10/13/2016
Argye E. Hillis
Argye Hillis has no financial conflicts of interest to
disclose.
This research was supported by NIH
National Institutes on Deafness and
Communication Disorders
At the conclusion of this activity, the participant
will be able to:
 Discuss potential neural/biological mechanisms
underlying the language recovery and
deterioration during the first year after stroke
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
Days, weeks, months
Changes in perfusion, activation, connectivity,
structure
Name variables that influence aphasia recovery
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Acute Recovery (first month after stroke)

Chronic recovery (starting 6 months later)
The Six-Item Screener (SIS) in 515 participants with incident stroke & 23 057
participants without incident stroke
“Incident stroke was associated
with an acute decline in cognitive
function and also accelerated and
persistent cognitive decline over 6
years.”
Participant-specific (conditional) predicted values of cognition were calculated for a 70-year-old black
woman with the average values of all covariates at baseline (high school education, stroke belt
residence, income <$20 000, never smoker, no alcohol use, systolic blood pressure 135 mm Hg,
diabetes present, waist circumference 95 cm, no self-reported stroke, CES Depression Scale score of 0.9
points, fair health status, and SIS score of 5 points).
Dhamoon MS, Moon YP, Paik MC, et al..
Stroke. 2009;40(8):2805-2811.
Neurology. 2010;75(4):328-334.
Stroke. 2012;43(8):2180-2184.
Most at risk for decline: no insurance
Medical Assistance
Iadecola C. Neuron. 2013;80(4):844-866
Stroke may potentiate amyloid
accumulation in subset of patients with
Preclinical AD
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“Improvement in aphasia scores after stroke is
well predicted by initial severity”
Lazar et al., Stroke, 2010
Achieved
Change
In WAB
Potential Change in WAB
100
90
80
70
pt 1
60
pt 2
50
pt 3
40
pt 4
30
pt 5
20
pt 6
10
0
Day 1-
Week 4
Month 6
Month 12
Patients with significant aphasia need intervention to improve!
A subset (maybe about 25% of patients) decline in language function after stroke


Hypothesis: Long-term language outcomes
in ischemic left hemisphere stroke are
influenced by atrophy in the contralateral
hemisphere.
Any decline be due preclinical AD, with
amyloid accumulation potentiated by stroke


Whitehead, Hachinski, Cechetto, 2005
Methods: BNT & MPRAGE at 6 & 12
months after stroke
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


In 6/8 patients, changes in BNT varied between
-3% to 3% between 6 and 12 months;
they showed a mean change of -1.03%
in right hemisphere (RH) volume.
One patient (who had a left frontal MCA
stroke) improved 33.3% on BNT and showed
the least volumetric changes in RH (0.03%)
One patient (with left thalamic lacune)
deteriorated by 19.3% on BNT & showed the
greatest volumetric reduction of RH (-3%).
100%
Establishing New Pathways and
Compensatory Mechanisms
% of
Aphasia
Recovery
Reorganization of Structure/
Function Relationships
Tissue Reperfusion
Hours
Days
Weeks
Years
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Changes in Blood Flow



Angioplasty/stenting
Embolectomy
Thrombolysis



IV, IA, IV/IA
Surgical revascularization
Induced blood pressure
elevation
Increasing systemic BP
increases blood flow
in ischemic tissue

Temporal relationship between mean arterial pressure (MAP) & language
MAP
⧫ = Oral naming accuracy; ▴ = word comprehension; ▪ = sentence comprehension.
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% correct
Before CEA
Word-picture
Verification
Task
After CEA
100
90
80
70
60
50
40
30
20
10
0
Day 1
Word-picture
Verification
Task
% correct
Pre-stent
Day 3
Post-stent
100
90
80
70
60
50
40
30
20
10
0
Day 1
Day 3
Day 1:
Day 3
100
90
80
70
60
50
40
30
20
10
0
% Correct
Naming
Day 1
Day 3
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Day 3
% Correct Naming
100
80
Day 1
60
% Correct
Naming
40
20
0
Day 1
Day 3
No language deficits on testing, but reported intermittent right-sided numbness
and word-finding problems. Aspirin & follow-up with NSU recommended
Mild aphasia: BNT: 90% correct
HANA: 88.6% correct
SOAP (sentence comprehension): 92.5% correct
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BNT deteriorated to 26.7% (from 90% correct) but not as severely
impaired as one might expect from this lesion, due to 3 years of
slowly progressive hypoperfusion in LMCA territory
1 month after symptom onset
After EMS: 6 months post stroke
% Correct on Language Tests
Task
Before EMS After EMS
Picture Naming
0%
76%
Tactile Naming
47%
100%
Written Word
0%
71%
Comprehension
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

Changes in blood flow can influence language
performance not only in the first few days after
stroke, but even weeks, months, or in rare cases
years after stroke
Chronic hypoperfusion can induce structurefunction reorganization
Reorganization of Structure-Function
Relationships
Studies with task-related fMRI in the
first 6 months after stroke

Average performance across groups of aphasic
patients irrespective of the site of lesion


Indicate that there is little activation in the acute stage of
stroke, increased RH activation in the subacute stage, and
then a shift back to the normal pattern of mostly LH
activation in the chronic stage, especially in those who
recover well (at least for auditory comp) (Saur et al., 2006)
But we have shown different patterns in individuals,
depending on:



Size & site of infarct
Language task
Individual factors (e.g. age or education?) (Jarso et al., 2013)
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Even individuals even whose strokes do not
involve left “language cortex” (IFG, STG,
MTG, ITG, SMG, or AG) show different
patterns of activation change over time in
these “language cortex” regions of interest.
Increases or decreases in activation in some
“language cortex” ROI are associated with
improvement or decline in naming.



5 right-handed participants with acute ischemic
left PCA stroke








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

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
Age from 46-60 years (mean age =52.5 years)
At least 12th grade education
2 right-handed healthy controls (age 52 years)
Cued-picture naming task (Holland et al., 2011).
Each picture was presented concurrently with an auditory cue:


3 thalamic
1 occipital/splenium/lingual/fusiform
1 occipital lingual
a whole word
an initial phoneme
an unintelligible auditory stimulus
60 grey-scale pictures taken from the international picture-naming
project database (Bates et al., 2003).
Control condition: passively viewing grey-scale scrambled picture
Stimuli: concrete nouns controlled for syllable length, frequency,
imageability, familiarity, and concreteness
order of pictures and accompanying cues was counterbalanced to
ensure that the same picture and cue pairing was not presented
during the runs
Each picture was preceded by a fixation cross for 500 ms and
displayed for 3500 ms.
Trials were presented in short blocks of 6 pictures, separated by the
control condition of 7 s. Participants completed 2 functional runs (i.e.,
10 blocks of each condition).
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Patient ID
Time Point
BNT
HANA
PPT
MMY
Acute
10
3W
47
71
100
IBR
WZI
ABR
WPL
60
6M
100
94
100
Acute
83
86
100
3W
83
80
100
6M
93
83
100
Acute
100
88.6
100
3W
96.6
94.2
100
6M
93.3
100
100
Acute
83.3
71.4
100
3W
86.6
82.8
100
6M
80
77.1
100
Acute
47
3W
57
57
100
6M
63
43
93
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MMY
WZI
ABR
IBR
WPL
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WZI-Left
WZI-Right
0
-1
STG
MTG
ITG
SMG
Regions
4W
OW
2
Mean % BOLD signal
1
IFG
1
0
-1
IFG
AG
STG
MTG
MMY-Left
SMG
AG
1
0
-1
LCG LHPC LMFG RCG RHPC RMFG
23W
MMY-Right
0
-1
STG
MTG
ITG
Regions
3W
OW
SMG
MMY-Cognitive
1
0
-1
AG
IFG
20W
STG
MTG
ITG
Regions
3W
OW
IBR-Left
SMG
0
-1
MTG
ITG
Regions
5W
-1
LCG LHPC LMFG RCG RHPC RMFG
20W
OW
SMG
AG
24W
Regions
3W
20W
IBR-Cognitive
2
Mean % BOLD signal
Mean % BOLD signal
1
STG
0
AG
2
IFG
1
IBR-Right
2
23W
2
Mean % BOLD signal
1
IFG
Regions
4W
OW
2
Mean % BOLD signal
Mean % BOLD signal
ITG
Regions
4W
OW
23W
2
Mean % BOLD signal
WZI-Cognitive
2
Mean % BOLD signal
Mean % BOLD signal
2
1
0
-1
IFG
STG
MTG
ITG
Regions
5W
SMG
AG
24W
1
0
-1
LCG LHPC LMFG RCG RHPC RMFG
Regions
5W
24W
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ABR-Left
ABR-Right
0
-1
STG
MTG
ITG
Regions
2W
OW
SMG
2
Mean % BOLD signal
1
IFG
1
0
-1
AG
IFG
22W
STG
MTG
ITG
Regions
2W
OW
WPL-Left
SMG
0
-1
STG
MTG
ITG
Regions
3W
-1
LCG LHPC LMFG RCG RHPC RMFG
22W
OW
SMG
AG
28W
Regions
2W
22W
WPL-Cognitive
2
Mean % BOLD signal
Mean % BOLD signal
1
OW
0
AG
2
IFG
1
WPL-Right
2
Mean % BOLD signal
ABR-Cognitive
2
Mean % BOLD signal
Mean % BOLD signal
2
1
0
-1
IFG
OW
STG
MTG
ITG
Regions
3W
SMG
AG
28W
1
0
-1
LCG LHPC LMFG RCG RHPC RMFG
OW
Regions
3W
28W
Changes (up or down) in language in the first 6
months after stroke may reflect changes in the
balance of neural activity between network
“nodes” in left and right hemisphere, reflected in
task-related fMRI
Best performance seems to be associated with
good balance across language cortex ROIs and
their right hemisphere homologues in overt
naming (a task with normal bilateral activation)
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10/13/2016
Time 1
20 controls
2
D
Lobes
frontal
limbic
parietal
occipital
temporal

There may be an ideal level of connectivity (or
balance) associated with best performance in
some regions such as ITG



As suggested by task-related fMRI
Change in connectivity might be induced by
transcranial direct current stimulation +
language intervention (or either alone)
MMY at Day 1 and Week 4 (when she had very
impaired naming) showed low connectivity
between left and right ITG (z < -1)
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Subacute tDCS (week 4)
A-tDCS + Naming therapy
In aphasia due to subacute stroke
Language network
Motor/Default
network
tDCS
Acute
4 weeks
20 weeks
20 weeks – 4 weeks
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Reorganization: Facilitated by
Neuromodulation + Language
Treatment

Transcranial Magnetic Stimulation or Transcranial
Direct Current Stimulation

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Hamilton et al. 2011, Shah et al 2011, Monti et al 2013
Can augment language therapy
Baker et al., 2010; Fiori et al., 2011; Fridriksson et al., 2011;
Marangolo et al., 2013
Thought to enhance synaptic plasticity

Nitsche et al., 2003, 2004; Monte-Silva et al., 2013; RioultPedotti et al., 2000

Stimulate perilesional areas (A-tDCS)

Inhibit contralesional areas (C-tDCS, rTMS)

Both simultaneously
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Baker et al., 2010; Fiori et al., 2011; Fridriksson et al., 2011
Naeser et al., 2005; Vines et al., 2011; Kang et al 2011
Marangolo, et al. 2014
Or cerebellar tDCS - which affects working
memory, language, and attention in healthy
controls (Ferruci et al., 2012; Pope & Miall, 2012)

Sebastian et al. (shown in previous session)
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Immediately after
Trained words
sham
tDCS
21
(p>0.0001)
39
(p>0.0001)
Trained Words
Untrained words
sham
tDCS
11
33
(p=0.0026) (p >0.0001)
2 months follow up
Untrained Words
sham
tDCS
sham
13
(p >0.0001)
39
(p >0.0001)
8
(p=0.13)
Before tDCS
tDCS
Untrained Task: PNT
sham
tDCS
121
(p=0.75)
143
(p=0.0003)
Untrained Task
sham
36
(p >0.0001) 122 (p=0.76)
After tDCS
tDCS
145
(p=0.0004)
After Minus Before
SMY
Control
14 ROIs corresponding to the left and right superior frontal gyrus,
prefrontal cortex, middle frontal gyrus, middle temporal gyrus pole,
inferior temporal gyrus, fusiform gyrus, and cerebellum
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
Among 270 chronic stroke survivors (most of
whom received therapy), the strongest single
predictor of recovery of speech production was
time post-onset (TPO) indicating that aphasia
recovery continues for months or years



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


Hypothesis: Recovery beyond 3 months is
influenced also by education and antidepressant
use.
45 patients with LH ischemic stroke, age 18 to 90
(mean 55); education of 6 to 20 years (mean 14.7);
mean of 35.4 months post-stroke.
Primary outcome variable: total of comprehension,
repetition, and naming summary scores from the
WAB.
Used multivariable logistic regression to identify
variables associated with WAB summary quartile
WAB Quartile was predicted by a model that
included education, age, infarct volume, and
antidepressant use
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
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
Hope, Seghier, Leff, Price, 2013
However, recovery of speech was best predicted
by subset of 37 variables studied, including TPO,
stroke volume, and involvement of 35 different
brain regions. Potential contributions of
medications or education were not evaluated.
χ2 for goodness of fit=207; p<0.0001;
Cox and Snell r2=0.47
Education had the highest Wald statistic of
17.3 (p<0.0001)
Infarct volume (Wald=7.0; p=0.008)
Antidepressant use (Wald=5.2; p=0.022)
Age (Wald=5.0; p=0.023).
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
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Compared to patients who had never taken
antidepressants (mostly SSRIs), patients taking
antidepressants had higher repetition scores
(mean 9.4 vs.7.6; p=0.039), even though they had
larger strokes (mean 225 vs 82 cc; p=0.008)
The 2 groups were not different in age,
education, or TPO.
Chronic aphasia recovery is positively
influenced by higher education and current
antidepressant use, as well as smaller lesion size
and younger age (independently of one another).
Changes (up or down) in language in the first
few days after stroke and sometimes later are
due to changes in blood flow in the brain
(brought about by intervention or changes in
vasculature or blood pressure)
Changes (up or down) in language in the first 6
months after stroke may reflect changes in the
balance of neural activity between network
“nodes” in left and right hemisphere, reflected
in task-related and resting state fMRI
Improvement in language even in the first year
after stroke requires some intervention in
people who have deficits
Any decline in language after stroke may
reflect structural changes (atrophy) possibly
related to the interaction between stroke and
pre-existing (preclinical) neurodegenerative
disease
Recovery may be influenced by education,
SSRI use, as well as age and infarct volume
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Cerebrovascular Division
John Krakauer, MD; Rebecca Gottesman, MD, PhD, Robert Wityk, MD;
Rafael Llinas, MD, Victor Urrutia, MD; Richard Leigh, MD, Steve Zeiler, MD, PhD,
Liz Marsh, MD; Roland Faigle, MD, PhD; Ryan Felling, MD; Jayne Zhang, MD; Mona Bahouth
Neuroradiology
Andreia Faria, MD, Susumu Mori, PhD, Peter Van Zijl, PhD; Ken Oichi, MD, PhD;
Kumiko Oishi, PhD; John Hsu, PhD, Edward Herskovits, MD, PhD, Mikolaj Pawlak, PhD
School of Public Health, Biostatistics
Brian Caffo, PhD, Martin Lindquist, PhD; Ciprian Crainiceanu, PhD
SCORE Lab
Amy Wright, Sadhvi Saxena, Rajani Sebastian, PhD; Donna Tippett, MA, Kyrana Tsapkini, PhD,
Jodi Nonnenmacher, MA; Shauna Barube, MA, Jeremy Purcell, PhD, Charltien Long,
Bonnie Breining, PhD; David Agis, Hinna Shahid, MD; Marlis Gonzalez-Fernandez, MD, PhD
Collaborators
Julius Fridriksson, PhD (USC), Chris Rorden, PhD (MUSC)
Greg Hickok, PhD (UCI), Jenny Crinion, PhD (UCL), Corianne Rogalsky (ASU);
Pablo Celnik, MD, PhD
John Desmond, PhD, Brenda Rapp, PhD
Neurology Residents & Stroke Fellows
Funding from: NIH (NIDCD, NINDS)
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