Imaging fear of painful touch: unraveling relationships between neural correlates of pain-related fear, somatosensory neuroplasticity, and sensory impairments in the context of chronic pain.

Chronic pain affects 20% of people worldwide leading to enormous personal
suffering and economic burden. A key factor contributing to chronic pain
disability that thus far has been neglected is fear of painful touch - a core
symptom in people with complex regional pain syndrome (CRPS) (Biggs et al.
2017). We will use a novel tactile fear conditioning paradigm to examine the
neural correlates of the acquisition, generalization, and extinction of fear of
painful touch and interrelationships with somatosensory neuroplasticity, and
sensory impairments. In this study we will include people with CRPS and age-
and gender matched healthy controls. They will be subjected to a pain-fear
conditioning experiment in the scanner using vibrotactile stimulation to the
fingers as a conditioned stimulus (CS) and a painful electrocutaneous stimulus
as the unconditioned stimulus (US) at the wrist. We will also include
questionnaires to examine self-reported outcomes, quantitative sensory testing
measurements to examine sensory impairments at the non-affected and affected
upper limb and anatomical and functional Magnetic Resonance Imaging (MRI) of
the brain.
Fear of touch due to allodynia is understudied and poorly understood, yet it is
a core symptom related to disability and suffering in CRPS. The project will
provide opportunities to alleviate CRPS stigma and improve treatments based on
newly gained insights in hypothesized intertwined underlying neural mechanisms
of pain-related fear and symptoms. The results are expected to have extensive
impact for CRPS patients, society, and healthcare providers. Our study will
contribute significantly to pain-related fear research and pain science in
general. CRPS patient and therapist partners have confirmed the project
relevance and impact potential during the design stage of this study. The
results can contribute to increased recognition of the suffering of individuals
with fear of touch and allodynia and better understanding of neurobiological
and psychological mechanisms. Patients are disbelieved and stigmatized for the
described symptoms, causing negative emotions, and showing the need to deepen
our understanding of the underlying mechanisms.

We hypothesize that fear of touch will (1) be acquired in both groups, but
there will be less differential learning (due to impaired safety learning) in
CRPS than controls, (2) generalize to new fingers in both groups, but CRPS will
show excessive fear generalization (i.e., also to fingers closer to the one
previously not paired with pain), and (3) extinguish slower in CRPS. (4) This
compromised fear learning will relate to changes in the neural underpinnings of
fear learning in our novel fMRI tactile fear conditioning paradigm in patients
compared to controls. We hypothesize that (5) impaired threat-safety learning
will be associated with allodynia (perceiving innocuous stimuli as painful),
hyperalgesia, and reduced tactile acuity, and (5) vulnerability and resilience
factors will modulate fear learning influencing pain-related outcomes in
patients, and (6) somatotopic imprecision in finger representations in the
primary somatosensory cortex will predict reduced tactile acuity and excessive
fear generalization. (6) Hence, the more *blurred or less precise*
somatosensory stimuli are encoded by the brain, the more fear generalization
will occur.

The overarching aim of this proposal is to unravel the neural correlates
related to acquisition, generalization and extinction of fear of touch in
individuals with upper limb CRPS compared to healthy controls (objective 1),
and to examine interrelationships with sensory disturbances including
allodynia, hyperalgesia and reduced tactile acuity (objective 2), and
somatotopic imprecision in finger representations in the primary somatosensory
cortex (S1) (objective 3). Furthermore, we aim to investigate how vulnerability
(e.g., fear avoidance beliefs) and resilience factors (e.g., positive affect,
optimism) modulate fear learning, and how they subsequently affect pain-related
outcomes such as pain severity and spreading, disability, and quality of life
(objective 4).

In this study we will include people with complex regional pain syndrome (CRPS)
(n=20) and age- and gender matched healthy controls (n=20). Participants will
come to the lab for two consecutive test days if possible (or test days with
maximum 72 hours in between).
Duration: The first session will take approx. 50 minutes. The second session
will take approx. 1h45 minutes.
Setting: Testing of participants will take place in person. Only the
questionnaires will be filled out using the secure online survey software
Qualtrics.
MRI scans will take place using the cutting-edge neuroimaging facilities (3.0
Tesla MRI scanner) through Scannexus (https://scannexus.nl/), the scanner
facility of the Maastricht Brain Imaging Centre (M-BIC). The QST measurements
will take place in a psychophysiology lab room at Scannexus or for patients if
they prefer at home.

Feasibility, burden and risks of the fMRI paradigm: based on previous
experience, we expect that vibrotactile stimulation at the affected hand could
be painful in some patients. Therefore, we will calibrate the intensity of the
mini-piezo tactile stimulation (mPTS) stimuli so that each patient and healthy
person perceives the stimuli above the sensation threshold but below the pain
threshold (VAS < 2/10), which increases feasibility of the experiment (for
healthy controls, the subjective intensity will be matched). This calibration
also serves as a familiarization, and a familiarization will also be included
for the US (unconditioned stimuli). We hypothesize that the fMRI fear
conditioning paradigm at the non-affected hand will always be possible and this
serves as a risk mitigation. Representative patient partners confirmed this
hypothesis.

Test day 1:
1. Completing a number of questionnaires about their complaints (30 minutes),
no risks.
2. Measuring sensitivity to stimuli (20 minutes), no risks.

Test day 2:
1. Completing questionnaires (15 minutes), no risks.
2. MRI scan during which vibration stimulation is given (25 minutes), risk of
incidental findings.
3. The MRI scans (vibration and electrical stimuli) (65 minutes), chance of
incidental findings.

A potential source of discomfort is represented by the use of painful stimuli.
However, these stimuli will be based on a calibration procedure during which
participants will be explicitly explained that they can choose their tolerance
intensity (defined as a stimulus that is painful, and demanding some effort to
tolerate). It will be made explicitly that this intensity can be chosen by
them, and no higher stimulations will be delivered during the experiment.
Participants are informed that they are able to stop the experiment at any
point with no further consequence.

Furthermore, MRI and related techniques such as fMRI, have been used
extensively for both clinical and research purposes. Scans pose no particular
risks outside general MRI Health and safety requirements. All scanning
protocols are approved by a safety officer. There is risk of physical injury
from MRI if a participant has metal in his/her body or other medical
circumstances that contraindicate exposure to a strong magnetic field. Thus,
all participants are carefully screened (verbally during a personal screening
interview and in writing using a detailed health check-screening questionnaire)
before being able to enter the MRI scanner environment. The operation of the
scanners is limited to qualified MRI certified users who have been trained and
accredited by the scanning facility. Measures, such as pillows, table padding,
are taken to minimize discomfort whilst lying in the scanner. Although
participants are pre-screened for claustrophobia, it is possible that some
individuals may experience claustrophobia in the scanner. Scanning will be
immediately discontinued if a participant reports feeling claustrophobic.

UM has its own standard operating procedures to deal with incidental findings
arising from brain imaging (i.e., detection of an unexpected brain abnormality
on a scan). Concerning incidental findings policies, UM stipulates that if the
researcher becomes aware of a potential abnormality he or she obtains a review
by a physician with the relevant qualification who will then inform the
participant and/or their general practitioner (or equivalent) if further
investigations are needed. Any such contact will previously have been
authorized by the participant who is informed that these are not clinical scans
and therefore do not provide a guarantee that abnormalities, if present, will
be detected.