Clinical trial NCT03588572
Conditions: Subcortical Aphasia Ischemic Stroke
Keywords: Behavioural evaluation Functional magnetic resonance imaging Venlafaxine
Sponsor: Guangzhou General Hospital of Guangzhou Military Command
Start date: 2018-08-01; Completion date: 2019-08-01
Enrollment: 43 participants; Allocation: RANDOMIZED; Intervention model: FACTORIAL

Brief summary:
Previous studies have demonstrated that venlafaxine significantly improves the language function of healthy subjects and increase of fMRI activation in cortical language area. This study was designed to investigate the relationship between venlafaxine on the cortical language functional reorganization and clinical language improvements in the stroke patients with subcortical aphasia.

It is a randomized, controlled, single-blind, longitudinal trial which has approved by the ethics committee of Guangzhou General Hospital of Guangzhou Military Command, and all patients and their guardian should sign an informed consent. The patients will divide into the venlafaxine group and the control group according to the principle of randomization (random number table). The patients in the venlafaxine group begin to take a venlafaxine hydrochloride capsule after enrollment ( each containing venlafaxine 75mg), qd, until 4 weeks after randomization, and the control group do not. Assessments of language functional behavior and examines of functional magnetic resonance imaging (fMRI) should be performed on the first days (V1), 28±3 days (V2) and 90±3 days (V3) after randomization.

Through all this procession, we expect improve the language function of participants in experiment and clarify its mechanism,the research may help develop a new treatment for other patients with similar conditions.

Detailed description:
The cases will recruit from inpatients with acute ischemic stroke in Department of Cerebrovascular disease, The Guangzhou General Hospital of Guangzhou Military Command from June 2018 to June 2019. The diagnose of ischemic stroke is made using the diagnostic criteria of the International Association of Neurological Diseases and Stroke Association in 1982. The classification criteria for subcortical ischemic stroke are based on the current international TOAST etiological classification method.

It is a randomized, controlled, single-blind, longitudinal trial which has approved by the ethics committee of Guangzhou General Hospital of Guangzhou Military Command, and all patients and their guardian should sign an informed consent. The patients will divide into the venlafaxine group and the control group according to the principle of randomization (random number table). The patients in the venlafaxine group begin to take a venlafaxine hydrochloride capsule after enrollment ( each containing venlafaxine 75mg), qd, until 4 weeks after randomization, and the control group do not. Assessments of language functional behavior and examines of functional magnetic resonance imaging (fMRI) should be performed on the first days (Visit1,V1), 28±3 days (Visit2, V2) and 90±3 days (Visit3, V3) after randomization. Language functional behavioral assessments included the Chinese version of Western Aphasia Battery(WAB), spontaneous language frequency test(SLFT) and picture naming test(PNT). Examines of fMRI included task-state fMRI and resting-state fMRI. All patients received language rehabilitation training (twice a week, one hour each) which will be conducted by a professional rehabilitation physiotherapist from the Visitation1 until the end of Visitation3. The blood pressure and heart rate of each patient will be monitored and recorded on each visit, and two routine blood tests are performed at V0 and V3, including the blood routine and the liver and kidney function.

The test sample quantity is estimated using the sample size estimated by the professional software nQuery Advisor7.0. According to the main evaluation index of the effect of the previous literature on the efficacy of venlafaxine, the experimental group and the control group are 7.5±3.8 and 4.3±2.6，The standard deviation will be 3.26, and 0.05 will be the statistical meaning level (double tail). The test efficiency will be set to 0.83. The balance design will be used to estimate the sample size of the experimental group and the control group in 16 cases. In addition, considering the 20% missing rate, a total of 45 samples will be included in the study.

Task-state fMRI: an fMRI block design will be adopted, and DMDX software will be used to present each picture in series alternated between baseline (B) and activation (A) \[B-A-B-A-B…\]. Thirty-six animal pictures and 36 tool pictures accurately recognized by all subjects will be selected from the Snodgrass picture database. Six blocks of animal naming and six blocks of tool naming will be repeated, and each block continued for 18s with six pictures.the block-design diagram of picture naming task. The abstract figure of an American skunk which is unrecognized by all the subjects will be selected for baseline of animal naming. A schematic drawn arrow will be chosen for baseline picture of tool naming.Patients will be required to silently name the object in each picture without moving their lips. To avoid practice effects, the pictures used for activation will be different from those used in the behavioral evaluation. In the baseline phase, the participants will be asked to identify the orientation of the pictures by silently saying "upright" or "inverted." The subjects will receive task familiarization training prior to the test to ensure that there will be no substantive picture naming but only positional judgment in the baseline task.

Rest-state fMRI: During the rest-state fMRI scan, no task instruction will be given to the patient, and the patient will be completely relaxing, closing his eyes, breathing calmly, keeping his head still, but can not fall asleep, try to avoid any systematic thinking activities, scanning 8min.

Functional magnetic resonance data acquisition

The cranial brain scan will be performed using the US GE Signa HDx 3.0T Tesla superconducting magnetic resonance imaging system. The scanning sequence and parameters are as follows:

1. T1 structure imaging using FSPGR BRAVO sequence. The parameters included: time of repetition, 8.86 ms; time of echo, 3.52 ms; field of view, 24×24 cm2; in-plane resolution,256×256; slice thickness, 1 mm;interslice gap, 1 mm; and number of slices, 176.
2. Echo-Planar Imaging (EPI) is used to acquire task-state fMRI data.The parameters included: time of repetition, 3000ms; time of echo, 40 ms; field of view, 24×24 cm2; in-plane resolution,64×64; slice thickness, 4 mm; interslice gap, 1 mm; and number of slices, 34. Scan a sequence of 240s, a total of 12 min.
3. Echo-Planar Imaging (EPI) is used to acquire rest-state fMRI data.The parameters included: time of repetition, 3000ms; time of echo, 40 ms; field of view, 24×24 cm2; in-plane resolution,64×64; slice thickness, 4 mm; interslice gap, 1 mm; and number of slices, 34. A total of 8 min.

Arms: arm 1: The patients in venlafaxine group begin to take the venlafaxine hydrochloride capsules after the first visitation ( each containing venlafaxine 75mg), 1 capsule per day, until 4 weeks after randomization. arm 2: the patients in controlled group do not use the drug during the experiment, and the other treatments are same as the venlafaxine group.
Interventions: intervention 1: Venlafaxine hydrochloride capsules
Intervention descriptions: intervention 1: The patients in venlafaxine group begin to take the venlafaxine hydrochloride capsules after the first visitation(the first day after randomization), each containing venlafaxine 75mg, 1 capsule per day, until 4 weeks after randomization

Protocol documents:
Prot_002.pdf: 
The Effect of Venlafaxine on Language Function in Patients
With Subcortical Aphasia: A fMRI Study
NCT03588572
Study Protocol
Guangzhou General Hospital of Guangzhou
Military Command
No. 111, Liuhua Road, Yuexiu District,
Guangzhou, China
August 2018


Study Protocol
1. Research object and Study design
1.1
Research object
The cases will recruit from patients with acute ischemic stroke in Department of
Cerebrovascular, the Guangzhou General Hospital of Guangzhou Military Command
from August 2018 to June 2019. The diagnose of ischemic stroke is base on the
diagnostic criteria of the International Association of Neurological Diseases and
Stroke Association in 1982. The classification criteria for subcortical ischemic stroke
are based on the current international TOAST etiological classification method.
1.1.1
Inclusion criteria
（1）The first stroke of the left single subcortical areas, within 72 hours.
（2）Primary school or higher level, aged between 18-75, native language Chinese.
（3）According to the commonly used eye chart examination, the corrected visual
acuity is more than 1.0.
（4）According to the Edinburgh Handedness Questionnaire (EHQ), participants are
identified as right-handed.
（5）The language function is normal before the stroke onset. After the onset, the
language function was mildly to moderately impaired with Western Aphasia Battery
(WAB) ,which Aphasia Quotient (AQ) between in 60 to 88.
（6）The patient cooperate with the examination, they or their guardian sign
the informed consent.
1.1.2
Exclusion criteria
（1）History of organic diseases of nervous system and history of TBI(Traumatic
brain injuries)
（2）History of epilepsy and psychosis.
（3）History of material abuse.
（4）Decompensation of important organic function.
（5）Hamilton Depression Scale(HAMD )>8 points.
（6）Hamilton Anxiety Scale(HAMA )>7 points.


（7）The Mini-Mental State Examination (MMSE)score <20 points.
（8）Dysphagia(difficult to take capsules).
（9）A history of allergens in component of venlafaxine capsule.
（10）Pregnant women and breast-feeding women.
（11）Any contraindication of MRI.
1.2
Study design
It is a randomized, controlled, single-blind, longitudinal trial which has approved
by the ethics committee of Guangzhou General Hospital of Guangzhou Military
Command. All patients and their guardian will sign an informed consent. The patients
will divid into the venlafaxine group and the control group according to the principle
of randomization (random number table). The patients in the venlafaxine group begin
to take a venlafaxine hydrochloride capsule(EFFEXOR XR: each containing
venlafaxine 75mg, qd) after enrollment, until 4 weeks after randomization, and the
control group do not. Assessments of language functional behavior and examines of
functional magnetic resonance imaging (fMRI) should be performed on the first days
(Visit1,V1), 28±3 days (Visit2, V2) and 90±3 days (Visit3, V3) after randomization.
Language functional behavioral assessments include the Chinese version of Western
Aphasia Battery(WAB), spontaneous language frequency test(SLFT) and picture
naming test(PNT). Examines of fMRI include task-state fMRI, resting-state fMRI,
and DTI(Diffusion Tensor Imaging). All patients will receive language rehabilitation
training (twice a week, one hour each) which are conducted by a professional
rehabilitation physiotherapist from the V1 to the V3. The blood pressure and heart rate
of each patient will be monitored and recorded on each visit. Two routine blood tests
are performed at V0 and V3, including the blood routine and the liver and kidney
function.The technical roadmap is shown in Figure1.
The sample size is estimated by the professional software nQuery Advisor7.0.
According to the previous literature on the efficacy of venlafaxine, the main
evaluation index of the effect of the experimental group and the control group are
7.5±3.8 and 4.3±2.6 respectively. The standard deviation are 3.26, and the statistical
meaning level(double tail) is 0.05. The test efficiency are set to 0.83. The balance


design will be used to estimate the sample size. Finally, the sample size of the
experimental group and the control group are 16 cases respectively. In addition,
considering the 20% missing rate, a total of 45 samples will be included in the study.
Figure 1
Technical roadmap for research and design
1.3
Functional magnetic resonance (fMRI)
1.3.1
Functional magnetic resonance (fMRI) design
Task-state fMRI: an fMRI block design will be adopted, and DMDX software
will be used to present each picture in series alternated between baseline (B) and
activation (A) [B–A–B–A–B…]. Thirty-six animal pictures and 36 tool pictures from
the Snodgrass picture database will be recognized by all subjects. Six blocks of
animal naming and six blocks of tool naming will be repeated, and each block
continue for 18s with six pictures. The abstract picture of an American skunk which is
unrecognized by all the subjects will be selected for baseline of animal naming. A
schematic drawn arrow will be chosen for baseline of tool naming. Patients will be
required to silently name the object in each picture without moving their lips. To
avoid practice effects, the pictures used for fMRI will not appear in the behavioral
Venlafaxine
Withdraw
V1
V2
V3
Grouping
Test1+fMRI1
Test2+fMRI2
Test3+fMRI3
V1
V2
V3
Grouping
Test1+fMRI1
Test2+fMRI2
Test3+fMRI3
Venlafaxine Group
Control Group


evaluation. In the baseline phase, the participants will be asked to identify the
orientation of the pictures by silently saying ‘upright’ or ‘inverted’. The subjects will
receive task familiarization training prior to the test to ensure that there will be no
substantive picture naming but only positional judgment in the baseline task. The
design as shown in Figure 2.
Rest-state fMRI: During the rest-state fMRI scan, no task instruction will be
given to the patient, and the patient will be completely relaxing, closing his eyes,
breathing calmly, keeping his head still, but can not fall asleep, try to avoid any
systematic thinking activities, scanning 8min.
DTI: The patient will remain quiet and awake during the DTI data scan.
3000ms×6
picture naming task（3000ms×12）
3000ms×6
B
A
B
A
B
A
B
A
B
A
B
A
24s
18s
18s
18s
18s
18s
18s
18s
18s
18s
18s
18s
18s
Figure 2
Picture naming task group block design sketch map
1.3.2
Functional magnetic resonance data acquisition
The fMRI scan will be performed by using the US GE HDX3.0 Tesla superconducting
magnetic resonance imaging system. The scanning sequence and parameters are as
follows:
(1)In
order
to
obtain
the
whole
brain
anatomical
structure
image
data,
a
three-dimensional fast spoiler gradient echo (FSPGR BRAVO sequence) is used.. The
parameters included: time of repetition, 8.86 ms; time of echo, 3.52 ms; field of view,
24×24 cm2; in-plane resolution,256×256; slice thickness, 1mm;interslice gap, 1 mm;
Activation
Baseline


and number of slices, 176.
(2)Echo-Planar Imaging (EPI) is used to acquire task-state fMRI data. The parameters
included: time of repetition, 3000ms; time of echo, 40 ms; field of view, 24×24 cm2;
in-plane resolution,64×64; slice thickness, 4mm; interslice gap, 1 mm; and number of
slices, 34. Scan a sequence of 240s, a total of 12 min.
(3) Echo-Planar Imaging (EPI) is used to acquire rest-state fMRI data.The parameters
included: time of repetition, 3000ms; time of echo, 40 ms; field of view, 24×24 cm2;
in-plane resolution,64×64; slice thickness, 4mm; interslice gap, 1 mm; and number of
slices, 34. A total of 8 min.
(4)Echo-Planar Imaging (EPI) is used to acquire DTI data. The parameters included:
time of repetition, 8500ms; time of echo, 93 ms; field of view, 24×24 cm2; in-plane
resolution,128×128; slice thickness, 3mm; interslice gap, 0 mm; b-value=1000mm2/s.
1.4
Outcome Measures
1.4.1
Primary Outcome Measure:
(1)A change of outcome measure: the Chinese version of Western Aphasia
Battery(WAB)
The main outcome measure for this scale is Aphasia Quotient(AQ) which mainly
tests the ability of spontaneous speech, oral comprehension, repetition, and naming,
and reflects the severity of aphasia, and can be used as a reliable indicator to evaluate
the improvement and deterioration of aphasia. Score fluctuation is 0-100 points, the
normal value is 98.4-100 points, AQ<93.8 can be judged as language dysfunction.
Time Frame: This is an outcome measure to assess the improvement of language
function from onset to 3 months after treatment. Thus, participates will undergo this
assessment on the first days (V1), 28±3 days (V2), and 90±3 days(V3) after
randomization.
1.4.2
Secondary Outcome Measure:
(1)A change of outcome measure: Spontaneous Language Frequency Test(SLFT)
This test mainly assesses spontaneous speech fluency of participants. It requires
participants name as many food names as possible within one minute, and each
correct one to give one point. The higher the score, the better the language function.


Time
Frame: This is an outcome measure to assess the improvement of language function
from onset to 3 months after treatment. Thus, participates will undergo this
assessment on the first days (V1), 28±3 days (V2), and 90±3 days(V3) after
randomization.
(2) A change of outcome measure: Picture Naming Test(PNT)
This test mainly assesses the ability of picture name of participants. we used a
program for displaying named pictures
on a computer screen (60 photos in total, of which 20 were Chinese celebrity faces).
Each image was displayed in 3 seconds, and 1 point was correctly named for an
image. The faces of celebrities were selected from the picture database of Chinese
celebrities in the State Key Laboratory of Cognitive Neuroscience and Learning at
Beijing Normal University. Score fluctuation is 0-60 points, the higher the score,
the better the ability of picture name.
Time Frame: This is an outcome measure to assess the improvement of
language function from onset to 3 months after treatment. Thus, participates will
undergo this assessment on the first days (V1), 28±3 days (V2), and 90±3 days(V3)
after randomization.
(3)Follow-up measurement: Hamilton Depression Rating Scale (HAMD)
The Hamilton Depression Rating Scale (HAMD) has proven useful for many
years as a way of determining a patient’s level of depression before, during, and
after treatment. It generally takes 15-20 minutes to complete the interview and
score the results. Eight items are scored on a 5-point scale, ranging from 0 = not
present to 4 = severe. Nine items are scored from 0-2. HAMD Scoring
Instructions:0-7=Normal, 8-13 = Mild Depression, 14-18 = Moderate Depression,
19-22 = Severe Depression, ≥23 = Very Severe Depression(i.e., the higher the
score, the greater the likelihood of depression).
Time Frame: We must determine that the participant is not in depression at
each follow-up. Thus, participates will undergo this assessment on the first days
(V1), 28±3 days (V2), and 90±3 days (V3) after randomization.


(4) Follow-up measurement: Hamilton Anxiety Rating Scale (HAMA)
The Hamilton Anxiety Rating Scale (HAMA) is a widely used and
well-validated tool for measuring the severity of a patient's anxiety. The HAMA is
composed of 14 items and takes 15-20 minutes to complete the interview and
score the results. Each item is scored on a 5-point scale, ranging from 0=not present
to 4=severe. HAMA Scoring Instructions:0-8=Normal, 8-13= Possible Anxiety,
14-17 = Mild Anxiety, 18-24 = Moderate Anxiety, 25-30 = Severe Anxiety(i.e., the
higher the score, the greater the likelihood of anxiety).
Time Frame: We must determine that the participant is not in anxiety at each
follow-up. Thus, participates will undergo this assessment on the first days (V1),
28±3 days (V2), and 90±3 days (V3) after randomization.
(5) Follow-up measurement: Mini-Mental State Examination (MMSE)
The Mini–Mental State Examination (MMSE) is a 30-point questionnaire that
is used extensively in clinical and research settings to measure cognitive
impairment. Administration of the test takes between 5 and 10 minutes. The MMSE
test includes simple questions and problems in a number of areas: the time and
place of the test, repeating lists of words, arithmetic such as the serial sevens,
language use and comprehension, and basic motor skills. Any score greater than or
equal to 24 points (out of 30) indicates a normal cognition. Below this, scores can
indicate severe(≤9 points), moderate (10–18 points) or mild (19–23 points)
cognitive impairment. The raw score may also need to be corrected for educational
attainment and age.
Time Frame: We must determine that the participant is not in moderate or
more cognitive impairment at each follow aup. Thus, participates will undergo this
assessment on the first days (V1), 28±3 days (V2), and 90±3 days (V3) after
randomization.
(6) Other observational outcome
Edinburgh hand check（EHQ）：It is used to assess the habitual hand of patient.
National Institute of Health stroke scale(NIHSS )：It is used to assess
neurological deficits in patients with aphasia


Water swallow test(WST）：It is used to assess the swallowing function of
patients with aphasia.

SAP_003.pdf: 
The Effect of Venlafaxine on Language Function in Patients
With Subcortical Aphasia: A fMRI Study
NCT03588572
Statistical Analysis Plan
Guangzhou General Hospital of Guangzhou
Military Command
No. 111, Liuhua Road, Yuexiu District,
Guangzhou, China
August 2018


Statistical Analysis Plan
1. Functional magnetic resonance data processing
1.1
Task-state fMRI processing
DPARSF software package (http://www.rfmri.org) and SPM8 software package
(http://www.fil.ion.ucl.ac.uk/spm) will be use to process the Task-state fMRI data on
the Matlab R2013b platform(https://cn.mathworks.com/). we will transform the
DICOM format into NIFTI format firstly. And then, the first 10 time points are
removed to eliminate the influence on the data acquisition due to the uneven magnetic
field or the patient's inadaptation to the data acquisition. Then the time correction and
head motion correction (the translation which is greater than the 2mm or more than 2
degrees on the X, Y, Z axis will be eliminated) will be perform. Next, Normalization
and Smoothing (6 mm x 6 mm x 6 mm FWHM Gauss kernel) will be performed. The
Normalization is carried out by the DARTEL method, which is divided into three
parts: first registration, matching the structure image with the functional image; then
dividing, dividing the transformed structure into gray matter, white matter and
cerebrospinal fluid with a uniform segmentation rule, and obtaining a conversion
matrix
from
functional
image
to
standard
space;
finally,
standardize
the
transformation matrix to write the function.
The first level analysis of the task-state fMRI image is used by the SPM12
software(http://www.fil.ion.ucl.ac.uk/spm). In order to produce a single contrast
image corresponding to each task and each of the subjects, FWE correction will be
used (p<0.05, ke>10). Then the activation files of each group will be extracted, and
the group analysis will be carried out by one-sample t test (p<0.05, FDR correction,
ke>10). The fMRI activation map of V1, V2 and V3 in each group will be obtained.
The comparison between the venlafaxine group and the control group will take the
age, the volume of lesion and the education as covariate to eliminate the interference
factors outside the activation level, and using the two-sample t test (p<0.001,
uncorrected, activation range ke>10). The average activation brain map will be
presented by xjview software (http://www.alivelearn.net/xjview). And then, the map


will be superimposed on the standard three-dimensional meninges, and the region of
interest (ROI) , MNI coordinates, activation volume (voxel) and activation intensity
(T) will obtain.
1.2
Rest-state fMRI processing
According to the seed point method, the DPARSF software package and the SPM8
software package are adopted on the Matlab R2013b platform, which mainly include
the following steps：
1.2.1
Data pre-processing
(1)Format conversion: converting files from DICOM format to NIFTI format.
(2)The data of the first 10 time points should be removed to eliminate the
influence of magnetic field inhomogeneity or patient's inadaptability on data
acquisition.
(3)Time correction.
(4)Head motion correction: data that moves more than 2mm or rotates greater
than 2°on X, Y and Z axes is eliminated.
(5)Normalization: registration firstly, matching the structure image with the
functional image; then dividing, the transformed structure is segmented into gray
matter, white matter and cerebrospinal fluid by a uniform segmentation rule, and a
conversion matrix from functional image to standard space is obtained; finally,
standardize the transformation matrix to write the function.
(6)Smoothing: using 4 mm x 4 mm x 4 mm FWHM Gauss kernel.
(7)Linear drift and low frequency filtering processing: to eliminate the influence
of low frequency drift and high frequency noise.
(8)Removal of covariates: including removal of six head motion parameters,
whole brain mean signal, white matter and cerebrospinal fluid signals.
1.2.2
Selection of seed point
According to the activation maps of the main brain regions in task-state fMRI,
and referring the language function area of previous the literature, we select the left
Broca’s area (equivalent to the posterior part of left inferior frontal gyrus) , and the
left Wernick’s area (equivalent to the posterior part of left superior temporal gyrus )


and the opposite side mirror area as seed point. In total four seed points which the
areas consist with the MIN coordinate(as the center of the sphere) and 6 mm as the
radius, see table 1.
Tab.1
MNI coordinates and range of 4 seed points
Seed Point
Anatomical location
MNI Coordinate of
Sphere
Radius
（mm）
x
y
z
Broca_L
posterior part of left IFG
-45
26
13
6
Broca_R
posterior part of right IFG
52
28
18
6
Wernicke_L
posterior part of left STG
-48
-53
36
6
Wernicke_R
posterior part of right STG
51
-48
37
6
IFG：Interior Frontal Gyrus; STG：superior Temporal Gyrus; MNI：Montreal
Neuro logical Institute
1.2.3
Functional connection analysis
DPARSF software is used to extract the time series of voxels defined in the
template, and then the time series are averaged to get the reference time series of four
seed points. The correlation analysis between the time series of the reference time
series and the other voxels of the whole brain is made by Pearson correlation analysis.
And the correlation diagram is obtained. The relative intensity of each element in the
correlation diagram represents the correlation between the region of interest and the
low frequency oscillation signal of the voxel. Finally, the correlation map is
transformed into Z diagram by Fisher-Z transformation, so that the correlation
coefficient is distributed as normal as possible. Based on the SPM12 software, the
one-sample t test will be used to show the brain regions associated with the function
of 4 seed points (p<0.05, FDR correction,ke>10). Next, the age, the volume of lesion
and the education will be used as the covariate, and the changes of the corresponding
functional connections of the two groups will be compared with the two-sample t test
(p<0.001, uncorrected, ke>10). The function connection diagram is presented by


xjview software, then superimposed on the standard three-dimensional meninges, and
positioning the activated brain area to obtain the MNI coordinates of the region of
interest, the volume (voxel representation) and the maximum activation intensity (T
value).
1.3
DTI data processing
1.3.1
Pre-processing
Tools
from
the
FSL
library
(FMRIB
Software
Library,
(http://www ．fmrib.ox.ac ．uk/fs1) will be used to process the DTI data and for
probabilistic tractography analysis. we extract the diffusion gradients and the
corresponding b-values from the DICOM files, Head motion and image distortions
(stretches and shears) due to eddy currents are corrected with affine transformation in
FDT. A binary brain mask will be created from the B0 image using Brain Extraction
Tool(BET) with fractional intensity set to 0.1. Then a diffusion tensor model is fit at
each voxel to the 4D DWI data series (with additional inputs of the binary brain mask
and gradient table) using DTIFit. The outputs from this process included fractional
anisotropy (FA) and mean diffusivity (MD) maps as well as 1st-3rd eigenvector and
eigenvalue maps, which are visually inspected as a quality control measure. Diffusion
parameters will be then modeled using FSL's Bayesian Estimation of Diffusion
Parameters Obtained using Sampling Techniques and modeling crossing fibers
(BEDPOSTX). BEDPOSTX models diffusion signal as ball (isotropic) and stick
(anisotropic) components to generate a distribution of likely fiber orientations within
each voxel as well as an estimate of the uncertainty on these orientations.
1.3.2
Region of interest selection
Regions of interest (ROIs) will be selected at template of ALL_116_2MM. ROIs
are drawn on T1 in register with each subject's FA map generated from native DWI
space.
1.3.3
Probabilistic
tractography
Probabilistic tractography will be performed using FSL's Probtrackx 2.0, default
settings of 5000 samples/voxel, step length (0.5 mm), curvature threshold (0.2).
1.3.4
Statistical analyses


Statistical analyses will be conducted in SPSS (23.0). Bivariate (Pearson)
correlations were initially used to explore the relationship between age, gender,
education, ROI-derived, and tractography variables. In group analysis, ANOVA
analysis of single factor repeated measurement will be used, and two samples t-test
will be used between group analysis, and correlation analysis will be done with
language test results. P value of< 0.05 areconsidered significant.
1.5
Statistical analysis of quantitative data
The general quantitative data will be represented by mean number±standard
deviation, Levenne variance homogeneity test (P>0.05, which can be considered
homogeneity of variance) and normal distribution test will be used firstly, and
two-samples t-test will be used for quantitative data which satisfied Levenne's
homogeneity of variance test and normal distribution, and the rates of two group will
be compared by Fisher exact probabilities. The repeated measurement data will be
analyzed by repeated measures analysis of variance. Comparisons inter-group will be
performed by using a two-samples t-test, and pair-samples t-test will be used to
compare pairs of time points. All the above analyses used SPSS23.0 software package,
P<0.05 (two-tailed) will be considered statistically significant. And the bivariate
correlation option in this software package will be used to analyze the correlation
between the improvement of Aphasia Quotient and the change of activation of
task-state fMRI.