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Impaired Functioning in Schizophrenia: Models, Mechanisms and Measurement. Dr Kathryn Greenwood Department of Psychology, University of Sussex & Sussex Partnership NHS Foundation Trust. Overview. Personal Accounts Theories of symptoms, cognition and function in schizophrenia Studies

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slide1

Impaired Functioning in Schizophrenia: Models, Mechanisms and Measurement

Dr Kathryn Greenwood

Department of Psychology, University of Sussex & Sussex Partnership NHS Foundation Trust

overview
Overview
  • Personal Accounts
  • Theories of symptoms, cognition and function in schizophrenia
  • Studies
    • 1 Executive impairment profiles in Schizophrenia (JINS)
    • 2 Executive impairments and symptoms models (Schiz Bull)
    • (including in materials in preparation)
    • 3 Cognitive impairments and Awareness (Schiz Bull)
    • 4 Genes and outcome (Neuroscience letters)
    • 5 VR as a measurement tool (in preparation)
  • Clinical implications and future directions
slide4
“My concentration is very poor. I jump from one thing to another. If I am talking to someone they only need to cross their legs or scratch their head and I am distracted and forget what I was saying.”

McGhie and Chapman, 1961

slide5

“I was looking at A or B for some subjects now I’m looking at C or D if I’m lucky.”

“Memory loss is the new thing that’s bothering me.”

“I have low concentration”

“I’m coming to terms with the fact that I have got a learning difficulty.”

Michael, Aged 16 years

Inside my head - Channel 4, June 2002

slide6

Work

“I want to be able to do things that other people do, like have a boyfriend and a job …”

Social Functioning“I want to have friends”

Community Function

“I want to be able to cook and eat when I want”

“I want to live in my own place not a hostel”

baddeley s working memory model
Baddeley’s Working Memory Model

Phonological

Loop

Visuospatial Sketchpad

Store

Central Executive

Baddeley and Hitch, 1978; Baddeley and Della Sala 1996

goldman rakic 1987
Goldman-Rakic 1987

Adjacent modality-specific working memory systems in DLPFC with own control systems: a fundamental impairment in schizophrenia

shallice s supervisory attentional system
Shallice’s Supervisory Attentional System
  • Automatic contention scheduling

Until

  • i) novel environment
  • ii) requirement to inhibit one strong or several weak competing schema
  • New Schema construction
  • Implementation in working memory
  • Monitoring and Inhibition

Norman and Shallice 1982; Shallice and Burgess 1992; 1996

frith s cognitive neuropsychology of schizophrenia 1992
Frith’s Cognitive Neuropsychology of Schizophrenia 1992

Three main (theory of mind) disorders:

  • Disorders of willed intentions (action driven by intention)
  • Disorders of self-monitoring
  • Monitoring the Intentions of others

Negative symptoms = absence of initiation of willed intentions, plans and strategies and impaired monitoring of others so missed communication cues

Thought disorder (incoherence of behaviour/affect) = poor inhibition of stimulus driven responses by intentions, as well as impaired self monitoring of communication goal to output and impaired monitoring of listener’s understanding

neurocognition and function are we measuring the right stuff green 2000
Neurocognition and function: Are we measuring the right stuff? Green 2000

Card Sort

Community/daily

activities

learning potential and skill acquisition as mediators of functional outcome

Verbal fluency

Social problem solving/

instrumental skills

Immediate verbal

memory

Psychosocial skill

acquisition

green s conclusions 2000
Green’s conclusions 2000

‘We have learned whether but not HOW

neurcognition is related to functional outcome?’

Need to know what mediates relation between neurocognition and outcome?

  • Processes (learning potential) that underlie the ability to acquire and perform life skills
  • Social cognition
slide17

There is a need for new cognitive models of negative symptoms and function in order to improve functional outcomes

lincoln et al in press
Lincoln et al. (in press)

Negative symptoms associated with Impaired Social Cognition:

difficulties in ToM

lower self-esteem

less self-serving bias

Negative self-concepts related to interpersonal abilities

Dysfunctional acceptance beliefs.

Some social cognitive impairments (ToM) were associated with negative symptoms only in people with low self-esteem.

So self-concepts related to social abilities, dysfunctional beliefs and global self-worth alone and in interaction with skill-deficits are associated with negative symptoms

rector beck and stolar 2005
Rector, Beck and Stolar (2005)
  • Low expectancies for pleasure, success, acceptance & perception of limited resources play a major role in the formation of negative symptoms
  • Dysfunctional performance beliefs (e.g. If I fail partly, it is as bad as being a complete failure) associated with negative symptoms
  • Indirect pathways between functional capacity (cognitive impairment), dysfunctional performance beliefs, and negative symptoms and real-world functioning
research aims
Research Aims

To understand the mechanisms through which bio-psychosocial factors including

  • Gene markers
  • Phenomenology of schizophrenia
  • Cognitive function &
  • Psychological function (thinking, mood and behaviour)

Affect functional outcome in schizophrenia

study 1 aims
Study 1 Aims

Categorisation of sub-groups by neuropsychological profile in all cases confounds the relationship between symptoms and chronicity.

Aims

To explore the severity and profile of executive functioning in relation to disorganisation and psychomotor poverty and simultaneously

To investigate the early and late profiles in first episode and chronic schizophrenia.

Hypothesis

Chronicity will associate with similar but more severe impairment

Disorganisation will associate with broad executive deficit

Psychomotor poverty with impaired working memory and response initiation

study 1 measures
Study 1 Measures
  • working memory
    • Digit span, word span, executive golf
  • planning and strategy formation
    • Tower of london, hayling and executive golf strategy scores
  • response initiation
    • Verbal fluency
  • response inhibition
    • Hayling test and complex reaction time test
  • IQ
    • WAIS-R and NART-R
slide24

Novel measures – the question

  • To assess similar processes in cognitive & function task
    • Working memory example
  • 3KA27
  • Crunchy Green salad 250g £1.09
  • Crunchy Green salad 500g £1.24
  • Mixed Salad 250g £1.15
  • Caesar Salad 120g £ 1.05
slide26

Novel measures – the answer

  • Example using Working Memory
  • 3KA27 237AK
  • Caesar Salad 120g £ 1.05 Crunchy Green salad 250g £1.09
  • Mixed Salad 250g £1.15
  • Crunchy Green salad 500g £1.24
study 1 analysis
Study 1 Analysis

Group differences in executive function

MANCOVA’s controlling for WAIS IQ

Executive profiles

  • Converted to z-scores and compared using generalised estimating equations (GEE). Group as between and executive function as within subject factor

Specific islets of strength/deficit

  • Domain score compared to average of all others while holding IQ constant
slide31

Distinct profiles and poorer performance in schizophrenia/and disorganisation than controls/pp

slide32

Parallel non-flat profiles and poorer performance in chronic schizophrenia (and FE) compared to controls

study 1 conclusions
Study 1 Conclusions
  • Schizophrenia - characterised by a single executive profile that reflects the make up of symptoms (psychomotor poverty / disorganisation) but not chronicity
  • Parallel but attenuated profile at first episode due to incorporation of those with intact function
  • Disorganisation - broad impairment profile incorporating planning and working memory
  • Psychomotor poverty - particularly impaired response initiation
  • Predictive power of either symptoms or cognition on outcome is short lived but stable symptom-cognition markers should be targets of intervention
study 2
Study 2
  • Schizophrenia - characterised by a single executive profile that reflects the make up of symptoms (psychomotor poverty / disorganisation) but not chronicity
  • Parallel but attenuated profile at first episode due to incorporation of those with intact function
  • Disorganisation - broad impairment profile incorporating planning and working memory
  • Psychomotor poverty - particularly impaired response initiation
  • Predictive power of either symptoms or cognition on outcome is short lived but stable symptom-cognition markers should be targets of intervention
slide39

Negative Symptoms matter in the Leap from Cognition to Community Function in Schizophrenia:

Implications for Intervention

Dr K Greenwood, Dr S Landau, Professor T Wykes

Department of Psychology, Institute of Psychiatry,

London, UK.

e-mail: k.greenwood@iop.kcl.ac.uk

introduction
Introduction
  • People with schizophrenia and negative symptoms have poor functioning (occupation, community and daily living skills)
  • Poor functioning is a source of distress for both people with schizophrenia and their families
negative symptoms associated with community function
Negative Symptoms associated with Community Function
  • Negative symptoms (flat affect, poverty of speech, apathy) affect function:
  • Only Indirectly through link with Cognition
  • Independently
cognitive impairments associated with community function
Cognitive Impairments associated with Community Function
  • Executive function predicts Community function, Occupation, Daily living
  • Working Memory predicts Occupation
  • Global cognition predicts Daily living
  • Cognition is a stronger predictor than symptoms (Green 2000)
cognitive impairments associated with negative symptoms
Cognitive Impairments associated with negative symptoms

Negative symptoms:

Linked theoretically with : Executive function and Working memory

Initiation/generation of strategies (Frith) Working memory (Goldman-Rakic)

Linked Empirically with:

Response Initiation (Franke et al. 1993)

Immediate/working memory (Pantelis et al 2001)

Focused/switching attention (Buchanan et al 1994) Initiation/working memory/strategy use (Greenwood 2000)

objective
Objective
  • To investigate specific relationships between negative symptoms, executive/working memory functions and community function and in particular to investigate the independent effect of negative symptoms
  • Reducing confounding of negative symptoms and low IQ
  • Using process approach and theoretically driven framework
  • Also using a novel measure to directly assess community function
design
Design
  • Cross sectional Comparison:

22 Healthy controls

28 Schizophrenia & negative symptoms balanced general

22 Schizophrenia & no negative symptoms cognitive impairment

  • Balancing: Age, Sex, Premorbid IQ,
  • Predictors: working memory, initation, inhibition, strategy, symptoms
  • Analysis: Identify individual associations to function, interactions, and final regression model
slide46

The measure A test of supermarket shopping Skills

  • Participants had to select 10 items from a
  • shopping list.
  • Measures were taken of:
    • accuracy (items correct)
    • Efficiency (time/route length)
    • Redundancy (no. aisles entered above minimum)
    • Strategy
  • (adapted from Test of Grocery Shopping Skills, Hamera and Brown 2000)
research questions
Research Questions
  • Is directly assessed community function more impaired in people with schizophrenia and negative symptoms

(when directly assessed and without IQ confound)

  • Do specific executive processes predict specific community functions

(working memory-accuracy; strategy-strategy)

  • Do the associations differ in different symptom groups (use of theoretical rationale to investigate moderator effect of negative symptoms)
statistical analyses
Statistical Analyses
  • Association Analyses

(GLR – with binomial, Poisson, normal distribution)*

Stage 1: Identify individual associations

(cognition x function)

Stage 2: Identify individual interactions

(cognition x symptom group x function)

Stage 3: Conduct final regression model

Premorbid IQ controlled

slide50

Poorer strategy, working memory, initiation

in negative group

Verbal fluency initiation

Verbal working memory

score

Spatial Strategy Score

40

4

12

35

10

30

3

8

25

6

20

2

15

4

10

1

2

5

0

0

0

control

neg

non-neg

neg

control

non-neg

control

non-neg

neg

community function poorer accuracy efficiency and strategy in negative group
Community function: Poorer accuracy, efficiency and strategy in negative group

Aisles above Minimum

Correct lowest price

Time Taken

60

16

8

14

50

7

12

40

6

Time taken

10

5

8

30

4

6

20

3

4

2

10

2

1

0

0

0

control

neg

non-neg

non-neg

neg

control

control

non-neg

neg

slide52

The results

  • Some cross group predicted associations between cognition and function (e.g. accuracy and strategy, efficiency and working memory)
  • Some executive-function associations only with negative symptoms
  • (working memory and accuracy, IQ and efficiency)
  • Not just because of poor general cognition and Not a threshold effect but a true interaction
executive premorbid factors associated with community function
Executive & premorbid factors associated with community function
  • Working memory associated with all function measures (p = .01- < .001)
  • Strategy associated with strategy measures and route length (p = .04- < .001)
  • Initiation associated with correct items, efficiency and strategy (p = .02 - <.001)
  • Premorbid IQ associated with most measures

(p = 0.04-<0.001)

independent cognition to community function associations are present only for specific groups
Independent cognition to community function associations are present only for specific groups
  • In Negative group

Working memory associated with size accuracy

price accuracy

Verbal fluency associated with aisles above minimum

Premorbid IQ associated with correct items

time

  • In Controls

Working memory associated with aisle strategy

Verbal fluency associated with aisles above minimum

conclusion so far
Conclusion so far…
  • Community functions are more impaired in schizophrenia with negative symptoms even compared to a group with equivalent general cognitive function
  • Executive functions associated with community function only in negative not non-negative schizophrenia
negative symptoms moderate the association between impaired executive and community functions
Negative symptoms moderate the association between impaired executive and community functions
  • No significant interaction of working memory severity factor within negative group
  • Moderating effect is not a cognitive threshold effect
a synergistic cognition symptom interaction predicts community function a working memory model
A synergistic cognition-symptom interaction predicts community function: A working memory model

Core Working Memory

Domain Specific WM

Community

Function

Ability

CF exp.

Negative Symptoms

research question 2
Research Question - 2
  • Do cognition or symptoms predict changes in community function when investigated longitudinally?
design 2
Design - 2
  • Longitudinal follow-up of shopping function (n=43) :
  • Comparing baseline (t1) to 6 months (t3)
  • Broader range Demographics, Cognition, Symptoms and function
slide60

Influences on recovery

  • Differences in baseline measures between improvers (n=21) and non-improvers (n=22)
    • initial community function (p <.001)
    • self-esteem (p = 0.026)
    • working memory (p=0.047)
  • Independent predictors of improvement on
    • Initial community function (p = 0.004)
    • Self esteem (p <0.001)
    • Working memory(p = 0.088)
a synergistic cognition symptom interaction predicts community function a working memory model1
A synergistic cognition-symptom interaction predicts community function: A working memory model

Core Working Memory

Domain Specific WM

Community

Function

Ability

CF Level

Negative Symptoms

Self esteem

slide62

The design III: the relationship of SST to other functions

  • Cross sectional comparison of standardised shopping function to other function measures(n=53) :
  • Accuracy correlated with social behaviour (SBS) (r = -0.4 p = 0.001) but not level of independence in day care, number of activities or self-reported shopping activities
  • Efficiency correlated with level of independence in day care and independence in handling money (Spearman’s rho = -0.4 p = 0.005 and -0.3 p = 0.047) but not with social behaviour, number of activities or other self-reported shopping activities
  • The ability to shop accurately seems linked to the appropriateness of other social behaviours and the ability to shop efficiently seems linked to other measures of independence in function. Shopping function is unrelated to activity levels in shopping or other behaviours.
implications
Implications
  • Synergistic interaction between negative symptoms and working memory impairments may contribute to progressively poorer community function
  • Remediation programmes that employ CBT/ CRT to target negative symptoms/ low self esteem AND domain specific cognition/working memory may break the reciprocal link, enhance generalisation and improve functional outcome
why consider a vr assessment of function
Why consider a VR assessment of function?
  • Most commonly used measures are the GAF and employment status (recent review Greenwood et al. unpublished data)
  • Rehabilitation may be maximised by identifying cognitive targets for intervention through refined assessment (Greenwood et al. 2005)
  • But few brief direct standardised assessments (McKibbin et al. 2004)
  • Need for brief, easily administered community function assessments in schizophrenia, validated against real life functions and underlying cognitive processes
the use of virtual reality in assessment and intervention
The Use of Virtual Reality in Assessment and Intervention
  • VR apartment for medication management and adherence
  • VR functional skills assessment for social competence
  • VR avatar for assessment of social approach and anxiety
  • VR street, tube train and library for understanding thinking patterns underpinning to psychosis
  • VR Park and Maze for real world navigation (allocentric and egocentric memory)
  • VR maze for real world sensory integration in working memory
  • VR supermarket to assess executive function in different clinical groups

BUT no studies in schizophrenia have compared RL and VR performance on same task and some suggest differential performance in VR dependent on environment and associated cognitive processes

Freeman et al. 2003;2005; Jang et al. 2005; Baker et al 2006; Sorkin et al. 2006; 2008; Kurtz et al. 2007; Ku et al. 2007; Weniger et al 2008; Kim et al. 2008; Park et al. 2009; Zanyi et al. 2009; Josman et al. 2009; Landgraf et al. 2010

the research questions
The research questions

1. Does performance in VR relate to the same in RL?

2. Do they share common or distinct cognitive processes?

3. Do these processes differ in different symptom groups?

community function measure
Community Function Measure
  • Supermarket Shopping Task

(adapted from TOGSS: Hamera and Brown, 2000)

  • Virtual Reality Shopping Task

presented on flat screen computer with joystick

(RG Morris et al.)

In each task participants had to select 10 items from a shopping list. Measures were taken of:

    • accuracy (items correct)
    • time
    • redundancy (no. aisles entered above minimum)
cognitive measures
Cognitive measures
  • Memory and Working Memory
    • Visual Reproduction and Letter-Number Span
  • Executive function
    • BADS- key search & Verbal fluency
  • Social Cognition
    • Intention Inference Test (Sarfarti et al. 1997)

(IQ NART-R and WASI also assessed)

does performance in vr relate to the same in rl
Does performance in VR relate to the same in RL?

*Significance remained (except trend for RL/VR accuracy) when IQ controlled

**No correlations with symptom measures

slide84

Do RL and VR shopping share the same cognitive underpinnings?

Verbal Fluency

R=0.29 p=0.058

Accuracy

Strategy

R=0.35 p=0.02

Verbal Fluency

Time

Working Memory

R=-0.27 p=0.08

R=0.29 p=0.06

Verbal Fluency

Spatial Memory

R=-0.26 p=0.09

Efficiency

Verbal Fluency

Social Cognition

R=-0.32 p=0.05

slide85

Do Cognitive underpinnings of RL and VR differ in Negative symptom group

Verbal Fluency

R=0.57 p=0.013

Accuracy

R=0.47 p=0.04*

Strategy

Verbal Fluency

Time

Working Memory

R=-0.52 p=0.02

Verbal Fluency

Spatial Memory

Efficiency

Verbal Fluency

Social Cognition

R=0.47 p=0.05*

slide86

Do Cognitive underpinnings of RL and VR differ in Negative symptom group

Verbal Fluency

R=0.57 p=0.013

Accuracy

R=0.47 p=0.04*

Strategy

Verbal Fluency

Time

Working Memory

R=-0.52 p=0.02

Verbal Fluency

Spatial Memory

Efficiency

Verbal Fluency

Social Cognition

R=0.47 p=0.05*

conclusions
Conclusions
  • Does performance in VR relate to the same in RL?

Yes

2. Do they share common or distinct cognitive processes?

Some shared (WM and strategy) but some distinct underlying cognitive processes

3. Do these processes differ in different symptom groups?

Some different and some similar cognitive underpinnings, greater overlap of VR and RL and stronger correlations in Negative symptom sub-group

Particular role for Social Cognition in RL where the social environment is more important (and in VR with negative symptoms where avatars treated as real) and for spatial memory in VR

conclusions and limitations
Conclusions and Limitations

VR may be seen as an intermediate assessment between cognition and RL but care should be taken in considering the nature of the VR environment, the underlying cognitive processes, and the clinical presentation of the client group

  • Risk of type 1 errors with current comparatively small sample
  • Participants had a wide range of cognitive performance with mean cognitive function largely in the average range and with mild-moderate negative symptoms.
  • A greater contribution of cognition to community function may occur when cognition is impaired and symptoms greater

(Greenwood, Landau & Wykes 2005)

  • Future study will consider the validity of VR assessments of community function within a cognitively impaired sample for whom interventions are developed
executive function
Executive function

A variety of fractionated cognitive processes concerned with the control, organisation and sequencing of higher cognition.

27-46% of people with schizophrenia have selective ‘executive’ profiles and 54-90% have at least one executive impairment (Johnson-Selfridge and Zalewski, 2001; Kremen et al. 2004; Chan et al. 2006a & b). Executive dysfunction is associated with poor social outcome (Kopelowicz et al. 2005, Laes and Sponheim 2006) . In studies of single symptoms, both syndromes have been associated with impaired verbal initiation and working memory and disorganisation also with attention, inhibition, discourse planning and monitoring (Liddle and Morris 1991; Hoffman et al. 1986; Pantelis et al 2001). First episode schizophrenia shows executive dysfunction at this early stage, with some degree of clinical heterogeneity (Joyce et al. 2005; 2007; Chan et al 2006b), but less impairment than is found in chronic schizophrenia (Saykin et al. 1994; Chan et al 2006b). Profiles have varied between studies, with parallel flat profiles of diffuse general impairment, parallel non-flat profiles with selective impairments, and selective impairments specific to chronic schizophrenia (Saykin et al. 1994, Blanchard and Neale 1994; Albus et al. 1996; Chan et al. 2006 a & b). These variations might result from studies that collapse test scores across broad domains.

frith
Frith

Disorganisation symptoms arise from impaired inhibition of habitual responses when plans must be constructed and implemented using working memory, whilst psychomotor poverty results from deficits in the initiation of activities due to impaired initiation of plans.

slide91

Conclusions

  • Theoretical understanding of function can provide target cognitive processes for remediation
  • Individual approach is important because of complex relationship between symptoms, cognition and function
  • Remediation should link to day-to-day function ti improve outcome