biological correlates of cognitive remediation in schizophrenia

BIOLOGICAL CORRELATES OF COGNITIVE REMEDIATION

IN SCHIZOPHRENIA

Barcelona Clinic Schizophrenia Unit Hospital Clinic of Barcelona

University of Barcelona

IDIBAPS CIBERSAM

Rafael Penadés, Ph.D.

Overview

• Neuroimaging of cognitive remediation

• Biomarkers of cognitive recovery: BDNF

• Conclusions

Neuroimaging in Schizophrenia

BrainMapping

HYPOFRONTALITY

Functional Mapping

NETWORKSDMN

ConnectomicsStructural Abnormalities

BRAIN MORPHOLOGY

PEG,CAT SPECT, PET MRI, fMRI, MEG

Regions of Interest

Whole Brain Analysis

CONNECTIVITY

Development of Image Analysis

TractographyGraph analysisRestingNeuroactivation

Multimodal studies

Penadés et al. (2017)

Neuroimaging Cognitive remediation

HYPOFRONTALITY NETWORKS

BRAIN MORPHOLOGY AND

VOLUME CONNECTIVITY

Wykes (1998)Wexler (2000)Penadés (2000)Penadés (2002)

Wykes (2002)Haut (2010)Rowland (2010)Edwards (2010)Bor (2011)Subramaniam (2012)Hooker (2012; 2013)

Penadés (2013) Subramaniam (2014)

Vianin (2014)

Eack (2010)

Penadés et al. (2017)

• CRT improves activation• Reduction of Hypofrontality• Individual differences

HYPOFRONTALITY

Wykes (1998)Wexler (2000)Penadés (2000)Penadés (2002)

Penadés (2000)

Wexler (2000)

Wykes et al (2002)N = 18

CRT (n = 6) Occupational Therapy (n = 6) Healthy Control (n = 6)

HYPOFRONTALITY

• Frontal activation improvement is related with improvement in working memory tasks• Specificity of the CRT

Wykes (2002)

HYPOFRONTALITY

Wykes (2002)Haut (2010)Rowland (2010)Bor (2011)Subramaniam (2012)Hooker (2012; 2013)Vianin (2014)Subramaniam (2014)

• Increased activity in: • Prefrontal cortex

• Lateral• Medial• Dorsolateral

• Parietal• Insula, caudate, thalamus

Bor (2011)

Haut (2010)

Meyer-Lindenberg et al. (2001)

PACIENTS >CONTROLS CONTROLS > PACIENTS

NETWORKS

NETWORKS

Reduction of the non-specific activation of CEN

Improvement of the deactivation of the DMN

Reduced activation is probably due to better efficiency of the networks

Penadés (2013)

BRAIN MORPHOLOGY AND

VOLUME

Penadés (2013) DTIIncrease of the white matter integrity in the genus of the corpus callosum

Eack (2010) VBMGreater preservation of grey matter volume over 2 years in the left hippocampus, parahippocampal gyrus, and fusiform gyrus

Greater grey matter increases in the left amygdala

Cortical Thickness and Memory Improvement after CRT

• LEFT:• Superior frontal• Caudal middle frontal• Precuneus• Paracentral Gyrus

• RIGHT:• Superior frontal• Caudal Middle frontal• Pars opercularis

• Greater baseline CTh in frontal and temporal lobes is related with more improvement in memory after CRT

Penadés et al. (2016)

Biomarkers for cognition

BDNF as a Biomarker of Treatment

Key modulator of synaptic transmission and plasticity

Brain-Derived Neurotrophic Factor (BDNF)Mediates hippocampal

long-term potentiation

Bai Lu et al. 2003

BDNF and cognition

Cognitive Remediation and BDNF

Vinogradov et al. (2009)

RCT (NCT 02341131)

• N = 70 patients with Schizophrenia • N = 15 healthy controls

• Primary Outcome: • Serum BDNF: Baseline, week-4, week-16

• Secondary Outcomes:• Cognitive function

• Experimental conditions:• CRT vs AC

Baseline cognition

Cognitive Outcomes

CRT and serum BDNF

Penadés et al (In preparation)

CRT and BDNF polymorphism Val66Met-rs6265

p = 0.006

Penadés et al (In preparation)

Conclusions• No significant effect of CRT on serum BDNF levels

• Cognitive and functional improvement after CRT were not correlated with changes in BDNF levels

• Genetic polymorphisms of BDNF gene could be playing a mediating role in CRT response

• Val/Val improved more than Met carriers although difference was not statistically significant

• The status of the BDNF as a biomarker of cognitive recovery is still premature

General Conclusions

• Cognitive remediation improves brain activation• Changes involve mainly prefrontal and thalamic regions • Improvement in the efficiency of Brain Networks have also been

described• Structural changes have been described both in grey and in white

matter• Findings are not linked to a particular remediation approach• No peripheral biomarkers for CRT have been stablished yet

Thanks for the kind attention!