Plasticity of the central nervous system in CRPS and RSI

Background information CPRS
Complex regional pain syndrome (CPRS) is a complication after tissue damage,
caused by surgery or trauma. Symptoms include pain, sensory, sudo and vasomotor
disturbances, throphic changes and a decreased motor performance.

Yearly incidence is 26.2 per 100.000 person-years (95% CI: 23-29.7). CPRS most
commonly occurs in the upper extremity. A bone fracture is often associated
with the onset of complaints. Women are more prone (3.4 x) to develop these
complaints then men. Highest incidence is found in females aged between 61 and
70 years (de Mos, 2007).

Until today, the pathofysiology of CRPS is still debated in the literature.
Afferent mechanisms such as inflammation, efferent mechanisms like deregulation
of the vegetative nervous system, but also central mechanisms like specific
psychological profiles have been described (Huygen et al., 2001).

In a series of recent publications (2003-2007) the group of Maihofner has shown
that the central representation of the hand in CPRS is dramatically altered.
Tactile stimulation of the non-affected hand only leads to activation of the
contralateral primary somatosensory cortex (S1), insula and bilateral secondary
somatosensory cortex (S2), stimulation of the affected side leads to wide
spread cortical activation, including contralateral S1 and motor cortex,
parietal associative cortex (PA), bilateral S2, insula, frontal cortex and both
anterior and posterior parts of the cingular cortex ((aACC and pACC). These
results show that not only nociceptive areas are activated, but also cognitive,
emotional and motor areas are activated during tactile stimulation.

In patients with CRPS a significant deterioration of the cortical hand
representation is seen during performance of motor tasks with the affected
hand. Also the location of this cortical representation is shifted towards the
cortical representation of the lip. The level of performance during these motor
tasks was related to the level of activation of the SMA, M1 and the posterior
parietal cortex (Maihofner, 2007). After clinical improvement recovery off
cortical organization is seen in CRPS patients.

Background information RSI
Complaints to the arm, neck and shoulder (CANS), otherwise known as repetitive
strain injury (RSI), is a loose group of conditions associated with the
excessive use of for instance a computer, guitar, knife or repetitive use of a
tool. In the majority of cases (70-80%) no physical damage can be identified.
However, recently inflammatory biomarkers have been identified that could give
an indication on the severity of complaints (Carp, Barbe 2007). Moreover, there
is evidence that micro-damage to muscles, tendons and nerves in arm and neck
play a role (Barr 2003-2004). Changes in central sensitization in patients with
chronic RSI have not been studied. Symptoms of RSI include pain, muscle
weakness, numbness, changes in temperature and loss of motor coordination

In the Netherlands prevalence of complaints is around 10-30%, depending on
profession (branch of industry). In 16 to 22% of the cases this leads to
absence of work and medical consumption. In a small percentage (5-8%)
complaints become chronic. Yearly costs at the societal level are estimated at
2.1 billion euros (TNO, 2004).

A number of factors have been associated with the occurrence of RSI. Besides
physical factors like excessive force, working in (awkward) static positions en
repetitive movement, also psychological factors such as deadlines, social
atmosphere and stress can contribute to the complaints. Moreover,
non-work-related factors like personality, coping strategies and kinephobia can
elevate the risk of developing complaints. Complaints are approximately twice
more common in women. These risk factors were recently confirmed in a
longitudinal study (2004-2006) (Slijper, Richter 2007) using a precise exposure
analysis.

Plastic changes caused by chronic pain
Pain hyper-sensitivity can remain even when affected tissue is healed or can
even occur without any tissue damage. In this case, pain is a manifestation of
a pathological change in the central nervous system. This central sensitization
is most commonly associated with an increased excitability of neurons in the
central nervous system. Consequently normal input will induce an abnormal
response. Despite the fact that the pain seems to originate in the periphery,
it is actually a manifestation of abnormal sensory processing by the central
nervous system.

Pain influences cognitive processing and demands attention (Eccleston &
Crombez, 1999). This disruptive function of pain seems to be influenced by
factors like pain-related fear and catastrophizing and can result in a
continued focus on the pain instead of other stimuli (Crombez et al., 1999,
Eccleston & Crombez, 1999, VanDamme et al., 2002). Patients with a strong focus
on pain indeed report a higher level of pain intensity (McCracken et al, 1997;
Rainville et al., 1997). Higher pain intensity is associated with
kinesiophobia (Lundberg et al., 2006) and seen in 50% of patients with
musculoskeletal complaints. In CRPS and other chronic musculo-skeletal
complaints, kinesiophobia is a potential predictor for chronic constraints (De
Jong et al., 2005, Swinkels-Meeuwisse et al., 2006, Buitenhuis et al., 2006).
Furthermore, disruption of cognitive functioning and attention through pain is
related to modulation of the anterior cingulated cortex (ACC), an area involved
with pain perception and attention (Buffington et al., 2005). Changes in ACC
activity during tasks in which continuous attention is demanded can be expected
in patients with RSI, when chronic pain and pain related fear are present.

The question, however, remains whether there are changes in pain processing in
chronic RSI and whether the general process of pain sensitization is comparable
to that seen in CPRS. In animal research (Byl, 1997) it has been shown that
after repetitive pinching movements the representation in the somato-sensory
cortex (S1-3b) was deteriorated. Although this has never been studied in
humans, it suggests that recovery of the hand representation is important in
the treatment of chronic RSI. Our hypothesis is that in patients with CPRS en
RSI pain sensitization plays an important role. The process of pain
sensitization could be a possible explanation for the widespread cortical
activation seen in CRPS patients. Fear for damage through movement
(kinesiophobia) and the tendency to catastrophize could enhance this process.

The aforementioned hypothesis is in accordance with the findings of Mainus &
van Hilten (2006). In a systematic review they found some striking similarities
in the patho-physiology and etiology of these complaints:
• Tissue damage of the musculoskeletal system is the origin of the complaints
• The progression of complaints that start in the periphery induce a cascade of
reactions leading to changes in the excitability of the central nervous system.
• Loss of coordination in the distal musculature
• The severity and progression of complaints is linked to psychological
characteristics and gender of the patient.

It is likely that there will be a large overlap in the areas involved and
plastic changes in cortical, sensory, motor, frontal and emotional areas in
both CPRS-1 and RSI. In this research we will therefore use fMRI to directly
compare activation of brain areas in both diseases.

In this research, we will systematically investigate brain activity in patients
with unilateral (chronic; >1 year) RSI, CPRS-1 and healthy control subjects
using functional Magnetic Resonance Imaging (fMRI). An fMRI experiment consists
of a detailed anatomical scan followed by functional scans. During the
structural scan, the subject is asked to lie still in the scanner. During the
functional scans subjects are offered motor and sensory tasks. In particular,
the following tasks will be administered:

Task 1. Finger tapping with the affected hand: Serial movement of the fingers,
starting with thumb touching index finger, middle finger, ring finger, little
finger, ring finger, etc.

Task 2. Finger tapping with the un-affected hand: Serial movement of the
fingers, starting with thumb touching index finger, middle finger, ring finger,
little finger, ring finger, etc.

Task 3. Sensory stimulus to the affected hand: The hand will be stimulated with
a soft brush (a pressure of 150-250 mN).

Task 4. Sensory stimulus to the unaffected hand: The hand will be stimulated
with a soft brush (a pressure of 150-250 mN).

Task 5. As a reference for changes in the hand representation the lower lip
will be stimulated with a brush, or the subject will be asked to purse the
lips. This way a comparison can be made with the results of Maihofner et al.
(2003), who used the same reference stimulus.

The motor tasks will first be practiced outside the scanner to ensure that a
stable movement pattern is acquired. During the functional scan, periods in
which one of the tasks is performed are followed with periods of rest. The
duration of these episodes in such a block paradigm is between 20-30 s. A
functional scan consists of 10-15 blocks, lasting 5 minutes in total. In the
experiment, five functional scans will be made. The total duration of the fMRI
experiment will last approximately 40 to 50 minutes. For statistical evaluation
we will use SPM5 and Matlab.

When patients are willing to participate in the experiment, they will be
offered questionnaires to assess whether they are suited to participate. We
will evaluate the inclusion and exclusion criteria such as the duration and
laterality of complaints. Based on the answers, subjects will be invited for a
physical examination to further assess whether they comply to our inclusion and
exclusion criteria. The physical examination will be performed by a research
nurse at the Pain Treatment Center of the Erasmus MC. The measurements and
examinations that this nurse will perform are described in more detail in
Appendix 1 and 2.

This research uses fMRI. The subject takes place inside the scanner consisting
of a large cylindrical magnet. The tunnel inside the magnet has a diameter of
55 cm and is 2 m long. When a subject suffers from claustrophobia, he or she is
recommended not to participate. During scanning a coil is placed over the
subject*s head to avoid head movement. The scanning itself creates a
significant amount of noise. Communication with the researchers is possible
using an intercom system. The subject can stop the scanning at any point during
the experiment and leave the scanner.