From
DEPARTMENT OF CLINCIAL SCIENCE AND EDUCATION,
Karolinska Institutet, Stockholm, Sweden
THE PROPRIOCEPTION AND
NEUROMUSCULAR STABILITY
OF THE BASAL THUMB JOINT
NATHALIE MOBARGHA
Stockholm 2015
All previously published papers were reproduced with permission from the publisher.
Published by Karolinska Institutet.
Printed by E-Print, Stockholm, Sweden.
© NATHALIE MOBARGHA, 2015
ISBN 978-91-7676-032-1
2
To my beloved ones.
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ABSTRACT
OBJECTIVES
The basal thumb joint, or the first carpometacarpal joint (CMC1) is an enigmatic construction. The
concavo-convex shape of the CMC1 and wide range of movement, allows for both precision and power
grips and is particularly susceptible to the development of osteoarthritis. Previous theories regarding the
development of CMC1 osteoarthritis have focused on the role of gender, excessive joint load and ligament
laxity as causative factors. An emerging theory is the role of proprioception and sensorimotor functions
that act to maintain adequate joint equilibrium. This concept constitutes the basis of this thesis with the
intent on examining both healthy and osteoarthritic joints. Using microscopic, biomechanical and
neurophysiological methods, we address the hypothesis that CMC1 holds proprioceptive and
neuromuscular properties that are integral for proper thumb function.
METHODS
Patients with CMC1 osteoarthritis that were treated surgically with complete trapeziectomy and
suspension arthroplasty were included. Two CMC1 ligaments were collected from these subjects: the
anterior oblique ligament (AOL) and the dorsal radial ligament (DRL). Following immunofluorescent
triple staining techniques using markers p75, PGP9.5 and DAPI, the ligamentous innervation and
mechanoreceptor populations were analyzed (study I-II). In study III, biomechanical assessment of the
role of isometric muscle load on CMC1 was performed by a FASTRAK® motion tracking device. In
study IV, two intrinsic (the first dorsal interosseous muscle; DI, abductor pollicis brevis; APB,) and two
extrinsic muscles (extensor pollicis longus; EPL, abductor pollicis longus, APL) were examined in healthy
subjects using electromyographic (EMG) analysis during functional thumb tasks. Post-stimulus reactions
following stimulation of the DRL were analyzed for each muscle and each thumb position.
RESULTS
The CMC1 ligaments investigated displayed a varying degree of innervation. AOL presented with little
innervation and was mainly composed of incoherent connective tissue and scarce collagen fibers, whereas
DRL presented with abundant innervation and well-organized collagen (study I). Unclassifiable
mechanoreceptors were the most frequent type of receptor found in AOL and DRL. No significant
difference in the innervation between the proximal and distal portions of these osteoarthritic ligaments was
identified (study II). The first dorsal interosseous muscle (FDI or DI) produced the highest level of distal
migration and the least dorsoradial translation of the base of the first metacarpal. APL was identified as
the main destabilizer as it increases dorsoradial misalignment (study III). Following stimulation of the
DRL, significant (p<0.05) post-stimulus changes were found in all four muscles (DI, APB, APL, EPL) and
positions tested. A mass inhibitory reaction was observed during tip pinch whilst key pinch produced rapid
co-contractions. During palmar pinch a rapid inhibitory response was evoked in antagonistic muscles
(study IV).
CONCLUSIONS
Ligaments from osteoarthritic patients displayed alterations in distribution and type of mechanoreceptors
as compared to previous studies on normal joints. The results reinforce DRL’s proprioceptive and
stabilizing role for the CMC1 joint. Isometric load of CMC1indicates that DI promotes joint congruency
by reducing dorsoradial translation, whereas APL acts in an opposing manner as a destabilizing force.
Ligamento-muscular reflexes were observed following the stimulation of DRL. Thus, the dorsoradial
ligament, in addition to being the primary static stabilizer of the joint, also possesses proprioceptive
qualities. The post-stimulus reactions detected in DI, APB, APL and EPL are indicative of protective
ligamento-muscular pathways, which facilitate neuromuscular functions and the maintenance of joint
stability.
CLINICAL RELEVANCE
Patients with CMC1 osteoarthritis constitute a large group. Their symptoms are of varying severity, where
some can be addressed within the scope of primary care units, whilst others are in need of operative
treatment. Patients with CMC1 osteoarthritis often present with impaired neuromuscular functions,
reduced range of motion, weakness, joint and ligamentous pathology as well as pain, which affect their
daily activities. Understanding the proprioceptive and neuromuscular characteristics of the basal thumb
joint is therefore essential in deciphering the complex pathophysiology of the basal thumb joint.
Key words: basal thumb joint, trapeziometacarpal joint, carpometacarpal joint, ligament, proprioception,
neuromuscular, osteoarthritis
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LIST OF SCIENTIFIC PAPERS
This thesis is based on the following scientific papers, which are referred to in the text
by their roman numerals.
I
Mobargha N, Ludwig C, Ladd AL, Hagert E.
Ultrastructure and innervation of thumb carpometacarpal ligaments in
surgical patients with osteoarthritis.
Clinical Orthopaedics and Related Research. April 2014, Vol 472, Issue 4.
II
Ludwig C*, Mobargha N*, Hagert E, Okogbaa J, Ladd AL.
* Shared first authorship
Altered Innervation Pattern in Ligaments of Patients with Basal
Thumb Arthritis.
Journal of Wrist Surgery. In press.
III
Mobargha N, Esplugas M, Garcia-Elias M, Lluch A, Megerle K, Hagert E.
The Effect of Isometric Muscle Load on the Basal Thumb Joint: a
Cadaveric Study.
Journal of Hand Surg (Eur) Vol. 2015 Aug 6.
IV
Mobargha N, Rein S, Persson KE J, Hagert E.
Ligamento-muscular reflex patterns following stimulation of a thumb
carpometacarpal ligament: an electromyographic study.
Manuscript.
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CONTENTS
1 THESIS AT A GLANCE .............................................................................................. 9
2 INTRODUCTION ....................................................................................................... 12
2.1 BACKGROUND ............................................................................................ 12
2.1.1 Osteology ............................................................................................ 13
2.1.2 Muscles ............................................................................................... 14
2.1.3 Ligaments ........................................................................................... 15
2.1.4 Innervation .......................................................................................... 17
2.2 PROPRIOCEPTION AND NEUROMUSCULAR MECHANISMS ............ 18
2.2.1 Mechanoreceptors............................................................................... 18
2.3 OSTEOARTHRITIS ...................................................................................... 19
2.3.1 CMC1 Osteoarthritis .......................................................................... 21
3 AIMS OF THE INVESTIGATION .......................................................................... 22
4 MATERIAL AND METHODS ................................................................................. 23
4.1 ETHICAL CONSIDERATIONS ................................................................... 23
4.2 MORPHOLOGICAL AND IMMUNOHISTOCHEMICAL
PROCEDURES .............................................................................................. 23
4.2.1 Immunohistochemistry ....................................................................... 23
4.2.2 Primary antibodies .............................................................................. 23
4.2.3 Secondary antibodies and nuclear labeling ........................................ 24
4.2.4 Immunofluorescence imaging ............................................................ 24
4.2.5 Morphological analysis ...................................................................... 24
4.3 BIOMECHANICAL ASSESSMENT ............................................................ 26
4.3.1 Preparation of specimens .................................................................... 26
4.3.2 Biomechanical analysis ...................................................................... 27
4.4 ELECTROMYOGRAPHIC PROCEDURES ................................................ 28
5 RESULTS ..................................................................................................................... 30
5.1 IMMUNOHISTOCHEMICAL STUDIES ..................................................... 30
5.1.1 Structural differences.......................................................................... 30
5.1.2 Innervation of ligaments ..................................................................... 31
5.1.3 Distribution of mechanoreceptors ...................................................... 32
5.2 BIOMECHANICAL STUDY ........................................................................ 33
5.3 NEUROPHYSIOLOGICAL STUDY ............................................................ 35
5.3.1 General observations .......................................................................... 35
5.3.2 Specific observations .......................................................................... 35
6 SUMMARY OF RESULTS ....................................................................................... 37
7 DISCUSSION............................................................................................................... 38
7.1 PROPRIOCEPTIVE FEATURES.................................................................. 38
7.2 NEUROMUSCULAR MECHANISMS ........................................................ 39
7.3 LIMITATIONS .............................................................................................. 41
6
7.4
7.5
7.3.1 Immunohistochemical methods .......................................................... 41
7.3.2 Biomechanical assessment .................................................................. 42
7.3.3 Electromyographic procedures ........................................................... 42
CLINICAL RELEVANCE ............................................................................. 43
FUTURE PERSPECTIVES ............................................................................ 44
8 CONCLUSIONS ..........................................................................................................45
9 ACKNOWLEDGEMENTS........................................................................................46
10 REFERENCES ...........................................................................................................48
11 STUDY I - IV ..............................................................................................................54
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LIST OF ABBREVIATIONS
ADD
Adductor pollicis
AOL
Anterior oblique ligament
APB
Abductor pollicis brevis
APL
Abductor pollicis longus
CMC1
First carpometacarpal joint
DAPI
49,69-diamidino-2-phenylindole
DI
First dorsal interosseous muscle (a.k.a FDI)
DRL
Dorsal radial ligament
EPB
Extensor pollicis brevis
EPL
Extensor pollicis longus
FDI
First dorsal interosseous muscle (a.k.a DI)
FPB
Flexor pollicis brevis
FPL
Flexor pollicis longus
HE
Hematoxylin and eosin staining
IP
Interphalangeal joint
IF
Immunofluorescence
MC1
First metacarpal
MCP
Metacarpophalangeal joint
OA
Osteoarthritis
OPP
Opponens pollicis
p75
Low-affinity nerve growth factor receptor p75
PGP9.5
Protein gene product 9.5
TMC
Trapeziometacarpal
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1 THESIS AT A GLANCE
STUDY I
Ultrastructure and innervation of thumb carpometacarpal ligaments in surgical
patients with osteoarthritis [1].
Are osteoarthritic CMC1 ligaments innervated with mechanoreceptors?
Material: Two ligaments, the anterior oblique ligament (AOL) and dorsal radial
ligament (DRL), were harvested from patients with CMC1 osteoarthritis during
trapeziectomy (fig. 1).
Methods: The ligaments were sectioned at a thickness of five µm and further analyzed
using immunofluorescent triple staining techniques.
Conclusions: The CMC1 joint in osteoarthritic patients has ligaments, which are
innervated with mechanoreceptors. DRL had the highest prevalence of
mechanoreceptors.
MC1
MC1
DORSAL
VOLAR
Figure 1. Illustration of dorsal and volar CMC1 ligaments. The DRL is composed of
organized collagen fibers and reported with significantly (p<0.001) more nerve endings
and mechanoreceptors than the AOL. Courtesy of M Garcia-Elias, MD.
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STUDY II
Altered innervation pattern in ligaments of patients with basal thumb osteoarthritis
[2].
How are mechanoreceptors distributed in the CMC1 joint ligaments of osteoarthritic
patients?
Material: Ligaments from patients with osteoarthritis.
Methods: Ligaments were marked for their proximal and distal ends respectively and
immunofluorescent triple staining microscopy was performed.
Conclusions: The innervation of ligaments with no to mild signs of osteoarthritis differs
from those of surgical patients with advanced osteoarthritis, in which a predominance of
unclassifiable mechanoreceptors were detected (fig. 2).
Figure 2. Unclassifiable mechanoreceptors. Two unclassifiable corpuscles are identified
(arrowheads) and a transected arteriole (*) from an anterior oblique ligament stained
with (a) p75 (b) PGP9.5 and (c) DAPI (blue). (Reprinted with permission from Ludwig
C et al. Altered Innervation Pattern in Ligaments of Patients with Basal Thumb
Arthritis. Journal of Wrist Surgery. 2015).
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STUDY III
The Effect of Isometric Muscle Load on the Basal Thumb Joint [3].
Do certain muscles exert a destabilizing effect on CMC1?
Material: Testing of ten cadaveric specimens without any signs of CMC1 joint
osteoarthritis.
Methods: FASTRAK® sensors were used at the proximal end of metacarpals I and III
and the distal radius to evaluate the effect of individual isometric muscle loading on the
base of the thumb metacarpal relative to the radius and to the base of the middle finger
metacarpal.
Conclusions: The first dorsal interosseous muscle (DI) has the most beneficial impact
on the basal thumb joint. As such, strengthening of this muscle is recommended to
patients with CMC1 osteoarthritis, or as a part of a pre- and post-operative rehabilitation
strategy.
STUDY IV
Ligamento-muscular reflex patterns following stimulation of a thumb
carpometacarpal ligament.
Is there a ligamento-muscular reflex pathway present between the DRL and the muscles
(DI, APB, APL and EPL) acting on the CMC1 joint?
Material: 10 healthy participants with no prior hand trauma.
Methods: Ultrasound guided insertion of the DRL was followed by stimulation of the
ligament while monitoring electromyographic activity the muscles during functional
thumb tasks.
Conclusions: A ligamento-muscular reflex response is present in the CMC1 joint. Mass
inhibitory response was evoked during tip pinch (fig. 3). During other tasks tested we
observed co-contractions, which are suggested to contribute to joint stability.
DI#
250%
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80% 100% 120% 140% 160% 180% 200% 220% 240% 260% 280% 300% 320% 340% 360% 380% 400% 420% 440% 460% 480% 500%
!150%
APB#
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!150%
APL#
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80% 100% 120% 140% 160% 180% 200% 220% 240% 260% 280% 300% 320% 340% 360% 380% 400% 420% 440% 460% 480% 500%
!150%
EPL#
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80% 100% 120% 140% 160% 180% 200% 220% 240% 260% 280% 300% 320% 340% 360% 380% 400% 420% 440% 460% 480% 500%
!150%
Figure 3. EMG amplitude for CMC1 muscles during tip pinch (p<0.05). Illustration of
significant changes (p<0.05) in the amplitude (Y-axis) for all four CMC1 muscles for the
time period (X-axis) 0-500 ms following stimulation of the dorsoradial ligament, divided
into 20 ms time intervals.
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2 INTRODUCTION
2.1
BACKGROUND
The human opposable thumb: get an evolutionary grip
The human opposable thumb is according to Aristotle, apart from the ability of speech
and sense of logic, what sets us apart from other creatures [4,5].
The human thumb and its ability to perform fine tuned tasks as well as power grips (fig.
4) [6], has developed over the course of a million of years and several lineages, resulting
in our capacity to construct and use advanced tools. Our simian ancestors were only
capable of flexion and extension towards the palm of the hand and did not have the
ability to oppose the thumb [7,8]. Thumb opposition is a primary motion in hand
function and allows for eloquent and controlled grips and is determined by the thumb’s
ability to oppose against the other digits of the hand.
In present day and age, we are still dependent on the precision and complexity of the
thumb machinery to function in our daily tasks. It has been suggested that the thumb
accounts for 40% of our hand function [9]. This may explain the high occurrence of
osteoarthritis of the thumb. In fact, thumb carpometacarpal joint (CMC1) osteoarthritis
constitutes the most common site of elective surgery in the upper extremity. The
radiographic prevalence of CMC1 osteoarthritis in persons older than 75-years is 40%
for women and 25% for men [10,11].
Figure 4. Power grip (left) and precision grip (right). Napier acknowledged these two
main grips as crucial for our evolution [6].
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Consequently, hand disorders and in particular thumb dysfunction, is not merely a
medical issue, but also a socio-economic matter. Regardless of the type of injury or loss
of function in the upper extremity, the daily work and leisure of this group of patients is
affected [12,13]. This causes major health care costs besides expenses attributed to their
absence from labor [13-15].
2.1.1 Osteology
The term saddle-joint is occasionally used to describe the biconcavo-convex shape of
CMC1 (fig. 5). To illustrate the shape of this joint even better, it has been likened to a
"scoliotic horse with a saddle", where the metacarpal is facing sideways in the saddle
[16]. This multifaceted joint allows for great modalities of motion including flexion,
extension, adduction, abduction and combinations of these motions which yields
complex movements such as radial and palmar abduction or adduction as well as
retropulsion, and opposition [17]. However, complete CMC1 joint rotation is not
possible due to the shape of the articular surfaces, just as a rider can't turn around freely
in a saddle.
Previous research has established that the incongruent articular facets of CMC1 have a
size difference of 34% when comparing the diameter of the first metacarpal (MC1) joint
surface (16.03 ± 1.27 mm) to that of the distal trapezium (11.96 ±1.32 mm) [18]. Due to
this innate incongruency of CMC1, this joint is highly dependent on surrounding soft
tissue, such as muscles and ligaments for its stability.
Figure 5. X-ray of the concavo-convex CMC1 joint. In the anterior-posterior view (left)
the convexity of metacarpal is noticeable while the trapezium is concave. Inversely, in
the lateral view of the CMC1 joint the trapezium is convex whilst the metacarpal is
concave. (From Edmunds JO. Traumatic dislocations and instability of the
trapeziometacarpal joint of the thumb. Hand clinics. 2006, 22: 365-92; with permission
to reprint).
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2.1.2 Muscles
Besides static restraint from surrounding ligaments, a joint is dependent on the dynamic
control from muscles that act on the joint to maintain stability and congruency [19,20].
The following muscles serve as primary CMC1 muscles: musculus abductor pollicis
brevis (APB), flexor pollicis brevis (FPB), opponens pollicis (OPP), flexor pollicis
longus (FPL), adductor pollicis (ADD), abductor pollicis longus (APL), extensor pollicis
brevis (EPB), extensor pollicis longus (EPL) and the first dorsal interosseous muscle
(DI). These muscles may differ in their characteristics due to anatomical variations,
trauma or as a consequence of congenital disorders. As muscular biomechanics are often
altered following nerve injury or osteoarthritis [21], it is of particular interest to
understand their course of action in normal conditions.
Intrinsic muscles
The intrinsic thumb muscles are APB, ADD, FPB, OPP and DI and are innervated by the
median, radial and the ulnar nerves.
APB primarily abducts and flexes MC1. This muscle is primarily innervated by the
median nerve (95%), but it can also be innervated by the ulnar nerve (2.5%) or by both
nerves (2.5%) [8]. This muscle arises by part from the scaphoid, trapezium and the
transverse carpal ligament and attaches to the radial sesamoid bone and the
metacarpophalangeal joint (MCP1) [8,22]
ADD consists of two heads and between these heads lays the ulnar nerve, which
innervates this muscle [22,23]. As its name implies, this muscle is an adductor of the
MC1.
DI has a deep head, which arises from the volar aspect of MC2, and a larger superficial
head that originates from MC1 medially [24]. This bipennate muscle is capable of
flexing as well as abducting the MCP1 [25,26]. The DI is often recognized as a muscle
innervated by the ulnar nerve, however it has also been suggested that this muscle
presents with considerable variance in its innervation [27].
FPB arises from the transverse carpal ligament and attaches to the MCP1 and the radial
sesamoid [8]. This muscle is a flexor of the proximal phalanx and MCP1. It is composed
of a superficial head, innervated by the median nerve, and a deep head innervated by the
ulnar nerve. However, there are many variations of the innervation of FPB [23,28,29].
OPP pronates and flexes the thumb. OPP is another thumb muscle with varying
innervation; either by the median nerve (83%), the ulnar nerve (10%) or by both of the
nerves (7%) [8,29].
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Extrinsic muscles
APL is located in the first extensor compartment, sometimes accompanied by single or
multiple auxiliary slips and receives its nerve supply from the posterior interosseous
nerve [30,31]. While the main tendon inserts on the radial base of the MC1, other slips
may insert on the volar CMC1 and other carpal bones. Although its name implies an
abduction function, the primary function is one of combined extension and slight
abduction of the MC1. An old term for this muscle was "extensor ossis metacarpi
pollicis", which in fact is more true to its function [16].
EPB is also located in the first extensor compartment and is likewise innervated by the
posterior interosseous nerve. Its action on the CMC1 is closely related, albeit weaker,
than that of the APL. In addition, it's a primary extensor of the MCP1.
EPL runs as a single tendon in the third extensor compartment and is also innervated by
the posterior interosseous nerve. The EPL is an extensor of the IP joint as well as an
important thumb adductor.
FPL is innervated by the anterior interosseous nerve and flexes the IP joint. FPL,
sometimes observed with an auxiliary head, originates from the anterior aspect of radius
and attaches to the base of distal phalanx of the thumb [8].
2.1.3 Ligaments
Because of the characteristic mobility and configuration of CMC1, this joint is highly
dependent on proper ligamentous support to maintain stability as well as flexibility
throughout all ranges of movement. A number of publications have investigated the
intricate ligamentous apparatus that supports the CMC1 [8,18,32,33]. The number of
CMC1 ligaments described ranges from three [34] to as many as sixteen [33]. The
primary ligaments of CMC1 are the dorsal ligaments and the volar “beak” ligament
(AOL), which will be further discussed below (fig. 6).
Figure 6. The volar beak ligament, also known as the anterior oblique ligament (AOL),
arises from the volar side of MC1 and inserts to the volar aspect of the trapezium. The
dorsal ligament complex arises from the tubercle of trapezium and attaches to the thumb
base. (From Edmunds JO. Traumatic dislocations and instability of the
trapeziometacarpal joint of the thumb. Hand clinics. 2006, 22: 365-92; with permission
to reprint.)
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The dorsal ligaments
The dorsal radial (DRL), dorsal central and posterior oblique ligaments constitute the
dorsal ligament complex. These ligaments originate from the tubercle of the trapezium
and attach at the thumb base (fig. 7). The dorsal ligaments are composed of distinct
collagenous bundles that contain nuclei and also possess proprioceptive qualities as
demonstrated by the presence of mechanoreceptors [1,35-37].
The debate whether the dorsal ligaments are the primary CMC1 stabilizers has gained
prominence in the past decade. Many argue that the dorsal group of ligaments is in fact
the primary stabilizer of CMC1 and not the thin volar ligaments [38-42].
Present evidence suggests that the dorsal ligaments constitute the thickest, strongest and
most robust group of the CMC1 ligaments [36,43]. The dorsal ligaments support the
CMC1 joint throughout rotational forces as well as dorsal dislocations [43-47].
The dorsal ligaments are central during the screw home torque mechanism. This
mechanism is central in the prevention of dorsal subluxation during the closing stage of
thumb opposition [40,43]. In addition, the dorsal ligaments are essential to counteract
and stabilize the large compressive forces applied at CMC1 during power grips and
power pinch [43].
Clinically, in cases where the dorsal ligaments are damaged, such as in CMC1
dislocations or following Bennett’s fracture, the overall stability of CMC1 is jeopardized
and may cause joint dislocation, even if the volar ligament is undamaged [43,44].
a
b
Figure 7. CMC1 ligaments. Two of the principal CMC1 ligament structures: a.) the
dorsal ligaments and b.) AOL. Note that the AOL is thin and practically
semitransparent.
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The anterior oblique ligament
The AOL, also known as the volar or palmar “beak” ligament, is a thin ligament that
originates from the volar side of MC1 and attaches to the volar aspect of the trapezium
(fig. 7). Formerly considered the primary ligament in CMC1 stability [34], existing
research now recognizes that the AOL is significantly thinner, weaker and does not
contain mechanoreceptors or organized collagen fibers with nuclei, unlike the dorsal
ligaments [1,35-37,43]. The AOL is not crucial for the screw home torque mechanism,
as this ligament remains lax during screw home torque and does not inhibit any tendency
of dorsal subluxation [43]. This is further implicated in cases where the AOL is injured,
in which no major destabilization of CMC1 is noted, unless there is any concurrent
damage to the dorsal structures [43].
2.1.4 Innervation
The hand and particularly the thumb accounts for a large section in the neural mapping
of motor and somatosensory cortex (fig. 8). This well-recognized schematic depiction of
the cerebral cortex, was first made by an illustrator named Mrs. Cantile in 1937 based on
the research of Penfield and Boldrey [48]. This graphic representation is based on
muscle contractions found in a specific body region, which are evoked following
electrical stimulus of the corresponding region in the cerebral cortex [49].
Although extensive research has been carried out since then to examine the bone
morphology, ligament functions and muscular dynamics of CMC1, the innervation of
this complex joint needs further attention. The CMC1 joint is particularly difficult to
assess as the median, radial as well as the ulnar nerve innervate the many muscles acting
on the joint. In addition, there is no real consensus regarding the innervation of the joint
itself. The CMC1 has been proposed to be innervated by branches from the radial and
median nerve [50], whereas others suggest the lateral antebrachial cutaneous nerve to
innervate the joint as well [51]. Additionally, more novel studies also propose the ulnar
nerve to contribute to the nerve supply of this complex joint [52].
Figure 8. Graphic representation of cerebral cortex. Note the proportionally large area
that represents the hand and especially the thumb, in both the motor and sensory cortex.
Both sensory input and motoric output tracts cross the midline (blue/red). Courtesy of
Mobargha A.
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2.2
PROPRIOCEPTION AND NEUROMUSCULAR MECHANISMS
Research on the subject of joint stability has previously been restricted to the matters of
muscles, ligaments and joint characteristics. However, evidence supports the notion that
sensory input from ligaments, muscles, skin and joints is central in the maintenance of
joint stability [53,54].
Neuromuscular control is the continuous muscular adaptive response to a motion, for the
purposes of preserving joint stability and accuracy of motion. The physiological basis of
neuromuscular control is founded on sensory afference from e.g. receptors in ligaments
and tendons and the central integration of this proprioceptive input [53,54]. If any part of
this integral construction is injured, whether it is the muscles, joint, ligament or nerves,
the management and adaptation of physiological load upon the joint and adaptation to
on-going movement may be inaccurate. Consequently, this may initiate and lead to
muscle weakness, pain, subluxation and ultimately osteoarthritis [55,56].
2.2.1 Mechanoreceptors
Afference from sensory neurons in ligaments and tendons are important for
neuromuscular control as they can impact muscle action [53,54]. There are different
types of sensory neurons; large myelinated, fine myelinated or unmyelinated [57].
The larger myelinated axons, also known as mechanoreceptors, are highly receptive to
mechanical stimulus, such as pressure or strain. The fine axons are primarily pain
sensors and terminate as free nerve endings. These thin myelinated axons, are also
recognized as fast Aδ-fibers, and respond to noxious input. The C-fibers, also known as
unmyelinated axons, are slow fibers that take part in inflammatory mechanisms by e.g.
the release of inflammatory substances such as substance P [57].
The different types of sensory neurons and their characteristics, based on Freeman and
Wyke’s classification, are further described below[58].
Ruffini ending (class I)
This mechanoreceptor detects changes in velocity and amplitude and senses changes in
joint position. The Ruffini ending is a slowly adapting mechanoreceptor with a low
threshold. It is typically 50-100 µm and partially encapsulated and often seen with
branches and bulbous endings.
By using the triple staining technique, PGP9.5 stained for the central axon and terminal
nerve branches, whilst p75 stained for the capsule that was frequently incomplete.
Pacini corpuscle (class II)
The Pacinian corpuscle is a mechanoreceptor with low threshold. This mechanoreceptor
rapidly detects and adapts to deceleration and acceleration. This corpuscle is either
round or oval, ranges from 20 to 50 µm and is characterized by a thick lamellar capsule.
Its central axon is visualized by PGP9.5 and the thick perineurial capsule by p75.
Golgi like receptor (class III)
The Golgi like receptor is also a rapidly adapting mechanoreceptor but with high
threshold. It detects extreme ranges of motion and is characteristically spherical,
measures > 150 µm and is partially encapsulated. It is recognized by groups of
18
arborizing and terminal nerve endings. PGP9.5 stains for the terminal nerve branches
and p75 stains for the incomplete capsule.
Free nerve endings (class IV)
Free nerve endings can be classified as either fast Aδ-fibers or slow C-fibers. The mutual
and typical features of the free nerve endings are that they respond to nociceptive and
noxious input and are involved in inflammatory activities. They can be found either in
groups or as single nerve fibers with varicose appearance. Their axons stain for PGP9.5.
Unclassifiable receptors (class IV)
This heterogeneous class of receptors varies in their size and level of encapsulation.
They often present with an incomplete capsule stained for by p75.
Although they have previously been described [59,60], their exact neurophysiological
functions and traits are still unknown and need further description.
2.3
OSTEOARTHRITIS
Osteoarthritis is a chronic disease with multiple etiologies, symptoms and treatments
where the disease progression involves a complex chain of biochemical processes [8,61].
Some of the causes that are associated with the onset of osteoarthritis are previous
trauma, increasing age, female gender, and ligament laxity due to idiopathic disease or
hormonal changes associated with e.g. obesity [11,62-64]. Typically, this disease debuts
amongst middle-aged women with pain as primary symptom [65].
Historically, osteoarthritis has been described as a disease restricted to the bone and
cartilage due to abnormal biomechanical loads. More recent developments in this field
have led to a description of a joint as a synovial organ where any component of that
organ, such as its ligaments, muscles, nerves, cartilage or bone, may contribute and be
engaged in the onset of osteoarthritis if compromised (fig. 9) [21]. Therefore, it is likely
that osteoarthritis may still develop even in cases where the biomechanical joint load is
normal, but where the other joint supportive tissues are impaired [56].
LIGAMENTS
BONE
MUSCLES
SYNOVIAL
ORGAN
NERVES
CARTILAGE
Figure 9. Osteoarthritis is not only a matter of bone and cartilaginous pathology. A joint
should be regarded as a synovial organ, where injury to any of its components may be a
part of the osteoarthritic process.
19
In light of recent events in the field of osteoarthritis, it is becoming difficult to ignore the
existence and importance of neuromuscular and proprioceptive functions and how the
failure of these mechanisms may contribute to onset of osteoarthritis [54,66,67]
This may also explain why radiographic findings do not always correlate with the
clinical presentation of the disease. This is especially true for osteoarthritic changes in
the soft tissues, which are not visualized through a classic X-ray [68]. Ligamentous
changes are often found during osteoarthritis and are frequently observed in the small
joints of the hand [56,69-71].
Nevertheless, the radiographic staging of CMC1 osteoarthritis proposed by Eaton and
Littler is frequently used to describe some of the osteoarthritic CMC1 changes that can
be visualized on an X-ray (fig. 10) [72,73]. Though osteoarthritis is a chronic disease,
often found with radiographic deterioration, some patients remain in a constant stage,
with no progressive joint disfiguration of their disease [74].
1
Normal cartilage and joint space
2
Normal joint configuration
Narrowing of joint space
Minimal sclerosis and joint debris (<2 mm)
3
Significant reduction of joint space
Sclerosis, cystic changes,
Osteophytes (>2 mm)
4
Severe reduction of joint space
Subluxation is common
Often involvement of
scaphotrapeziotrapezoid (STT) osteoarthritis
Figure 10. Radiographic staging of CMC1 osteoarthritis based on Eaton and Littler’s
classification [73].
20
2.3.1 CMC1 Osteoarthritis
The inherent incongruency of the CMC1 joint makes it prone to osteoarthritis and
particularly dependent on its surrounding soft tissue for normal function. Therefore, soft
tissue imbalance often accompanies CMC1 osteoarthritis. Regardless if these changes
are pertained to ligamentous pathology or due to muscular deficiency, the global
equilibrium of the CMC1 joint will be affected. Changes of the ligament structure, such
as increased laxity and/or thickening of the ligament, may impact the onset of
osteoarthritis due to the subsequent biomechanical changes [71,75].
Recent evidence suggests that ligamentous osteoarthritis can be described as its own
stage in CMC1 osteoarthritis and has been suggested as a precursor of the disease
[70,73,76]. Hormonal changes following menopause most likely contribute to joint
laxity and may impact collagenous tissue. This may explain why females are more
predisposed to CMC1 osteoarthritis [8,11].
Patients with CMC1 osteoarthritis often suffer from functional limitations, pain, joint
instability or joint stiffness and even subluxation in more advanced stages (fig. 10) [7779]. This subluxation manifests as a dorsoradial translation of the base of the MC1
relative to the CMC1. In the final stages, this subluxation is further accompanied by a
secondary contracture of the adductor muscle, rendering the thumb metacarpal fixed in
adduction toward the index metacarpal.
The role of joint innervation, neuromuscular control and proprioception in this
pathophysiological process has yet not been illuminated.
21
3 AIMS OF THE INVESTIGATION
The general aim of this investigation was to explore and assess the proprioceptive and
neuromuscular characteristics of the CMC1 joint. Specifically, the aims of this
investigation were as follows:
I. To investigate CMC1 ligaments in patients with osteoarthritis and analyze if
they possess neural properties besides evident stabilizing functions.
II. To examine the intraligamentous innervation of osteoarthritic patients and
evaluate if it differs from normal subjects.
III. To analyze the role of the muscles that act on the CMC1 with regard to
promotion or prevention of joint instability.
IV. To investigate if a CMC1 ligament has the ability to impact CMC1
controlling muscles through ligamento-muscular reflexes, and what role these
reflexes may have in proprioception and neuromuscular joint control.
22
4
MATERIAL AND METHODS
4.1
ETHICAL CONSIDERATIONS
All studies performed have been granted ethical approval and were handled according to
ethical guidelines and regulations. All participants were included following written and oral
information and consent.
4.2
MORPHOLOGICAL AND IMMUNOHISTOCHEMICAL PROCEDURES
Study I-II
The AOL and DRL were obtained from patients with advanced CMC1 osteoarthritis during
trapeziectomy and suspension arthroplasty. These ligaments were selected based on their
acknowledged importance in stabilizing CMC1 as well as the fact that they present with the
highest mean difference of ligamentous innervation in normal subjects [35,36,46].
We used hematoxylin and eosin staining (HE) [80] for structural visualization of ligament
histology. In addition, we employed triple staining techniques to visualize and distinguish
nerves and mechanoreceptors from arteries and collagenous tissue.
4.2.1 Immunohistochemistry
The ligaments were sectioned in five mm width and five µm thickness. In addition,
ligaments were labeled for their proximal and distal insertions respectively. The slides were
further prepared for immunohistochemistry (see studies I and II for detailed description).
Control staining
Both positive and negative control stains were performed. The negative control stains
consisted of elimination of primary antibodies, resulting in loss of specific stains. For
positive controls, staining was performed on cadaveric nerve tissue (median nerve
samples), verifying proper staining of neural contents.
4.2.2 Primary antibodies
We used rabbit anti-protein gene product 9.5 (PGP9.5), and p75 rabbit anti-nerve growth
factor receptor (p75) as primary antibodies.
PGP9.5 is a neuronal marker involved in the signaling of cell differentiation, cell death,
neuronal growth and migration. All mammals have this protein, which is found in the
neuronal cytoplasm and is particularly expressed in metabolically active areas. This
primary antibody operates as a general nerve marker and as such labels axons of nerve
fascicles and nerve corpuscles and their terminal branches. Therefore, this primary antibody
is essential in the identification of mechanoreceptors, such as the Ruffini corpuscle and free
nerve endings.
p75 is important as primary antibody due to its ability to detect nerve fascicles and their
perineurial cells, and the capsule of nerve corpuscles. This antibody is crucial for detection
of the Pacinian corpuscle by staining for its perineurial layers.
23
4.2.3 Secondary antibodies and nuclear labeling
Detection and amplification of primary antibodies was performed using goat anti-rabbit
Alexa Fluor 488 for p75 and goat anti-rabbit Alexa Fluor 647 for PGP9.5.
In addition, we used 49,69-diamidino-2- phenylindole (DAPI) to label nuclei and to
distinguish ligamentous tissue from nerves and vascular structures.
4.2.4 Immunofluorescence imaging
The immunohistochemical slides were systematically visualized and analyzed by a
fluorescence microscope set at multidimensional acquisition to achieve full
immunofluorescent array. First, the sections were imaged at larger magnification (x20) to
identify p75 or PGP9.5 immunofluorescence (IF) and thus regions of interest. Following
this, higher magnification (x40) was used to analyze details of the IF regions.
4.2.5 Morphological analysis
The innervation of the ligaments was graded using semi-quantitative analysis (table 1).
The classification of the microscopic ligamentous innervation was based on an adapted
version of the classification of mechanoreceptor (table 2) first proposed by Freeman and
Wyke [58]. This type of morphological classification of ligaments and their microscopic
innervation has previously been applied to other studies of human ligaments [35,81,82].
ORDINAL GRADING SYSTEM FOR
QUANTIFICATION OF
MECHANORECEPTORS
+++
Numerous nerve fascicles and
mechanoreceptors
++
Solitary nerve fascicle and
mechanoreceptor present
+
Nerve fascicle present, but no
mechanoreceptors
-
No nerve fibers, nerve fascicles or
mechanoreceptors identified
Table 1. An ordinal grading system was used to quantitatively evaluate the degree of
innervation of ligaments.
24
!
Class
Name
!
I!
!
!
!
II!
!
!
III!
!
IV!
!
V!
Role in joint
function
Appearance
!
Low!threshold!
Slowly!adapting!
!
Changes!in!
velocity!and!
amplitude!
Joint!position!
sense!
Pacinian!
Corpuscle!
!
Low!threshold!
Rapidly!adapting!
!
Acceleration!
Deceleration!
!
!
!
50=100μm!
Partially!
encapsulated!!
Sprouting!nerve!
branches!with!
bulbous!ending!
!
20=50μm!
Round/oval!
Thick!lamellar!
capsule!
Golgi!like!
receptor!
!
High!threshold!
Rapidly!adapting!
!
Extreme!
ranges!of!
motion!
Free!nerve!
endings!
!
Fast!Aδ=fibers!
Slow!C=fibers!
!
Noxious!and!
nociceptive!
input!
Inflammatory!
activity!
!
!
Unknown!
Ruffini!
!
Unclassifiable!
!
Neurophysiological
traits
!
Unknown!
!
>!!150μm!
Spherical!
Partial!encapsulation!
Groups!of!arborizing!
and!terminal!nerve!
endings!
!
Varicose!appearance!
In!groups!or!single!
fibers!
Variable!size!and!
encapsulation!
Immunoreactive
patterns
Central!axon!
(PGP9.5)!
Terminal!nerve!
branches!
(PGP9.5)!
Incomplete!
capsule!(p75)!
!
Central!axon!
(PGP9.5)!
Thick!capsule!
(p75)!
!
!
Terminal!nerve!
branches!
(PGP9.5)!
Incomplete!
capsule!(p75)!
!
Axon!(PGP9.5)!
Incomplete!
capsule!(p75)!
Table 2. Mechanoreceptors in ligaments based on Freeman and Wyke’s classification [58],
modified by Hagert E [83] (Reprinted with permission from Hagert E ‘Wrist Ligaments—
Innervation Patterns and Ligamento-Muscular Reflexes’, PhD thesis, Karolinska Institutet,
2008).
25
4.3
BIOMECHANICAL ASSESSMENT
Study III
In this study, fresh frozen human cadaveric hands and forearms with no signs of CMC1
osteoarthritis were used. X-rays of the specimens were taken prior to the experiments to
exclude osteoarthritis.
4.3.1 Preparation of specimens
Specimens were thawed at room temperature. Following this, the distal third of the forearm
and the metacarpophalangeal joins to digits 2-5 were transected.
The thumb was preserved, but soft tissues other than the thenar tendons and muscles, the
CMC1 ligaments, flexor and extensor retinaculi, carpal ligaments and tendons of the
extrinsic and intrinsic muscles, were removed.
Pins were used to mark the insertions and origins of the intrinsic thenar muscles. A 2.4 mm
Steinmann pin was drilled though the third metacarpal intramedullary and another pin was
positioned through the first interphalangeal joint, to ensure control of the CMC1 joint.
Radius and ulna were also fixed to the jig by pins stabilizing the carpus and forearm. The
thumb was positioned in neutral position and the specimen was firmly attached to a jig,
especially designed and used for the purposes of biomechanical assessment.
Figure 11. Measurements were obtained from sensors S1, S2 and S3 respectively.
Courtesy of M Garcia-Elias, MD.
26
4.3.2 Biomechanical analysis
FASTRAK® three-dimensional motion tracking system (figs. 11 and 12) was used to
identify spatial changes. Three sensors (S1, S2 and S3) were inserted into the base of the
first and third metacarpals (S1 and S2, respectively) and a third sensor (S3) positioned on
the dorsal aspect of the distal radius, 5 cm proximal from the CMC1. This system produced
co-ordinates x, y and z which could then be used for analysis of three-dimensional spatial
changes between the sensors. The intrinsic (APB, APL, OPP, DI) and extrinsic (FPL, APL,
EPB, EPL) muscles acting on CMC1 were investigated individually.
Simulation of muscle tone was achieved by attachment of nylon strings to the insertion of
the tendons and by loading them with 1N. Next, attachment of weights proportional to
every muscle’s physiologic cross-sectional area were used to obtain isometric conditions.
The system was reset after analysis of each muscle to minimize error of measurement. To
reaffirm the pre-experimental radiographs, each joint was opened and macroscopically
assessed after finalization of the experiment, confirming that there were no signs of
osteoarthritis.
Figure 12. Illustration of sensor placement of sensor 1 (S1) and sensor 2 (S2). The distance
between sensors S1 and S2 (green arrow) quantifies the horizontal displacement. Changes
in this distance are representative of the movement of MC1 to MC2 as a result of isometric
loading of CMC1. Positive values suggest that MC1 moves away from MC2, whereas
negative values signify approximation of MC1 to MC2.
27
4.4
ELECTROMYOGRAPHIC PROCEDURES
Study IV
Subjects enrolled in this study were all healthy, with no signs of CMC1 osteoarthritis or
dysfunction, nor prior wrist or hand trauma. Four primary CMC1 muscles, of which two
were intrinsic (DI, APB) and two were extrinsic (APL, EPL), were investigated. The
ligamento-muscular relation between DRL and the four muscles was analyzed following
electrical stimulation of DRL by the means of electromyography (EMG).
Experimental protocol
Participants were seated in a chair with the arm and shoulder in resting neutral position and
slight flexion of the elbow. The skin was cleansed with alcohol and shaved when necessary.
Ultrasound procedures
The muscle bellies of DI, APB, APL and EPL were first identified clinically, and then
confirmed using an ultrasound system equipped with a transverse 8-MHz transducer
(Esaote My Lab Five, Biomedica Ltd.). A 0.35 mm/diameter needle electrode was inserted
into each muscle. As a positive control, EMG signals on the oscilloscope were observed
during voluntary muscle activity to further ensure correct placement of electrodes.
Ultrasound was used to identify DRL and ensure correct placement of the stimulation
electrode (fig. 13). Following visualization of DRL a 0.5 mm puncture needle was placed
into the ligament and a hooked fine-wire electrode was inserted into DRL via the puncture
needle. The fine-wire electrode was equipped with a hook to ensure firm placement into
DRL so that the puncture needle could be removed without electrode dislocation.
A reference electrode was placed distally from the stimulation electrode on the dorsal
aspect of the hand. Following this the electrodes were connected to a 4-channel
electromyograph.
A
Figure 13. Identification of DRL by ultrasound. The stimulation electrode was inserted into
the DRL (A).
28
Stimulation procedures and electromyographic analysis
The sensory threshold was determined by the input of a series of 200 Hz pulsations to DRL,
each 1 ms long. The value obtained set the foundation for the experimental threshold,
which was set at 2 times the sensory threshold but always below the pain threshold.
EMG recordings began 100 ms before stimulation (pre-stimulus or t1) of the DRL, until 500
ms after stimulation (post-stimulus or t2).
Positions tested
The EMG activity after stimulation of the DRL was examined during the functional CMC1
thumb tasks tip pinch, key pinch and palmar pinch (fig. 14). The positions were performed
during isometric conditions and at submaximal force to avoid muscle fatigue. To obtain this
precondition, the maximum strength in each position was assessed using an intrinsic meter,
or pinch gauge. The volunteers were subsequently instructed to use only 25% of their
maximal force for each of the positions.
As a negative control, the DRL was stimulated when the four muscles were relaxed and the
thumb in neutral position, to ensure that this did not elicit any signs of EMG activity.
Figure 14. CMC1 positions investigated. Subjects were instructed to use only 25% of their
maximal force for a.) tip pinch b.) key pinch and c.) palmar pinch to avoid muscle fatigue
29
5 RESULTS
5.1
IMMUNOHISTOCHEMICAL STUDIES
Study I-II
Previously established grading systems [35,81,82] were implemented to perform a semiquantitative assessment of the innervation of ligaments investigated.
5.1.1 Structural differences
Study I
HE stain was used to examine the possible existence of nuclei and the microscopic structure
of the ligaments. The HE staining (fig. 15) revealed distinct differences in the structural
appearance of AOL compared to DRL. Whereas AOL was mostly composed of disordered
connective tissue, DRL presented with well-organized collagen strands. This observation is
in agreement with previous studies made on CMC1 ligaments with no signs of
osteoarthritis [36].
DAPI labeling (fig.16) further exposed significant structural changes between AOL and
DRL. Visualization using DAPI displayed presence of nuclei in DRL’s well-organized
collagenous network. On the contrary, AOL lacked nuclei (fig. 16), in line with previous
findings in non-osteoarthritic ligaments [36].
Figure 15. Hematoxylin and eosin stain of (A) DRL and (B) AOL.
The DRL is characterized by organized collagen bundle whereas the AOL contains
disorganized connective tissue. (Reprinted with permission from Mobargha N et al.
Ultrastructure and innervation of thumb carpometacarpal ligaments in surgical patients
with osteoarthritis. Clinical orthopaedics and related research. 2014, 472: 1146-54).
30
DRL
AOL
Figure 16. Structural differences between DRL and AOL observed following DAPI
labeling. DRL contains a large number of nuclei while AOL is disorganized and
distinctively free from nuclei.
5.1.2 Innervation of ligaments
Study I
All of the 22 osteoarthritic CMC1 ligaments examined contained mechanoreceptors.
Statistical analysis (p<0.001) demonstrates that the innervation differs between DRL and
AOL. There were significantly more mechanoreceptors and free nerve endings found in the
DRL. No significant relationship between the innervation and age of patients could be
established.
Mechanoreceptors
Immunofluorescence imaging revealed that nerve fibers and mechanoreceptors were most
easily detected close to vascular structures, embedded near the ligament’s epifascicular
regions. Mechanoreceptors were identified in all ligaments. Pacini corpuscles, Ruffini
endings and unclassifiable corpuscles were recognized and distinguished from arterioles by
triple staining techniques.
31
5.1.3 Distribution of mechanoreceptors
Study II
In this study, the ligaments were investigated with regard to their proximal and distal
portions respectively. This analysis did not provide with any statistically significant mean
difference of the innervation of proximal and distal endings of DRL or AOL.
General distribution
A striking observation was the many type V unclassifiable corpuscles (fig. 2) observed in
both AOL’s and DRL’s proximal and distal regions respectively. No significant difference
was found when the distal end of DRL was compared to the distal end of AOL. Likewise,
no significant difference between the examined ligaments’ proximal regions could be
detected.
Free nerve endings (fig. 17) were also frequently found in the ligaments, mostly near
vascular structures and connective tissue. They were observed in both DRL and AOL. No
significance was found when the distal segment of DRL was compared to the distal end of
AOL. This was also true for the ligaments’ proximal segments.
Only one Pacinian corpuscle was observed in the samples, and was found in the distal DRL.
This corpuscle was characterized by its clear p75 immunofluorescence and lamellar
corpuscle.
Figure 17. Free nerve endings were frequently identified in both AOL and DRL.
32
5.2
BIOMECHANICAL STUDY
Study III
The results obtained from isometric loading of individual muscles indicate that certain
muscles tested may have an advantageous and stabilizing impact on the joint. Contrarily,
other muscles may act as destabilizers by increasing the tendency of dorsoradial
subluxation.
Distance between sensors S1 and S2
When DI was loaded, a decrease in the distance between sensors S1 and S2 was observed
(fig. 18). This is indicative of a reduction of the radioulnar or horizontal translation of
CMC1 and suggests a stabilizing mechanism. Contrarily, an increase in S1-S2 was seen
upon loading of OPP, suggesting a radial subluxation of the CMC1.
S2
S2
III
III
I
I
I
I
S1
I
S1
I
M. Opponens
Figure 18. Increase of the distance between sensors S1 and S2. The distance between
sensors S1 and S1 is representative of a radial subluxation of the base of the first
metacarpal or a pronation, but most likely a combination of both these movements.
Courtesy of M Garcia-Elias, MD.
33
Distance between sensors S1 and S3
When loading the APL, a reduction in the distance between sensors S1 and S3 was
observed (fig.19). This distance represents a vertical translation of the sensor S1, and thus a
proximal migration of the base of the MC1.
Contrarily, a positive value suggests a combination of MC1 flexion and distal migration.
The most clinically relevant finding was that DI was the only muscle that caused an
increase in the distance between sensors S1 and S3, thus indicating a stabilizing role to the
DI in avoiding dorsoradial translation.
S1
S1
S3
S3
Fig 19. Distance between sensors S1 and S3. Reduction of the distance between sensors S1
and S3, is an indication of proximal migration of MC1, possibly combined with an
extension of MC1. Isometric loading of APL reduced this distance most, suggesting
possible harmful impact on CMC1. On the contrary, the only muscle that increased this
distance was DI. Courtesy of M Garcia-Elias, MD.
34
5.3
NEUROPHYSIOLOGICAL STUDY
Study IV
The results obtained from EMG analysis of CMC1 muscles following stimulation of DRL
revealed significant (p<0.05) changes in the post-stimulus (t2) activity of DI, APB, APL
and EPL during functional CMC1 tasks.
Positive amplitudes represent excitatory muscle activity whereas inhibitory responses are
negative in amplitude, as compared to pre-stimulus baseline (t1).
5.3.1 General observations
Intrinsic muscles
DI demonstrated an early excitatory response during both palmar and key pinch within 4060 ms following stimulation. During key pinch, DI only presented with excitatory action
whereas it was inhibited during the other positions test.
APB reports with only late (>100 ms) excitatory reactions during palmar pinch whilst this
muscle demonstrated an early excitatory response within 40 ms during key pinch followed
by mixed activity. APB was solely inhibited during tip pinch.
Extrinsic muscles
Both APL and EPL are rapidly inhibited during palmar pinch. This reaction occurs within
20-40 ms followed by late phase excitations, which suggests co-contraction reactions.
A rapid monophasic reaction was observed in APL during key pinch in form of an
excitation, whereas this rapid response was an inhibitory reaction in palmar pinch. Overall,
APL was the only muscle to react within 20 ms following stimulation. APL and EPL
generally revealed reduction of their amplitudes after stimulation of DRL.
5.3.2 Specific observations
Post-stimulus histograms represent the time after stimulation of DRL. The data is divided
into 20 ms time intervals until 500 ms after stimulus (t2) and is compared to baseline (t1),
100 ms before the stimulus.
Tip pinch
Interestingly, the post-stimulus reactions during tip pinch reveal a mass inhibition of all
muscles investigated (figs. 3 and 20). This response is found around 60ms after stimulus
and is the most consistent reaction found in any of the positions studied. Tip pinch
presented with most cases of significant amplitudes (p<0.05) throughout the 500 ms run
compared to both key pinch and palmar pinch.
35
Key pinch
An immediate excitatory response is noted in DI, APB and APL during key pinch and
implies fast co-contractions, most distinctly found in DI. However, DI became completely
inactive after this reaction. The primary excitatory response was followed by inhibitory
activity and was first observed in EPL around 200 ms. EPL was almost entirely inhibited
during key pinch from 200 ms onwards. APB and APL fluctuated between inhibition and
excitation for the entire post-stimulus time interval.
Palmar pinch
Instant inhibition was observed in both APL and EPL from 20-60ms and was followed by
excitation of DI at 60-80 ms. After this, DI mainly demonstrated inhibitory activity for the
remainder of the time. Co-contractions were lastly observed in APB, APL and EPL from
280-480 ms.
Figure 20. Post-stimulus time histograms for tip pinch. Each column represents statistically
significant (p<0.05) median values of amplitudes (Y-axis) for each 20 ms time interval from
0-500 ms (X-axis), following stimulation of the dorsoradial ligament. Inhibitory activity is
present and predominant for all muscles throughout tip pinch following stimulation of the
dorsoradial ligament.
36
6 SUMMARY OF RESULTS
The results from study I-IV can be summarized as follows:
!
Mechanoreceptors have been identified in the CMC1 ligaments of osteoarthritic
patients by immunohistochemical methods.
!
The DRL was the ligament in which most mechanoreceptors were identified.
!
The innervation of ligaments in non-osteoarthritic specimens differs from patients
with CMC1 osteoarthritis, where the latter have a reduction of Ruffini-Pacini
innervation and a high frequence of unclassifiable receptors.
!
Biomechanical evaluation of the CMC1 joint in isometric conditions suggests that
DI has a stabilizing impact on the joint as it decreases dorsoradial translation,
wheras APL acts destabilizing.
!
Ligamento-muscular reactions were found following stimulation of DRL.
Post-stimulus reactions, either inhibitory or excitatory, were observed in DI, APB,
APL and EPL after stimulation of DRL.
!
Mass inhibitory reactions were observed during tip pinch, whereas other functional
CMC1 tasks displayed co-contractions.
!
The only muscle to react within 20 ms was the APL, suggesting a primary DRLAPL ligamento-muscular reflex for joint control.
37
7 DISCUSSION
The findings of this thesis collectively suggest that the CMC1 joint is a joint with
proprioceptive and neuromuscular functions. Therefore, this thesis proposes the idea of the
CMC1 joint to be viewed as a synovial organ, to which all aspects of neurosensory,
biomechanical, neuromuscular functions are crucial for proper joint control and stability.
Consequently, any alteration of the integral parts of this complex organ may result in
disrupted ligamentous, muscular or reflex characteristics, potentially rendering the joint
susceptible to osteoarthritis [54,67].
7.1
PROPRIOCEPTIVE FEATURES
The median, ulnar and radial nerve all innervate the CMC1 joint. This contributes to the
complexity of this joint as all three nerves to the hand contribute to thumb function.
As declared in previous sections, the DRL of osteoarthritic patients presented with
significantly more mechanoreceptors than the AOL. This observation is consistent with
previous research in the field, in which immunohistochemical studies of wrist ligaments
revealed that their dorsal regions were more innervated than the volar structures [82,84].
Additional investigations have been made on CMC1 ligaments. These studies are based on
non-osteoarthritic CMC1 joints, in which the dorsal ligaments were also found with rich
innervation compared to the volar ligaments [35-37]. However, the findings from those
studies differ significantly compared to this investigation on the matter of actual
mechanoreceptor populations.
In the prior studies made on non-osteoarthritic CMC1 ligaments, the Ruffini ending was the
most frequent type of mechanoreceptor identified, whereas the unclassifiable corpuscles
and free nerve endings were dominant in this investigation. Other mechanoreceptors, such
as Ruffini endings and Pacinian corpuscles were not as frequently found in the
osteoarthritic ligaments, as compared to non-osteoarthritic specimens. These two types of
mechanoreceptors adapt rapidly to joint position, rotation and joint
acceleration/deceleration respectively. This reduction of Ruffini endings and Pacinian
corpuscles in osteoarthritic ligaments, suggest that osteoarthritic ligaments may have
inferior proprioceptive and neuromuscular abilities. This since afference from
mechanoreceptors is a prerequisite for proper joint control and stability and conduce
continuous adaptation to movement [54,85]. Similar results have been observed in studies
on the mechanoreceptor populations of patients with hip osteoarthritis. The hip ligaments of
these patients revealed that the general ligamentous innervation was significantly altered as
compared to healthy hips and exhibited a predominance of free nerve endings [60].
A plausible explanation for the divergent report between non-osteoarthritic ligaments
compared to osteoarthritic specimens may lie in the osteoarthritic process itself. The
abundance of unclassifiable mechanoreceptors identified, may be the result of continuous
traumatic loads, trauma or modification of the receptors due to complex inflammatory
processes, which occur as osteoarthritis evolves. A similar course of development is noted
in the hand where hyperplasic changes of Pacinian corpuscles have been observed, a
condition often associated with local pain and history of trauma [86,87].
38
Another group of mechanoreceptors frequently identified in our material, were the free
nerve endings. The free endings are likely involved in inflammatory activity, as they are
carriers of vesicles containing inflammatory elements, such as substance P [88,89]. With
this in mind, it is clear that the role of free nerve endings and their role in the course of
osteoarthritis progression needs further investigation, since noxious input, inflammation
and pain are common symptoms amongst osteoarthritic patients.
7.2
NEUROMUSCULAR MECHANISMS
Neuromuscular deficiency and weakness often precede the onset of osteoarthritis [21,67].
Hence, patients with CMC1 osteoarthritis often present with poor neuromuscular capacity
and instability of the joint [10]. With this in mind, we investigated the neuromuscular
mechanisms of the CMC1 joint in normal conditions, which provides for the foundation of
future investigations of osteoarthritic CMC1 joints.
Previous investigations of CMC1 musculature have reported the beneficial effects of DI as
a stabilizer of the thumb, which is in agreement with our findings [16,90,91].
However, because DI does not actually span across the CMC1 joint, it has not typically
been valued as a key component of the CMC1 joint [16]. Yet, this muscle possesses the
capacity to stabilize the CMC1 joint by reducing the tendency of dorsoradial subluxation, a
condition noted in patients with severe CMC1 osteoarthritis. In concordance with this, the
favorable properties of DI have been noted in patients with CMC1 osteoarthritis; patients
who were treated specifically with DI targeted exercises demonstrated less pain and
disability, compared to patients with conventional CMC1 osteoarthritis exercise [92].
On the contrary, we identified APL as the muscle with more disadvantageous effects on
CMC1. When isometrically loading the APL, we noted that the CMC1 was compressed and
dorsoradially translated. This type of load is not beneficial for joint stability and joint
alignment as it may contribute to the onset of osteoarthritis. In fact, APL has previously
been acknowledged for its detrimental role and it has been recommended to perform
tenotomy of auxiliary tendons in early stages of CMC1 osteoarthritis [93].
Interestingly, the APL was the only muscle to react immediately (within 20 ms) following
stimulation of the DRL in healthy subjects. These reactions indicate a particular importance
in ligamento-muscular control of the joint. Since the APL is disadvantageous in established
CMC1 osteoarthritis, a disturbance of this ligamento-muscular reflex may be hypothesized.
Future EMG investigations should thus include subjects with known CMC1 osteoarthritis.
Besides proper muscular equilibrium, joint innervation and the integration of joint
afference, e.g., ligamento-muscular pathways, are essential for neuromuscular control and
joint stability [53,54]. It has been established that during the process of aging, a natural
denervation process occurs [69, 70]. This may in part play a role in the complex etiology of
osteoarthritis and its increasing prevalence with age, as denervation may result in
ineffectual neuromuscular mechanisms and proprioceptive functions [94-96].
Previous research has proposed that joint denervation may in fact intensify cartilage
degeneration, alter joint reflexes and thus result in osteoarthritis [71, 72]. Joint innervation
is also central as denervated joints loose their free nerve endings and vessels and
consequently obtain disadvantageous healing abilities [94]. Consequently, this also
increases the risk for osteoarthritis to develop [96,97].
39
Yet, the dynamics and interplay between CMC1 muscles and innervated CMC1 ligaments
have not been previously explored. Our investigation has for the first time established a
ligamento-muscular pathway between CMC1 muscles and a CMC1 ligament, namely the
richly innervated DRL. Our data adds to present knowledge about possible protective
ligamento-muscular functions [85,98-100].
One interesting finding of our study, was the identification of a mass inhibition of muscular
activity during tip pinch. This position is especially straining for the CMC1 joint as large
force amplification, equivalent of 1200%, occurs at the CMC1 joint during tip pinch [47].
Moreover, tip pinch is a particularly biomechanically challenging position as the CMC1 is
positioned at mid-axis [47] and engages all four muscles investigated in our material, in
order to maintain joint equilibrium. Therefore, the major inhibition of muscle activity noted
during tip pinch is indicative of a protective ligamento-muscular response by self-limitation
of excessive joint load.
Another important finding that supports the idea of joint protective ligamento-muscular
reactions was observed during key pinch. After stimulation of DRL, a rapid co-contraction
was identified just after 20-40 ms. This type of ligamento-muscular reaction is similar to a
monophasic reaction, and suggests the presence of a rapid monosynaptic spinal reflex
[85,101].
We were also able to identify co-contractions during all three functional CMC1 tasks
investigated, as have been described in other joints [102-104]. The co-contractions facilitate
joint stability by concurrent activation of agonist and antagonistic muscles and generate
joint stiffness, which further promotes joint stability.
Overall data obtained from our investigations demonstrate and confirm that proprioceptive
and neuromuscular functions are present in CMC1 and that these functions are in all
likelihood of importance for proper joint functions. Further work is required to fully
understand these mechanisms and their probable course of transformation during the onset
and progression of CMC1 osteoarthritis.
40
7.3
LIMITATIONS
The studies in this thesis have certain limitations, which will be considered and discussed in
the following section.
7.3.1 Immunohistochemical methods
There are several known limitations to immunohistochemical methods and these can be
divided into pre-analytic, analytic and post-analytic limitations (fig. 21).
Pre-analytical limitations
Once removed, it is important to fixate the tissue e.g. in formalin and paraffin promptly to
avoid autolysis [105,106]. The paraffinization and deparaffinization procedures of the
samples also contribute to unwanted exposure of the tissue. On the other hand, our samples
were fresh paraffin-embedded, rather than fresh-frozen tissue as used in previous studies
[35-37]. This reduces the exposure of the tissues and reduces the risk for artifacts to form.
Another pre-analytic phase of importance is the sectioning of the ligaments. This step was
performed by a microtome that segmented the samples into five µm sections. This may
result in cases where important structures are lost if divided as they may be localized in the
transected area. However, this matter is still existent even if larger sections would have
been used.
Analytical limitations
The analytical aspects of immunohistochemistry are much dependent on the protocol,
antigen and antibodies used, as well as proper use of controls. The antibodies used in our
studies have been used extensively before [35-37].
To avoid possible sources of error a standardized protocol is necessary. This is also true for
the staining procedures themselves, as they are shown to be more reproducible when using
immunohistochemistry through automated systems [107]. This type of automated systems
requires large number of samples to be feasible. Therefore, this was not in the scope of our
studies, as we used smaller sample sizes. Moreover, the use of optimal antibodies and the
characteristics of antigens, are key factors in the reliability and accuracy of
immunohistochemical methods.
PRE-ANALYSIS
Handling of
specimens
Fixation
Embedding, storage
and sectioning of
tissue
Deparaffinization
ANALYSIS
Staining
Retrieval of antigen
Antibody specificity
Reagent evaluation
Reference/Control
POST-ANALYSIS
Quantification
Evaluation
Figure 21. Limitations to immunohistochemical methodologies. Adapted from US Biologic
Stain Commission 1991 [108].
41
Post-analytical limitations
Post-analytical limitations of immunohistochemical studies are often regarding the
interpretation of the results. In our investigations, we used a semi-quantitative scoring
system, based on previous published studies on microscopic analysis of human ligaments
[36,58,84,109]. Manual interpretation of immunohistochemical stains, are probably not as
reliable as automated systems [110-112]. The semi-quantitative analysis used is often
labeled as a blunt method of data evaluation, but remains the preferred method of choice
until completely standardized methods of immunohistochemistry are introduced [106].
Lastly, another post-analytic challenge associated with immunohistochemistry and
immunofluorescent labeling, is the photo bleaching that occurs due to cumulative light
exposure of the prepared tissue.
7.3.2 Biomechanical assessment
The biomechanical model used in study III is a simplified representation of the complex
and multifaceted CMC1 joint. Naturally, a complete reconstruction and deconstruction of
the anatomical and biomechanical conditions of CMC1 is not feasible ex vivo. The model
used has kept the joint intact, but it is still difficult to assess all aspects of muscular control
of this joint, which in real life encompasses both dynamic, isotonic and isometric muscle
activity. Furthermore, our study set-up was unable to include aspects of thumb supination
and pronation, which also play a role in the dynamics of CMC1 function. Nevertheless, the
FASTRAK® motion tracking device is reported as a reliable method to evaluate a threedimensional analysis of joint motion [113-118], as opposed to e.g. the use of manual
goniometer which is a device known to be disposed to sources of measurement error.
7.3.3 Electromyographic procedures
Factors that commonly may impact EMG signals are often different forms of electrical
noise interference. Noise interference stems from either electromagnetic devices, also
known as ambient noise interference, or it can also be due to noise generated from the
electrical device used [119]. Other sources of electrical noise that can disturb EMG
signaling include motion artifacts due to interference of the electrode or the cable itself.
There are also extrinsic causes of disturbance of EMG signals, which can vary due to the
type of electrode used and the positioning of the electrode. Intrinsic causes, which may
disturb EMG signaling, are primarily physiological issues such as blood flow or fiber type
and localization [119,120].
A weakness of our electromyographic study was that we did not include all muscles, which
control CMC1. However, the muscles included were selected for representation of both
intrinsic and extrinsic muscle activity in addition to their varying innervation by the
median, radial and ulnar nerves. In addition, the muscles were selected to reduce the
possibility of crosstalk, which is known as a frequent source of error in electromyographic
procedures [121]. Additional steps taken to reduce the risk of crosstalk were use of a
reference electrode as well as meticulous skin preparation and visual inspection of signals
to ensure that signals from the different muscles were not symmetrical.
Another imaginable source of uncertainty was the possible interference of pain afferents in
the examined area. To minimize the risk of such events, the stimulus applied to DRL was
consistently below the pain threshold. Consequently, the risk of involvement of
nociceptive Aδ- or C-fibers was eliminated, and paved the way for detection of Aβafferents of mechanoreceptors present in the DRL [1,57,122]. In addition, none of the
participants experienced pain during the stimulus.
42
7.4
CLINICAL RELEVANCE
The clinical implications based on this thesis, may serve to aid in the prevention and
treatment of CMC1 instability and osteoarthritis. The results indicate an association
between impaired proprioceptive and neuromuscular functions, abnormal joint load and
osteoarthritis, in agreement with previous research [56,123,124]. Traditional rehabilitation
often aims at improving muscle strength and when this is combined with neuromuscular
exercise, positive outcomes such as pain reduction and improved functions have been
observed [125].
Previous researchers have demonstrated that if effective proprioceptive exercises are used
to target ligament injuries, in e.g. the ankle and the knee, the need for surgery will decrease
[126-128]. A specific type of neuromuscular exercise, named perturbation exercise, has
been employed for the rehabilitation of the anterior cruciate ligament injuries in the knee,
with positive outcomes as patients improved their gait patterns and knee function
[125,129,130]. Also in the shoulder, another joint highly subjected to instability with
dependency on proper proprioceptive and neuromuscular functions, neuromuscular
exercises are also recognized as key components in the restoration of joint control and joint
function [131].
Both surgical and non-surgical treatments of CMC1 osteoarthritis aim at improving muscle
strength and range of movement whilst reducing pain, stiffness, instability and joint
incongruency. This is especially important, as the biconcavo-convex shape of the CMC1
joint does not provide for optimal intra-articular stability and support.
Conventional non-surgical treatments of the thumb include pain medication, orthotic
treatments, strengthening exercises and joint protection education [132,133]. The purpose
of dynamic, neuromuscular exercise of CMC1 is to ensure stability and precision
throughout the large range of motion, which this joint is capable of.
Central to this discipline is the importance of DI strengthening exercises, combined with
restoration of the muscular equilibrium of CMC1’s intrinsic and extrinsic musculature [92].
This resonates with the findings observed in our biomechanical study [3], in which the DI
counteracts dorsoradial shift. However, much remains to be investigated on the topic of
proprioceptive re-education of the hand and the CMC1 joint, as this is still a subject without
real consensus [134].
As we have confirmed the presence of a ligamento-muscular reflex following stimulation of
the DRL, we advocate that this should also be taken into consideration during surgical
treatments of CMC1 by employing nerve-sparing techniques. In cases with carpal
instability, ligament insufficiency has reportedly been treated with electro thermal
shrinkage through arthroscopic approach [135,136]. Although these reports present with
positive outcomes, this type of treatment should be used with caution, whether it is for the
treatment of carpal instabilities or CMC1 instability. This is based on the notion that this
treatment may cause irreversible damage of mechanoreceptors and free nerve endings that,
according to the findings of this thesis, are central for optimal joint stability and joint
functions.
In conclusion, neuromuscular and proprioceptive features of CMC1 should be taken into
consideration during treatment of CMC1, whether surgically or conservatively. As such, we
propose early post-operative rehabilitation and perhaps even pre-surgical proprioceptive
strategies to optimize surgical outcomes.
43
7.5
FUTURE PERSPECTIVES
In order to understand the pathophysiology of this intricate joint, one needs to outline
normal physiological conditions, which partially have been described in this thesis.
The conclusions regarding the proprioception and neuromuscular stability of CMC1 as
presented herein, are steps towards deciphering the pathophysiology of this complex thumb
joint. Still, there are still many questions that remain unanswered but these are outside the
scope of this thesis.
Research questions that could be asked include the function and exact role of unclassifiable
receptors. Are these receptors degenerated or injured mechanoreceptors with new
functions? Or do they represent non-functional neural remnants? Have these receptors been
present in osteoarthritic patients all along, making them susceptible to osteoarthritis, or are
they a result of the osteoarthritic process?
To characterize these receptors further, one could design a set-up in which different stages
of osteoarthritis are compared and assessed. In a best-case scenario, one could examine
whether a linear relationship is present between the various stages of osteoarthritis and the
prevalence of unclassifiable receptors, as opposed to the present comparison of end stage
osteoarthritis to normal specimens.
Further work is required to evaluate the beneficial effects of neuromuscular exercise of DI
as a treatment option in early CMC1 osteoarthritis. A possible way to do so would be to
compare patients with neuromuscular exercise of DI to those with traditional strengthening
exercises and patients who receive no treatment. This can also be evaluated with regard to
surgical intervention; do patients who undergo dynamic exercise of DI prior to surgery have
better surgical outcomes, as noted in patients who undergo reconstruction of the anterior
cruciate ligament of the knee [137-139]?
To develop a full picture of the neurophysiological conditions in CMC1, additional studies
will be needed to characterize the ligamento-muscular patterns in patients with CMC1
osteoarthritis. In addition further research should be undertaken to investigate the role of
maintained innervation of CMC1, as some surgeons advocate joint denervation as treatment
in osteoarthritic patients. But how does this affect the proprioceptive function of the joint?
If one were to widen the perspectives further, the methods used in this thesis can also be
applied to investigate other joints or neuromuscular pathologies, such as affected joint
and/or muscle functions following nerve palsy or injury.
44
8 CONCLUSIONS
This thesis began by describing the characteristics and innervation of CMC1 ligaments in
osteoarthritic patients, followed by a biomechanical assessment of CMC1 muscles.
Finally, electromyographic observations of CMC1 and its ligamento-muscular relations
revealed the presence of protective ligamento-muscular pathways.
Some of the principal issues and conclusions are provided below:
!
CMC1 ligaments are essential for proper joint stability and control, not simply due
to their mechanical support, but also because they embody sensorimotor and
neuromuscular qualities.
!
The DRL is a robust ligament with ample innervation, whereas AOL is thin and
hypocellular. The most common type of mechanoreceptor found in DRL, was the
unclassifiable receptor. This finding differs from specimens investigated without
CMC1 osteoarthritis, and may be an implication of altered sensorimotor features as
a result of osteoarthritis, natural senescence, or due to post-traumatic changes.
!
Biomechanical assessment of CMC1 in isometric conditions revealed that certain
CMC1 muscles may act as stabilizers of the joint by preventing dorsoradial
translation, whereas other muscles actually advance joint malalignment.
!
Functional evidence for the proprioceptive and neuromuscular functions of the
CMC1 joint was established by the electromyographic observations of CMC1
muscles after stimulation of DRL. The ligamento-muscular reflex responses
identified likely serve to promote joint stability.
!
Overall, these findings support the view that the CMC1 joint is not merely a
biomechanical unit, but a joint with complex proprioceptive and neuromuscular
functions that are needed to maintain the stability of this inherently incongruent and
multifaceted joint.
!
Clinically, these results advocate nerve-sparing surgical techniques and highlight
the need to further explore the effects of early rehabilitation following trauma or
surgery. By doing so, neuromuscular and proprioceptive functions are preserved and
the onset of osteoarthritis may be delayed or at its best, prevented.
45
9 ACKNOWLEDGEMENTS
It gives me great pleasure to thank everyone who supported and guided me through this
fascinating journey.
Firstly and foremost, I would like to express my deepest gratitude to my principal
supervisor Dr. Elisabet Hagert. Your never-ending optimism, support and knowledge sets
the bar for any distinguished surgeon or researcher, and you manage to balance the two so
successfully. Your passion for science and surgery is contagious. This journey would not
have been possible without your patience and support, thanks for the confidence you have
shown in me. You are true source of inspiration in all aspects of life!
I would like to express my sincere gratitude to my co-supervisor and former chief of staff
Professor Sari Ponzer. Your support and great knowledge of academics has been essential
for me. Without you, the commencement and finalization of this thesis would have been a
much more tedious and overwhelming process. Your leadership skills and professionalism
is unprecedented.
I would also like thank my co-supervisor Dr. Jonas Persson for helping in the difficult setup and trial of study IV.
I am deeply grateful to Dr. Pål Krøger. Thank you for offering me the perfect combination
of research and surgery. This journey would have been miles further without your support!
I would also like to thank Dr. Stein Tore Nilsen for believing in my project and for
guiding me through the bureaucratic, yet important, aspects of research.
I consider it an honor to have worked with Dr. Marc Garcia-Elias. I am intellectually
indebted to you. Your passion for hand surgery and science is truly unparalleled. Your
knowledge, encouragement and patience is endless. I am truly honored to be invited to the
CISTY association by you!
My sincere thanks also go to Dr. Mireia Esplugas, Dr. Alex Lluch and Dr. Kai Megerle.
Your heartfelt support and optimism have inspired me to not give up. Working with you
has been fun, inspiring and motivating. I miss really our days in the lab!
I owe sincere and earnest thankfulness to Dr. Amy Ladd for inviting me to Stanford
University and for great collaborations. Your great knowledge, professionalism and
encouragement have been invaluable.
Co-author Cassie Ludwig, you have a bright future ahead of you! Thanks for making the
many hours in the lab fun and for great teamwork.
Dr. Susanne Rein, working with you has been such a pleasure! I have greatly benefited
from our collaboration as your meticulous comments, work ethics and knowledge have
guided and inspired me.
I am indebted to my many colleagues at work; Dr. Bruns Kleppe for making work fun and
fabulous. Special thanks to fellow co-workers and friends Drs. Furholt, Rasdal, Jåthun
and Styles for your support. I would also like to take the opportunity to express my greatest
appreciation to senior colleagues Drs. Söderberg, Kjøsen, Tiller, Miksch, Panczel,
46
Bajszczak and Nyström for great clinical supervision, support and for creating a nice work
atmosphere.
My sincere gratitude goes to all nurses and staff members in our department. Thanks for
showing interest in my research and for being so supportive and kind in our daily work; you
make work so easy and fun!
I would also like to take this opportunity to express my gratitude to all of my former
colleagues at SÖS. I miss the days spent with interesting medical cases, laughter and hard
work. Many of you have been, and still are, great sources of inspiration! I especially miss
my former colleagues at “plan 8”; how is it possible to have so much fun and work so hard
simultaneously?
I have received generous support and guidance from staff members at the Department of
Clinical Science and Education. Special thanks to Jeanette Öhrman and Britta Barkeling
for always being so helpful and kind.
My wonderful group of friends, who encourage me and fill me with optimism, and to
whom I owe an apology for periods of radio silence due to work related travels far away
from home.
Karin and Stefano, thank you for your friendship and for introducing me to Palo Alto,
Stanford Cardinals and for all of the good times at spent at the campus and beyond. My stay
at Stanford would not have been the same without you.
My extra family Kristina, Lars, Jonas and Susanna; thank you for your total support and
kindness at all times. And not the least for endorsing me as a member of Bästerö Supporter
Club!
My amazing parents and my beloved sister: no words can describe the tremendous love
and support I feel from you – you are truly the best! I will forever be in debt to you for all
the sacrifices you have made in life for me. You are wonderful role models for me as well
as for others. Your thoughtfulness, work ethics, and passion for science have always
inspired me and been of great value for me throughout this journey.
My beloved Rickard, my significant (p<0.0001) other;
Everything would mean nothing without you.
This thesis is the result of research collaboration between Karolinska Institutet, Stanford
University, Barcelona University/Institut Kaplan, Dresden University, Hand & Foot
Surgery Center, Stockholm and Stavanger University Hospital.
This research was supported by grants from Karolinska Institutet and Hirsch foundation.
47
10 REFERENCES
1. Mobargha N, Ludwig C, Ladd AL, Hagert E (2014) Ultrastructure and innervation of
thumb carpometacarpal ligaments in surgical patients with osteoarthritis. Clin
Orthop Relat Res 472: 1146-1154.
2. Ludwig C, Mobargha N, Okogbaa J, Hagert E, Ladd A (2015. Accepted mauscript)
Altered Innervation Pattern in Ligaments of Patients with Basal Thumb Arthritis.
Journal of Wrist Surgery.
3. Mobargha N, Esplugas M, Garcia-Elias M, Lluch A, Megerle K, et al. (2015) The effect
of individual isometric muscle loading on the alignment of the base of the thumb
metacarpal: a cadaveric study. J Hand Surg Eur Vol.
4. Ross WD (1928) The Works of Aristotle Translated Into English: Clarendon Press.
5. Smith JA RW The works of Aristotle (translated into English). De partibus animalium., .
W. VO, translator: Oxford: Clarendon Press.
6. Napier JR (1956) The prehensile movements of the human hand. J Bone Joint Surg Br
38-B: 902-913.
7. Pellegrini VD, Jr. (2005) The ABJS 2005 Nicolas Andry Award: osteoarthritis and injury
at the base of the human thumb: survival of the fittest? Clin Orthop Relat Res 438:
266-276.
8. Leversedge FJ (2008) Anatomy and pathomechanics of the thumb. Hand clinics 24: 219229, v.
9. Slocum DB, Pratt DR (1946) Disability evaluation for the hand. J Bone Joint Surg Am
28: 491-495.
10. Van Heest AE, Kallemeier P (2008) Thumb carpal metacarpal arthritis. The Journal of
the American Academy of Orthopaedic Surgeons 16: 140-151.
11. Armstrong AL, Hunter JB, Davis TR (1994) The prevalence of degenerative arthritis of
the base of the thumb in post-menopausal women. Journal of hand surgery 19: 340341.
12. Saxena P, Cutler L, Feldberg L (2004) Assessment of the severity of hand injuries using
"hand injury severity score", and its correlation with the functional outcome. Injury
35: 511-516.
13. Rosberg HE, Carlsson KS, Hojgard S, Lindgren B, Lundborg G, et al. (2005) Injury to
the human median and ulnar nerves in the forearm--analysis of costs for treatment
and rehabilitation of 69 patients in southern Sweden. J Hand Surg Br 30: 35-39.
14. Rosberg HE, Carlsson KS, Dahlin LB (2005) Prospective study of patients with injuries
to the hand and forearm: costs, function, and general health. Scand J Plast Reconstr
Surg Hand Surg 39: 360-369.
15. de Putter CE, Selles RW, Polinder S, Panneman MJ, Hovius SE, et al. (2012) Economic
impact of hand and wrist injuries: health-care costs and productivity costs in a
population-based study. J Bone Joint Surg Am 94: e56.
16. Brand PW HA (1993) Clinical mechanics of the hand. . St. Louis: Mosby.
17. Cooney WP, 3rd, Lucca MJ, Chao EY, Linscheid RL (1981) The kinesiology of the
thumb trapeziometacarpal joint. J Bone Joint Surg Am 63: 1371-1381.
18. Bettinger PC, Berger RA (2001) Functional ligamentous anatomy of the trapezium and
trapeziometacarpal joint (gross and arthroscopic). Hand Clin 17: 151-168, vii.
19. Linscheid RL, Dobyns JH, Beabout JW, Bryan RS (2002) Traumatic instability of the
wrist: diagnosis, classification, and pathomechanics. The Journal of bone and joint
surgery American volume 84-A: 142.
48
20. Linscheid RL, Dobyns JH (2002) Dynamic carpal stability. The Keio journal of
medicine 51: 140-147.
21. Brandt KD, Dieppe P, Radin E (2009) Etiopathogenesis of osteoarthritis. The Medical
clinics of North America 93: 1-24, xv.
22. Gupta S, Michelsen-Jost H (2012) Anatomy and function of the thenar muscles. Hand
Clin 28: 1-7.
23. Rowntree T (1949) Anomalous innervation of the hand muscles. J Bone Joint Surg Br
31B: 505-510.
24. Masquelet AC, Salama J, Outrequin G, Serrault M, Chevrel JP (1986) Morphology and
functional anatomy of the first dorsal interosseous muscle of the hand. Surg Radiol
Anat 8: 19-28.
25. An KN, Ueba Y, Chao EY, Cooney WP, Linscheid RL (1983) Tendon excursion and
moment arm of index finger muscles. J Biomech 16: 419-425.
26. Hudson AL, Taylor JL, Gandevia SC, Butler JE (2009) Coupling between mechanical
and neural behaviour in the human first dorsal interosseous muscle. J Physiol 587:
917-925.
27. Brokaw J, Craig S, DeNeal S, Morris K, Halle J (2010) Radial nerve innervation of the
first dorsal interosseous muscle: A functional study. Clin Anat 23: 227-233.
28. Day MH, Napier JR (1961) The two heads of flexor pollicis brevis. J Anat 95: 123-130.
29. Ajmani ML (1996) Variations in the motor nerve supply of the thenar and hypothenar
muscles of the hand. J Anat 189 ( Pt 1): 145-150.
30. van Oudenaarde E (1991) Structure and function of the abductor pollicis longus muscle.
J Anat 174: 221-227.
31. Gonzalez MH, Sohlberg R, Brown A, Weinzweig N (1995) The first dorsal extensor
compartment: an anatomic study. J Hand Surg Am 20: 657-660.
32. Colman M, Mass DP, Draganich LF (2007) Effects of the deep anterior oblique and
dorsoradial ligaments on trapeziometacarpal joint stability. J Hand Surg Am 32:
310-317.
33. Bettinger PC, Linscheid RL, Berger RA, Cooney WP, 3rd, An KN (1999) An anatomic
study of the stabilizing ligaments of the trapezium and trapeziometacarpal joint. J
Hand Surg Am 24: 786-798.
34. Pellegrini VD, Jr. (1991) Osteoarthritis of the trapeziometacarpal joint: the
pathophysiology of articular cartilage degeneration. I. Anatomy and pathology of
the aging joint. J Hand Surg Am 16: 967-974.
35. Lee J, Ladd A, Hagert E (2012) Immunofluorescent triple-staining technique to identify
sensory nerve endings in human thumb ligaments. Cells, tissues, organs 195: 456464.
36. Ladd AL, Lee J, Hagert E (2012) Macroscopic and microscopic analysis of the thumb
carpometacarpal ligaments: a cadaveric study of ligament anatomy and histology.
The Journal of bone and joint surgery American volume 94: 1468-1477.
37. Hagert E, Lee J, Ladd AL (2012) Innervation patterns of thumb trapeziometacarpal
joint ligaments. The Journal of hand surgery 37: 706-714 e701.
38. Bettinger PC, Smutz WP, Linscheid RL, Cooney WP, 3rd, An KN (2000) Material
properties of the trapezial and trapeziometacarpal ligaments. J Hand Surg Am 25:
1085-1095.
39. Bettinger PC, Linscheid RL, Cooney WP, 3rd, An KN (2001) Trapezial tilt: a
radiographic correlation with advanced trapeziometacarpal joint arthritis. J Hand
Surg Am 26: 692-697.
40. Edmunds JO (2006) Traumatic dislocations and instability of the trapeziometacarpal
joint of the thumb. Hand Clin 22: 365-392.
41. Imaeda T, An KN, Cooney WP, 3rd (1992) Functional anatomy and biomechanics of
the thumb. Hand Clin 8: 9-15.
49
42. Imaeda T, An KN, Cooney WP, 3rd, Linscheid R (1993) Anatomy of
trapeziometacarpal ligaments. J Hand Surg Am 18: 226-231.
43. Edmunds JO (2011) Current concepts of the anatomy of the thumb trapeziometacarpal
joint. The Journal of hand surgery 36: 170-182.
44. Strauch RJ, Behrman MJ, Rosenwasser MP (1994) Acute dislocation of the
carpometacarpal joint of the thumb: an anatomic and cadaver study. J Hand Surg
Am 19: 93-98.
45. Van Brenk B, Richards RR, Mackay MB, Boynton EL (1998) A biomechanical
assessment of ligaments preventing dorsoradial subluxation of the
trapeziometacarpal joint. J Hand Surg Am 23: 607-611.
46. Bosmans B, Verhofstad MH, Gosens T (2008) Traumatic thumb carpometacarpal joint
dislocations. The Journal of hand surgery 33: 438-441.
47. Cooney WP, 3rd, Chao EY (1977) Biomechanical analysis of static forces in the thumb
during hand function. J Bone Joint Surg Am 59: 27-36.
48. Schott GD (1993) Penfield's homunculus: a note on cerebral cartography. J Neurol
Neurosurg Psychiatry 56: 329-333.
49. Kahle W, Frotscher M (2011) Color Atlas of Human Anatomy: Thieme.
50. Wilhelm A (1966) [Articular denervation and its anatomical foundation. A new
therapeutic principle in hand surgery. On the treatment of the later stages of
lunatomalacia and navicular pseudarthrosis]. Hefte Unfallheilkd 86: 1-109.
51. Fukumoto K, Kojima T, Kinoshita Y, Koda M (1993) An anatomic study of the
innervation of the wrist joint and Wilhelm's technique for denervation. J Hand Surg
Am 18: 484-489.
52. Miki RA, Kam CC, Gennis ER, Barkin JA, Riel RU, et al. (2011) Ulnar nerve
component to innervation of thumb carpometacarpal joint. Iowa Orthop J 31: 225230.
53. Riemann BL, Lephart SM (2002) The sensorimotor system, part I: the physiologic basis
of functional joint stability. Journal of athletic training 37: 71-79.
54. Lephart SM RB, Fu FH ( 2000) Proprioception and neuromuscular control in joint
stability; Introduction to the Sensorimotor System. : Champaign, II: Human
Kinetics.
55. Lichtman DM, Wroten ES (2006) Understanding midcarpal instability. J Hand Surg
Am 31: 491-498.
56. Brandt KD, Radin EL, Dieppe PA, van de Putte L (2006) Yet more evidence that
osteoarthritis is not a cartilage disease. Ann Rheum Dis 65: 1261-1264.
57. Grigg P (2001) Properties of sensory neurons innervating synovial joints. Cells Tissues
Organs 169: 218-225.
58. Freeman MA, Wyke B (1967) The innervation of the ankle joint. An anatomical and
histological study in the cat. Acta Anat (Basel) 68: 321-333.
59. Abraira VE, Ginty DD (2013) The sensory neurons of touch. Neuron 79: 618-639.
60. Moraes MR, Cavalcante ML, Leite JA, Macedo JN, Sampaio ML, et al. (2011) The
characteristics of the mechanoreceptors of the hip with arthrosis. J Orthop Surg Res
6: 58.
61. Lee AS, Ellman MB, Yan D, Kroin JS, Cole BJ, et al. (2013) A current review of
molecular mechanisms regarding osteoarthritis and pain. Gene 527: 440-447.
62. Haara MM, Heliovaara M, Kroger H, Arokoski JP, Manninen P, et al. (2004)
Osteoarthritis in the carpometacarpal joint of the thumb. Prevalence and
associations with disability and mortality. J Bone Joint Surg Am 86-A: 1452-1457.
63. Yao J, Park MJ (2008) Early treatment of degenerative arthritis of the thumb
carpometacarpal joint. Hand Clin 24: 251-261, v-vi.
64. Tsai P, Beredjiklian PK (2008) Physical diagnosis and radiographic examination of the
thumb. Hand Clin 24: 231-237, v.
50
65. Hawker GA, Stewart L, French MR, Cibere J, Jordan JM, et al. (2008) Understanding
the pain experience in hip and knee osteoarthritis--an OARSI/OMERACT initiative.
Osteoarthritis Cartilage 16: 415-422.
66. Hurley MV (1999) The role of muscle weakness in the pathogenesis of osteoarthritis.
Rheum Dis Clin North Am 25: 283-298, vi.
67. Sharma L (1999) Proprioceptive impairment in knee osteoarthritis. Rheumatic diseases
clinics of North America 25: 299-314, vi.
68. Guermazi A, Burstein D, Conaghan P, Eckstein F, Hellio Le Graverand-Gastineau MP,
et al. (2008) Imaging in osteoarthritis. Rheum Dis Clin North Am 34: 645-687.
69. Valderrabano V, Hintermann B, Horisberger M, Fung TS (2006) Ligamentous
posttraumatic ankle osteoarthritis. Am J Sports Med 34: 612-620.
70. McGonagle D, Tan AL, Carey J, Benjamin M (2010) The anatomical basis for a novel
classification of osteoarthritis and allied disorders. Journal of anatomy 216: 279291.
71. Tan AL, Toumi H, Benjamin M, Grainger AJ, Tanner SF, et al. (2006) Combined highresolution magnetic resonance imaging and histological examination to explore the
role of ligaments and tendons in the phenotypic expression of early hand
osteoarthritis. Annals of the rheumatic diseases 65: 1267-1272.
72. Eaton RG, Glickel SZ (1987) Trapeziometacarpal osteoarthritis. Staging as a rationale
for treatment. Hand clinics 3: 455-471.
73. Eaton RG, Littler JW (1973) Ligament reconstruction for the painful thumb
carpometacarpal joint. J Bone Joint Surg Am 55: 1655-1666.
74. Lachance L, Sowers MF, Jamadar D, Hochberg M (2002) The natural history of
emergent osteoarthritis of the knee in women. Osteoarthritis Cartilage 10: 849-854.
75. Hunter DJ, Zhang Y, Sokolove J, Niu J, Aliabadi P, et al. (2005) Trapeziometacarpal
subluxation predisposes to incident trapeziometacarpal osteoarthritis (OA): the
Framingham Study. Osteoarthritis and cartilage / OARS, Osteoarthritis Research
Society 13: 953-957.
76. Pellegrini VD, Jr., Smith RL, Ku CW (1994) Pathobiology of articular cartilage in
trapeziometacarpal osteoarthritis. I. Regional biochemical analysis. J Hand Surg Am
19: 70-78.
77. Damen A, van der Lei B, Robinson PH (1996) Carpometacarpal arthritis of the thumb. J
Hand Surg Am 21: 807-812.
78. Glickel SZ (2001) Clinical assessment of the thumb trapeziometacarpal joint. Hand Clin
17: 185-195.
79. Katarincic JA (2001) Thumb kinematics and their relevance to function. Hand Clin 17:
169-174.
80. Slaoui M, Fiette L (2011) Histopathology procedures: from tissue sampling to
histopathological evaluation. Methods Mol Biol 691: 69-82.
81. Rein S, Semisch M, Garcia-Elias M, Lluch A, Zwipp H, et al. (2015)
Immunohistochemical Mapping of Sensory Nerve Endings in the Human Triangular
Fibrocartilage Complex. Clin Orthop Relat Res.
82. Hagert E, Garcia-Elias M, Forsgren S, Ljung BO (2007) Immunohistochemical analysis
of wrist ligament innervation in relation to their structural composition. J Hand Surg
Am 32: 30-36.
83. Hagert E (2008) Wrist Ligaments - Innervation Patterns and Ligamento-Muscular
Reflexes; Ph.D. Thesis, in Dept of Clinical Science and Education, Section of Hand
Surgery. 2008, Karolinska Institutet: Stockholm. p. 1-51.
84. Hagert E, Forsgren S, Ljung BO (2005) Differences in the presence of
mechanoreceptors and nerve structures between wrist ligaments may imply
differential roles in wrist stabilization. Journal of orthopaedic research : official
publication of the Orthopaedic Research Society 23: 757-763.
51
85. Hagert E, Persson JK, Werner M, Ljung BO (2009) Evidence of wrist proprioceptive
reflexes elicited after stimulation of the scapholunate interosseous ligament. J Hand
Surg Am 34: 642-651.
86. Shinji Imai KK, Yoshitaka Matsusue (2003) Digital pacinian corpuscle hyperplasia.
Journal of the American Society for Surgery of Hand - Pages 175-180.
87. Jones NF, Eadie P (1991) Pacinian corpuscle hyperplasia in the hand. The Journal of
hand surgery 16: 865-869.
88. Hanesch U (1996) Neuropeptides in dural fine sensory nerve endings--involvement in
neurogenic inflammation? Progress in brain research 113: 299-317.
89. McDonald DM, Bowden JJ, Baluk P, Bunnett NW (1996) Neurogenic inflammation. A
model for studying efferent actions of sensory nerves. Advances in experimental
medicine and biology 410: 453-462.
90. Masquelet AC, Salama J, Outrequin G, Serrault M, Chevrel JP (1986) Morphology and
functional anatomy of the first dorsal interosseous muscle of the hand. Surgical and
radiologic anatomy : SRA 8: 19-28.
91. Witthaut J, Leclercq C (1999) [The interosseous palmaris muscle of the thumb. Results
of an anatomic study of a muscle of the first ray]. Handchir Mikrochir Plast Chir 31:
66-69.
92. O'Brien VH, Giveans MR (2013) Effects of a dynamic stability approach in
conservative intervention of the carpometacarpal joint of the thumb: a retrospective
study. Journal of hand therapy : official journal of the American Society of Hand
Therapists 26: 44-51; quiz 52.
93. Zancolli EA (2001) The trapeziometacarpal joint. Tenotomy of the accessory tendons in
early osteoarthritis. Hand Clin 17: 13-43.
94. Ivie TJ, Bray RC, Salo PT (2002) Denervation impairs healing of the rabbit medial
collateral ligament. J Orthop Res 20: 990-995.
95. Salo PT, Seeratten RA, Erwin WM, Bray RC (2002) Evidence for a neuropathic
contribution to the development of spontaneous knee osteoarthrosis in a mouse
model. Acta Orthop Scand 73: 77-84.
96. Salo P (1999) The role of joint innervation in the pathogenesis of arthritis. Can J Surg
42: 91-100.
97. Salo PT, Hogervorst T, Seerattan RA, Rucker D, Bray RC (2002) Selective joint
denervation promotes knee osteoarthritis in the aging rat. J Orthop Res 20: 12561264.
98. O'Connor BL, Palmoski MJ, Brandt KD (1985) Neurogenic acceleration of
degenerative joint lesions. The Journal of bone and joint surgery American volume
67: 562-572.
99. O'Connor BL, Brandt KD (1993) Neurogenic factors in the etiopathogenesis of
osteoarthritis. Rheum Dis Clin North Am 19: 581-605.
100. Johansson H, Sjolander P, Sojka P (1991) Receptors in the knee joint ligaments and
their role in the biomechanics of the joint. Crit Rev Biomed Eng 18: 341-368.
101. Solomonow M, Krogsgaard M (2001) Sensorimotor control of knee stability. A
review. Scand J Med Sci Sports 11: 64-80.
102. Hirokawa S, Solomonow M, Lu Y, Lou ZP, D'Ambrosia R (1992) Anterior-posterior
and rotational displacement of the tibia elicited by quadriceps contraction. Am J
Sports Med 20: 299-306.
103. MacWilliams BA, Wilson DR, DesJardins JD, Romero J, Chao EY (1999) Hamstrings
cocontraction reduces internal rotation, anterior translation, and anterior cruciate
ligament load in weight-bearing flexion. J Orthop Res 17: 817-822.
104. Solomonow M, Zhou BH, Harris M, Lu Y, Baratta RV (1998) The ligamentomuscular stabilizing system of the spine. Spine (Phila Pa 1976) 23: 2552-2562.
52
105. Taylor CR, Levenson RM (2006) Quantification of immunohistochemistry--issues
concerning methods, utility and semiquantitative assessment II. Histopathology 49:
411-424.
106. Grube D (2004) Constants and variables in immunohistochemistry. Arch Histol Cytol
67: 115-134.
107. Warford A, Howat W, McCafferty J (2004) Expression profiling by high-throughput
immunohistochemistry. J Immunol Methods 290: 81-92.
108. Taylor CR (1992) Quality assurance and standardization in immunohistochemistry. A
proposal for the annual meeting of the Biological Stain Commission, June, 1991.
Biotech Histochem 67: 110-117.
109. Hagert E, Garcia-Elias M, Forsgren S, Ljung BO (2007) Immunohistochemical
analysis of wrist ligament innervation in relation to their structural composition. The
Journal of hand surgery 32: 30-36.
110. McClelland RA, Finlay P, Walker KJ, Nicholson D, Robertson JF, et al. (1990)
Automated quantitation of immunocytochemically localized estrogen receptors in
human breast cancer. Cancer Res 50: 3545-3550.
111. Ruifrok AC, Johnston DA (2001) Quantification of histochemical staining by color
deconvolution. Anal Quant Cytol Histol 23: 291-299.
112. Lehr HA, Jacobs TW, Yaziji H, Schnitt SJ, Gown AM (2001) Quantitative evaluation
of HER-2/neu status in breast cancer by fluorescence in situ hybridization and by
immunohistochemistry with image analysis. Am J Clin Pathol 115: 814-822.
113. Salva-Coll G, Garcia-Elias M, Leon-Lopez MM, Llusa-Perez M, Rodriguez-Baeza A
(2012) Role of the extensor carpi ulnaris and its sheath on dynamic carpal stability.
The Journal of hand surgery, European volume 37: 544-548.
114. Salva Coll G, Garcia-Elias M, Lluch Bergada A, Leon Lopez MM, Llusa Perez M, et
al. (2013) [Carpal dynamic stability mechanisms. Experimental study]. Rev Esp Cir
Ortop Traumatol 57: 129-134.
115. Salva-Coll G, Garcia-Elias M, Leon-Lopez MM, Llusa-Perez M, Rodriguez-Baeza A
(2011) Role of the extensor carpi ulnaris and its sheath on dynamic carpal stability.
The Journal of hand surgery, European volume.
116. Leon-Lopez MM, Garcia-Elias M, Salva-Coll G, Llusa-Perez M, Lluch-Bergada A
(2014) [Muscular control of scapholunate instability. An experimental study]. Rev
Esp Cir Ortop Traumatol 58: 11-18.
117. Jordan K, Dziedzic K, Jones PW, Ong BN, Dawes PT (2000) The reliability of the
three-dimensional FASTRAK measurement system in measuring cervical spine and
shoulder range of motion in healthy subjects. Rheumatology (Oxford) 39: 382-388.
118. Jordan K, Haywood KL, Dziedzic K, Garratt AM, Jones PW, et al. (2004) Assessment
of the 3-dimensional Fastrak measurement system in measuring range of motion in
ankylosing spondylitis. J Rheumatol 31: 2207-2215.
119. Reaz MB, Hussain MS, Mohd-Yasin F (2006) Techniques of EMG signal analysis:
detection, processing, classification and applications (Correction). Biol Proced
Online 8: 163.
120. Merlo AC, I. (2010) Technical Aspects of Surface Electromyography for Clinicians.
The Open Rehabilitation Journal 98-99.
121. Farina D, Merletti R, Stegeman DF (2005) Biophysics of the Generation of EMG
Signals. Electromyography: John Wiley & Sons, Inc. pp. 81-105.
122. Gilman S (2002) Joint position sense and vibration sense: anatomical organisation and
assessment. J Neurol Neurosurg Psychiatry 73: 473-477.
123. Buckwalter JA (1995) Osteoarthritis and articular cartilage use, disuse, and abuse:
experimental studies. J Rheumatol Suppl 43: 13-15.
124. Griffin TM, Guilak F (2005) The role of mechanical loading in the onset and
progression of osteoarthritis. Exerc Sport Sci Rev 33: 195-200.
53
125. Fitzgerald GK, Piva SR, Gil AB, Wisniewski SR, Oddis CV, et al. (2011) Agility and
perturbation training techniques in exercise therapy for reducing pain and improving
function in people with knee osteoarthritis: a randomized clinical trial. Phys Ther
91: 452-469.
126. Ageberg E (2002) Consequences of a ligament injury on neuromuscular function and
relevance to rehabilitation - using the anterior cruciate ligament-injured knee as
model. Journal of electromyography and kinesiology : official journal of the
International Society of Electrophysiological Kinesiology 12: 205-212.
127. Ageberg E, Pettersson A, Friden T (2007) 15-year follow-up of neuromuscular
function in patients with unilateral nonreconstructed anterior cruciate ligament
injury initially treated with rehabilitation and activity modification: a longitudinal
prospective study. Am J Sports Med 35: 2109-2117.
128. Eils E, Rosenbaum D (2001) A multi-station proprioceptive exercise program in
patients with ankle instability. Med Sci Sports Exerc 33: 1991-1998.
129. Chmielewski TL, Hurd WJ, Rudolph KS, Axe MJ, Snyder-Mackler L (2005)
Perturbation training improves knee kinematics and reduces muscle co-contraction
after complete unilateral anterior cruciate ligament rupture. Phys Ther 85: 740-749;
discussion 750-744.
130. Fitzgerald GK, Axe MJ, Snyder-Mackler L (2000) Proposed practice guidelines for
nonoperative anterior cruciate ligament rehabilitation of physically active
individuals. J Orthop Sports Phys Ther 30: 194-203.
131. Wilk KE, Macrina LC, Reinold MM (2006) Non-operative rehabilitation for traumatic
and atraumatic glenohumeral instability. N Am J Sports Phys Ther 1: 16-31.
132. Boustedt C, Nordenskiold U, Lundgren Nilsson A (2009) Effects of a hand-joint
protection programme with an addition of splinting and exercise: one year followup. Clin Rheumatol 28: 793-799.
133. Poole JU, Pellegrini VD, Jr. (2000) Arthritis of the thumb basal joint complex. J Hand
Ther 13: 91-107.
134. Kjeken I, Smedslund G, Moe RH, Slatkowsky-Christensen B, Uhlig T, et al. (2011)
Systematic review of design and effects of splints and exercise programs in hand
osteoarthritis. Arthritis Care Res (Hoboken) 63: 834-848.
135. Hargreaves DG (2014) Arthroscopic thermal capsular shrinkage for palmar midcarpal
instability. J Wrist Surg 3: 162-165.
136. Mason WT, Hargreaves DG (2007) Arthroscopic thermal capsulorrhaphy for palmar
midcarpal instability. J Hand Surg Eur Vol 32: 411-416.
137. Zdunski S, Rongies W, Ziolkowski M, Koziel T, Slomka B, et al. (2015) Evaluation of
the Effectiveness of Preoperative Physiotherapy Using the Lysholm-Gillquist Scale
in Patients Qualified for Surgical Arthroscopic Anterior Cruciate Ligament
Reconstruction - Pilot Study. Ortop Traumatol Rehabil 17: 249-258.
138. Grindem H, Granan LP, Risberg MA, Engebretsen L, Snyder-Mackler L, et al. (2015)
How does a combined preoperative and postoperative rehabilitation programme
influence the outcome of ACL reconstruction 2 years after surgery? A comparison
between patients in the Delaware-Oslo ACL Cohort and the Norwegian National
Knee Ligament Registry. Br J Sports Med 49: 385-389.
139. Shaarani SR, O'Hare C, Quinn A, Moyna N, Moran R, et al. (2013) Effect of
prehabilitation on the outcome of anterior cruciate ligament reconstruction. Am J
Sports Med 41: 2117-2127.
11 STUDY I - IV
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