IPRP Repeated Transcranial Magnetic Stimulation (rTMS)
IPRP Repeated Transcranial Magnetic Stimulation (rTMS)
Severe chronic pain is defined as pain persisting for three months or more that significantly
 impacts daily functioning. It is highly prevalent, occurring in 100,000 to 160,000 youth. If
 left unmanaged it can lead to persistent pain and mental health problems in adulthood, posing
 enormous costs to society ($7.2 billion CAD/year). In 2014, health professionals at the
 Alberta Children's Hospital (ACH) established a pediatric Intensive Pain Rehabilitation
 Program (IPRP) to target youth with severe chronic pain and consequent functional disability
 who do not respond to outpatient pain therapies. The IPRP at the ACH is a three-week
 intensive day-treatment intervention provided by an interdisciplinary team, which helps youth
 resume engagement in normal daily functioning. Following IPRP, youth reported less anxiety,
 less depressive symptoms, and greater function, although their self-reported pain remained
 unchanged. In August 2016, the investigators began to explore brain areas related to severe
 chronic pain in youth. The investigators scanned a subset of youth at the start (baseline)
 and end (discharge) of IPRP (23 youth with 2 brain scans). From baseline to discharge, the
 investigators saw decreases in activity in the dorsolateral prefrontal cortex (DLPFC).
 Decrease in DLPFC activity was related to better mental health outcomes. The DLPFC is a
 well-known target for non-invasive brain stimulation. Repeated brain stimulation has been
 used to treat adults, but not youth with chronic pain. For the first time, the investigators
 will use image-guided brain stimulation (37 minutes/day, 5 days/week) to enhance the brain
 changes observed with IPRP. The investigators will examine whether three weeks of brain
 stimulation helps to reduce pain symptoms in youth. The investigators will also compare pain,
 brain, and mental health outcomes to our historical program data. By adding brain stimulation
 to our pain intervention, the investigators have the chance to target an area of the brain
 investigators know to be altered by chronic pain to improve outcomes.
Severe chronic pain in youth is debilitating, common, and has limited treatment options,
 rendering it as a major public health problem. Severe chronic pain is defined as pain
 persisting for three months or more that significantly impacts daily functioning (e.g. sleep,
 mental health, school, work, activity). It is highly prevalent, occurring in 100,000 to
 160,000 youth in Canada - comparable to the rates of autism spectrum disorder. If left
 unmanaged, it can lead to persistent pain and mental health problems in adulthood, posing
 enormous costs to society ($7.2 billion CAD/year). Most treatments to address chronic pain
 take a "one-size-fits-all-approach," which does not account for comorbid mental health
 conditions, contributing to small treatment effects.

 In 2014, the Vi Riddell Children's Pain and Rehabilitation Program at the Alberta Children's
 Hospital (ACH) established the first pediatric Intensive Pain Rehabilitation Program (IPRP)
 in Canada to target youth with severe chronic pain and consequent functional disability who
 do not respond to standard outpatient pain therapies. The IPRP at the ACH involves three- to
 sex-weeks of day-treatment rehabilitation, provided by an interdisciplinary team (e.g.
 Psychology, Physiotherapy, Family Therapy). This rehabilitative program teaches
 self-management strategies with the goal of helping youth and their families resume normal
 daily functioning. Similar to other intensive rehabilitation programs, at discharge from
 IPRP, youth reported less anxiety, less depressive symptoms and better functioning, although,
 their self-reported pain intensity remained unchanged. It is generally thought that by
 returning to normal daily activities, youth will learn to function with their pain, and their
 pain will dissipate over time. However, there is limited evidence to support this. Long-term
 follow-up of youth in IPRP revealed a reduction of pain interference in daily activities.
 However, at one-year post-IPRP, youth's self-reported ratings of depression and quality of
 life did not differ from their ratings prior to completing IPRP. In order to improve
 long-term recovery and reduce the burden of suffering on the individual, their family and
 society, evidence-based and targeted interventions are needed to reduce pain and pain-related
 disability in youth with severe chronic pain.

 For a chronic pain treatment to be evidence-based, it needs to draw on the known
 neurobiological and psychological processes underlying the development and maintenance of
 severe chronic pain. In August 2016, investigators began scanning a subset of youth in our
 IPRP at baseline and again at discharge from the program. Preliminary analysis of this
 neuroimaging data (23 youth with 2 scans each) suggested decreased functional responses to
 emotional stimuli in the dorsolateral prefrontal cortex (DLPFC) from baseline to discharge of
 affected youth, commensurate with decreases in internalizing mental health symptoms.

 The DLPFC is a large and functionally heterogeneous brain region. It is generally associated
 with driving appropriate behavioral responses, and top-down modulation. Therefore, with
 regards to pain it has been shown to be involved in both pain detection and in pain
 suppression. Given its involvement in pain modulation, it is feasible that the DLPFC could
 serve as a therapeutic target.

 By targeting the DLPFC using repetitive transcranial stimulation (rTMS), the investigators
 may be able to enhance outcomes associated with IPRP. Work from our institution demonstrated
 that rTMS of the DLPFC is a safe and effective method for treating youth with treatment
 resistant major depressive disorder. In addition to treatment resistant major depressive
 disorder, rTMS of the DLPFC has also been found to be effective in managing chronic pain in
 adults. rTMS uses a magnetic field to non-invasively stimulate small targeted regions of the
 brain. The magnetic coil produces small electric currents in the region of the brain just
 under the coil via electromagnetic induction. Magnetic resonance imaging (MRI) can be used to
 help identify and target specific brain regions, such as the DLPFC, providing an
 individualized approach to treat the patient's symptoms. To date, rTMS has not been utilized
 to manage pain and comorbid mental health conditions in youth. Using an open-label clinical
 trial study design, the investigators will examine whether the addition of rTMS to IPRP
 reduces pain intensity and enhances brain and behavioral changes associated with standard
 IPRP care to improve outcomes of youth with severe chronic pain.

 Aim 1: Determine whether rTMS in addition to IPRP reduces self-reported pain intensity from
 baseline to discharge in youth with severe chronic pain. Hypothesis 1: The addition of rTMS
 to IPRP will result in decreases in self-reported pain intensity from baseline to discharge
 in youth with severe chronic pain.

 Aim 2: Examine whether youth that undergo rTMS in addition to IPRP versus IPRP alone have
 greater improvements in outcomes from baseline to discharge. Hypothesis 2: The addition of
 rTMS to IPRP will result in greater decreases in DLPFC responsivity to emotional stimuli and
 greater decreases in self-reported pain intensity, functional disability, anxiety, depressive
 and post traumatic stress disorder (PTSD) symptoms between baseline and discharge as compared
 to youth that underwent the standard IPRP.

 Aim 3: Examine whether changes following IPRP persist beyond discharge in youth that
 underwent rTMS in addition to IPRP versus IPRP alone. Hypothesis 3: Parent and self-reported.

 Methods: Between November 2020-2023, 25 youth aged 10-18 years with severe chronic pain will
 be invited to partake in IPRP. In addition to the standard three-week IPRP, youth will
 receive an rTMS intervention utilizing a robot-controlled, Magstim SuperRapid2, air-cooled
 90mm figure-of-8-coil (Magstim, Wales UK). Following standardized protocols for youth with
 treatment resistant major depressive disorder, rTMS will be applied to the individual's DLPFC
 as defined by functional imaging for 37.5 minutes per weekday, at the same time of day, for a
 period of three weeks (15 days total). Participants will be monitored for adverse events and
 tolerability using a Pediatric TMS Safety and Tolerability Measure (20) on days 1, 6, and 11.
 Youth will undergo a 3T MRI at baseline and discharge from IPRP. Both structural and
 functional images will be acquired. At baseline and discharge, youth will also complete a
 battery of reliable and validated questionnaires assessing pain, functional disability,
 anxiety, depressive and PTSD symptoms.

 rTMS: Motor evoked potentials will be recorded to determine the resting motor threshold.
 Initially, to locate the DLPFC target site, the five centimetre rule will be applied in which
 the scalp position five centimetres anterior to the hotspot along a line to the nation will
 be marked. Using a neuronavigation system (Brainsight2, Rogue Research, Montreal), the TMS
 coil will be monitored in real time and co-registered with the individual's functional MRI.
 Neuronavigation will be used to confirm accurate DLPFC targeting. The TMS coil will
 subsequently be placed tangential to the scalp, and angled at 45 degrees to the midline and
 fixed over the DLPFC using a mechanical arm.

 rTMS will be applied at 10 Hz. Each train will consist of 40 threshold (100% resting motor
 threshold) pulses over 4 seconds with an inter-train interval of 26 seconds. Treatment
 sessions will last 37.5 minutes (75 trains/3,000 pulses), and occur at the same time of day
 on every weekday for a period of three weeks (15 days total). During TMS, only passive
 activities will be allowed (i.e., watching movies or TV, listening to music). Three weeks of
 treatment was selected based on existing rTMS evidence in youth with treatment resistant
 major depressive disorder.

 Neuroimaging: Cortical volumes will be acquired from a T1-weighted anatomical scan.
 FreeSurfer will be used for processing, editing, and segmenting structural brain images. The
 automated recon-all pipeline will be used to perform brain extraction, image registration,
 motion and intensity correction, and segmentation/parcellation. Each image will be manually
 checked, and cortical volumes will be extracted.

 Functional magnetic resonance imagine (fMRI) will be used to detect blood oxygen
 level-dependent (BOLD) signal changes during the presentation of validated pictures of facial
 affect that were used in the previous IPRP neuroimaging study. This paradigm consists of 36,
 standardized photos from female and male individuals depicting neutral, happy and fearful
 facial expressions. These photos will be randomized into 4 blocks presented 4 times, and each
 face will be presented for 200-ms with a 300-ms interstimulus. The investigators will apply
 standard preprocessing (slice-time correction, B0-unwarping, motion correction, bandpass
 temporal filtering, template registration and smoothing) in SPM. Motion will be censored
 using the ART toolbox. Second-level analyses will be used to compare differences in contrasts
 over time and between groups. All statistical tests will be corrected for multiple
 comparisons (cluster-corrected false discovery rate q<0.05, with cluster-forming height
 threshold of p<0.001).

 Finally, a resting-state fMRI scan will be acquired and undergo standard preprocessing in
 SPM. Motion will be censored using the ART toolbox. Cortical masks derived from FreeSurfer
 will be used as seed regions for fMRI functional connectivity analysis. Time courses for the
 DLPFC will be extracted and used as a regressor to identify correlations with all other brain
 regions. Second-level analyses will be used to test differences in functional connectivity
 over time and between groups. All statistical tests will be corrected for multiple
 comparisons.
Inclusion Criteria:

 -  Between the ages of 10-18 years

 -  Patient has had the appropriate medical work-up

 -  Participation in accessible, evidenced based pain therapies has not demonstrated
 return to functional goals

 -  Pain is significantly impacting the patient's life and they are not meeting their
 functional goals in areas of life, which may include: physical function, sleep,
 self-care, school attendance/academic performance, social function, recreational
 engagement, and mood

 -  Patient and family agree and understand that an active, self-management approach to
 functional restoration is the mainstay of treatment in the IPRP

 Exclusion Criteria:

 -  Significant developmental delay or brain injury

 -  Functional neurological disorder/conversion disorder

 -  Youth who require opioid weaning

 -  Extensive medical needs and/or untreated psychiatric illness that would impede a
 rehabilitative approach to care.