NERVE COMPRESSION, MEMBRANE EXCITABILITY, AND SYMPTOMS

OF CARPAL TUNNEL SYNDROME

S. ERIC HAN, BE, CINDY S.-Y. LIN, PhD, ROBERT A. BOLAND, PhD, and MATTHEW C. KIERNAN, DSc
Neuroscience Research Australia & Prince of Wales Clinical School, University of New South Wales,
Barker Street, Randwick, New South Wales 2031, Australia
Accepted 15 February 2011
ABSTRACT: Introduction: In this study we investigated the
changes in axonal excitability and the generation of neurological
symptoms in response to focal nerve compression (FNC) of the
median nerve in carpal tunnel syndrome (CTS). Methods: Sensory excitability recordings were undertaken in 11 CTS patients
with FNC being applied at the wrist using a custom-designed
electrode. Results: During FNC, refractoriness increased significantly (62.4 6 3.4%; P < 0.001), associated with a rapid reduction in superexcitability (16.9 6 2.8%; P < 0.001) and sensory
nerve action potential amplitude (SNAP) (32.4 6 3.9%; P <
0.001), consistent with axonal depolarization. Associated with
these changes, paresthesiae steadily increased throughout
FNC, as did numbness. Reductions in SNAP amplitude and
superexcitability developed more rapidly for CTS patients during
FNC compared with controls, and these changes were associated with more marked symptoms. Conclusions: Axonal
responses to compression are impaired in CTS. This may suggest a greater reliance on axonal membrane Na/K-ATPase
function.
Muscle Nerve 44: 402409, 2011

Carpal tunnel syndrome (CTS) is the most prevalent human entrapment neuropathy, encompassing 45% of all non-traumatic nerve lesions.1 Despite the high direct medical, nancial, and
occupational costs associated with CTS,2,3 the
pathophysiology still remains a subject of debate.
The key factors that appear to underlie the pathophysiology and consequent symptoms are primarily
linked to the effects of nerve compression and
ischemia.46 Pathological studies in CTS have demonstrated focal disturbances in myelin and paranodal demyelination,79 perhaps suggesting that pure
compression is the more signicant contributor. In
support of such an hypothesis, nerve conduction
studies demonstrate focal slowing of the median
nerve at the level of the wrist, and compound
amplitudes may be reduced in the absence of
objective sensory loss.10,11
Recently, it was demonstrated that focal compression applied to the median nerve in healthy
individuals resulted in axonal depolarization.12,13
Although focal slowing of median nerve conduction in CTS may suggest evidence of altered restAbbreviations: ATPase, adenosine triphosphatase; CTS, carpal tunnel
syndrome; CV, conduction velocity; FNC, focal nerve compression; K,
potassium ion; Kv, voltage-dependent potassium (channel); Na, sodium
ion; NCS, nerve conduction studies; SDTC, short-duration threshold
change; SNAP, sensory nerve action potential; vFF, von Frey filament
Key words: carpal tunnel syndrome, nerve compression, nerve excitability,
numbness, paresthesiae
Correspondence to: M. C. Kiernan; e-mail: m.kiernan@unsw.edu.au
C 2011 Wiley Periodicals, Inc.
V

Published online 15 August 2011 in Wiley Online Library (wileyonlinelibrary.

com). DOI 10.1002/mus.22078

402

Focal Nerve Compression in CTS

ing membrane potential, this remains unresolved.

Meanwhile, it has been suggested that morphological changes involving axons in CTS patients are
perhaps a more crucial factor underlying the generation of symptoms, rather than purely ischemia.
In a previous study that compared the sensitivity
of sensory axons to the effects of ischemia in both
CTS patients and controls, it was suggested that
CTS patients have a greater reliance on axonal
membrane Na/K-ATPase function for the maintenance of resting membrane potential.11 If axons of
CTS patients exhibited greater reliance on Na/KATPase function, it may be further hypothesized
that CTS patients would demonstrate greater sensitivity to the effects of compression than controls,
potentially precipitating a depolarization conduction
block. Consequently, in this study we applied focal
compression to CTS patients to determine whether
subsequent alteration in the function of axonal
membrane ion conductances may contribute to the
development of conduction failure and thereby
patient symptoms and signs.
METHODS

Sensory nerve excitability was monitored before, during, and after focal nerve compression in patients
diagnosed with CTS. Studies were approved by
the South East Sydney Area Health Service Human
Research Ethics Committee (Eastern Section) and
the human research ethics committee of University
of New South Wales. Informed consent was provided
by each subject, and studies were undertaken in
accordance with the Declaration of Helsinki.
Patients were diagnosed with CTS based on the
combination of clinical presentation, ndings on
neurological examination, and the results of nerve
conduction studies (NCS). For inclusion in this
study, in addition to a typical clinical presentation,
NCS were required to demonstrate objective slowing of median sensory conduction at the level of
the wrist and, similarly, focal slowing of the median nerve when compared with ulnar and radial
nerve studies, as per established practice parameters.10,14 A positive result for electrophysiological
diagnosis of CTS was derived from a combination
of electrodiagnostic studies as follows14,15:
1 The orthodromic proximal and distal median
sensory conduction velocity (CV), and distal
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September 2011

2
3
4
5

ulnar nerve sensory CV from the digit to the

wrist.
The amplitudes of distal and proximal median
sensory nerve action potentials (SNAPs).
The comparison of radial and median nerve
latencies after stimulation of the thumb.
The comparison of ulnar and median nerve
latencies after stimulation of the fourth digit.
The median nerve distal compound motor action
potential (CMAP) and distal motor latency (DML).

A test was considered positive abnormal if any

of the following were present:
Median distal CV less than ulnar distal CV.16
Difference of >0.4 ms between radial and median, or ulnar and median sensory latencies
taken at a distance of 100140 mm.16,17
Prolongation of median motor terminal latency
>4.6 ms.16,18
Previously established values from our laboratory
were used as normative values.19 Patients with coexisting peripheral neuropathy, cervical radiculopathy,
or metabolic disorders known to affect nerve function, such as diabetes or renal impairment, were
excluded.2022 Patients with an orthodromic median
SNAP amplitude <5 lV were ineligible for the
study, because such reduced amplitudes could not
be studied using threshold tracking techniques.
Protocol. The median nerve was stimulated electrically using a purpose-built isolated linear bipolar
constant-current stimulator (maximum output 650
mA). Electrical stimuli were delivered at the wrist
through non-polarizable surface electrodes (Unilect Long-Term; Unomedical, Ltd.). Prior to
attaching surface cathodes, the optimal stimulation
position was determined for each patient using a
hand-held electrode. A reference electrode was
positioned on the bony surface of the radius, 10
cm proximal to the cathode.
Recordings of the resultant SNAP were made
from digit II, using ring electrodes. The amplitude
of the SNAP was measured from negative to positive peak, after subtraction of the effects of conditioning stimuli (where appropriate). The resultant
response was amplied (Medelec, Ltd., Old Woking, Surrey, UK), digitized with an analog/digital
board (DAQ card for PCMCA; National Instruments) and then imported to a personal computer. Stimulation and recording protocols were
C Institute of Neurology,
determined by QTRAC (V
London). Skin temperature was recorded at the
site of stimulation using a purpose-built thermometer. It was monitored throughout each study and
was maintained around 32
C.
Focal Nerve Compression in CTS

Focal compression was delivered at the site of

electrical stimulation using a custom-designed and
-developed compression device.12 The functional
components of the device included an arm-stabilizing platform, compression electrode, and strain
sensors (GFLA-6.350-70 strain gauges; Tokyo Sokki
Kenkyujo Co.). The arm of each CTS patient was
encased and strapped using Velcro into a stabilizing platform. The threaded compression electrode
was lowered using a gradual rotation maneuver to
achieve focal compression. Strain sensors were
used to monitor the level of compression achieved.
The voltage signals from the sensors were amplied (Strain Gauge Transmitter WT127; APCS, Lilyeld, Australia), digitized with a DAQ card,
imported into QTRAC, and displayed in real time.
Using real-time feedback, focal compression was
carefully achieved to 154.3 kPa (equivalent to 12.1
N) and maintained using the lower threaded section of the electrode making compensatory adjustments in response to any subsequent tissue
relaxation.
A multitrack protocol was used for real-time
monitoring of focal compression and also for
recordings of nerve excitability. Nerve excitability
was measured across different channels as follows.
A target response from the steepest portion of the
stimulusresponse curve of SNAP was tracked
using two different stimulus durations on channel
1 (0.5 ms) and channel 6 (0.1 ms). Superexcitability, measured at 6.3 ms after a supramaximal conditioning stimulus (channel 9), was tracked on
channel 10. Refractoriness, measured at 2.5 ms after a supramaximal conditioning stimulus (channel
11), was tracked on channel 12. The ratio between
thresholds from channels 1 and 6 was used to calculate the strengthduration time constant.2325
Prior to application of focal compression, a stable baseline recording was established for at least 4
min. Focal compression was then slowly and steadily applied. Once the target compression level had
been achieved, the level of compression was maintained for a mean duration of 18.8 6 1.3 min (median duration of 20 min), followed by 15 min of
recovery. Nerve excitability was recorded at a frequency of 1 HZ. Patients were seated in a chair
and were encouraged to remain still for the duration of the study.
Prior to application of FNC and while baseline
nerve excitability recordings were being undertaken, CTS patients were asked to rate the perceived intensity of paresthesiae, using a 010
visual-analog scale, with 0 reecting no symptoms
and 10 indicating unbearable symptoms.2,26
Patients were then asked to rate the intensity of
their symptoms every 30 s throughout the remainder of each study. In addition, von Frey laments
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403

Table 1. Results of standard nerve conduction studies recorded from the 11 CTS patients.
Patient

Digit IIwrist SNAP

amplitude (lV)

Digit IIwrist
CV (m/s)

Median forearm
CV (m/s)

Digit Vwrist
CV (m/s)

Latency
difference (ms)

1
2
3
4
5
6
7
8
9
10
11
Mean

13.5
11.1
6.1
5.7
22.7
13.7
22
16
19.9
16
18.5
15.0 6 1.7

42.6
52.7
43.5
38.4
50.5
39.3
44.7
38.2
40.7
41.4
47.1
43.6 6 1.5

67.8
57.3
65.0
58.8
61.5
62.1
58.5
61.2
48.8
55.3
56.6
59.4 6 1.5

53.5
52.7
45.6
54.9
56.5
55.3
54.4
50.0
52.3
48.6
55.2
52.6 6 1.0

1.50
0.60
0.30
1.15
0.60
0.65
1.10
0.75
0.90
0.90
0.30
0.80 6 0.11

SNAP amplitudes were measured peak to peak. Latency difference was calculated as the mean difference between median/radial and median/ulnar comparisons (see Methods).

(Marstocknervtest; Fruhstorfer, Schriesheim, Germany) were applied to the tip of the third digit every minute to objectively rate the development of
numbness. Again, tactile sensitivity was tested prior
to FNC during the baseline recording of nerve
excitability. A von Frey lament (vFF) force scale
was used to assess tactile sensitivity.11,12
Analysis. All results were expressed as mean 6
standard error of the mean. Measurements
recorded during FNC were normalized to the rst
measurements obtained after stabilization of FNC
to eliminate any artifact that may have resulted
during the process of applying compression.
Paired t-tests were used for single comparisons of
excitability parameters, with P < 0.05 considered
signicant.
For the purpose of comparing FNC-induced
excitability changes in CTS patients with controls,
data from a previous series were utilized.12 This
previous series involved monitoring 10 control subjects (5 men and 5 women, aged 2245 years,
mean 31.5 years) for changes in nerve excitability
before, during, and after the application of FNC.
The experimental paradigm and protocols used to
record nerve excitability were identical to those utilized in this study.
RESULTS

Experimental protocols were successfully completed in all 11 CTS patients (5 men and 6
women, aged 4766 years, mean 55.5 years). Each
study lasted, on average, 47.7 6 1.3 min. The
results of standard NCS, conrmatory for the CTS
patient cohort, are detailed in Table 1. Prior to
application of FNC, baseline sensory excitability of
CTS patients established a strengthduration time
constant (0.55 6 0.03 ms), refractoriness (14.5 6
2.7%), and superexcitability (16.7 6 0.9%). Skin
temperature was recorded at the site of stimulation
404

Focal Nerve Compression in CTS

and monitored throughout each study (mean temperature 32.7 6 0.2
C for CTS patients and 32.7 6
0.4
C for controls).
Changes in Threshold Induced by Focal Nerve Compression. A stimulusresponse curve was recorded
prior to undertaking excitability measures and was
utilized to determine changes in maximal SNAP
amplitude that may develop in association with
application of FNC. During FNC, for both shortand long-duration stimuli, there were minor reductions in threshold, as illustrated for a representative CTS patient (Fig. 2A and B). In most patients,
threshold reached greatest reduction in the early
phase of FNC. Despite an apparently minimal
reduction in threshold, SNAP amplitude decreased
rapidly (Fig. 2C). Mean data conrmed this signicant reduction in SNAP amplitude for CTS
patients (32.4 6 3.9%; P < 0.001), with 1 patient
developing conduction block (amplitude reduction
56.2%).
Associated with these changes in threshold and
SNAP amplitude, latency increased accordingly
during FNC (Fig. 2D), with signicant prolongation for the CTS cohort (7.7 6 0.5%; P < 0.001).
Associated with these indications of gradual inactivation of Na channels, thresholds started to
increase toward the end of the FNC period.2729
With release of FNC, the threshold for the shortand long-duration stimuli increased above baseline
levels, indicative of the development of axonal hyperpolarization (Fig. 2A and B). Analysis of mean
data for CTS patients established that this increase
in threshold was signicant for both short-duration
(20.1 6 4.1%; P < 0.005) and long-duration (26.4
6 5.9%; P < 0.005) stimuli.
This increase in threshold was relatively
reduced in CTS patients, as supported by measurement of the maximal threshold change after
release of compression for CTS patients (short
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September 2011

FIGURE 1. (A) Stimulation paradigm: threshold tracking (indicated by vertical arrows) in channels 1, 6, 10, and 12 aimed to elicit a
SNAP amplitude corresponding to the steepest portion of the stimulusresponse curve in channel 7. (B) Focal nerve compression
(FNC) and nerve excitability setup: a custom-designed and purpose-built compression device was utilized for achieving both electrical
stimulation and focal nerve compression. The SNAP generated from stimulation of the median nerve at the wrist was recorded from
the second digit. (C) The profile of compression achieved during FNC. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

duration: 21.2 6 3.6%; long duration: 27.1 6

5.4%; Fig. 3A and B), when compared with controls [short duration: 39.5 6 7.4% (P < 0.05); long
duration: 51.4 6 9.1% (P < 0.05)]. Furthermore,
within the rst 10 min of FNC application, SNAP
amplitude reduction developed more rapidly in
CTS patients (9.9 6 2.8%; Fig. 3C) compared with
controls (2.2 6 0.9%; P < 0.05).
Excitability Changes Induced by Focal Nerve Compression. The changes in threshold induced by FNC
were consistent with the development of axonal
depolarization. Specically, refractoriness, a marker
of voltage-gated transient Na channels, rose steadily
during the period of FNC (Fig. 2E), with a mean
increase of 62.4 6 3.4% (P < 0.001) relative to baseline. Consistent with membrane depolarization, there
was reduction in superexcitability (Fig. 2F), a marker
of paranodal fast K conductances. Analysis of mean
data for CTS patients established a signicant reduction in superexcitability of 16.9 6 2.8% (P < 0.001)
from baseline.
Focal Nerve Compression in CTS

To conrm that the mechanism underlying

these excitability changes related to membrane
depolarization, excitability parameters were plotted
against normalized threshold to reect the changes
in axonal membrane potential during the rst 10 min
of FNC.29 This analysis established correlations with
normalized SNAP amplitude, refractoriness, superexcitability, and short-duration threshold change (SDTC)
(Fig. 4). Of further relevance, nerve excitability
changes correlated with the neurophysiological severity
of CTS, as determined by standard NCS (Fig. 5).
Symptom Generation. After the application of
FNC, there was a rapid generation of paresthesiae
in CTS patients. Paresthesiae continued to increase
during FNC (7.6/10 6 0.8; P < 0.001; Fig. 6A),
although the rate of increase in symptom intensity
subsequently slowed over time. Gradual resolution
was then observed after release of FNC. Overall,
this pattern of change was similar to that previously observed for control subjects.
In terms of numbness, vFF was used to quantitatively indicate skin tactile sensitivity. Higher vFF
MUSCLE & NERVE

September 2011

405

(Fig. 6B), indicating signicantly impaired tactile

sensitivity compared with controls (0.8 6 0.4 mN;
P < 0.05). During the period of FNC there was an
overall increase in the mean vFF score (14.1 6 4.7
mN), greater than the changes observed in
controls.
Similarly, paresthesiae developed more rapidly
and intensely in CTS patients than controls. During the rst 10 minutes of FNC application, the cumulative score of paresthesiae for CTS patients was
43.6 6 6.6, compared with 22.7 6 6.7 for controls
(P < 0.05). During the same duration of FNC,
CTS patients demonstrated a more pronounced
increase in vFF score (7.4 6 1.8; Fig. 6B), compared with controls (2.1 6 0.8; P < 0.05).
DISCUSSION

To clarify pathophysiology, we have investigated

the effects of nerve compression on the axonal
excitability of patients with typical clinical features
and electrodiagnostic ndings of carpal tunnel syndrome. Our results have established that the
focally compressed segment of the median nerve
develops membrane depolarization during FNC

FIGURE 2. Representative excitability responses for a CTS

patient before, during, and after the application of focal nerve
compression (FNC) applied at the wrist. Lightly shaded vertical
bar represents the period during which focal compression was
applied to the target level, and the darkly shaded vertical bar
indicates the release of compression. Normalized values showing the following: (A) threshold for stimuli of 0.1-ms duration;
(B) threshold for stimuli of 0.5-ms duration; (C) supramaximal
SNAP decreasing during FNC; (D) latency increasing during
FNC; (E) refractoriness, the percentage change in threshold at
a conditioningtest interval of 2.5 ms, increasing; and (F) superexcitability, the percentage change in threshold at a conditioningtest interval of 6.3 ms, decreasing.

scores (0.25, 0.5, 1, 2, 4, 8, 16512 mN) indicated

lower tactile sensitivity, concurrent with the development of prominent numbness. Patients with
CTS had a mean score of 4.7 6 1.6 mN at rest
406

Focal Nerve Compression in CTS

FIGURE 3. Comparison between CTS and controls in their

response to FNC applied to the wrist: (A) change in short-duration threshold; (B) change in long-duration threshold; and (C)
SNAP reduction observed in the first 10 min of FNC.
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September 2011

FIGURE 4. Correlation of nerve excitability parameters with normalized threshold during 10 min of FNC in the CTS patient cohort.
Changes in (A) SDTC, (B) refractoriness, (C) SNAP amplitude, and (D) superexcitability were sensitive to threshold.

and becomes hyperpolarized with release. This pattern of change was qualitatively similar to that
observed in healthy individuals. However, the magnitude of change in nerve excitability parameters
differed for CTS patients. In addition, the development of clinical symptoms during FNC suggests

that CTS patients had a greater sensitivity to the

effects of compression. Overall, these differences
suggest impaired axonal function in CTS in
response to compression and would support an
hypothesis of greater reliance on the function of
the axonal Na/K-ATPase. Altered sensitivity and

FIGURE 5. Correlation of baseline nerve excitability parameters

compared with conventional NCS measures of CTS severity.
(A) Pre-FNC SNAP amplitude correlated with refractoriness at
baseline. (B) Distal median velocity correlated with superexcitability at baseline.

FIGURE 6. Rating of symptoms associated with FNC (filled diamond: CTS patients; open triangles: healthy controls). Black
horizontal bar indicates period of FNC. (A) Paresthesiae (010).
(B) Numbness objectively assessed by von Frey filaments.

Focal Nerve Compression in CTS

MUSCLE & NERVE

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407

axonal function in response to FNC in CTS

patients may further contribute to the pathophysiological processes responsible for the clinical features associated with this most common entrapment neuropathy.
Prior to interpretation of ndings, it is worth
noting that we recruited patients with SNAP amplitudes >5 lV. As such, patients would be classied
as mild or moderate CTS. Although patients with
severe CTS were not studied, the effects of morphological factors, such as axonal loss, axonal
attenuation, disordered myelination, and intraneural brosis, may also contribute to symptoms in
this group, at least as much as the effects of ischemia and between compression. Furthermore, correlation between severity of CTS (reected by
SNAP amplitude and median nerve conduction velocity) and baseline nerve excitability parameters
may suggest that, although SNAP amplitude correlated with refractoriness, an excitability parameter
dependent on nodal transient Na conductances,3033 it did not correlate as well with superexcitability, an excitability parameter determined by
paranodal properties (Fig. 5A).30 As such, the
study enrollment requirement of having SNAP amplitude >5 lV may have ensured a level of nodal
integrity (i.e., being morphologically intact).
Similarly, paranodal integrity, and thereby function, may also exert an inuence on the interpretation of ndings from CTS patients, given the likely
redistribution of juxtaparanodal fast K (Kv) channels that may occur with paranodal demyelination.
For instance, it is now known that juxtaparanodal
Kv channels become exposed below damaged myelin.34 Consequently the membrane potential may
come to lie closer to the K equilibrium potential,
with an overall reduction in excitability.34 It
remains plausible that such morphological and
functional processes may also contribute to the
limited extent of depolarization that developed in
CTS patients during FNC, as observed here.
Nerve Compression and Axonal Excitability. The
application of nerve compression in this study
resulted in reduction in threshold and prolongation in latency. These changes were associated with
an increase in refractoriness and reduction in
superexcitability. Excitability changes were indicative of axonal depolarization, with subsequent
reduction in SNAP amplitude, and development of
depolarization conduction block.
Although the changes in threshold appeared
less prominent in CTS patients than in controls,
there were correspondingly greater reductions in
amplitude of the SNAPs (Fig. 3). However, it
remains plausible that these greater reductions
observed in CTS patients may simply reect a
408

Focal Nerve Compression in CTS

lower baseline SNAP amplitude in patients, particularly given that the changes in excitability and
amplitude also corresponded with the severity of
CTS (Fig. 5). However, it is also noted that FNC
resulted in more rapid development of paresthesiae in CTS patients and that CTS patients experienced more prominent numbness. Such processes
may provide a basis for understanding the mechanisms of symptomatic therapy in CTS. Specically,
the use of wrist splints has remained the hallmark
of conservative therapy for CTS. Splints maintain
the wrist in a neutral or slightly extended position,
thereby preventing the development and subsequent release of compression, to provide symptomatic relief.
Given that focal nerve compression is also
known to paralyze the axonal Na/K pump, the
quantitatively greater effects documented for CTS
patients may suggest a greater reliance of axons on
normal pump function. Previous studies have demonstrated that inhibition of the Na/K pump
results in axonal depolarization.35 If the Na/K
pump exerts a hyperpolarizing inuence on resting membrane potential,36,37 inhibition of pump
function would further predispose to the development of axonal depolarization and development of
spontaneous activity such as paresthesiae, a typical
symptom of CTS.
This study was supported by a Prince of Wales Clinical School Postgraduate Research Scholarship, the National Health and Medical
Research Council of Australia (Project Grant 400938, Biomedical
Postgraduate Scholarship), and a Medical Advances without Animals Doctoral Research Scholarship.
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