModelWorking ModelEtiology:Etiology:

DNA Gene Expression Viruses Toxins Nutrition Birth Injury Psychological ExperiencesDNA Gene Expression Viruses Toxins Nutrition Birth Injury Psychological Experiences

Pathophysiology:Pathophysiology:

Brain Development (e.g., neuron formation, migration, pruning, apoptosis)Brain Development (e.g., neuron formation, migration, pruning, apoptosis)

Neuronal Connectivity and CommunicationNeuronal Connectivity and Communication

Impairment in a Fundamental Cognitive ProcessImpairment in a Fundamental Cognitive Process

Impairment Second-Order Cognitive Processes Impairment Second-Order Cognitive Processes (e.g., attention, memory, language)(e.g., attention, memory, language)

Symptoms of Schizophrenia Symptoms of Schizophrenia (e.g., hallucinations, delusions, negative symptoms, disorganized speech)(e.g., hallucinations, delusions, negative symptoms, disorganized speech)

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The Mechanisms and The Mechanisms and Phenotype of SchizophreniaPhenotype of Schizophrenia• Multiple cumulative hitsMultiple cumulative hits• May affect brain development and connectivity at May affect brain development and connectivity at

multiple stages, with young adulthood being most multiple stages, with young adulthood being most criticalcritical

• When sufficient hits accumulate, the phenotype When sufficient hits accumulate, the phenotype appearsappears

• The phenotype is defined by a impairment in some The phenotype is defined by a impairment in some basic cognitive process (e.g., impaired gating or basic cognitive process (e.g., impaired gating or filtering, cognitive dysmetria)filtering, cognitive dysmetria)

• Simple models of this type are heuristic and Simple models of this type are heuristic and facilitate the search for specific mechanisms or facilitate the search for specific mechanisms or preventive measurespreventive measures