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Biological Sciences, University of Calgary, Calgary, Alberta, CanadaPsychology, University of Calgary, Calgary, Alberta, CanadaThe Mathison Centre for Mental Health Research & Education, Hotchkiss Brain Institute, Calgary, Alberta, Canada
Radiology, University of Calgary, Calgary, Alberta, CanadaThe Mathison Centre for Mental Health Research & Education, Hotchkiss Brain Institute, Calgary, Alberta, CanadaChild Brain & Mental Health Program, Alberta Children's Hospital Research Institute, Calgary, Alberta, CanadaOwerko Centre, Alberta Children's Hospital Research Institute, Calgary, Alberta, CanadaBrain and Mental Health, Hotchkiss Brain Institute, Calgary, Alberta, Canada
Anesthesiology, Perioperative & Pain Medicine, University of Calgary, Calgary, Alberta, CanadaVi Riddell Children's Pain & Rehabilitation Centre, Alberta Children's Hospital, Calgary, Alberta, CanadaOwerko Centre, Alberta Children's Hospital Research Institute, Calgary, Alberta, Canada
Psychology, University of Calgary, Calgary, Alberta, CanadaAnesthesiology, Perioperative & Pain Medicine, University of Calgary, Calgary, Alberta, CanadaVi Riddell Children's Pain & Rehabilitation Centre, Alberta Children's Hospital, Calgary, Alberta, CanadaThe Mathison Centre for Mental Health Research & Education, Hotchkiss Brain Institute, Calgary, Alberta, CanadaChild Brain & Mental Health Program, Alberta Children's Hospital Research Institute, Calgary, Alberta, CanadaOwerko Centre, Alberta Children's Hospital Research Institute, Calgary, Alberta, CanadaBrain and Mental Health, Hotchkiss Brain Institute, Calgary, Alberta, Canada
Psychology, University of Calgary, Calgary, Alberta, CanadaAnesthesiology, Perioperative & Pain Medicine, University of Calgary, Calgary, Alberta, CanadaVi Riddell Children's Pain & Rehabilitation Centre, Alberta Children's Hospital, Calgary, Alberta, CanadaThe Mathison Centre for Mental Health Research & Education, Hotchkiss Brain Institute, Calgary, Alberta, CanadaChild Brain & Mental Health Program, Alberta Children's Hospital Research Institute, Calgary, Alberta, CanadaOwerko Centre, Alberta Children's Hospital Research Institute, Calgary, Alberta, CanadaBrain and Mental Health, Hotchkiss Brain Institute, Calgary, Alberta, Canada
Radiology, University of Calgary, Calgary, Alberta, CanadaChild Brain & Mental Health Program, Alberta Children's Hospital Research Institute, Calgary, Alberta, CanadaOwerko Centre, Alberta Children's Hospital Research Institute, Calgary, Alberta, CanadaBrain and Mental Health, Hotchkiss Brain Institute, Calgary, Alberta, Canada
Pain interference decreased and 6-minute walk distance increased following Intensive interdisciplinary pain treatments (IIPT) in youth.
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Left posterior insular gamma-aminobutyric acid (GABA) decreased following IIPT.
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Decreases in left posterior insular GABA were related to improvements in physical functioning.
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IIPT-related GABA decreases may allow for the neuroplasticity required for recovery in youth.
Abstract
Intensive interdisciplinary pain treatments (IIPT) have been developed to treat youth with unmanaged chronic pain and functional disability. Dysregulation of metabolites gamma-aminobutyric acid (GABA) and glutamate are thought to play a role in the chronification of pain due to imbalances in inhibition and excitation in adults. Using magnetic resonance spectroscopy (MRS), we investigated the effect of IIPT on GABA and Glx (glutamate + glutamine) in 2 pain-related brain regions: the left posterior insula (LPI) and the anterior cingulate cortex (ACC). Data were collected in 23 youth (mean age = 16.09 ± 1.40, 19 female) at entry and discharge from a hospital-based outpatient IIPT. GABA and Glx were measured using GABA-edited MEGA-PRESS and analyzed using Gannet. Physical measures including a 6-minute walk test were recorded, and patients completed the PLAYSelf Physical Literacy Questionnaire, PROMIS Pain Interference Questionnaire, and Functional Disability Inventory. LPI GABA (P < .05) significantly decreased, but not ACC GABA (P > .05), following IIPT. There were no significant Glx changes (P > .05). The decrease in LPI GABA was associated with increased distance in the 6-minute walk test (P < .001). IIPT may decrease GABAergic inhibitory tone within the LPI, thereby promoting plasticity and contributing to improvements in physical outcomes with IIPT.
Perspective: Regional GABA changes are associated with a reduction in pain interference and improvement in physical function in youth following intensive pain rehabilitation. GABA may serve as a possible biomarker for IIPT; and may also further aid in the development of IIPT, and other treatments for chronic pain in youth.
Chronic pain (pain > 3 months), seen in 10 to 50% of youth, involves significant emotional distress, reduced daily functioning, and imposes a large economic burden on the healthcare system (estimated $19.5 billion USD annually).
The neurobiological mechanisms which underly pain chronification and recovery are not well understood.
Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the human brain and is also involved with inhibitory tone more broadly. Glutamate is the primary excitatory neurotransmitter in addition to having multiple other roles in the central nervous system (CNS). Central sensitization occurs due to hyperexcitability in the CNS. Glutamate is a precursor of GABA, making both GABAergic inhibition and glutamatergic excitation dependent on levels of glutamate, and its precursor, glutamine (see Fig 2 in Schultz et al
for a summary of precursors and products of glutamate). Dysregulation of GABA and glutamate in the CNS are thought to play a significant role in chronic pain conditions.
Brain GABA and glutamate levels across pain conditions: A systematic literature review and meta-analysis of 1H-MRS studies using the MRS-Q quality assessment tool.
One hypothesis behind chronic headache, the most common type of pediatric chronic pain, includes the presence of glutamatergic hyperexcitation due to neural changes associated with injury and/or avoidance learning.
GABA may be increased as a result of increased levels of its precursor glutamate, and as a compensatory mechanism for hyperexcitation. However, excess inhibitory tone prevents neuroplasticity required for recovery, further promoting pain chronification.
Brain GABA and glutamate levels across pain conditions: A systematic literature review and meta-analysis of 1H-MRS studies using the MRS-Q quality assessment tool.
Brain GABA and glutamate levels across pain conditions: A systematic literature review and meta-analysis of 1H-MRS studies using the MRS-Q quality assessment tool.
Moreover, increased glutamate has been shown in multiple chronic pain conditions and, with treatment, larger decreases in insular glutamate are correlated with greater clinical improvements in adults.
Brain GABA and glutamate levels across pain conditions: A systematic literature review and meta-analysis of 1H-MRS studies using the MRS-Q quality assessment tool.
Some studies have shown no difference in GABA levels between adults with musculoskeletal pain conditions and controls, suggesting that different pain conditions may operate under different biological mechanisms.
Brain GABA and glutamate levels across pain conditions: A systematic literature review and meta-analysis of 1H-MRS studies using the MRS-Q quality assessment tool.
Despite this variation, previous studies largely support the suggestion that GABA and glutamate are involved in chronic pain and may be involved in its treatment in youth.
Brain GABA and glutamate levels across pain conditions: A systematic literature review and meta-analysis of 1H-MRS studies using the MRS-Q quality assessment tool.
Non-surgical treatment for adult spinal deformity: Results of an intensive combined physical and psychological programme for patients with adult spinal deformity and chronic low back pain-a treatment-based cohort study.
IIPTs aim to help patients reengage in normal daily physical and psychosocial functioning by improving self-management of pain symptoms. IIPTs produce both immediate and long-term improvements to pain interference, functional disability, physical and psychological functioning.
Further, studies have shown neurobiological changes as a result of IIPTs, including changes in cortical thickness, volume, and brain connectivity in pediatric samples.
Evidence supports the use of IIPTs for youth with chronic pain; however, the relationship between IIPT, physiological changes in GABAergic inhibition and glutamatergic excitation, and improved physical outcomes remains unknown.
We investigated changes in GABA and Glx (glutamate + glutamine) in the anterior cingulate cortex (ACC) and left posterior insula (LPI) with IIPT using GABA-edited MRS, a non-invasive magnetic resonance-based approach, which quantifies regional GABA and Glx (composite signal of glutamate and glutamine). The ACC and LPI belong to the salience network, are the among the most consistently activated regions in response to pain, and are implicated in chronic pain.
We investigated whether GABA and Glx were associated with improvements in physical functioning following IIPT. The overall research aim was to identify neurobiological effects on brain chemistry of IIPTs, which will provide objective evidence to support IIPTs in the management of severe pediatric chronic pain.
This study obtained ethics approval from the University Health Research Ethics Board. All participants provided informed assent, and parents provided informed consent to their children's’ participation in the study.
Participants
Inclusion criteria for this study included being between the ages of 12 to 18, referral and admission to the Alberta Children's Hospital IIPT, and appropriate medical workup. Additionally, patients must have previously engaged in 2 to 3 other evidence-based pain therapies without returning to their functional goals, and patients’ chronic pain must have had a significant impact on their lives (including physical function, sleep, self-care, school attendance/performance, social function, recreational engagement, and/or mood). The patient and family must have agreed to fully engage in IIPT with the understanding that the IIPT emphasizes an active, self-management approach to functional restoration. Participants were excluded on the following bases: significant developmental delay or brain injury, functional or neurological disorder or conversion disorder, requirement for opioid weaning, extensive medical needs and/or unmanaged psychiatric illness that would impede this rehabilitative approach, and contraindications for magnetic resonance imaging (MRI).
Intensive Interdisciplinary Pain Treatment
The IIPT at this site was developed in 2014 for youth with severe treatment-resistant chronic pain. Recruitment for the current study was between August 2016 and March 2020. Youth underwent 3-to-6 weeks of daily (Monday through Friday, 8 hours/day) intensive rehabilitation including psychotherapy, physiotherapy, occupational therapy, recreational therapy, family therapy, and art therapy. Time in program was approximately 3 to 6 weeks, dependent on the cohort and/or each individual's improvement toward clinical and personal goals. Sessions were held in both group and individual formats. The program also included parent-group therapy and academic support sessions for the youth. Customized at-home exercise programs, relaxation practice, and other homework were assigned and completed after program hours.
Measures
All measures (physical measures, physical literacy, PROMIS, functional disability inventory (FDI) and MRS) were completed at baseline and at discharge from IIPT.
Physical Measures
At baseline and discharge from IIPT objective physical measures were recorded, including the 6-minute walk test, power output jump, left and right grip strength, balance on firm and foam surfaces, stair use variables, pain assessment, and physical literacy. These measures were chosen as they had the potential to be tracked and reflect physical change over time.
Physical Literacy Assessment for Youth Self-Evaluation (PLAYSelf)
To assess physical literacy, the Physical Literacy Assessment for Youth self-evaluation (PLAYSelf) was used.
This is a questionnaire used for children and youth to assess their own physical literacy and how it compares to other measures of literacy. The questionnaire includes environmental efficacy (ability to do activities in a variety of environments), a physical literacy self-description (assesses self-efficacy in physical activity), literacy, numeracy, and physical literacy. Each category is measured on a Likert scale in which participants indicate the extent to which they can participate in certain activities (eg, sports and activities on ice; “never tried” to “excellent”), how much they agree with statements (eg, “reading and writing are very important”; “strongly disagree” to “strongly agree”), and how well statements apply to them (eg, “I worry about trying a new sport or activity”; “not true at all” to “very true”). Studies have reported good construct and convergent validity and acceptable internal consistency for PLAYSelf scores (ω ≥ 0.75).
Patient Reported Outcomes Measurement Information System (PROMIS)
Participants completed the short form Patient Reported Outcomes Measurement Information System (PROMIS), a standardized item bank designed to address a host of self-reported health measures, including pain interference.
The pain interference scale contains 8 items, assessed on a 5-point Likert scale ranging from 0 (“never”) to 4 (“almost always”) using a reporting time frame of the past 7 days. Total raw scores are transformed into standardized t-scores and used for analysis. A higher PROMIS t-score represents greater pain interference. Pain interference scores have demonstrated good construct validity and high internal consistency (α > .906).
Participants responded to the 15-item FDI which assesses functional disability by having participants rate the difficulty of performing daily activities on a 5-point Likert scale (“no trouble” to “impossible”).
Magnetic Resonance (MR) data were acquired on a 3T General Electric 750W scanner using a 32-channel head coil at baseline and discharge from IIPT. Youth were scanned at a time befitting with their clinical schedule, thus were scanned at different times in the day. However, previous research suggests GABA as measured with MRS does not fluctuate throughout the day.
Youth were asked to select a movie from a set list to listen to and watch during their scan as this dramatically improves participant compliances and provides a common task, thereby decreasing variance due to mind-wandering. Youth were instructed to, “relax and remain still,” while attending to their movie during scanning. T1-weighted anatomical images (BRAVO; TR/TE = 6.8 ms/3.0 ms, 1 mm3 isotropic voxels) were collected for MRS voxel placement and tissue segmentation. Detailed instructions and reference images for the placement of the voxels were provided to the MRI operators. The ACC voxel was placed parallel to the AC-PC line in front of the genu of the corpus collosum. If necessary, it was moved back into the white matter if the voxel extended outside of the cerebral cortex upon placement, in order to avoid lipid and macromolecular signal contaminations (Fig 1). The LPI voxel was placed anterior to the posterior horn of the lateral ventricles, ensuring the voxel stayed within the cerebral cortex, and when possible, minimizing the amount of cerebral spinal fluid included from the lateral ventricles (Fig 1). Upon placement, all planes and slices were viewed to verify correct and accurate voxel placement.
Figure 1Voxel placements in the ACC (top), and LPI (bottom). ACC and posterior insula voxel intensity plot of all participants masks from baseline overlaid on MNI 1mm atlas. Colour bar is from 0 to 100 for no overlap to all voxels overlapping.
GABA and Glx were measured using GABA-edited MEGA-PRESS (TR/TE = 1800 ms/68 ms, 4096 points, 5 kHz bandwidth, 320 averages, 14 ms editing pulses applied at 1.9 ppm and 7.46 ppm, 3 × 3 × 3 cm3 voxels in both regions) and 16 water unsuppressed averages. GABA-edited MEGA-PRESS allows for the removal of the 3.0 ppm creatine (Cr) signal to isolate the GABA signal at 3.0 ppm and the co-edited Glx signal at 3.75 ppm; for more information about this method, readers are referred to Mullins et al, 2014.
Experts' Working Group on Reporting Standards for MRS. Minimum Reporting Standards for in vivo Magnetic Resonance Spectroscopy (MRSinMRS): Experts' consensus recommendations.
including retrospective frequency and phase correction, and fits the GABA and Glx signals for quantification. Data were reregistered to the T1-weighted anatomical image and the voxels were segmented to determine voxel fractions of white matter, grey matter, and CSF. Data were then fully tissue-corrected using tissue-specific water density, T1, and T2 water relaxation constants.
Additionally, the “α-correction” was used for the GABA data (α = .05) to account for the higher concentration of GABA in grey matter compared to white matter.
All spectroscopy data were visually inspected to ensure data quality and individual measurements were rejected based on excessive noise and/or GABA and Glx measurements (IU) beyond 3 SD of the mean.
Statistical Analysis
All measures were collected at baseline and discharge for within-subject comparison before and after IIPT. Statistical testing was performed using SPSS Statistics (SPSS version 28, IBM, Armonk, NY). Data was checked for violations of normality. Only stair railing use, balance on firm surfaces, and alternating while descending stairs were non-normally distributed, so Wilcoxon signed rank tests was applied to examine change from baseline to discharge from IIPT. All other measures were normally distributed, therefore paired t-tests were used to examine changes in physical parameters, pain interference, and functional disability. False discovery rate was applied to determine, which variables are significant after correction for multiple comparisons. Repeated measures ANOVA was used to examine changes in LPI and ACC GABA and Glx, as well as fGM, fWM, and fCSF, controlling for time between scans (as time in IIPT varied on an individual basis). Generalized Estimating Equations were used to examine changes in GABA and Glx between pre- and post-IIPT, accounting for time between scans for any physical or questionnaire measures that showed a significant change following IIPT discharge.
Results
Characteristics of the Cohort
This study included 23 youth (19 female) aged 16.09 ± 1.40 years. Participants varied according to primary pain type, including abdominal (n = 1), neuropathic (n = 8), headache (n = 8), and musculoskeletal (n = 6) pain.
Changes in GABA and Glx from Pre- to Post-IIPT
After exclusion due to inferior data quality, 23 complete LPI datasets and 15 complete ACC datasets were included in the final analyses (Fig 2). Fig 3 shows all spectra (overlapped) for the ACC (3A) pre- and (3B) post-IIPT, and LPI (3C) pre- and (3D) post-IIPT. Table 1 provides a summary of the metabolite data.
There was a significant decrease in GABA levels in the LPI pre- to post-IIPT, controlling for time between scans (F(1, 1, 21) = 5.374, P = .031) but there was no significant change in GABA levels in the ACC (F(1, 1, 13) = 1.812, P = .201). There were no significant changes in Glx levels in the LPI (F(1, 1, 21) = .063, P = .805) or the ACC (F(1, 1, 13) = .370, P = .554) between baseline and discharge from IIPT. There were no significant differences in LPI fGM (F(1, 1, 21) = .397, P = .536), fWM (F(1, 1, 21) = .231, P = .635), or fCSF (F(1, 1, 21) = .333, P = .570). There were no significant differences in ACC fGM (F(1, 1, 13) = .355, P = .561), fWM (F(1, 1, 13) = .114, P = .741), or fCSF (F(1, 1, 13) = .100, P = .757).
Physical Parameters Pre- to Post-IIPT
All paired t-tests are outlined in Table 2. Pain interference decreased significantly from baseline to discharge from IIPT (t(18) = 2.323, P = .032) and there was a significant increase in 6-minute walk test distance (t(22) = -3.543, P = .002). Surprisingly, there was a significant increase in pain at best (t(22) = -2.343, P = .029). No other changes in physical functioning were observed or reported following IIPT. Only the 6-minute walk test remained significant after applying a false-discovery rate correction.
Table 2Comparison Between Pain and Physical Measures Pre- to Post-IIPT
Decreases in LPI GABA levels were associated with a significant decrease in pain interference (B = 5.744, P = .014; Table 3, Fig 4), and a significant increase in 6-minute walk test distance (B = -149.378, P < .001; Table 3, Fig. 5) from baseline to discharge from IIPT, controlling for time between scans. However, GABA was not associated with the observed increase in pain at best ratings (B = -.562, P = .584; Table 3) following IIPT.
Table 3Associations Between LPI GABA and Self-Reported Pain, Pain Interference and Objective Physical Functioning
Figure 4Decreases in LPI GABA concentration are associated with less pain interference pre- to post-IIPT. Baseline GABA and pain interference T-scores are represented by black dots. GABA and pain interference T-scores at discharge are represented by the red dots. A black line connects each individual participants’ IIPT baseline and discharge GABA and pain interference T-scores. The regression line, in blue, shows the relationship between GABA and pain interference. Overall, a positive relationship between LPI GABA and pain interference is observed, pre- to post-IIPT.
Figure 5Decreases in LPI GABA concentration are associated with increases in 6-minute walk test distances pre- to post-IIPT. Baseline GABA and 6-minute walk test distances (m) are represented by black dots. GABA and 6-minute walk test distances at discharge are represented by the red dots. A black line connects each individual participants’ IIPT baseline and discharge GABA and 6-minute walk test distances. The regression line, in blue, shows the relationship between GABA and 6-minute walk test distances. Overall, a negative relationship between LPI GABA and the 6-minute walk test is observed, pre- to post-IIPT.
This study investigated the relationships between GABA and Glx, both measured in the ACC and the LPI, with changes in physical functioning and pain interference in youth with chronic pain following IIPT. LPI GABA decreased with IIPT, suggesting that IIPT influenced inhibitory tone within this region. Furthermore, decreases in LPI GABA were associated with reduced pain interference, and greater distances in the 6-minute walk test at discharge from IIPT, suggesting that decreasing GABA is related to effective rehabilitation or improvements in physical functioning. GABA in the ACC and Glx in both regions did not change with IIPT indicating the regional and chemical specificity of these LPI GABA results.
Chronic headache is the most common chronic pain condition in youth,
however, IIPT is more commonly used to treat neuropathic pain conditions, hence the equivalent group numbers in our sample. GABA appears to be increased in youth and adults with chronic headache, possibly as a compensatory mechanism for excess glutamate/hyperexcitation, which may extend to other chronic pain conditions.
Brain GABA and glutamate levels across pain conditions: A systematic literature review and meta-analysis of 1H-MRS studies using the MRS-Q quality assessment tool.
It follows that impaired function of the LPI in youth, including dysregulation of glutamate and GABA, may contribute to the chronification of pain. Furthermore, increased GABA may inhibit plasticity required for pain rehabilitation, as previous work has shown GABA decreases with neuroplasticity and learning in adults.
We speculate that the improvements in physical outcomes across IIPT coupled with the overall reduction in GABA suggest that functional changes may be related to more constructive pain-related learning and memory in the LPI, which is facilitated by the reduction in GABA. This is consistent with a previous study that demonstrated increased connectivity in the salience network (including the ACC and insula) with pain reductions in youth.
Future studies including follow-up assessments could investigate whether GABA remains low or if it increases once reorganization and consolidation is complete.
The current study provides preliminary neuroimaging and objective (ie, 6-minute walk test) evidence to suggest that IIPT may impact physiology and pain pathways in youth, as most studies on IIPT efficacy in youth have used questionnaires to assess improvement in physical functioning.
To our knowledge, no pediatric studies of IIPTs to date have employed objective measures of physical function, such as the 6-minute walk test. In accordance with our findings, adult data has demonstrated improvement in the 6-minute walk test with multidisciplinary pain treatment.
Importantly, the reduction in LPI GABA appears to be specifically associated with the positive physical changes following IIPT (ie, increase in 6-minute walk test distance, and decrease in self-reported pain interference), as opposed to the increase in self-reported pain at best. Given the relationships found, consideration of physical improvements in the context of physiological or imaging studies provides many avenues of future investigation.
Studies have shown that biomarkers such as glutamate in biofluids (eg, blood, cerebrospinal fluid) may be of diagnostic use in neurodegenerative and pain disorders.
However, measurement of biofluid concentrations does not reflect site of action or suggest how increased glutamate and/or GABA act at pain processing brain regions. Therefore, if replicated to confirm that greater GABA reductions across IIPT are associated with greater physical improvement, baseline GABA and glutamate measured by MRI could be used as predictive biomarkers in future rehabilitation programs, and provide more specific information behind the mechanism of pain chronification. We therefore suggest that future studies examining GABA changes with treatment may be useful to both validate and improve IIPTs.
A limitation of the study was that not all of the youth completed all of the questionnaires. When the study first began, once youth were discharged home, they were asked to complete the discharge questionnaire on their own time. However, this sometimes led to loss-to-follow-up, so we later added time in the schedule to allow youth the opportunity to complete the questionnaires before going home. The PLAYSelf questionnaire was added after the study had commenced, hence five of the youth did not complete this questionnaire. The effect sizes in this study are modest, likely due to the sample size and pooling of chronic pain types due to the small number of participants in each pain category. After correction for multiple comparisons, only the 6-minute walk-test remained significantly changed from baseline. Therefore, results with both pain interference and pain at best should be interpreted with caution until replicated in a larger sample. The small sample size also precluded investigation of potential confounding factors, such as mental health comorbidities and sex or gender differences. The large proportion of females, while reflective of the chronic pain population in existing studies and tertiary care, may limit generalizability of these results. Finally, by compiling all treatment modalities into a single rehabilitation program, the effects of one treatment cannot be differentiated from those of another and dismantling studies are needed.
In terms of limitations associated with the spectroscopy measures, previous studies have indicated that group differences in GABA and glutamate as compared to controls vary based on the type of chronic pain.
Brain GABA and glutamate levels across pain conditions: A systematic literature review and meta-analysis of 1H-MRS studies using the MRS-Q quality assessment tool.
If different types of pain also physiologically respond to IIPT differently, this may impact the detection of changes between baseline and discharge, which may be why changes were not found in the ACC or in Glx analyses. Moreover, this study did not include a control group, therefore it cannot be ruled out that the change in GABA LPI was demonstrative of spontaneous physiological fluctuation in pediatric patients with a higher degree of developmental-related plasticity. However, given that patients had chronic pain that had not previously spontaneously resolved and had failed at least 2 to 3 treatments for entry into the Intensive Interdisciplinary Pain Treatment Program, and the change in GABA LPI was associated with both self-reported and observed improvements in functioning, our data supports that this is a true and important neurophysiological change in youth undergoing intensive therapy for chronic pain. Furthermore, the decrease in GABA with a decrease in pain is consistent with prior literature showing increased GABA in chronic pain compared to a comparison group.
Brain GABA and glutamate levels across pain conditions: A systematic literature review and meta-analysis of 1H-MRS studies using the MRS-Q quality assessment tool.
Due to the proximity of the sinuses, GABA data from the ACC is generally lower quality, as seen here with more data excluded from this region and the greater variability in ACC GABA. This may have also limited our ability to detect changes in this region. Due to time limitations in the scanner, this study was limited to measures of 2 brain regions, and thus cannot conclude whether GABA or Glx change in other regions of the brain, or specifically the right posterior insula. GABA and Glx were not assessed at a long-term follow-up after discharge from IIPT, making it unclear whether changes in LPI GABA are temporary (eg, plasticity during recovery) or long-lasting (eg, normalization). There are also general limitations GABA-MRS.
Chronic pain in youth is prevalent as well as costly to the healthcare system, and can have long-term consequences on mental and physical health lasting into adulthood.
Improved understanding of the mechanisms underlying chronic pain interventions will help identify who is most likely to benefit from current interventions, as well as assist in developing new evidence-based interventions. Neurobiological changes, specifically in excitation and inhibition, may underpin chronic pain.
Brain GABA and glutamate levels across pain conditions: A systematic literature review and meta-analysis of 1H-MRS studies using the MRS-Q quality assessment tool.
This research indicates that IIPT is associated with reductions in GABA, an inhibitory metabolite, in the LPI, and these GABA changes are associate with reduced pain interference and greater distances in the 6-minute walk test. Therefore, we suggest that IIPT contributes to changes in GABAergic tone in pain-processing brain regions resulting in objective, physical functioning improvements in youth with chronic pain. Multiple lines of research support the use of IIPT in youth with severe, treatment-resistant chronic pain, to our knowledge, this is the first work to associate the effects of IIPT with a neurochemical change. As such, in the future, LPI GABA may be a biomarker for IIPT, either as an indicator for progress or to select patients for IIPT. In addition to the utility of understanding the neurobiology of IIPTs, GABA metrics may also be used to further aid the development of IIPT, and other treatments for severe chronic pain in youth.
Non-surgical treatment for adult spinal deformity: Results of an intensive combined physical and psychological programme for patients with adult spinal deformity and chronic low back pain-a treatment-based cohort study.
Experts' Working Group on Reporting Standards for MRS. Minimum Reporting Standards for in vivo Magnetic Resonance Spectroscopy (MRSinMRS): Experts' consensus recommendations.
Brain GABA and glutamate levels across pain conditions: A systematic literature review and meta-analysis of 1H-MRS studies using the MRS-Q quality assessment tool.
Disclosure: The authors have no conflicts of interest relevant to this article to disclose. Financial assistance was provided by generous community donations to the Vi Riddell Pain & Rehabilitation Centre through the Alberta Children's Hospital Foundation. Additional support was provided by the Alberta Children's Hospital Research Institute and the Hotchkiss Brain Institute. Taylor Pigott was supported by The Mathison Centre for Mental Health Research & Education. Ashley Harris holds a CRC in Magnetic Resonance Spectroscopy in Brain Injury.
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