Some General Tests of Cognition

1. Some General Tests of Cognition • WAIS-R • Raven Progressive Matrices • Multilingual Aphasia Battery • Mini-mental Status Exam

2. Some Tests of Attention • Continuous Performance Task • Trails A and B • Stroop

3. Some Tests of Executive Function • Wisconsin Card Sorting Test • Porteus Mazes • Tower of London

4. Wisconsin Card Sorting Test

6. Fluency • Controlled Oral Word Association • Category Fluency • Letter Fluency

7. Verbal Memory • Logical Memory (Wechsler Memory Scale) • Rey Auditory Verbal Learning • Paired Associated Learning

8. Visual Reconstructive Memory • Rey Osterreith Complex Figure • Benton Visual Retention Test

11. Neurophysiology

12. Advantages of Neurophysiological Techniques • Noninvasive • Acceptable to disturbed patients • Require very little technical equipment • Inexpensive to use • Good temporal resolution • Can capture brain activity during very brief periods

13. Neurophysiological Techniques • Electroencephalography (EEG) • Brain Electrical Activity Mapping (BEAM) • Event Related Potentials (ERPs) • Smooth Pursuit Eye Movements (SPEM)

14. EEG and BEAM • Neither currently has significant research application in schizophrenia • No specific abnormalities found with these tools • EEG may be used clinically to rule out a neurological or medical condition

15. Event Related Potentials • Involve the study of brain electrical activity in response to some type of stimulus • Can be used to study information processing • Have been useful in the search for the mechanisms of schizophrenia

16. N100 • A negative wave occurring at 100 milliseconds after a stimulus • Thought to be related to selective attention • Paradigms require that subjects focus attention (e.g., dichotic listening, or focussing attention on the right or left ear while hearing stimuli in both ears)

17. P300 • A positive wave occurring at 300 milliseconds • Increases in size when subjects are given a new or unexpected type of stimulus • Decreased in schizophrenia, as compared with normal controls • Correlated with a decrease in temporal lobe size • Reflects an abnormality in attentional resources or the ability to allocate them • Improves with treatment

18. P50 • Positive wave occurring at 50 milliseconds • Used to study sensory gating (the ability to filter stimuli, or to inhibit irrelevant information) • Abnormal in schizophrenic patients and may also be abnormal in first degree relatives • A potential endophenotypic “marker”

19. Prepulse Inhibition • The most widely used P50 paradigm • Involves delivering a weak sensory stimulus (the “inhibiting prepulse”) prior to a very strong one that would invoke a startle response • P50 reduced in normals after prepulse inhibition, but not in patients with schizophrenia • Implies a basic deficit in filtering or gating information

20. Smooth Pursuit Eye Movements • Evaluates the ability to smoothly follow a visual target • Abnormalities in schizophrenia consistently replicated • Abnormalities also observed in first degree relatives • Also a potential “endophenotypic marker”

21. Nongenetic Factors Birth Injuries Viral Infections Nutrition

22. The Copenhagen High Risk Study • A prospective longitudinal study of individuals at risk for schizophrenia • 207 children of schizophrenic mothers and 104 matched low risk normal controls evaluated between 1962 and 1964 • Goal: to determine why some individuals at risk become ill while others do not

23. Prenatal Injuries and Obstetrical Complications • Intrauterine bleeding • Eclampsia or pre-eclamsia • Forceps delivery, potentially causing regional injury • Prolonged labor, producing hypoxia or tissue compression • All carefully documented in the Copenhagen High Risk Study

24. Early Results • Individuals who developed schizophrenia had a higher rate of obstetrical complications • High risk individuals with schizotypal disorder had a low rate of complications • Interpretation: schizophrenia is a neurologically complicated form of schizotypal disorder • Schizotypal disorder might be a more direct representation of the genetic phenotype than schizophrenia itself

25. Additional Information Using CT Scanning • Individuals who developed schizophrenia had the largest ventricles • Individuals with schizotypal disorder had the smallest ventricles • A modest correlation between ventricular size and level of perinatal complications

26. Implications • Pregnancy and birth complications may be important contributing factors to the development of schizophrenia • Could be used for primary prevention in high risk samples (e.g., close monitoring, early medication use) • However, such preventive strategies also raise important ethical considerations, such as creating anxiety in the mother or self-fulfilling prophecies in the child

27. Viral Infections • A frequently-replicated relationship between season of birth (winter birth) and increased rates of schizophrenia • Also a relationship between birth in urban areas and increased rates of schizophrenia • Both these factors might predispose to an increased rate of viral infections, and in turn to schizophrenia

28. Direct Studies of Influenza Epidemics • First empirical report of an increased rate of schizophrenia after the 1957 influenza pandemic in Finland published by a Finnish group in 1988 • Subsequently, replications of the findings have been reported from Japan, England, Ireland, Scotland, Wales, and Australia

29. Implications • The influenza virus could be a contributing factor to the development of schizophrenia • Findings have epidemiological significance, since influenza can potentially be prevented through vaccination • No evidence for fetal risk in connection with the vaccination of pregnant women

30. Nutritional Factors • Studies of children born to pregnant mothers who survived the “Dutch Hunger Winter” of World War II • Offspring have an increased risk for schizophrenia • Implicates nutrition as another potential contributor to the pathophysiology of schizophrenia

31. Working Model Etiology: DNA Gene Expression Viruses Toxins Nutrition Birth Injury Psychological Experiences        Pathophysiology: Brain Development (e.g., neuron formation, migration, pruning, apoptosis)  Neuronal Connectivity and Communication  Impairment in a Fundamental Cognitive Process  Impairment Second-Order Cognitive Processes (e.g., attention, memory, language)  Symptoms of Schizophrenia (e.g., hallucinations, delusions, negative symptoms, disorganized speech)

32. The Mechanisms and Phenotype of Schizophrenia • Multiple cumulative hits • May affect brain development and connectivity at multiple stages, with young adulthood being most critical • When sufficient hits accumulate, the phenotype appears • The phenotype is defined by a impairment in some basic cognitive process (e.g., impaired gating or filtering, cognitive dysmetria) • Simple models of this type are heuristic and facilitate the search for specific mechanisms or preventive measures