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Why, how and when does the brain y recover after stroke?

Disclosures

• Research Support

–NINDS

– Harris Stroke Fund


Objectives

•To review the essentials of clinical recovery after

ischemic stroke

•To review relevant elements of preclinical

evidence supporting specific mechanisms of

stroke recovery

•To review the evidence from structural and

functional imaging i in regard to changes related ltd

to stroke recovery


Main principles of clinical recovery

• Most spontaneous recovery tends to occur within

the first 3 months after stroke onset

• Cognitive deficits are more likely than motor deficits

to show spontaneous gains beyond 3 months

• Patients with milder deficits achieve e recovery

er

quicker than those with more severe deficits

• Different patterns of recovery can exist it across

different neurological domains within the same

patient.


Factors influencing stroke recovery

• Stroke topography

• Time after stroke

• Age

• Hemispheric

dominance and

side affected

• Depression

• Injury to other

network nodes

• Infarct volume

• Initial stroke

deficits

• Arterial patency

• Co‐morbidities

i

• Pre‐stroke

disability

• Pre‐morbid

education &

experience

• Status of

unaffected brain

• Type & amount of

post‐stroke

therapy

• Acute

interventions

• Medications

during recovery

period

• Medications at

time of imaging

• Stroke

mechanism

• Genes

• ????

• …………


i. Brain function and behavior can be globally deranged.

Few restorative structural changes have started.

ii.

A period of growth then begins, lasting several weeks.

iii. Pruning, reduction in functional over‐activation, and

establishment of a static pattern of brain activity and

behavior.


Two distinct phases of recovery

1. Early: First several weeks

a. Cellular response

b. Production of new vascular and axonal

elements

2. Late: After 6 months

a. Reduction of functional overactivation

b. Static pattern of activity


Neuroprotection vs. Neurorestoration

Neuroprotection

Neurorestoration

Neurorestoration


Neuro‐Restoration


What are the factors leading to recovery?

•The lesion itself

– Recovery of penumbra

• The perilesional areas

– Angiogenesis, axonogenesis, synaptogenesis

• Resolution of diaschisis

•The unaffected brain ‐ Neural plasticity

– Healthy brain

• Endogenous ability to repair ‐ ?Genes

•External factors

– Behavioral compensation strategies.


The lesion


Diffusion Tensor Tractography y( (DTT)

•3D pathways of WM

tracts reconstructed by

sequentially piecing

together discrete and

shortly spaced

estimates of fiber

orientation

•The dissected fiber

tracts are virtual

• Corticospinal tract is

the most successfully

studied


Ischemic stroke affecting the

corticospinal tract

8 patients t with sudden onset hemiparesis

i

Acute/early subacute IS involving IC/corona radiata.

Lacunar infarcts

Identified on T2WI & DWI

Target points: corticospinal i tract t within the PLIC

and in the pre‐central gyrus

3D corticospinal tract was superimposed on 2D DWI

The authors were able to trace the corticospinal

tract in all patients

Kunimatsu et al, Neuroradiology 2003


CORTICOSPINAL TRACT NOT INVOLVED

In 5 patients, tracking suggested that the tract was in

close proximity but not affected directly by the infarct.

These patients had an excellent recovery within weeks

These patients had an excellent recovery within weeks

from the onset of symptoms.


CORTICOSPINAL TRACT INVOLVED

•In 3 patients, the whole or part of the tract was

shown to pass through the infarct

• Their motor stroke did not improve and in almost

• Their motor stroke did not improve and in almost

all of them, weakness lasted longer


Structural integrity of corticospinal motor

fibers predicts motor impairment in chronic stroke

• Correlations between motor impairment and DTI‐derived

measures of motor tract integrity.

•35 chronic stroke patients

• Pyramidal tract t (PT) and alternate t motor fibers (aMF).

• Fiber number and regional FA value asymmetry

significantly differed between the groups with lower values

in the patients’ lesional hemispheres.

•Both measures significantly predicted motor impairment

• DTI–derived measures are valid structural markers of motor

impairment. The integrity of all descending motor tracts

appears to account for stroke recovery

Lindenberg et al, Neurology 2010


Lindenberg et al, Neurology 2010


Lindenberg et al, Neurology 2010


The Peri‐lesional Region


Preclinical studies

•Certain treatments improve recovery if applied after

the acute phase of stroke

•Treatments

•Sildenafil, Niaspan, Statins, TB4

•EPO

•Cell‐based therapies

•Observed changes in brain:

– Angiogenesis and vascular remodeling

–Axonal remodeling

– Neurogenesis & Synaptogenesis


White matter remodeling & DTI

•Within cerebral white matter, water molecules

diffuse more freely along myelinated tracts than

across them

• Fractional anisotropy (FA) directly correlates with

histologic i markers of myelination

i

• White matter reorganization, histologically

confirmed by increase in axons and myelination,

after neurorestorative treatments, coincides with

increases of FA in the ischemic recovery regions

•(Jiang et al, 2006)


MRI detects white matter reorganization after

cell therapy of stroke

•Rat embolic stroke

•Neural progenitor cell

treatment vs. no treatment

• MRI vs. histology

•White matter reorganization:

– Increases in FA

• Fiber tracking maps showed

similar pattern to histology

WM orientation patterns

•FA and FT can characterize

WM remodeling after stroke

Jiang et al, Neuroimage, 2006


FA Changes After Cell Therapy of Stroke

T2

FA

Bielshowsky

Luxol fast blue

staining

Jiang, Neuroimage, 2006


Angiogenesis gog & Vascular Remodeling

• Newly formed cerebral vessels are inherently leaky as

it can take several weeks to form a functional blood

brain barrier

– Carmeliet, 2000

• Monitoring changes in CBV over time may reflect

growth of new blood vessels

– Brasch, 2000

•Significant correlation between CBV from DCE MRI

g

with histological determination of MVD in angiogenic

hotspots


Susceptibility‐Weighted MRI (SWI)

• Excellent sensitivity in detecting brain hemorrhage,

even of extremely small size

• High‐resolution SWI (+ phase information) has

exhibited excellent sensitivity in imaging small veins ‐

small vein venography and MVD

•The advantages of small vein venography using SWI

are:

– Intrinsic contrast mechanism

– Sensitivity in detecting slow flowing blood in small vessels

–Direct visibility.


SWI Detection of Angiogenesis after Stroke


SWI

Very good recovery

Poor recovery

NIHSS 20 – mRS 2 NIHSS 12 – mRS 4


Angiogenesis & CBV

• Complex and dynamic processes

• Monitoring changes in cerebral blood volume (CBV) over

time reflects growth of new blood vessels

•Brasch, 1997 & 2000&2000; Gossmann, 2002

• Significant correlation between CBV (CE MRI) and

histology (microvascular density) in angiogenic hotspots

• Histologically confirmed angiogenesis after

neurorestorative treatments, coincides with increases of

CBF and CBV

•Li et al, 2007


MRI Detection of Angiogenesis after NPC Treatment of Stroke


Angiogenesis and improved CBF after sildenafil treatment

Li et al, Brain Research 2007

• Rat embolic stroke

• Sildenafil vs. saline

• MRI at 1 d, 2 d, weekly x 6 w

• Correlations: CBF, histology,

functional

• Enhanced angiogenesis, no change

in lesion size, improved function


Li et al, Brain Research 2007


Courtesy of Z. Zhang, PhD & Q. Jiang, PhD


Translation to clinical studies

• Elevated FA & CBV values in ischemic recovery zone at 6

weeks after stroke would correlate with greater

neurological improvement from baseline‐3 months

• Included d adult patients t with ischemic i stroke, NIHSS ≥ 4

• Clinical scores and MRI scans at three time points

– Baseline, 6 weeks, >12 weeks

•3T GE MRI scanner

• Diffusion Tensor Imaging, g,55

diffusion attenuate directions

•Dynamic contrast enhanced cerebral perfusion, 100 sets of

EPI images


•18 patients, Mean NIHSS score: 10

• Ischemic lesion (6 wks) divided into core and recovery regions

• Recovery region = 3 month T2WI – baseline DWI

•FA& CBV values defined in:

–Infarct core and recovery regions, contralateral hemisphere

•Ratio of ischemic region/contralateral normal region


N Spearman p

FA ‐ recovery region of ischemic lesion at 6 weeks 17 0.486 0.048

FA ‐ core region of ischemic lesion at 6 weeks 17 0.194 0.456

FA ‐ lesion size at 6 weeks 18 0.015 0.954

N Spearman p

CBV 6 weeks – recovery zone 15 0.296 0.284

CBV 6 weeks – infarct core 15 0.537 0.039

•FA change pattern follows the preclinical study

paradigms

• Pattern of CBV change not similar to preclinical study

paradigms.

•Both need further investigation and analysis


MR Images aiming at defining vascular remodeling

A B C

D

E

F


MR images aiming at defining axonal remodeling

A B C

D

E

F


The Unaffected Brain


fMRI

• Blood oxygenation level‐dependent ld d contrast

t

(BOLD)

• Physiologic brain activation associated with change

in CBV or concentration of deoxy‐Hg leads to a

change in regional magnetic susceptibility.

•Subtraction techniques

• Importance in revealing reallocation of neurologic

function to other areas during stroke recovery

• Measures shifts in blood flow which correlate with

Measures shifts in blood flow which correlate with

neuronal activity


Insights from fMRI

In normal right‐handed h d persons, performance of a

unilateral motor task by the right hand is

associated with activation that is largely contra‐

lateral, with brain activity ipsi‐lateral to the active

hand being very small by comparison

(Kim et al, Science 1993)


fMRI in post‐stroke hemiparesis

•8 recovering hemiparetic

stroke patients

•8 normal controls

•Patient characteristics

– 46 years

– right handed

– thumb‐index opposition

– single unilateral hemispheric

ischemic infarct

• Finger opposition task

• Controls

– LIFL (IFG, MFG)

– LIPSTL (SMG, AG, STG)

Cao et al, Stroke 1999


fMRI in

post‐stroke

hemiparesis

• Extended activation

of ipsilateral SM

cortex

• Bilateral activation of

primary SM

• Extended areas of

ipsilateral premotor

and dorsolateral

l

prefrontal cortex

• Contralateral SMG

and premotor cortex


fMRI in

post‐stroke stroke aphasia

•7 recovering aphasic stroke

patients (>5 months after

stroke), 37 normal controls

• Patient characteristics

– 20‐56 years, right handed

– native English speakers

– single left hemispheric

ischemic infarct

• Picture naming paradigm

Verb generation paradigm

• Controls

– LIFL (IFG, MFG)

– LIPSTL (SMG, AG, STG)

Cao et al, Stroke 1999


• Language g activity increased in R & decreased in L hemisphere

• BL language networks from partial restitution of damaged L hemisphere and

compensated areas in R hemisphere.

• Failure to restore any language function in L hemisphere led to mainly R

hemispheric networks.

• Better language recovery with BL than R hemisphere‐predominant networks.


fMRI activation maps are superimposed on brain anatomy,

with significance of activation indicated on the color bar

Cramer SC,

Stroke 2004


Results in 3 patients during index finger tapping

demonstrate anatomical variability in hand motor site

Cramer et al.

Stroke 2005


• Group ‘recovery map’: all patients were assumed to have a R‐side lesion

• Results are surface rendered onto a canonical brain.

• All clusters are significant at P


• Voxels for in which there was a negative (linear) correlation between

recovery and task‐related BOLD signal within different stroke subtypes.

• The brain is shown (from left to right) from the left side, from above (left

hemisphere on the left) and from the right.

Ward et al, Brain 2003


Post‐stroke fMRI patterns

•Motor activity by the affected hand is associated with

greater degree of bilateral motor cortex activity

reduced laterality of brain activation

• Pti Patients t with rapid and good motor recovery have

activation patterns similar to healthy volunteers

• Patients with ih slow recovery exhibit secondary

reorganization of the motor system

•This cortical reorganization usually starts after the

first month post‐ictus


•Increased activity in the contra‐lesional hemisphere is

suggestive of greater injury and poorer recovery

• Negative correlation between outcome and extent

and degree of task‐related activation ation in secondary

motor system 3‐6 months after stroke, in patients

with poor motor recovery

•Progressive expansion of the area of excitable motor

cortex is associated with superior motor outcome

•Best outcomes are associated with greatest return of

brain function to the normal


Early fMRI (Marshall et al, Ann Neurol, 2009)

• 23 patients with first ever ischemic stroke and hemiparesis

•24‐48 hours from onset, follow‐up in 3 months

• Motor task fMRI, UE Fugl‐Meyer assessment

• Correlations between activation and FM score

– Ipsilesional postcentral gyrus and cingulate cortex

• BLUE: Activation pattern related to hand closure – nonparetic hand

• RED: Activation related to hand closure ‐ paretic hand

• GREEN: Activation pattern derived from hand closure task of the

paretic hand that correlated with subsequent motor recovery


Genes and recovery

• Correlation o between ee genetic et polymorphisms o p s and dstroke

recovery (GAIN Americas & GAIN International Studies)

• Genetic polymorphisms associated with impaired neural

repair or plasticity might reduce recovery from stroke

• Hypothesis: ApoE ε4 & val(66) met BDNF are each

associated with poorer outcome after stroke.

•255 stroke patients who received behavioral evaluations

• Primary outcome measure: recovery during first month

post‐stroke

Cramer et al, Eur J Neurol., 2012


ApoE ε4 was associated with significantly poorer recovery over the

first month post‐stroke (18.2% vs. 35.5%, 5% P=0.023) 023) and with lower

proportion of subjects with mRS 0‐1 (P=0.01) at 3 months


Conclusions

• Recovery after stroke occurs in two phases: the

early (first few weeks) and late (after 6 months)

• It is the result of a complex interplay between

lesional characteristics, perilesional structural

changes, degree of health of the unaffected brain,

and endogenous/genetically‐defined ability of the

brain for recovery

• DTI, DCE‐MRI and fMRI can be useful in defining

brain structural and plasticity changes and static

reorganization patterns leading to clinical recovery


Acknowledgments

• Research supported by:

• NIH/NINDS Grant R01‐070922

070922

• NIH/NINDS Grant PO1‐NS23393

• Harris Stroke Center Fund

• Michael Chopp’s Lab:

• Michael Chopp, PhD

• Quan Jiang, PhD

• Zheng Zhang, PhD

• Clinical stroke research group

• Panos Mitsias,MDMD

• Andrew Russman, DO

• A. Katramados, MD

• Shaneela Malik, MD

• S. Maraka, MD

• Patricia Penstone, RN

• Joyce Jones, RN

• Lian Li, PhD

• Research NMR Lab

• Lian Li, PhD

• Quan Jiang, PhD

• James Ewing, PhD

• Suresh Patel, MD

• Siamak Pourabdollah, MS

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