NeurocognitiveDeficits in

SchizophreniaColin Hawco, PhD

Oct 5 2015York University

Magnitude of Cognitive Deficits in Schizophrenia

Meta-Analysis: 204 studies, 7420 patients and

5865 controls

Heinrichs & Zakzanis. Neuropsychology. 1998 Jul;12(3):426-45.

SD below mean of controls

Trajectory of Cognitive Deficits

Lewandowski et al. Psychol Med. 2011 Feb;41(2):225-41.

Cognitive Deficits Predict Functional Outcomes

Functional Outcomes

Learning & Memory

Attention

Executive Function

Green. Am J Psychiatry. 1996; 153:321-330Velligan et al. Schizophr Res. 1997 May 3;25(1):21-31.

Cognitive Deficits and Short-Term Clinical Outcome

Controls (n = 31)

Good Outcome (n = 73)

Poor Outcome (n = 78)

Clinical outcome assessed at 6 monthsGood outcome: > 2 on all global SAPS and > 3 on all global SANS (except attention)

Bodnar et al. The British Journal of Psychiatry 2008 193: 297-304

Domain specific vs. generalized deficits?

MATRICS Consensus Battery • based on domain specific hypothesis

• Speed of Processing• Attention/Vigilance• Working Memory• Verbal Learning and Memory• Visual Learning and Memory• Reasoning and Problem Solving

If generalized deficit, why engage in long neuropsych testing?

• Probably a combination• Generalized deficits, with some

domains affected more than others• Variability in specific domains across

individuals?

3 Clu

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2 Clu

ster

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4 Clu

ster

s

5 Clu

ster

s

6 Clu

ster

s C2p = 17c = 23

C6p = 5

C5p = 20

C4p = 10 c = 1

C1p = 67c = 37

C3n = 71

0.00

0.10

0.20

0.30

0.40

0.50

0.60

0.70

C2 (n = 14) C1 (n = 57) C3 (n = 57) C4 (n = 9) C5 (n = 20)

Perc

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ents

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sion

Pat

ient

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core

Above average cognition

Severe cognitive impairments

Hierarchical Clustering of Cognition in First Episode Psychosis

Why such a large deficit for Trails B?

Highly multi-factorial test

Scored by time, allowing “unlimited failure”

• Select, via consensus, specific tasks to evaluate different cognitive functions

• Emphasis on imaging• “Domain specific” in approach• Tasks intended to be highly specific to a particular

cognitive domain or function• Avoids “multifactorial” problem of traditional

neuropsychological tests

Verbal Memory and Encoding Strategies

Incidental encoding (supported ‘deep’ encoding) vs.

Intentional encoding (instruction to memorize)

Bonner-Jackson et al., Psychiatry Research: Neuroimaging 164 (2008) 1–15

Controls > patients

Patients > controls

Meta analysis of fMRI studies of Memory Encoding

Ragland et al. Am J Psychiatry 2009; 166:863–874

Memory deficits mainly related to prefrontal cortex

LTM effects (high subsequent memories)

Working and Long-term Memory Interactions

Greater DLPFC activity for rehearse over reorder related to less negative symptoms

Ragland et al., NeuroImage 59 (2012) 1719–1726

Green ControlRed Schizophrenia

Patients with Schizophrenia have a Deficit in Source Monitoring

Keefe et al., Schizophrenia Research 57 (2002) 51 – 67

- Tendency to attribute internally generated stimuli to an external source

- Particularly in patients who hallucinate

Wang et al. Schizophrenia Research 125 (2011) 136–142

fMRI of Source Memory in Schizophrenia

- Encoding session with two tasks- Source memory: identifying the task associated with a word- 13 Patients and 13 controls

Green: ControlsRed: Schizophrenia

Ragland et al. Schizophr Res. 2006 , 87(1-3):160-171.

Recognition:• Person• Place• Object

Source Memory in Schizophrenia: An fMRI VR Study

Lisa Buchy

X = -45

X = -30

X = -15

X = 0

X = 15

X = 30

X = 45

X = -45

X = -30

X = -15

X = 0

X = 15

X = 30

X = 45

Controls Schizophrenia Controls Schizophrenia

Person > objectPlace > objectPerson AND place > object

Object > personObject > placeObject > person AND place

Schizophrenia vs. Controls

A

X = -55

A

X = -55

0

2

4

6

controls schizophrenia

A: -50, 23, 30

person place objec

Control >Schizophrenia,Personvs. Object Control >Schizophrenia, Placevs. Object Schizophrenia>Control, Placevs. Object

X = -35

B

0

1

2

3

4

controls schizophrenia

B: -36 -70, 40

person place obje

X = 5

C

-1

0

1

2

3

controls schizophrenia

C: 2, -64, 36

person place objec

X = -15 D

0

0.5

1

1.5

controls schizophrenia

D: -8, 14, 34

person place objec

X = 25

E

-1

-0.5

0

0.5

controls schizophrenia

E: 30, 44, 26

person place objec

X = 55

F-1

-0.5

0

0.5

controls schizophrenia

F: 56, -2, -16

person place obje

Cognitive insight in Schizophrenia

Current Project: TMS-fMRI during working memory in Schizophrenia

2 sec 6 sec 2 sec

Single TMS pulse at 500ms into delayHigh TMS vs. Low TMS

500ms TMS to assess Maintenance vs. manipulation4000ms as a control: Manipulation should have completed and now maintaining

Jennifer Steeves

Reorder Reorder

+

TMS-fMRI gives us a measure of temporally specific connectivity

Treating Cognitive Deficits

• Behavioural Interventions: Cognitive remediation– Transfer effects? Efficacy? Duration?

• Pharmaceutical Interventions: Aripiprazole• Neural Modulation: rTMS, TDCS

– Efficacy? Duration of effects?• Combined approaches

– Brain stimulation combined with cognitive remediation

Neurological effects of Cognitive Remediation

Changes from CRTWorking memory (HCL > SCZ)WM and CRTAffective processing

CRT Changes activity in the left prefrontal cortex, thalamus, caudate, and right anterior insula and parietal cortex

Some regions showing changes overlap areas where SCZ shows reduced activity during working memory.

There is some suggestions that CRT normalized brain function as opposed to compensatory patterns.

Ramsay and McDonald. Schiz Bulletin. 20015,

Future of Brain Stimulation: Targeting?

Summary

• Cognitive deficits are present throughout the lifespan and functionally important.

• While generalized deficits may be present, some domain specificity exits (e.g. worse verbal memory)

• Multi-factorial nature of neuropsychological test may affect results and interpretations

• Cognitive neuroscience approach may better detect specific effects (but longer tests limit utility)

• Patients show deficits across a range of brain regions, often reduced activity.

• Particularly in HUB regions (e.g. DLPFC).• Reduced activity related to less supporting cognitive processing?

• Understanding and treating these deficits may lead improved outcome and quality of life for these patients.

Merci!

Martin Lepage

Jeff Daskalakis

Faranak Farzan George Foussias

Aristotle Voineskos Jennifer

Steeves

Yoon et al., Am J Psychiatry 2008; 165:1006–1014

Functional Connectivity and Cognition

AX-BX continuous performance task

Control > SCZBX-AX

Controls showed increased connectivity between DLPFC and these regions while patients did not.