doi:10.

1093/brain/awx015 BRAIN 2017: 140; 914–927 | 914

Rewiring the primary somatosensory cortex in

carpal tunnel syndrome with acupuncture
Yumi Maeda,1,2, Hyungjun Kim,1,3, Norman Kettner,2 Jieun Kim,1,3 Stephen Cina,1
Cristina Malatesta,4 Jessica Gerber,1 Claire McManus,4 Rebecca Ong-Sutherland,4
Pia Mezzacappa,1 Alexandra Libby,1 Ishtiaq Mawla,1 Leslie R. Morse,5 Ted J. Kaptchuk,6
Joseph Audette7 and Vitaly Napadow1,2


These authors contributed equally to this work.

Carpal tunnel syndrome is the most common entrapment neuropathy, affecting the median nerve at the wrist. Acupuncture is a
minimally-invasive and conservative therapeutic option, and while rooted in a complex practice ritual, acupuncture overlaps
significantly with many conventional peripherally-focused neuromodulatory therapies. However, the neurophysiological mechan-
isms by which acupuncture impacts accepted subjective/psychological and objective/physiological outcomes are not well under-
stood. Eligible patients (n = 80, 65 female, age: 49.3  8.6 years) were enrolled and randomized into three intervention arms:
(i) verum electro-acupuncture ‘local’ to the more affected hand; (ii) verum electro-acupuncture at ‘distal’ body sites, near the ankle
contralesional to the more affected hand; and (iii) local sham electro-acupuncture using non-penetrating placebo needles.
Acupuncture therapy was provided for 16 sessions over 8 weeks. Boston Carpal Tunnel Syndrome Questionnaire assessed pain
and paraesthesia symptoms at baseline, following therapy and at 3-month follow-up. Nerve conduction studies assessing median
nerve sensory latency and brain imaging data were acquired at baseline and following therapy. Functional magnetic resonance
imaging assessed somatotopy in the primary somatosensory cortex using vibrotactile stimulation over three digits (2, 3 and 5).
While all three acupuncture interventions reduced symptom severity, verum (local and distal) acupuncture was superior to sham in
producing improvements in neurophysiological outcomes, both local to the wrist (i.e. median sensory nerve conduction latency)
and in the brain (i.e. digit 2/3 cortical separation distance). Moreover, greater improvement in second/third interdigit cortical
separation distance following verum acupuncture predicted sustained improvements in symptom severity at 3-month follow-up. We
further explored potential differential mechanisms of local versus distal acupuncture using diffusion tensor imaging of white matter
microstructure adjacent to the primary somatosensory cortex. Compared to healthy adults (n = 34, 28 female, 49.7  9.9 years
old), patients with carpal tunnel syndrome demonstrated increased fractional anisotropy in several regions and, for these regions
we found that improvement in median nerve latency was associated with reduction of fractional anisotropy near (i) contralesional
hand area following verum, but not sham, acupuncture; (ii) ipsilesional hand area following local, but not distal or sham, acu-
puncture; and (iii) ipsilesional leg area following distal, but not local or sham, acupuncture. As these primary somatosensory cortex
subregions are distinctly targeted by local versus distal acupuncture electrostimulation, acupuncture at local versus distal sites may
improve median nerve function at the wrist by somatotopically distinct neuroplasticity in the primary somatosensory cortex
following therapy. Our study further suggests that improvements in primary somatosensory cortex somatotopy can predict
long-term clinical outcomes for carpal tunnel syndrome.

1 Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown,
MA, 02129, USA
2 Department of Radiology, Logan University, Chesterfield, MO, 63017, USA
3 Clinical Research Division, Korean Institute of Oriental Medicine, Daejeon, 34054, South Korea
4 Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, Medford, MA, 02155, USA

Received August 11, 2016. Revised December 8, 2016. Accepted December 17, 2016. Advance Access publication March 2, 2017
ß The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
For Permissions, please email: [email protected]
S1 neuroplasticity from acupuncture in CTS BRAIN 2017: 140; 914–927 | 915

5 Department of Physical Medicine and Rehabilitation, Harvard Medical School, Spaulding Rehabilitation Hospital, Boston, MA,
02114, USA
6 Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
7 Department of Pain Medicine, Harvard Vanguard Medical Associates, Atrium Health, Boston, MA, 02215, USA
Correspondence to: Vitaly Napadow, PhD,
Martinos Center for Biomedical Imaging,
#2301 149 Thirteenth St.,
Charlestown, MA 02129,
USA
E-mail: [email protected]

Keywords: carpal tunnel syndrome; nerve conduction studies; neuropathic pain; entrapment neuropathy; neuromuscular disease:
imaging
Abbreviations: BCTQ = Boston Carpal Tunnel Syndrome Questionnaire; CTS = carpal tunnel syndrome; DTI = diffusion tensor
imaging; S1 = primary somatosensory cortex

representations of adjacent median nerve innervated fingers,

Introduction digits 2 and 3 (D2/D3)—a reproducible finding in different
Entrapment neuropathies are common sources of pain and CTS cohorts, using both functional MRI (Napadow et al.,
paraesthesia (Neal and Fields, 2010), and entrapment of 2006; Maeda et al., 2014) and MEG (Dhond et al., 2012).
the median nerve at the wrist, termed carpal tunnel syn- Interestingly, reduced D2/D3 separation in S1 has
drome (CTS), accounts for 90% of such neuropathies been associated with median sensory nerve conduction
(Atroshi et al., 1999; Papanicolaou et al., 2001; Kleopa, latency (Napadow et al., 2006), symptom severity, reduced
2015). Prior to surgical approaches for severe CTS, conser- fine motor performance, and diminished sensory discrimin-
vative therapies are commonly recommended (Kleopa ation accuracy (Maeda et al., 2014), demonstrating
2015), and acupuncture has been proposed as a viable that such functional brain neuroplasticity is indeed
option (Yang et al., 2009). Acupuncture is a minimally- maladaptive.
invasive therapeutic modality that originated in China Acupuncture was suggested as a promising adjunct ther-
2000 years ago as a component of traditional Chinese apy for CTS at the 1997 NIH consensus conference, orga-
medicine (Kaptchuk, 2002). While acupuncture therapy is nized to critically evaluate acupuncture research (NIH
1998). Since then, randomized controlled trials have
rooted in a complex practice ritual, the acupuncture needle
found improved nerve conduction and reduced symptom
procedure, particularly when coupled with electrical needle
severity following acupuncture, compared to either sham
stimulation, overlaps significantly with many conventional
acupuncture (Khosrawi et al., 2012) or oral steroids
peripheral neuromodulatory therapies (Langevin et al.,
(Yang et al., 2009, 2011). Other trials have not found
2015) that have generated significant excitement as ‘electro-
symptom severity reduction (Yao et al., 2012) following
ceuticals’ targeting peripheral nerve receptors (Famm et al.,
acupuncture. Importantly, while later Yao et al. trials did
2013; Waltz, 2016). However, the neurophysiological
not confirm CTS by nerve conduction studies and likely
mechanisms by which acupuncture impacts subjective/psy- enrolled both CTS and idiopathic hand pain patients, the
chological (i.e. symptom report) and objective/physiological earlier Yang et al. trials did enrol based on conduction
(e.g. median nerve conduction studies) outcomes in CTS are latency (Yang et al., 2009), and evaluated long-term
not well understood. follow-up (Yang et al., 2011). A meta-analysis, performed
Previous neuroimaging studies have demonstrated that prior to some of the recent trials, noted encouraging but
while CTS results from compression of the median nerve not yet convincing evidence for acupuncture in the treat-
at the wrist, this disorder is also characterized by structural ment of CTS (Sim et al., 2011), advocating for more ran-
(Maeda et al., 2013a, 2016) and functional (Druschky domized controlled trials.
et al., 2000; Tecchio et al., 2002; Napadow et al., 2006; Our multi-modal randomized neuroimaging trial follows-
Dhond et al., 2012; Maeda et al., 2014) neuroplasticity in up on our smaller (n = 13) and uncontrolled (no sham
the primary somatosensory cortex (S1) of the brain. acupuncture) pilot imaging study assessing acupuncture
Specifically, CTS patients show decreased S1 grey matter outcomes for CTS (Napadow et al., 2007a). The current
volume and cortical thickness contralateral to the more af- study assessed whether (i) verum acupuncture is superior to
fected hand, which is further pronounced in paraesthesia- sham acupuncture for reducing symptom severity, improv-
dominant symptom subgroups (Maeda et al., 2016), and is ing median nerve conduction latency, and increasing
associated with aberrant median nerve conduction (Maeda functional MRI-assessed D2/D3 separation distance in S1;
et al., 2013a, 2016). Functional MRI evaluation has (ii) verum acupuncture at distal acupoints (i.e. no local
demonstrated reduced separation between S1 cortical needle-induced physiological response) is also superior to
916 | BRAIN 2017: 140; 914–927 Y. Maeda et al.

sham acupuncture; (iii) improvements in physiological out- anticoagulation therapy. Healthy control subjects, 20–65
comes immediately following verum acupuncture predict years old, were also recruited for baseline neuroimaging
long-term symptom reduction; and (iv) neuroplasticity in comparisons.
S1-adjacent white matter microstructure, as assessed by dif-
fusion tensor imaging (DTI), can also inform potential Study timeline
brain-based mechanisms by which local versus distal acu-
Following baseline clinical and MRI assessment, eligible sub-
puncture improves CTS outcomes. We hypothesized that jects were randomly assigned to one of three parallel study
while both verum and sham acupuncture reduce CTS arms (Fig. 1). We used computer generated permuted block
symptom severity, only verum acupuncture improves randomization (blocks of six), stratified by CTS severity
physiological outcomes and such changes predict long- (mild/moderate). The acupuncturist was informed of group al-
term clinical outcomes. Moreover, we hypothesized that location at the first treatment visit. The three intervention
improvement in median nerve conduction after acupuncture arms were (i) verum acupuncture ‘local’ to the more affected
is associated with plasticity in somatotopically-specific S1- hand; (ii) verum acupuncture at ‘distal’ body sites, contrale-
adjacent white matter microstructure targeted by local sional to the more affected hand; and (iii) sham acupuncture
using non-penetrating placebo needles. Brain MRI scans were
versus distal acupuncture.
obtained at baseline and post-therapy. Nerve conduction stu-
dies were obtained at baseline and after acupuncture therapy
while symptom severity, assessed with the Boston Carpal
Materials and methods Tunnel Syndrome Questionnaire, BCTQ (Levine et al.,
1993), was additionally assessed at 3-month follow-up (see
below).
Experimental design
This was a single-centre, blinded, placebo controlled, rando- Acupuncture treatment
mized parallel-group longitudinal neuroimaging study, pre-
registered with ClinicalTrials.gov (NCT01345994). The study Subjects received 16 acupuncture treatments over 8 weeks
took place at Spaulding Rehabilitation Hospital (SRH) and using a tapering schedule common to the clinic: three treat-
Athinoula A. Martinos Center for Biomedical Imaging, ments/week for 3 weeks; two treatments/week for 2 weeks;
Department of Radiology, Massachusetts General Hospital and one treatment/week for 3 weeks. Acupuncture was de-
(MGH), in Boston, MA from January 2009 to December livered to subjects in supine position by one of four trained,
2014. All study protocols were approved by MGH and licensed acupuncturists with at least 3 years of clinical experi-
Partners Human Research Committee and all subjects pro- ence. For the local acupuncture group, based on the protocol
vided written informed consent. used in our pilot study (Napadow et al., 2007b), a hybrid
design balanced standardized acupuncture therapy with more
ecologically valid individualized acupoint selection. For all sub-
Subjects jects, acupuncture needles were placed at acupoints TW5 and
PC7 (Fig. 1 for all point locations), on the dorsal and ventral
Patients with CTS, 20–65 years old, were recruited at MGH and aspects of the forearm of the more affected hand. Electrodes
SRH. Subjects were consented and evaluated by study physician were attached to these needles, and 2 Hz electrical stimulation
(blinded to allocation), who captured history of symptoms, exam- was performed for 20 min using a constant-current electro-acu-
ination for Phalen’s manoeuvre (Phalen, 1966) and Durkan’s sign puncture device (Acus II, Cefar). Current intensity was set to a
(Durkan, 1991), and nerve conduction studies (Cadwell Sierra percept level of ‘moderately strong but not painful.’
EMG/NCS Device). The latter evaluated median and ulnar, sen- Acupuncture needles were also inserted, and manually stimu-
sory and motor nerve conduction for both hands. Inclusion cri- lated, at three additional acupoints on the more affected fore-
teria for mild/moderate CTS subjects required a history of pain/ arm, chosen by the acupuncturist from HT3, PC3, SI4, LI5,
paraesthesia in median nerve innervated territories, greater than 3 LI10, and LU5, according to subjects’ individual presentation.
months duration, median sensory nerve conduction la- Manual stimulation at all locations was performed to induce
tency 43.7 ms for mild CTS, 44.2 ms for moderate CTS, and/ characteristic deqi acupuncture sensation (Kong et al., 2007).
or 40.5 ms compared to ulnar sensory nerve latency for both For the distal acupuncture group, electro-acupuncture was per-
mild and moderate CTS, with normal motor conductions. formed with needles placed at SP6 and LV4 on the lower leg
Subjects with 44.2 ms median nerve motor latency and 450% on the opposite side of the body to the more affected hand.
loss of motor amplitudes were considered to be ‘severe’ and Manual acupuncture was also performed at three additional
excluded from this study. For subjects diagnosed with bilateral acupoints: GB34, KD3, and SP5 on this limb. All verum
CTS, the more affected hand, by symptom report, was used for acupuncture needles were single-use disposable needles (0.20–
primary outcomes. Exclusion criteria were as follows: contraindi- 0.25 mm diameter, 20–40 mm length, stainless steel needle;
cations to MRI, history of diabetes mellitus, rheumatoid arthritis, Asiamed) inserted 10–30 mm deep, depending on location.
wrist fracture with direct trauma to median nerve, current usage Additionally, to maintain credibility for this procedure, a
of prescriptive opioid medication, severe thenar atrophy, previous single non-insertive sham acupuncture needle (Streitberger
acupuncture treatment for CTS, non-median nerve entrapment, Needle; Asiamed) was placed at non-acupoint SH1 on the
cervical radiculopathy or myelopathy, generalized peripheral forearm of the more affected hand. For the sham acupuncture
neuropathy, severe cardiovascular, respiratory, or neurological group, non-insertive Streitberger needles were placed on non-
illnesses, blood dyscrasia or coagulopathy or current use of acupoints (SH1 and SH2) on the ulnar aspect of the more
S1 neuroplasticity from acupuncture in CTS BRAIN 2017: 140; 914–927 | 917

Figure 1 Study overview. (A) Study design of randomized control neuroimaging trial with acupuncture intervention; multi-modal assessments
were conducted at baseline, post-acupuncture, and 3-month follow-up. (B) Location of acupoints for all three study arms: local (verum, near the
more affected hand), distal (verum, near contralesional ankle), and sham (non-penetrating needles over non-acupoints near the more affected
hand). Acupoints where electrical stimulation was provided via electrodes attached to needles (i.e. electro-acupuncture) are marked (lightning
bolt). fMRI = functional MRI.

affected forearm. Similar to the local verum acupuncture arm,

electrodes were attached to these needles, the electro-acupunc-
MRI outcomes
ture device was turned on, but the electrodes were not inserted
S1 cortical mapping with functional MRI
into an active port on the device. Subjects were told they ‘may
or may not feel electrical sensations’ from this procedure. At baseline and post-therapy, imaging data were acquired with
Additionally, three other sham needles were placed over non- a 3 T Siemens Trio equipped with a 32-channel head coil.
acupoints SH3 on the radial aspect of the more affected fore- Structural MRI data were acquired with a multi-echo
arm, and non-acupoints SH4, SH5 on the opposite lower limb. MPRAGE T1-weighted pulse sequence (repetition time = 2530
Throughout the evaluation and treatment period, subjects, ms, echo time 1/echo time 2 = 1.64/30.0 ms, inversion
study physician, and experimenters were blinded to group al- time = 1200 ms, flip angle = 7 , field of view = 256  256,
location and all data capture forms used neutral group codes 176 slices, sagittal acquisition, spatial resolution = 1  1  1
to conceal allocation: ‘ektorp,’ ‘klobo,’ ‘poang.’ Subjects’ per- mm3). Functional MRI data were acquired using a gradient
ception of whether they received active acupuncture therapy echo blood oxygen level-dependent T2-weighted pulse se-
was assessed after the first treatment. After the post-therapy quence adapted for improved spatial resolution (repetition
MRI visit, subjects were unblinded as to group allocation. time/echo time = 2000/30 ms, field of view = 200  200 mm,
32 coronal slices parallel to the central sulcus, voxel
size = 2.1  2.1  2.5 mm, flip angle = 90 ). We used an
event-related functional MRI design to evaluate brain response
Clinical outcomes to vibrotactile stimulation over three digits (D2, D3, and D5)
The BCTQ (Levine et al., 1993) was administered at baseline, on the more affected hand. D2 and D3 are innervated by the
post-therapy, and at 3-month follow-up. It is composed of a median nerve (affected by CTS), while D5 is innervated by the
symptom severity scale, which includes 10 items regarding unaffected ulnar nerve. Computer controlled vibrotactile
pain and numbness severity, and an 8-item Function Severity stimulation was provided by a custom-built MR-compatible
Scale related to precise hand movement tasks using a 1–5 device as described in our previous study (Maeda et al.,
scale. The symptom severity scale served as the primary clinical 2014). In brief, the device contained four piezoelectric trans-
outcome measure for symptom assessment. ducers (T220-A4NM-303Y, Piezo Systems) set inside an ad-
Nerve conduction studies were performed according to pre- justable four-finger shell that allowed for directed vibrotactile
viously described methods (Ma et al., 1983), at baseline and stimulation to the distal finger pad provided by Cortical
post-therapy. Median sensory nerve conduction latency was Metrics. Stimulation was produced with sinusoid input voltage
calculated from the average of digit 2 (D2) and digit 3 (D3) from an analogue signal generator (HM8030_5, HAMEG
measurements from the affected hand (more affected hand for Instruments), and transmission was set according to an event
bilateral CTS subjects). related schedule through electronic relays, controlled by
918 | BRAIN 2017: 140; 914–927 Y. Maeda et al.

customized software (Labview 7.1, National Instruments

Corporation). A separate functional MRI scan was performed
Diffusion tensor imaging of S1-adja-
for each of the three digits using an event-related design (27 cent white matter
stimuli, duration = 2 s, randomized jittered inter-stimulus inter- Diffusion-weighted images were also obtained using spin-echo
val = 6–12 s, total scan time = 306 s). The order of digit stimu- pulse sequence (repetition time/echo time = 8040/84 ms, voxel
lation was also randomized. For all functional MRI scans, size = 2  2  2 mm, 64 slices, b-value = 700 s/mm2, 60 non-
subjects lay supine in the scanner with ear plugs and were collinear directions, 10 b0volumes). Diffusion-weighted
instructed to close their eyes and focus attention on the images were aligned to the b0 image using affine registration,
finger being stimulated during the scan. Following each scan, which serves to correct distortion due to eddy currents. After
subjects reported which finger was stimulated and the intensity removal of non-brain tissue, DTI metric (fractional anisotropy,
of stimulus perception on a scale of 0 (no sensation) to 10 and mean, radial and axial diffusivity) maps were computed
(very strong but not painful) to confirm proper device oper- from the diffusion-weighted images using FMRIB’s
ation and attentiveness during the scan. DiffusionToolbox (FDT, FSL), which fits a diffusion tensor
Functional MRI data were analysed using previously model to each voxel. Maps for patients with CTS whose
described methods (Maeda et al., 2014), and were automated, more affected hand was the left hand were flipped across the
thus blind to group allocation. Briefly, functional MRI data mid-sagittal plane for group analyses with right hand affected
were registered to each subject’s structural data (bbregistra- subjects, similar to functional MRI analyses.
tion; Greve et al., 2009; Freesurfer v.5.1). Preprocessing We adopted a longitudinal diffusion processing scheme similar
included slice-timing correction, head motion correction, to previous analyses (Douaud et al., 2009; Engvig et al., 2012).
skull stripping, high pass filtering (cut-off period = 90 s) and First, the initial alignment between brain-extracted images at
minimal spatial Gaussian smoothing (full-width at half-max- baseline and post-treatment time points were conducted using
imum = 1 mm, FSL v.4.1; Jenkinson et al., 2012). Preprocessed FMRIB’s Linear Image Registration Tool (FLIRT, degrees of free-
dom = 6), and both images were resampled to a common space
functional MRI data were analysed with a general linear
halfway between the two (Jenkinson et al., 2002), which only
model (GLM).
requires a single registration per volume and thus minimizes regis-
To calculate group functional MRI response maps, the re-
tration bias towards one of the two time points. Next, we aver-
sultant parameter estimates and variances for each digit on the aged the two registered fractional anisotropy maps to generate a
single subject level GLM were projected on to the average subject-wise mid-space template, and images were aligned to the
surface brain (fsaverage, Freesurfer) and smoothed on the FMRIB58_FA template using FMRIB’s Nonlinear Registration
spherical cortical surface (full-width at half-maximum = 5 mm, Tool (Jenkinson et al., 2012). The mean fractional anisotropy
mri_vol2surf, mri_surf2surf, Freesurfer). CTS subjects whose map was thinned and thresholded at fractional anisotropy 4
more affected hand was the left and, thus, experienced finger 0.2 to generate a white matter tract skeleton representing the
stimulation on the left hand, had their functional and struc- centre of the tracts common to all subjects (Smith et al., 2006).
tural data flipped across the mid-sagittal plane to perform Each image was warped to the standard MNI space using these
group analyses with right hand affected subjects, similar to transformations, and skeletonized after spatial smoothing (full-
our previous analyses (Napadow et al., 2006, 2007a; Maeda width at half-maximum = 4 mm).
et al., 2013a, 2014). Accurate registration was ensured by Statistical comparisons of the fractional anisotropy skeletons
between healthy controls and patients were performed using a
visualization (tkmedit, tkregister, Freesurfer). Group maps
non-parametric permutation test (n = 5000 permutations). As
were cluster corrected for multiple comparisons (z = 2.3,
age significantly correlated with mean skeleton fractional an-
P 5 0.05). isotropy at baseline (r = 0.39; P = 0.002) but sex did not
For region of interest analysis, an unbiased group activation (P = 0.33), age served as a covariate of no-interest.
map across all digits and all subjects was calculated and inter- Significance threshold was set at P 5 0.05, family-wise error
sected with the Freesurfer anatomical postcentral gyrus label (FWE) corrected for multiple comparisons across voxels using
for Brodmann area 3b and 1 (BA3b/1) to better localize digit threshold-free cluster-enhancement (Randomise 2.0, FSL;
representations to subregions of S1 known to demonstrate Winkler et al., 2014).
more precise somatotopic organization. This region of interest In addition, as previous studies have demonstrated specific
mask was then used to localize the peak z-stat vertex within neuroplasticity in S1 structure and function in patients with
the most significant cluster for each subject (mri_surfcluster, CTS (Napadow et al., 2006; Maeda et al., 2013a, 2016), ana-
Freesurfer v.5.1). The geodesic surface distance between pairs lyses were focused on S1-adjacent white matter. This region of
interest was defined by a dilated mask of the postcentral gyrus
of peak z-stat vertices for D2, D3 and D5 was then calculated
taken from the Harvard-Oxford atlas, and intersected with the
using an edge cost and Dijkstra’s algorithm (mris_pmake,
white matter skeleton (Supplementary Fig. 1). Notably, this mask
Freesurfer v.5.1). Based on our previous studies, the primary did not include the superior longitudinal fasciculus, located
outcome for functional S1 plasticity was defined as post-acu- medial to S1-adjacent U-fibres, as it is difficult to interpret frac-
puncture change in D2/D3 separation distance. D2/D5 and tional anisotropy in crossing-fibre areas (Douaud et al., 2011).
D3/D5 separation were also calculated as D5 is ulnar, not
median, nerve innervated and can be used as a stable reference
location (Napadow et al., 2006, 2007a) to determine if, for Statistical analyses
example, increased D2/D3 separation was due to ventral shift For assessment of change in BCTQ scores, nerve conduction
in D2 or dorsal shift in D3. studies, and digit separation distance, repeated measures
S1 neuroplasticity from acupuncture in CTS BRAIN 2017: 140; 914–927 | 919

ANOVA were performed (IBM SPSS version 20, Chicago, IL) n = 65, 2.8  0.7, mean  SD; male: n = 15, 2.3  0.5,
and Greenhouse–Geisser corrected for sphericity (when appro- P = 0.02), subsequent analyses used a repeated measures
priate). When the results for local and distal acupuncture analysis of covariance ANCOVA (factors: Time, Group),
groups did not differ (non-significant Group  Time inter- controlling for age and sex. Furthermore, as there was no
action), we combined data from these two groups to produce
significant Group (local, distal acupuncture)  Time (base-
a single ‘verum’ acupuncture group, which was then compared
line, post-therapy, 3-month follow-up) interaction for the
with the sham acupuncture. Post hoc testing was two-tailed for
verum versus sham contrasts, and single-tailed for follow-up two verum acupuncture groups [F(1.9,65.4) = 1.82;
individual group contrasts (e.g. local versus sham), when the P = 0.17], the local and distal acupuncture groups were
verum versus sham contrast was significant or trending. While merged into a single verum group for subsequent analyses.
randomization was stratified by CTS severity (i.e. nerve con- A repeated measure ANCOVA then found a trending sig-
duction studies), other outcomes were not used to stratify ran- nificance [F(2.0,102.2) = 2.39; P = 0.098] for the Group
domization. As previous studies have found that % change (verum, sham)  Time (baseline, post-therapy, 3-month
scores, which effectively normalize difference scores by the follow-up) interaction. Post hoc testing demonstrated that
baseline value, are less sensitive to baseline differences than both verum ( 21.3  22.0%, mean  SD, P 5 0.001, one-
absolute difference scores (Farrar et al., 2001; Jensen et al., sample t-test) and sham ( 22.7  22.6%, P = 0.001) acu-
2003; Hanley et al., 2006), the former were also used for puncture significantly reduced the BCTQ symptom severity
BCTQ and functional MRI outcomes. Significance was set at
scale score immediately following therapy (Fig. 2 and
alpha = 0.05.
Table 1), and did not differ (P = 0.92) controlling for age
and sex. Comparisons of baseline to 3-month follow-up
showed significant per cent improvement was retained for
Results verum ( 25.1  20.8%, P 5 0.001) and only a trending
A total of 80 CTS subjects [65 female, age: 49.3  8.6 improvement was retained for sham ( 11.1  24.7%,
years, mean  standard deviation (SD)] were enrolled and P = 0.08) acupuncture, with a significant difference between
79 subjects with CTS were randomized into three acupunc- the two groups at follow-up (P = 0.04), controlling for age
and sex. Within the verum acupuncture group, both local
ture groups, local (n = 28, 22 female, age: 48.5  10.1
( 24.6  22.2%, P 5 0.001) and distal ( 25.6  19.7%,
years), distal (n = 28, 22 female, age: 49.9  8.4 years),
P 5 0.001) acupuncture demonstrated a significant reduc-
and sham (n = 23, 20 female, 50.6  7.8 years). There
tion of BCTQ symptom severity scale at the 3-month
was no significant difference in age or male/female distri-
bution between groups [F(2,76) = 0.37, P = 0.69. Fisher’s
exact test, P = 0.72]. Symptom duration (local = 9.9  8.9
years, distal = 6.8  6.6 years, sham = 9.4  9.3 years) also
did not differ significantly between groups [F(2,76) = 1.12,
P = 0.33]. Due to scheduling difficulties, a total of 65
subjects with CTS completed their post-therapy MRI evalu-
ation, and 56 subjects completed the BCTQ at 3-month
follow-up (Supplementary Fig. 2). No significant differences
were found between local, distal, or sham groups in sub-
jects’ perception of whether they received active acupunc-
ture, at baseline (Fisher’s exact test, n = 64, P = 0.29) or
after the final acupuncture session (Fisher’s exact test,
n = 62, P = 0.51), with 85% of subjects across all
groups reporting that they indeed thought they had
received active acupuncture. To provide better context for
DTI analyses, a cohort of 34 age- and sex-matched healthy
control subjects (28 female, age = 49.7  9.9 years) were
included for comparison with CTS subjects (baseline com-
parisons for clinical and functional MRI metrics were pre-
viously reported) (Maeda et al., 2014).

Boston Carpal Tunnel Syndrome

Figure 2 BCTQ response to therapy. Symptom assessment
Questionnaire with the BCTQ symptom severity scale (SSS) demonstrated
The primary clinical outcome for symptom assessment was reduced symptom severity following all three acupuncture treat-
ments. Note that CTS verum combines results across both CTS-
the symptom severity scale for the BCTQ. As the BCTQ
local and CTS-distal study arms. Error bars represent standard
symptom severity scale correlated with age at baseline
error of the mean (SEM). P 5 0.001.
(n = 80, r = 0.22, P = 0.046) and differed by sex (female:
920 | BRAIN 2017: 140; 914–927 Y. Maeda et al.

Table 1 Demographics and clinical assessments

Local acup Distal acup Sham acup Verum Local Distal

versus versus versus
sham sham sham
P-value P-value P-value
Age (years) 48.5  10.1 49.9  8.4 50.6  7.8 0.53 0.42 0.77
Symptom duration (years) 9.9  8.9 6.8  6.6 9.4  9.3 0.60 0.86 0.24
Change in BCTQ (Post-Acup Baseline)
Symptom severity score (%) 27.0  22.9 14.7  19.6 22.7  22.6 0.92 0.26 0.26
Function status score (%) 26.2  19.1 6.8  37.6 18.2  33.6 0.93 0.23 0.22
Change in BCTQ (3M Baseline)
Symptom severity score (%) 24.6  22.2 25.6  19.7 11.1  24.7 0.04 0.04 0.04
Function status score (%) 16.8  32.4 17.4  18.1 2.3  33.7 0.12 0.18 0.25
Change in median nerve conduction latency (Post-Acup Baseline)
Median sensory latency (ms) 0.16  0.42 0.17  0.35 0.12  0.51 0.02 0.03 0.02
Change in S1 cortical separation distance (Post-Acup Baseline)
D2/D3 (mm) 2.3  2.3 1.3  3.9 0.1  3.2 0.1 0.02 0.18
D3/D5 (mm) 0.8  5.3 0.1  3.4 0.6  2.6 0.48 0.40 0.69
D2/D5 (mm) 2.5  4.0 1.3  4.9 0.1  3.0 0.15 0.07 0.37

Data are shown as mean  SD. Verum denotes combined local and distal acupuncture groups if local does not statistically differ from distal. Values in bold denote significance at
P50.05; values in italics denote trending significance, which may help guide the design of future research.

follow-up. Results from the BCTQ functional scale are pro-

vided in Table 1.

Nerve conduction studies

The primary clinical outcome for nerve conduction studies
was median sensory nerve conduction latency, which did
not differ by sex, nor was correlated with age. Data from
two subjects were unusable due to missing values. A 2  2
repeated measures ANOVA found no significant Group
(local, distal acupuncture)  Time (baseline, post-therapy)
interaction for the verum acupuncture groups [F(1,40)
= 0.01, P = 0.95], and thus the local and distal acupuncture
groups were merged into a single verum group for subse-
quent analyses. A repeated measures ANOVA for verum
and sham acupuncture demonstrated a significant Group
(verum, sham acupuncture)  Time (baseline, post-therapy)
interaction [F(1,61) = 6.25, P = 0.02]. Post hoc testing
found a significant difference for change in latencies between
verum and sham acupuncture (unpaired t-test, P = 0.02;
Fig. 3 and Table 1). Furthermore, a significant reduction
for median sensory nerve latency was found following
verum acupuncture ( 0.16  0.38 ms, mean  SD,
P = 0.01, t-test compared to nil), while sham acupuncture
did not significantly change conduction latency (0.12 
0.51 ms, P = 0.28). Based on these results, we further evalu- Figure 3 NCS and S1 somatotopy response to therapy.
ated if either verum acupuncture group individually demon- (A) Nerve conduction studies of the median sensory nerve
strated reduced median sensory nerve conduction latency, demonstrated significant improvement in conduction latency fol-
and found that both local and distal acupuncture reduced lowing verum but not sham acupuncture. (B) Separation distance of
latency compared to sham acupuncture (P = 0.03 and cortical representations in the primary somatosensory cortex for
P = 0.02, respectively; single-tailed unpaired t-test) and com- affected digits 2 and 3, as assessed by functional MRI, demonstrated
pared to nil (local: 0.16  0.42 ms, P = 0.048, single tailed significant increase following verum, but not sham, acupuncture.
t-test; distal: 0.17  0.35 ms, P = 0.02, single tailed t-test). Note that CTS verum combines results across both CTS-local and
CTS-distal study arms. Error bars represent SEM. P 5 0.05;
Reduced median sensory nerve latency following verum acu- 
P 5 0.01.
puncture therapy showed a trending correlation (r = 0.26,
S1 neuroplasticity from acupuncture in CTS BRAIN 2017: 140; 914–927 | 921

P = 0.09) with % change in BCTQ symptom score. A signifi-

cant correlation (r = 0.37, P = 0.03) between reduced latency
following verum acupuncture and BCTQ symptom score at
3-month follow-up was also noted.

Somatosensory cortical mapping

with functional MRI
For each subject, the peak vertex for the most significant
cluster in S1 was extracted for each digit and cortical sep-
aration distance for each digit pair was calculated, with D2/
D3 separation serving as primary outcome based on past
research (Napadow et al., 2006, 2007a; Dhond et al.,
2012; Maeda et al., 2014). Due to subject drop-out and
technical limitations (e.g. head motion 4 3 mm, scanner
artefacts, etc.), for either the baseline and/or post-therapy
Figure 4 S1 somatotopy response predicts clinical re-
MRI evaluations of the two digits, change in D2/D3 separ- sponse. Change in S1 cortical separation distance for affected digits
ation distance was calculated for 36 subjects (local: n = 11, 2 and 3 immediately following verum acupuncture was negatively
distal: n = 13, sham: n = 12). A 2  2 repeated measures correlated with change in symptom severity assessed by BCTQ at
ANOVA found no significant Group (local, distal 3-month follow-up, demonstrating capacity of S1 neuroplasticity
acupuncture)  Time (baseline, post-therapy) interaction metrics to predict long-term clinical outcomes following acupunc-
for verum acupuncture groups [F(1,22) = 0.64, P = 0.43], ture therapy for CTS.
and thus local and distal acupuncture groups were com-
bined into a single verum group for subsequent analyses.
A repeated measures ANOVA demonstrated a significant
Group (verum, sham acupuncture) main effect change: P = 0.92; D3/D5: 0.6  2.6, P = 0.42, % change:
P = 0.35).
[F(1,34) = 7.30, P = 0.01], but no Time (baseline, post-ther-
We then investigated whether changes in D2/D3 separ-
apy) main effect [F(1,34) = 2.19, P = 0.15], nor
ation distance following verum acupuncture were asso-
Group  Time interaction [F(1,34) = 2.64, P = 0.11].
ciated with post-therapy or 3-month follow-up CTS
Post hoc analysis found trending significance for greater
clinical outcomes. We found that change in D2/D3 separ-
increase in D2/D3 separation distance for verum (post-acu-
ation distance was negatively correlated with % change in
puncture baseline = 1.8  3.2 mm, mean  SD), compared
BCTQ symptom score at 3-month follow-up (r = 0.48,
to sham ( 0.1  3.2 mm) acupuncture (unpaired t-test,
P = 0.03, Fig. 4). This association also existed for %
P = 0.10), and a significant group difference using %
change in D2/D3 separation (Spearman rho = 0.51,
change scores (Mann-Whitney U-test, P = 0.04), which
P = 0.02). Change in D2/D3 separation (r = 0.10,
were non-normally distributed (Shapiro-Wilk test).
P = 0.65; or % change, rho = 0.13, P = 0.58) was not asso-
Furthermore, D2/D3 separation distance (P = 0.014, one-
ciated with % change in BCTQ symptom score immedi-
sample t-test) and % change (P = 0.004, Wilcoxon Signed
ately after therapy.
Rank test) were significantly increased for verum, but not
sham (P = 0.93; % change: P = 0.94) acupuncture. Based
on these results, we also evaluated if either verum acupunc- Assessment of S1-adjacent white
ture group individually demonstrated increased D2/D3 sep- matter microstructure with diffusion
aration distance compared to sham acupuncture, and found
that local (2.3  2.3 mm, P = 0.02, one-sample t-test; % tensor imaging
change: P = 0.02, Wilcoxon), but not distal To better understand the mechanisms by which different
(1.3  3.9 mm, P = 0.18; % change: P = 0.21) acupuncture, forms of acupuncture improve CTS clinical outcomes, we
increased D2/D3 separation (Fig. 3 and Table 1). also evaluated white matter microstructure adjacent to S1
Exploratory analyses also evaluated D2/D5 (n = 39, local: using a masked-skeleton analysis. First, we found that com-
n = 12, distal: n = 14, sham: n = 13) and D3/D5 (n = 40, pared to healthy adults, CTS patients demonstrate
local: n = 14, distal: n = 13, sham: n = 13) S1 separation increased fractional anisotropy within four distinct clusters
distance, and found that verum acupuncture also increased along the white matter skeleton adjacent to: (i) S1-hand
D2/D5 distance (1.8  4.5 mm, mean  SD, P = 0.047, one- area contralesional to the more affected CTS hand
sample t-test; % change: P = 0.02) but not D3/D5 distance [x = 34.2, y = 27.8, z = 44.5; FWE corrected P 5 0.05,
(0.4  4.4, P = 0.68; % change: P = 0.29), while sham did threshold-free cluster enhancement (TFCE)]; (ii) S1-hand
not change either metric (D2/D5: 0.1  3.0, P = 0.88, % area ipsilesional to the more affected hand (x = 40.0,
922 | BRAIN 2017: 140; 914–927 Y. Maeda et al.

significant correlation between fractional anisotropy and

median sensory nerve latency changes (r = 0.37, P = 0.03)
after verum acupuncture. Fractional anisotropy change
after sham acupuncture showed no correlation with latency
change (r = 0.26, P = 0.28). Interestingly, for the ipsilesional
hand area cluster, we found a significant correlation be-
tween changes in fractional anisotropy and median sensory
nerve latency changes (r = 0.46, P = 0.04) after local, but
not after distal (r = 0.05, P = 0.87) or sham (r = 0.01,
P = 0.96) acupuncture. In contrast, for the ipsilesional leg
area cluster, we found a significant correlation between
changes in fractional anisotropy and median sensory
nerve latency changes (r = 0.56, P = 0.03) only after
distal, and not local (r = 0.09, P = 0.72) or sham
(r = 0.33, P = 0.16) acupuncture. For the S1-face area clus-
ter, there were no significant correlations for any therapy
group. Additionally, no significant correlations for changes
Figure 5 S1-adjacent white matter microstructure differs
in radial diffusivity were noted.
between CTS and healthy control subjects. DTI analyses of
white matter adjacent to S1 showed increased fractional anisotropy
(FA) and correspondingly reduced radial diffusivity (RD) in both
contralesional and ipsilesional hand areas, and ipsilesional leg area,
for CTS compared to healthy controls (HC).
Discussion
Our randomized controlled neuroimaging trial evaluated S1
neuroplasticity supporting acupuncture mechanisms for
CTS. We found that while both verum and sham acupunc-
y = 22.0, z = 45.7); (iii) S1-leg area ipsilesional to the
ture reduced CTS symptoms, verum was superior to sham
more affected hand (x = 11.8, y = 38.2, z = 60.9); and
(iv) S1-face area contralesional to the more affected hand in producing improvements in neurophysiological out-
(x = 49.5, y = 16.7, z = 35.7) (Fig. 5). The S1 masked comes, both local to the wrist (i.e. median sensory nerve
skeleton analysis also found that compared to healthy conduction latency) and central (i.e. D2/D3 S1 cortical sep-
adults, CTS patients demonstrated reduced radial diffusiv- aration distance in the brain). In fact, while both D2/D3
ity in a similar S1 ipsilesional hand and leg area (FWE and D2/D5 were increased by verum acupuncture, D3/D5
corrected P 5 0.05, TFCE). There was also a trend (FWE was not, suggesting that D2 shifted ventrally along S1,
corrected P 5 0.08, TFCE) for reduced radial diffusivity in away from both D3 and D5. Furthermore, greater improve-
an S1-hand area contralesional to the more affected CTS ment in D2/D3 separation following verum acupuncture
hand (similar in location to the region with increased frac- predicted sustained improvement in symptom severity at
tional anisotropy, above). No significant group differences 3-month follow-up, thus linking improvements in S1 soma-
for mean or axial diffusivity were noted. totopy with long-term clinical outcomes. Interestingly,
We thereafter assessed fractional anisotropy and radial verum acupuncture at distal sites on the lower leg contrale-
diffusivity changes following therapy. As age significantly sional to the more affected hand also reduced symptoms
correlated with mean fractional anisotropy and radial dif- and was superior to sham acupuncture in improving
fusivity in the skeleton at baseline (r = 0.39; P = 0.002; median nerve conduction latency. DTI of S1-adjacent
r = 0.44, P 5 0.001, respectively) but sex did not white matter found increased fractional anisotropy and
(P = 0.33, P = 0.68, respectively), subsequent analyses used reduced radial diffusivity in CTS near bilateral hand areas
a repeated measures ANCOVA (factors Cluster, Time and and ipsilesional leg area compared to healthy control sub-
Group), controlling for age. For fractional anisotropy, there jects. Longitudinal results demonstrated that improvement
was no significant Cluster (four S1 areas)  Group (verum, in median nerve latency was associated with reduced frac-
sham acupuncture)  Time (baseline, post-therapy) inter- tional anisotropy near (i) contralesional S1-hand area fol-
action [F(2.6,142.9) = 1.17; P = 0.32] nor Group  Time lowing verum, but not sham, acupuncture; (ii) ipsilesional
interaction [F(1,55) = 1.67; P = 0.20]. For radial diffusivity S1-hand area following local, but not distal or sham, acu-
there was also no significant Cluster  Group  Time inter- puncture; and (iii) ipsilesional S1-leg area following distal,
action [F(2.7,148.1) = 1.73; P = 0.17] nor Group  Time but not local or sham, acupuncture. As these S1 subregions
interaction [F(1,55) = 0.11; P = 0.74]. We then investigated are distinctly targeted by local versus distal acupuncture
if interindividual differences in fractional anisotropy electrostimulation, acupuncture at local versus distal sites
changes following therapy were associated with improve- may improve median nerve function at the wrist by soma-
ments in median sensory nerve conduction latency (Fig. 6). totopically distinct S1-mediated neuroplasticity following
For the contralesional S1-hand area cluster, we found a therapy.
S1 neuroplasticity from acupuncture in CTS BRAIN 2017: 140; 914–927 | 923

Figure 6 Post-therapy improvement in nerve conduction studies is associated with somatotopically-specific post-therapy
improvements in white matter microstructure. Longitudinal DTI analyses demonstrated somatotopic specificity for improvements fol-
lowing acupuncture therapy at distinct body sites (i.e. local versus distal acupuncture therapy arms). Specifically, reduction in median nerve latency
was associated with decreased fractional anisotropy (FA) near (i) contralesional hand area following verum, but not sham, acupuncture;
(ii) ipsilesional hand area following local, but not distal or sham, acupuncture; and (iii) ipsilesional leg area following distal, but not local or sham,
acupuncture.

Following up on our pilot acupuncture neuroimaging electro-acupuncture interventions that do provide more
study for CTS (Napadow et al., 2007b), this study is the prolonged (compared to sham acupuncture) and regulated
first sham controlled neuroimaging acupuncture study for afference to the brain.
CTS. Other acupuncture clinical trials for CTS (Yao et al., Interestingly, while local and distal acupuncture therapy
2012), similar to our study, found no difference between did not differ in post-treatment change in median nerve
verum and sham acupuncture for symptom reduction—a conduction latency (and both showed improvements rela-
subjective/psychological outcome. However, our results tive to sham acupuncture), the mechanisms supporting
demonstrate that objective/physiological outcomes (both these improvements may be associated with distinct, soma-
at the wrist and in the brain) do show specific improvement totopically-mediated plasticity in S1-adjacent white matter
for verum acupuncture. Controversy persists as to whether (Fig. 7). Specifically, for CTS patients treated with local
or not acupuncture differs from placebo. Sham acupunc- acupuncture, improvements in median nerve latency were
ture, which certainly imparts afference via cutaneous recep- associated with reduction of fractional anisotropy, a DTI
tors and subsequent brain response (Huang et al., 2012) measure of white matter integrity, near ipsilesional S1-hand
may, as a sham device coupled with specific ritual, produce area. In contrast, for CTS patients treated with distal acu-
a stronger placebo effect than a placebo-drug pill, for in- puncture, improvements in median nerve latency were in-
stance (Linde et al., 2010). In fact, our results may be stead associated with reduction of fractional anisotropy
analogous to a sham-controlled study of albuterol inhaler near ipsilesional S1-leg area. A baseline comparison found
for asthma, which demonstrated that while sham acupunc- that CTS patients showed increased fractional anisotropy in
ture and placebo inhaler was as effective as an albuterol these S1-adjacent areas compared to healthy control sub-
inhaler in terms of symptom reduction, objective physio- jects, with concomitantly decreased radial diffusivity in the
logical outcomes (i.e. spirometry to assess forced expiratory same areas, suggesting that increased diffusion anisotropy
volume) did demonstrate significant improvement for albu- was due to reduced diffusion perpendicular to principle
terol (Wechsler et al., 2011); the authors suggested that white matter fibre direction. While the interpretation of
patient self-report of symptom severity may be less reliable such changes is not well understood, it may be compensa-
from a clinical management standpoint compared to object- tory, e.g. increased myelination (Beaulieu, 2002) as a form
ive physiological outcomes. Chronic pain disorders simi- of maladaptive neuroplastic response to CTS-associated
larly lack established biomarkers or objective outcomes afference. Neuronal activity can regulate myelination in
(Tracey, 2011). However, for CTS, a neuropathic pain dis- the brain (Baraban et al., 2016), and reduced radial diffu-
order, local peripheral nerve outcomes are well established sivity and increased fractional anisotropy is consistent with
and candidate S1-based outcomes have also been described. increased myelination, with the latter noted in human and
Our results suggest that such outcomes may be less suscep- animal models of learning (Blumenfeld-Katzir et al., 2011;
tible to sham acupuncture, which may instead modulate Zatorre et al., 2012). Thus, fractional anisotropy reduc-
known placebo circuitry (e.g. prefrontal cortex, ventral stri- tions (e.g. in S1-adjacent white matter for CTS) may be
atum etc.) (Wager et al., 2015). In turn, median nerve con- beneficial, and have been noted following sensorimotor
duction and S1 neuroplasticity may be more sensitive to training in musicians, ballet dancers, and car racing
924 | BRAIN 2017: 140; 914–927 Y. Maeda et al.

Figure 7 Schematic summarizing CTS response to acupuncture therapy. (A) While distal acupuncture at the leg can modulate median
nerve function via indirect S1 interhemispheric neuroregulatory pathways, local acupuncture can modulate median nerve function at the wrist via
both indirect (e.g. S1 influences on the central autonomic control of local vasa nervorum) and direct pathways (e.g. direct axon reflex mediated
control of local vasa nervorum). (B) Our results demonstrate that electro-acupuncture can produce improvement in symptoms, median nerve
function, and S1 neuroplasticity, with objective changes following therapy (median nerve function, functional S1 neuroplasticity) directly predicting
long-term symptom improvement.

gamers (Imfeld et al., 2009; Hanggi et al., 2010; Hofstetter acupuncture, ipsilesional S1-leg area is activated by distal
et al., 2013). In our study, improvements in median nerve acupuncture (Maeda et al., 2013b). Thus, clinically-relevant
latency following acupuncture were indeed associated with fractional anisotropy changes for both local and distal acu-
reduced fractional anisotropy in S1-adjacent white matter. puncture were not diffusely distributed throughout S1-ad-
While speculative, repetitive electrical stimulation in verum jacent white matter, but were instead localized to areas
acupuncture may reduce white matter myelination, though adjacent to S1 subregions specifically targeted by wrist
other mechanisms may also play a role (e.g. axonal mem- versus leg acupuncture. Notably, a combined sample of
brane, glial morphometry changes) to reduce fractional an- local and distal acupuncture treated CTS patients showed
isotropy and increase radial diffusivity in conjunction with that improvement in median nerve latency was associated
beneficial changes in peripheral median nerve function with reduction of fractional anisotropy near contralesional
(Beaulieu, 2002). S1-hand area following therapy. Hence, fractional anisot-
Our previous functional MRI results showed that while ropy reduction in this contralesional region likely plays a
ipsilesional S1-hand area is deactivated by local role in the common pathway for both groups in
S1 neuroplasticity from acupuncture in CTS BRAIN 2017: 140; 914–927 | 925

neuroregulatory control of peripheral nerve function in nerve conduction latencies, and suggests that brain neuro-
CTS (Fig. 7). Notably, while the associations between frac- plasticity following therapy can also be sustained.
tional anisotropy change and changes in median nerve la- Interestingly, we found that cortical D2/D3 separation in-
tency were provocative, we did not find group-level crease following verum acupuncture predicted sustained re-
improvements (i.e. reduction) in fractional anisotropy fol- duction in symptom severity at 3-month follow-up, thus
lowing acupuncture for any group. The lack of fractional linking improvements in S1 somatotopy with prediction
anisotropy reduction on a group level may have been due of long-term clinical outcomes. The fact that symptom se-
to a longer duration of time required for structural, in this verity reduction immediately after verum acupuncture did
case white matter, plasticity. Hence, correlations between not correlate with D2/D3 separation improvements suggests
median nerve latency improvements and fractional anisot- a more gradual mechanism by which S1 cortical plasticity
ropy reduction may have been driven by a subset of highly steadily affects plasticity in other brain regions that play an
responsive patients with faster changes in white matter important role in determining symptom severity ratings,
microstructure. Furthermore, while local acupuncture such as prefrontal cognitive and limbic affective brain re-
increased cortical representation D2/D3 separation distance gions. Alternatively, S1 plasticity may require time to affect
in contralesional S1-hand area, distal acupuncture did median nerve function, potentially by the central autonomic
not, suggesting that functional cortical re-mapping is control pathways noted above, and future studies should
downstream of peripheral nerve changes, as both local also assess long-term changes in median nerve conduction
and distal acupuncture improved nerve conduction latencies to better understand the interrelatedness of plasti-
study outcomes, and that, similar to above, a longer dur- city in the central and peripheral nervous system with pa-
ation of time is also required for functional plasticity fol- tient reported symptom outcomes.
lowing peripheral nerve improvements. Future Limitations to our study should be noted. Due to the
longitudinal studies should sample imaging outcomes at duration of therapy and human subjects research ethics
a greater number of time points and determine the tem- board stipulations, subjects were un-blinded as to treat-
poral order of peripheral versus central changes following ment group following post-therapy MRI scan session, po-
acupuncture therapy. tentially confounding our finding of worsening symptom
While the mechanism by which brain-based plasticity severity for sham acupuncture at 3-month follow-up.
might influence median nerve function in CTS is unknown, Therefore, links to long-term clinical outcomes were re-
possibilities include central autonomic control of the vascular stricted to the verum group only. Reduced symptom se-
tone for arterioles feeding the vasa nervorum of the median verity following verum acupuncture was found to be
nerve, as intraneural blood flow is known to be controlled by maintained 3-months following therapy, consistent with
sympathetic innervation (Lundborg, 1988). In fact, a recent prior clinical trials (Yang et al., 2011), and our data
neuroimaging meta-analysis noted S1 as part of a network of demonstrated that such long-term relief may depend on
brain regions regulating autonomic, particularly sympathetic, successful reversal of maladaptive plasticity in S1, i.e.
outflow (Beissner et al., 2013). In addition, our recent study D2/D3 separation distance (an objective measure). Thus,
in patients with chronic pain found that pain-evoked increase un-blinding post-therapy may not have confounded the
in S1 connectivity to the anterior/middle insula cortex was verum as much as sham acupuncture arm. In addition,
associated with reduced cardiovagal modulation (Kim et al., we did not correct for multiple regions of interest in our
2015). These studies link S1 with central control of auto- analyses linking nerve conduction study changes with lon-
nomic tone and future studies should explore if, for example, gitudinal changes in DTI metrics. However, these regions
S1-insula connectivity is also associated with both autonomic of interest were localized in white matter adjacent to dis-
(e.g. sympathetic) and median nerve conduction response to tinct somatotopically-defined subregions of S1. Thus,
acupuncture in CTS patients. Another mechanism by which we made regionally-bounded hypotheses for these
acupuncture, particularly local acupuncture, modulates comparisons as regions of interest were differentially tar-
median nerve vasa nervorum blood flow may be via anti- geted by different acupuncture intervention groups, allow-
dromic vasodilation following stimulation of spinal dorsal ing for a region of interest-specific hypothesis for each
roots–an effect mediated by calcitonin gene-related peptide group.
(Sato et al., 1994, 2000). Ultrasound studies have explored In conclusion, while both verum and sham acupuncture
median nerve hypervascularity (Ghasemi-Esfe et al., 2011; reduced CTS symptoms, verum acupuncture was superior
Ooi et al., 2014), a compensatory response to ischaemia to sham in producing improvements in both peripheral and
within the tunnel, and future studies should link median brain neurophysiological outcomes. Furthermore, improve-
nerve vascularity with neuroplasticity response to acupunc- ment in functional S1 plasticity immediately following acu-
ture therapy. puncture predicted long-term symptom relief. Interestingly,
We also found that CTS symptom reduction persists DTI analysis of white matter microstructure found that
3 months after cessation of verum acupuncture therapy. acupuncture at local versus distal acupuncture sites may
These improvements are in-line with previous clinical improve median nerve function at the wrist by somatoto-
trials of acupuncture for CTS (Yang et al., 2011), which pically distinct S1-mediated neuroplasticity following ther-
reported lasting improvements for both symptoms and apy. Our study suggests that acupuncture may improve
926 | BRAIN 2017: 140; 914–927 Y. Maeda et al.

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