Functional Brain Mapping of Plasticity in Nerorehabilitation...Motor Learning &...

KOREAN BRAIN MAPPING & PLASTICITY RESEARCH GROUPKOREAN BRAIN MAPPING & PLASTICITY RESEARCH GROUP

Functional Brain Mapping of Plasticity in Nerorehabilitation

Yun-Hee Kim, MD, PhDDepartment of Physical Medicine and Rehabilitation,

Brain-Neurorehabilitation Research Lab.College of Medicine Pochon CHA University


Understanding the mechanism of plasticity after brain injuryTherapeutic interventions promoting adaptive/successful plasticity

Specific training methodsPhysical methods (electrical/magnetic) Medications

Issues in Neurorehabilitation


Motor Learning & Plasticity-Functional Remodeling of the Hand Representation in M1

after Stroke in Monkey-Nudo RJ, 1997, 2001


Changes in Neuronal Morphology after Motor Skill Learning

Increased dendriticbrenchingIncreased Increased dendriticdendriticbrenchingbrenching

Increased dendriticspine densityIncreased Increased dendriticdendriticspine densityspine density

Increased perforated synapsesIncreased Increased perforated synapsesperforated synapses

Increased multiple synaptic boutonIncreased multiple Increased multiple synaptic synaptic boutonbouton


Functional MRI Evidence for Adult Motor Cortex Plasticity during Motor Skill Learning

Karni et. al., Nature 1995

19 pixels 31 pixels

Control subject Trained subject

Plasticity and Reorganization of Motor Network


•Mechanism of motor recovery

•Effect of specific training on reorganization of motor system (training-induced reorganization)


1) Perilesional reorganization

2) Ipsilateral motor pathway

3) Supplementary motor or other brain areas

Possible Motor Recovery Mechanisms after Brain Injury

Cramer SC et. al., Stroke 1997

1

3

2


Mapping Plasticity after StrokeCramer et. al, Neurophamacology 2000


Combined fMRI & TMS Study in the Patients with Recovered Paralytic Upper Limb

Eight patients with hemiparesis (7 stroke, 1 traumatic), 7 male & 1 femaleMean age: 49.4 years (8-70)Mean modified Edinburgh score: +100Mean post-onset duration: 18.6 months (4-35) Brain mapping with both fMRI & TMSMotor activation task: active grasping vs. rest


Bilateral Cortical Activation in fMRI (5/8: 62.5%)

Case 1R L

Case 2R L

Ipsilateral motor pathway confirmed by TMS

Lt

Rt

Stimulation: Rt motor cortex

MMT/FMA=51.5/56.5MMT/FMA=51.5/56.5

Case 6R L

Case 4R L

Case 5R L

Lt

Rt


Only contralateral motor pathway confirmed by TMS

MMT/FMA=62.4/56.7MMT/FMA=62.4/56.7


Unilateral Cortical Activation in fMRI (3/8: 37.5%)

Ipsilateral activationIpsilateral activationIpsilateral motor pathway

confirmed by TMS

Lt

Rt


Case 3R L

MMT/FMA=59.6/61

Contralateral activationContralateral activationContralateral motor pathway

confirmed by TMS

Lt

Rt

Stimulation: Lt motor cortex

Case 7R L

Case 8R L

MMT/FMA=62.5/64


Summary of fMRI & TMS Study

Ipsilateral pathway confirmed: 3/8 (37.5%)Congruency ratio: 5/8 (62.5%)Reasons of discripancy between modalities

Associated (mirror) movement during fMRI (1 case)Increased TMS threshold of ipsilateral pathwayContribution of ipsilateral cortex may be

Not directly from the corticospinal pathwayBut through the polysynaptic pathways such as corticoreticulospinal or transcallosal tracts


32 32 Patients with Cerebral Infarct Patients with Cerebral Infarct Mean age 54 y-o (29-70), M/F : 29/3

Inclusion CriteriaInclusion CriteriaLess than PLess than P-- grade of finger extensor at onsetgrade of finger extensor at onsetRevoveryRevovery period : more than 1 monthperiod : more than 1 monthBrain MRI : focal lesion on the Brain MRI : focal lesion on the corticospinalcorticospinal tracttractfMRI : at maximum recovery ( minimum 6 months elapsed)fMRI : at maximum recovery ( minimum 6 months elapsed)

Reorganization of Motor System According to the Lesion Location

Classification of lesionClassification of lesion1. Cerebral Cortex (4)1. Cerebral Cortex (4)

2. Corona 2. Corona RadiataRadiata (17)(17)

3. Posterior Limb of Internal Capsule (6)3. Posterior Limb of Internal Capsule (6)

4. Brainstem (5)4. Brainstem (5)

123

4

Jang SH, Youngnam Univ., 2002


Region of Interest (ROI)Primary Sensori-Motor Cortex (1)Premotor Cortex (2)Supplementary Motor Area (3)

Results of Normal Subjects

12

3

17 normal subjects / 34 hands32 hands : contralateral SM1 (A) 2 hand : bilateral SM1 (B)4 hand : bilateral SMA (C)

A B C


Cerebral Cortical Lesion

4 patientsRecovery Mechanism

perilesionalperilesionalreorganization (100%)reorganization (100%)

Hand function•• Grade 4 (2/4, 50%)Grade 4 (2/4, 50%)• Grade 3 (1/4, 25%)• Grade 2 (1/4, 25%)


Corona Radiata Lesion17 patientsRecovery Mechanism

Bilateral motor cortex Bilateral motor cortex activation (11/17, 65%)activation (11/17, 65%)Contralateral motor cortex activation (6/17, 35%)

Hand function• Grade 4 (2/17, 12%)• Grade 3 (1/17, 6%)• Grade 2 (4/17, 24%)• Grade 1 (10/17, 58%)

2

8


Posterior Limb Lesion


Bilateral motor cortex activation Bilateral motor cortex activation (100%)(100%)

Hand function• Grade 3 (1/6, 17%)• Grade 2 (1/6, 17%)•• Grade 1 (4/6, 66%)Grade 1 (4/6, 66%)


Brainstem Lesion


Contralateral motor cortex Contralateral motor cortex activation (3/5, 60%)activation (3/5, 60%)Bilateral motor cortex activation (2/5, 40%)

Hand function•• Grade 4 (3/5, 60%)Grade 4 (3/5, 60%)• Grade 3 (2/5, 40%)


Summary: Reorganization of Motor Network According to the Lesion Location

Perilesional reorganization to the S1 or PMC is the major mechanism of motor recovery in cortical lesion

Use of ipsilateral motor pathway is the significant mechanism of motor recovery in the subcortical brain lesion but it is less efficient


Training-Induced Reorganization

Constraint-induced therapy (CIT)Intensive movement trainingTask-oriented trainingCross educationNeurodevelopmental therapyMenral imagery therapy


CI therapy consists ofCI therapy consists of- Constraint of nonaffected limb- Intensive practice of affected limb 7-8 hours a day for 2-3 consecutive weeks: "massed practice“, “forced use”

Motor evaluationMotor evaluation- MMT, Fugl-Meyer Assessment (FMA) scale, 9 hole peg test - Jebsen hand function test, Hand grasp strength, Sensory test

Constrain methodConstrain method- Custom-designed suit- 8 hrs per day (10 minutes break per each hour)

TrainingTraining- More affected upper extremity- Gross motor activities: ball activities, hockey, etc..- Fine motor activities: writing, peg game, etc.. - ADL training

- Less affected upper extremity during each break time- Strengthening & ROM exercise to avoid disuse

Constraint-Induced Therapy (CIT)


Constraint Garment & Training


50

52

54

56

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60

62

64

66

Before After 2mon. F/U

Case 1

Case 2

Case 3

Case 4

Case 5

50

52

54

56

58

60

62

64

66

Before After 2mon. F/U

Case 1

Case 2

Case 3

Case 4

Case 5

Change of Change of FuglFugl--Mayer Scores Mayer Scores


fMRI Changes before and after CIT

Case 1

Case 2

Case 3

Before After

Case 4

Case 5

Newly Newly appeared appeared activation of activation of contralateral contralateral motor/ motor/ premotor premotor cortices cortices after CITafter CIT

Increased activation of Increased activation of ipsilateral motor cortex ipsilateral motor cortex

or SMAor SMA

Before After


Effect of Intensive Training on Reorganization of Motor Cortex

Clinical Test& fMRI (3T)

Intensive Training5~6 hours/day for 2wksIntensive TrainingIntensive Training5~6 hours/day for 2wks5~6 hours/day for 2wks

Clinical Test& fMRI (3T)with constraint or

without constraintwith constraint orwithout constraint

Gross Motor ActivitiesFine Motor Activities

Occupational Therapy

Gross Motor ActivitiesFine Motor Activities

Occupational Therapy



6

16

26

36

46

56

66

Pre Post

Patient 1

Patient 2

Patient 3

Patient 4

Patient 5

Patient 6

Patient 7

Patient 8

Change of Change of FuglFugl--Meyer Scores Meyer Scores


PrePre--TrainingTraining PostPost--TrainingTraining

Patient 1

Patient 2

Increased Activation of Contralateral Motor Cortex (7/8 Cases)

Patient 3

Patient 4



63 202 26 57

118 166 72182


Patient 6

Patient 8

Patient 7



Increased Activation of Contralateral Motor Cortex (7/8 Cases)

118 185

0 9

13 100


Task-oriented Training

• 6 tasks • 40 minutes/day• 4 days/week • For 4 weeks • Practice the same

tasks at home• fMRI and HFT before

and after training


Demographic and Clinical Data of Patients

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8

22

12

15

Post

-0.5

0.9

-0.7

-1.0

-1.0

Pre

Lat. Index(affected)

0.6

1.0

1.0

0.6

-0.4

Post

0.9

1

0.7

1

1

Pre

Lat. Index(unaffec.)

Grip Strength

PurduePegboard

1102012Average

14306Rt. Cortical infarct

M/664

1203027Lt. ICHM/333

181010Lt. ICHM/492

18106Rt. Cortical infarct

M/541

PostPrePostPre

1stfMRI

(month)LesionSex/AgePt.

Changes of Cortical Activation after Task-oriented Training in Chronic Stroke Patients

•Contralateral SMC was newly activated in 2 patients (patients 1, and 2)

•Ipsilateral SMC activity disappeared in 2 patients (patients 3, and 4)

•Ipsilateral PMC (patient 1) and SMA (patient 3) disappeared

•Contralateral PMC was newly activated in patient 2


Summary: Training-induced Reorganization of Motor Network

Intensive and purposeful motor training induce the reorganization of motor system by

Recruitment of contralateral cortical neural activities as a main mechanismInhibition of ipsilateral pathway



Partial injury Partial injury of CST with of CST with good motor good motor recoveryrecovery

Multimodality Mapping of Motor System: DTI, fMRI, and TMS

Affected

Unaffected 22.5/4.0

23.5/0.3

24.0/0.6

23.9/2.2

Affected

Unaffected

20.3/5.1

21.1/5.0Affected

Unaffected

Sparing of Sparing of CSTCST

Disruption of Disruption of CST: CST:

Bilateral Bilateral cortical cortical

activation in activation in fMRI and fMRI and dispersed dispersed

MEPMEP

Plasticity and Reorganization of Attentional Network



The Large Scale Neural Network for Spatial Attention

Attentional network in normal person: frontal, parietal, cingulate gyriKim Y-H, et. al. Neuroimage, 1999


0

10

20

30

40

50

60

70

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90

100

Accuracy Response time

* P < .001

*

*

normal patient

(%)

1000

900

800

700

600

500

400

300

200

100

0

(msec)

94.3

51.9

300

512

Behavioral ResultsBehavioral Results of Normal and of Normal and Patient GroupPatient Group


Cortical Activation in Normal Volunteers (n=11)

Random effect analysis, p


Cortical Activation in TBI Patients (n=11)

Random effect analysis, p


Difference in Medial Frontal and Cingulate Acvtivation

Normal Group Normal Group TBI PatientsTBI Patients


Changes in Cortical Activation after Cognitive Rehabilitation Training

PrePre--trainingtraining PostPost--trainingtraining

0

10

20

30

40

50

60

70

80

(%)

800

700

600

500

400

300

200

100

0

(msec)

Accuracy Response time * P < .05

pre post

**505

427

68.556.8

Plastic Changes in AttentionalNetwork after TBI

Impaired cognitive performance was associated with the reorganization of neural network

The most prominent finding: disappearance of cingulateactivation in TBI patients

Additional activation of right inferior frontal gyrus: presumably due to the compensatory hyperactivation for better cognitive performance

Activation of cortical and cingulate network was modulated by short-term cognitive intervention



Two strategies to recover from post-stroke aphasia

Structural repair of primarily speech-relevant regions (damaged language network)Activation of compensatory areasSMA: most prominent compensatory activation in the subacute stageRestitution of the left STC determine the long-term prognosisRight hemisphere compensation was less effective than the repair of original speech network

Karbe et. Al. Brain and Language, 1998

Brain Plasticity in Poststroke Aphasia


•Contralateral frontal with small perilesional activation

Mainly Contralateral Frontal Activation in Cortical Injury

•Contralateral frontal activation only

Final language Score: 61.4%


Bilateral frontal Activation in Subcortical Injury

Final language Score: 71.8%


Factors Influencing on Reorganization and Language Recovery

Severity of language area damageLesion locationTiming and type of rehabilitationMedications

DopaminergicCholinergic


Functional Imaging of Plasticity

Powerful tool for in vivo studyPossible compounds

Performance difference of pre- and post-training status can affect on activationTime of imaging

Initial anxietyHead motionTime-task interaction


ConclusionsHuman brain has capacity of reorganization after injuryWell designed purposeful rehabilitation accelerates efficient reorganization in patients with brain injuryGoal of neurorehabilitation

Maximizing neural plasticity and functional recovery after brain injuryDevelopment of specific therapeutic interventions and combination of therapies to achieve additive or synergistic responses


AcknowledgementKorean Brain Science and Engineering Research Korean Brain Science and Engineering Research ProgramProgramKorean Scientific and Engineering FoundationKorean Scientific and Engineering FoundationKorean Research FoundationKorean Research FoundationMembers of Korean Brain Mapping & Plasticity Members of Korean Brain Mapping & Plasticity Research Group in Research Group in PochonPochon CHA Univ., CHA Univ., ChonbukChonbukNational Univ., and National Univ., and YoungnamYoungnam UniversityUniversity

SungSung--Ho Jang, MD, PhD, Assistant professorHo Jang, MD, PhD, Assistant professorMyoungMyoung--Hwan Hwan KoKo, MD, PhD, Clinical professor, MD, PhD, Clinical professorSeSe--HoonHoon Park, MDPark, MDSeungSeung--Hun Shin, MDHun Shin, MDJiJi--Won Park, RPT, MSWon Park, RPT, MSHwanHwan--TaekTaek ByunByun, MD, MDYongYong--Hyun Kwon, RPTHyun Kwon, RPTEunEun--HaeHae Jang, MSJang, MSYongYong--Hyun Kwon, RPT, BSHyun Kwon, RPT, BS

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