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Translational Neuroscience Networks in Cerebral Palsy:

From Cell to Person

Darcy Fehlings MD MSc FRCP(C)Head, Division of Developmental Paediatrics

Professor of Paediatrics, U of TBloorview Children’s Hospital Foundation Chair in Developmental Paediatrics

Flow of the Talk

A) CP-NET – Translational Neuroscience Network

B) Clinical Findings of Hemiplegic CP from CP-NET

C) Science of Constraint Therapy for Hemiplegic CP – from Child to Mouse

D) Genomics of Hemiplegic CP from CP-NET

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Bridging the gap

Pre-clinical Clinical

Translational Neuroscience Networks

Stakeholders

Translational Neuroscience NetworksAdvantages and Challenges

• Enhanced opportunity to accelerate applied neuroscience innovation

• Basic scientists have enhanced understanding of clinical pathophysiology and potential applications for translation

• Clinician scientists/clinicians/stakeholders have enhanced understanding of mechanisms/cellular function

• Speak a different language• Shift away from unilateral setting of research goals to collaborative research goals

• Teamwork• Managing expectations

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CP-NET Organizations•Holland Bloorview Kids Rehabilitation Hospital (lead)

•The Hospital for Sick Children•The University of Toronto

•Toronto Western Hospital, University Health Network•Robarts Research Institute, University of Western Ontario•McMaster Children’s Hospital, Hamilton Health Sciences

•McMaster University•Child Development Centre, Hotel Dieu Hospital

•Queen’s University•Children’s Treatment Centre, Health Sciences North

•Laurentian University•Grandview Children’s Centre

•ErinoakKids Centre for Treatment and Development•Ottawa Children’s Treatment Centre, Children’s Hospital of

Eastern Ontario•Thames Valley Children’s Centre, Lawson Health Research

Institute•Rotman Research Institute, Baycrest

•Brock University•Children’s Treatment Network of Simcoe York

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CP-NET: drive neuroscience discovery to impact care in CP

• How does the developing brain repair injuries?

• What factors have the greatest impact on improving the lifestyle and quality of life of individuals with CP?

• What are the optimal treatments for CP?

Guiding Perspectives: Stakeholder Priorities

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Clinical Database Platforms

Clinical Risk Factors

Neuro-imaging

Genomics Neuro-developmental

Psychosocial & Participation

Medical Chart Review & Parent

Interview

Classification of Clinically-

Acquired Images (MRIs)

Population-based DNA Database

Functioning, co-morbidities, pain, and

standardized neurologic examination

Psychosocial markers, child & family health related quality of life,

self-esteem, behaviour, sleep and participation

Hemi-NET Clinical DatabaseOverview

• Participants were recruited according to the following eligibility criteria:

1) Aged 2-18 years 11 months

2) Confirmed diagnosis of hemiplegic cerebral palsy

3) Residing in Ontario, Canada at the time of

registration

• Overall recruitment = 320 children

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Rodent Models of CP

Neuroimaging Patterns 

Childhood Hemiplegic Cerebral Palsy Integrated Neuroscience Discovery Network (Hemi‐CP‐NET)

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Hand Preference and Symmetry are Important! Stakeholder Message!

• Hand preference starts to develop at 24 months!RED FLAG: strong hand preference prior to 18 months!!

• Motor movements of children under 18 months are very symmetrical

RED FLAG: asymmetry of motor movements or motor skills (compare grasp of each hand as well as hand usage)

6 monthsPediatric NeuroLogic Exam Website: http://library.med.utah.edu/pedineurologicexam

• Website for teaching videos for typical early childhood development

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Define “Constraint Induced Movement Therapy Intervention (CIMT)”

• Constraining the unaffected limb with a cast or removable restraint

AND• Providing repetitive, intensive practice to the affected limb

• Modified – Enhance bilateral activities

• Goal = improve amount of spontaneous “hemiplegic” limb use and motor control

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•What are the potential underlying neural mechanisms of constraint in hemiplegic CP?

Sutcliffe T, Gaetz W, Logan W, Cheyne D, Fehlings D: “Cortical reorganization after modified constraint-induced movement therapy in pediatric hemiplegic cerebral palsy”, Journal of Child Neurology 2007 Nov;

Vol 22, No. 11, 1281-87

Magnetoencephalography: MEG Example

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Hemiplegia: MCA Infarct

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ꜜMEPs in infarcted hemisphere linked to

ꜛ Ipsilateral axon size and ꜜ hand function

? Maladaptive Plasticity

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Baseline 1

Postconstraint 1

Baseline 2

MEG

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Constraint Research StudyFehlings/Manon/Manning/Switzer/Mesterman/Gorter/Campbell

M1 M1 M1 M1

Interhemispheric inhibitionbefore CIMT

Interhemispheric inhibitionafter CIMT

P P

Misbalance ? Rebalance

ConstrainedIntensivetraining

P=Paretic hand

Resting State Networks

• The sensorimotor resting state network (RSN):

• Shows areas of connectivity, ie. the fMRI signal is correlated in these areas of healthy subjects

5Figure from supporting info Smith et al. PNAS, 2009

Supplementary motor area (SMA)

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Improved RSNs after CIMT?

bilateral network, closer to healthy subjects

Pre

PostCIMT

Constraint Research Study

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How does Constraint work?

• Central Mechanisms of action for constraint can include:1. Enhanced activity in the contralateral primary

somatosensory cortex (S1)2. Enhanced activity in the primary motor cortex (M1)3. Rebalancing of hemispheric activation and resting state

from Ipsi>contra to Ipsi=contra

• Is there enhanced neurogenesis post CIMT?

Potentially relevant CNVs to hemi-CP

(18/97 = 18.6%)

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Genomics ‘Comments’

• Elevated de novo and inherited CNVs similar to other CP studies

• CNVs impacting brain expressed genes (e.g. neurexin/contactin, K+ and Na channels)

• Higher rates of CNVs in CP compared to other neurodevelopmental disorders (e.g. autism) where microarray testing has become part of the standard work-up

•? Role of genomic testing in CP?

Summary

• Vision for CP Research driven through Translational Neuroscience Networks

• Clinical Features of Hemiplegia: imaging reveals a high number of children with periventricular injuries

• Discussed potential “neural” mechanisms of action of constraint therapy in children with cerebral palsy (CP-NET)

• Genomics of hemiplegic CP (CP-NET)