Cerebellar white matter volume and clinical pain in older individuals Rachna Sannegowda Supervisory committee: Dr. Kyle Allen, Dr. Mingzhou Ding, Dr. Yenisel Cruz Almeida Oral defense: April 16, 2018
Abstract: Recent work shows that w hite matter (WM) significantly contribute s to the detrimental effects of chronic pain on mobility in community dwelling older adults ( Cruz Almeida et al. 2017 ) The cerebellum specifically plays a key role both in motor and pain processing ( Moulton et al. 2010) T he aim of the present study was to determine the associations between WM volumes in the cerebellum and chronic pain intensity and disability in older individuals. Methods: Participants (n=39) over 60 years of age enrolled in the Neuromodulatory Examination of Pain and Mobility Across the Lifespan (NEPAL) study filled out the Graded Chronic Pain Scale (GCPS) to assess characteristic pain intensity and pain disability during the past six months and underwent a structural MRI scan. all function was used to determine cerebellar WM volumes Subcortical segmentation (aseg) statistics were extracted and statistical a nalyses were conducted with Rstudio. Results: Given the large differences in cerebellar WM volume between males (n=9) and females (n=30) and the small sample size of male participants, associations were further examined specifically with in the female sample GCPS Characteristic Pain Intensity was negatively correlated with WM volume in the cerebellum (r = 0.39, df = 36, p value = 0.01435) but no associations w ere detected with GCPS Pain Dis ability Conclusion: The finding that lower WM volume in the cerebellum was associated with higher self reported chronic pain intensity, but not pain disability, may be explained by perception and processing that are likel y to become dysregulated with age and chronic pain
Introduction Chronic pain is reported to be the most prevalent and expensive public health condition in the United States, affecting 100 million people in the United States, with about a $635 billion annual cost to society ( Gereau et al. 2014). While chronic pain affects individuals of all ages, races, and genders, it disproportionately impacts older adults. Along with its significant societal burden, chronic pain in older adults is associated with substantial disability from reduced physical function (Mansour et al. 2013) The lack of successful treatment options to target chronic pain is the result of incomplete understandi ng of the underlying, neurobiological mech anisms involv ed across different populations who experience chronic pain G ender and demographic differences exist within the older population, especially in populations of individuals with co morbiditi es and cognitive impairments who are often undertreated for pain Relieving Pain in America M usc uloskeletal pain i s highly prevalent in the older, community dwelling population and severely limits physical function including mobility (Wilkie et al., 2007) Bothersome pain in the last month was reported by half o f the older, community dwelling adult population in the United States and was strongly associated with lower physical function (Patel et. al, 2013). This limitation on mobility and ability to participate in activities negatively impacts quality of life Definition and Neurobiology of Pain The International Association for the Stud sensory and emotional experience associated with actual or potential tissue damage, or described P ain is a multidimensional experience with sensory, affec tive and cognitive evaluative components, each of which interacts and contributes to the final highly individualized pain experience (Mel zack and Casey, 1968). As treatments should not be initiated wi thout proper a ssessment measuring pain is the first cri tical step of pain management. Chronological a ge also impacts the dimensions of pain, and therefore, t he assessment and treatment of pain in the elderly population requires a holistic approach (Gagliese and Melzack, 1997). Since pain is a subjective, cognitive percept s elf report measures are widely used and are the gold standard t o quantify it Thus, the multidimensional pain exp erience can be studied as a percept ion requiring the involvement of a widespread and distributed number of brain regions and their interactions. In acute pain, noxious stimuli are transduced to the dorsal horn of the
spinal cord where a variety of transmitters signal the brain through spinal neurons via various ascendin g pathways The acute pain signal reaches the primary and secondary somatosensory, insular, cingulate, prefrontal as well as limbic brain regions. Conversion to chronic pain may be promoted by d ysfunction in descending pain modulatory circuits and exogenous facto rs arising from higher structures that govern em otional and cognitive processes (Ossipov et al., 2014). Neuroimaging studies in persons with chronic pain demonstrate distinct brain activity and morphological brain alterations ( Apkarian et al. 2005 2009 2011). Studies also show partial reversal of brain morphology with treatments that reduce the burden of chronic pain (Seminowicz et al., 2011 ) White matter (WM) structure in the brain has been implicated in recent literature related to chronic pain and aging and in transition from acute to chronic pain (Mansour et al. 2013) C hronic pain can contribute to white matter structure change and therefore, to disability in older adults, suggesting that change s in white matter structure predic t transition to chronic pain and reduced mobility In the paper by Sullivan and colleagues (2001) regional differences in white matter microstructural intravoxel coher ence, and macrostructural intervoxel coherence, were measured According to the study, age related decline in white matter microstructure was equally strong and similar in both men and women, with greater age dependent deterioration in frontal rather than parietal regions (Sullivan et al., 2001). This is consistent with other studies indicating that areas associated with cognition, processing speed, and memory are more likely to undergo age related decline. While the study indicated that large scale, macrostructural intervoxel coherenc e did not change significantly w ith age, this could be because WM microstructure become s less packed with age, where axonal fibers are macrostructurally oriented similarly in neighboring voxels, maintaining a false sense of white matter integrity. For this reason, studies also include WM volume and white matter hyperintensity ( WMH ) as measure s of WM structure. In addition to research focused on the brain anisotropy ) in normal aging unmarked by lesions, recent studies have integrate d chronic pain into the relationship between WM structure and aging. A study conducted at the Univers ity of Pittsburgh first reported significantly lower white matter volume in older adults with chronic low
back pain compared to older adults without chronic low back pain (Bu ckalew et al., 2008). Their results also showed that disabled participants with chronic pain had statistically significant reg ional WMH burden (Buckalew et al., 2013) Although these studies had small sample sizes of sixteen and twenty four people respectively, results suggest that WMH could be accelerated by chronic pain manifesting as perceived disability because increased WMH was associated with decreased gait speed in all ch ronic pain participants. Furthermore, r ecent resear ch specifically implicates white matter (WM) integrity both macro and microstructural in contributing to the detrimental effects of musculoskeletal pain on mobility in community dwelling, older adults ( Cruz Almeida et al. 2017 ). In this study, cerebral mechanisms were explored as a potential mediator between musculoskeletal pain and physical performance. This provides specifically macrostructural WMH and microstructural WM fractional a nisotropy (FA) significantly mediate s the relationship between pain and mobility in high functioning, community dwelling older adults. Pain and the Cerebellum Certain regions of the brain have been identified as key players in pain pathway s and modulation. While the cerebellum has classically been considered as an important region for motor processing, and it is also believed to play a role in non motor, higher cognitive processes ( Schmahmann 1991 ). More recently, t he cerebellum has been implicated in somatosensory processing including nociception (Saab et al., 2003). A fferent input from nociceptors rea ches the cerebellum through two different and segregated pathways, the spino ponto cerebellar and the spino olivo cerebellar path ( Ekerot et al., 1987) Both animal and human research indicates that primary afferents conduct nociceptive input to the cerebellum and that electrical and pharmacological stimulation of the cerebellum can modulate nociceptive processing. Furthermore, i ncreas ed cerebellar activity has been associated with acute and chronic pain ( Moulton et al. 2010 ). Encoding of nociceptive information after it reaches the cerebellum remains unclear T he cerebellar influence on pain processing however, is believed to be inhibitory on the primary motor cortex due to Purkinje cells, with a recent study in monkeys describing this me chanism as cerebellum brain inhibition (Kelly and Strick, 2003).
N euroimaging studies with human subjects have specifically revealed pain intensity related activation that occurs bilaterally in the cerebellum (Coghill et al., 1999). Another neuroimaging st udy show ed evidence that nociceptive specific activation is processed in the deep cerebellar nuclei, anterior vermis, and bilaterally in cerebellar hemispheric lobule VI (Helmchen et al., 2003). While this was the first study to explicitly associate activi ty in the cerebellum with human pain perception, a follow up paper published a year later showed contrasting evidence, as cerebellar activity varied with pain ratings only when the noxious stimuli were self administered by the subjects being scanned, and t his was no longer the case when pain was applied by experimenters (Helmchen et al., 2004). The discrepancy between results was not explained and details about how nociceptive information is encoded once it reaches the cerebellum is lacking (Moulton et al. 2010 ) nociceptive encoding needs to be further explored in both humans and animal models. Additionally, structural cerebellar changes related to aging with pain remain understudied. While it has been shown that the c erebellum at the molecular level ages slower than other human brain tissues (Horvath et al., 2015) specific cerebellar changes with age have been observed recently, showing decline with age in t otal cerebellar volume, global cerebellar white matter volume and mean volume of Purkinje cell body (Andersen et al., 2003). Furthermore, g ender differences in gross cerebellar neuroanatomy have been recorded by many studies, particularly in the vermis region, with differential hemispheric cerebellar volume observe d in men and women (Raz et al., 1998). While cerebellar pain pathways have been studied recently, r elationships between changes in cerebellar white matter structure and chronic pain in the aging population are understudied Un derstanding this relationship could pave the way for successful pain management to improve both mobility function and brain health. Therefore, the aim of the present study was to determine the associations between self reported pain both intensity and disability and cere bellar WM volumes in older adults. Given previous evide nce of whole brain WM structure decline in older individuals with chronic pain, we hypothesized a negative correlation between WM volume specifically in the cerebellar region, with clinical pain inten sity and disability
Methods Participants (n=39) over 60 years of age, enrolled in the Neuromodulatory Examination of Pain and Mobility Across the Lifespan (NEPAL) study at the University of Florida, filled out the Graded Chronic Pain Scale (GCPS) to assess characteristic clinical pain intensity and pain disability during the past six months (Figure 1) and underwent a structural MRI scan. As part of this study, experiment al sessions and neuro imaging were scheduled after successful completion of phone screening to ensure specific MRI eligibility including claustrophobia and presence of any metal in the body At the first study visit, informed consent was obtained and participants were further screened for major disorders such as depression, bipolar disorder, multiple sclerosis, tumors, which are all known to affect brain structu re and function The University of Florida Institutional Review Board (IRB 01) approved the study. Graded Chronic Pain Scale (GCPS) GCPS sub scales were used to determine the chronic pain experience of participants during the past six months Since chroni c pain is a multidimensional phenomenon, pain intensity and pain related disability are important attributes of any chronic pain condition ( von Korff et al. 1992). Characteristic Pain Intensity is a score derived from quest ions 1 3 with a scale range 0 100, while the disability score is derived from questions 5 7 with the same scale range 0 100. GCPS evaluates global pain severity and pain related interference with a 0 10 numeric rating scale for each question as shown in figure 1 The three items in e ach section were averaged and multiplied by 10 to generate both a GCPS characteristi c pain intensity and disability score (Cruz Almeida et al., 2014).
Figure 1: Graded Chronic Pain Scale used to assess self report clinical chronic pain in the past six months Neuroimaging A T1 weighted MPRAGE (sagittal plane, FOV = 240 mm 240 mm 170; 1 1 1 mm isotropic voxels) was acquired at the McKnight Brain Institute using a 3T Phillips scanner with a 32 channel head coil to determine cerebellar WM volume. All preprocessing steps were run using the HiperGator 2.0 supercomputer and individual participant data was processed i n parallel using all function that perform ed a whole brain structural segmentation to measure gross regional volume in a conformed space (256256256 matrix, with coronal re slicing to 1mm 3 voxels) ( Fischl et al. 2004) The recon all tool performed an image reorientation, brain extraction, B1 bias field correction, gray white matter segmentation, gray white matter boundary reconstruction, pial surface reconstruction, labeling of structures, stereotaxic atlas registration of cortical surface, and provided morphological measurements In cases of multiple source volumes, the motion correction step averaged them together and normalization scaled all voxel intensities to a mean intensity of 110 for white matter. The function also computed statistics on the segmented subcortical
structures from mri/aseg.mgz and wrote an output to file stats/aseg.stats. WM segmentation was performed to separate WM fr om the rest of the brain with input mri/brain.mgz and output mri/wm.mgz. In the last stage of volumetric processing, the mid brain was cut from the cerebrum, and the hemispheres were cut from each other; the left hemisphere was binarized to 255, while the right hemisphere was binarized to 127. All output files were maintained in sepa rate directo ries for individual s on the University HiperGator supercompu ting database. Figure 2 : WM segmentati on of th e brain with Freesurfer 6.0 recon all function When Freesurfer crashed without providin g an output after repeated attempts, that scan was omitted and noted in results. No manual correction of Freesurfer segmentation was performed. Automated s egmentations and parcellations were quality checked using the Freeview utility by a graduate student and myself Freesurfer also provided an estimate d total intracranial volume (eTIV) to check for individual differences in head size, and this value was internally extrapolated from the transform of each brain from native to standard space. Prior investigators have noted the difficul ty in determining the best method for normalizing regional volumes and there is no standard method used for volumetric data (Arndt, et al., 1991). In this study, controlling for eTIV in the linear regression model did not change the significance of result s and it was subsequently excluded from the final statistical model Using the HiperGator 2.0 supercomputer scripts were run in parallel for multiple sets of data with a run time of about one day for each all function was utilized in the present analysis with the following script: $ recon all subjid i /T1.nii all sd
Next, s ubcortical segmen tation (aseg) statistics were extracted to a text file and then converted to CSV format, allowing for user friendly import into statistical software packages using the following scripts: $ asegstats2table i /stats/aseg.stats -meas volume -tablefile asegstats.txt $ sed 's/ \ +/,/g' asegstats.txt > asegstats.csv Statistical Analysis A nalyses were conducted on the local workstation with Rstudio. To avoid assigning arbitrary cut offs for pain and no pain phenotypes a linear regression approach was chosen for statistical analysis. Within the Rstudio application, ggplot 2 was used to create scatter plots and display regression lines ( Wickham 2009). The following code was used to create the regression plot: > ggplot(data = < asegstats.csv>, aes(x = GCPS_Characteristic_Pain_Intensity _Score, y = Bilateral_Cerebellum_White_Matter, subset = Sex == "")) + geom_point(color='blue') + geom_smooth(method = "lm", se = FALSE) The YaRrr package was used to run Pearson's product moment correlations between hemispheric cerebellum WM volumes and GCPS subscales ( Phillips, 2017) The statistical analysis excluded one female participant and one male participant due to incompatible structural MRI data with Freesurfer software and a missing GCPS score Associations were examined in a sample size o f thirty seven partici pants consisting of twenty nine females and eight males. As there were no significant differences between hemispheric volumes, l eft and right hemispheric cerebellar WM volumes were added together to obtain a bilateral cerebellar WM vo lume and statistical analyses were conducted using the following R script: > cor.test(formula = ~ GCPS_Characteristic_Pain_Intensity_Score + Bilateral_Cerebellum_White_Matter, data = < asegstats.csv>)
Results The majority (89%) of participants (mean age of 727.8 years) reported chronic pain during the past six months. Given the large differences in cerebellar WM volume between males (n=9) and females (n=30) and the small sample size of male participants, assoc iations were examined within gender sub groups after analysis of the full sample. Table 1 shows demographics for the more closely examined, older female sub group. Table 1: Demographics for female participants over the age of 60 years GCPS Characteristic Pain Intensity was negatively correlated with WM volume in both hemispheres of the cerebellum (right hemisphere: r = 0.41, df = 36, p value = 0.0112 left hemisphere: r = 0.37, df = 36, p value = 0.0203). While the observed negative correlation was stronger in the right hemisphere than in the left hemisphere both showed a similar trend and white matter hemispheric volumes were added together and further examined bilaterally. GCPS Characteristic Pain Intensity was significantly assoc iated with bilateral cerebellar white matter volume (r = 0.39, df = 36, p value = 0.01435) while GCPS Pain Disability did not show this trend (r = 0.11, df = 36, p value = 0.497 ) In the subset of females, this negative correlation between pain intensit y and c erebellar WM volume was strengthened (r = 0.50, df = 28 p value = 0.005769 ), while the relationship was not observed within the male subset o f participants (r = 0.11, df = 7, p value = 0.782). Following the recon all segmentation and parcellation procedures two participants were excluded due to an incompatible structural MRI image and a missing GCPS score. The incompatible MRI image failed Freesurfer processing, defined as program failure to produce an output. Figure 3 shows the strong negative c orrel ation for female participants, indicating that lower cerebellar WM volume was significantly associated with higher clinical pain intensity. Figure 4 shows the negative correlation between cerebellar WM volume and clinical pain intensity for all partic ipants. Figure 5 shows three representative figures as seen in the Freeview utility with their corresponding self report clinical pain intensity scores.
Figure 3 : Associations between cerebellar WM volume and clinical pain intensity in older women particip ants (r = 0.50, df = 28*, p value = 0.005769 ). Figure 4 : Associations between cerebellar WM volume and clinical pain intensity in older participants (r = 0.39, df = 36*, p value = 0.01435). One male was excluded due to incompatible structural MRI data with Freesurfer software and one female was excluded due to a missing GCPS score.
Figure 5: Sagittal slice of cerebellar WM segmentation in vivo for participant with GCPS intensity score of 0 ( left ), sagittal slice of cerebellar WM segmentation in vivo for participant with GCPS score of 46 ( middle ), sagittal slice of cerebellar WM segmentation in vivo for participant with GCPS score of 80 ( right ) Discussion The aim of the present study was to determine the associations between self reported pain intensity and disability with cerebellar WM volumes in community dwelling older adults. While self reported pain intensity was negatively correlated with cerebellar WM volume in older adults, pain d isability did not show any significant association with cerebellar WM volume These results indicate that cerebellar white matter is implicated in pain processing, specifically in the perception of clinical intensity of pain in older individuals Support of Existing Literature The se results further support research studies that indicate role in somatosensory and pain processing. The two ascending pathways to the cerebellum are well known : mossy fibers convey the excitatory input from the pontine nuclei to granule cells which bifurcate and synapse on Purkinje cells, a class of GABAergic neurons located in the cerebellum; excitatory cerebellar afferents convey input from the inferior olive to Pu rkinje cells. In the efferent pathway, cerebellar nuclei project to the brainstem and thalamus, reaching different parts of the cerebral cortex. Direct evidence that the cerebellum receives nociceptive afferents has mainly come from electrop hysiologic al studies which evoked neural activity in the cerebellum with the
stimulation of nociceptors in animal models. In cats, stimulation of cutaneous A delta a nd C fiber nociceptors activated climbing fibers that terminate on Purkinje cells in the cerebellar anterior lobe ipsilateral to stimulation (Ekerot et al., 1987). Likewise, in rats, nociceptive v isceral stimulation modulated Pu rkinje cell activity in the posterior cerebellar vermis (Saa b and Willis, 2001). The present study further supports that the animal models. Although previous research has demonstrated that whole brain WM structure changes contr ibute to the pain mobility association in older adults, this study focus ed on potential cerebellar mechanisms. S pecific brain areas are likely affected by pain differentially so by further examining WM structure in a specific region of the brain in this study changes in total brain WM measure were assessed more closely These results support the present hypothesis that similar changes previously observed in the WM of the cerebrum in individuals with musculoskeletal pain, would also be observed in cerebellar WM volume The finding that lower WM volume in the cerebellum was associated with higher self reported chronic pain intensity, but not pain disability, may be explained by the are likely to become dysregulated with age. Previous studie s have shown non uniformity of change in specific cerebellar regions with aging (Andersen et al., 2003 ) while the cerebellum at the molecular level wholistically ages slow ly according to the epigenetic clock (Horvath et al., 2015) Inconsistent a ctivation of the cerebellum with painful stimulus in humans has added to the discrepancy in current literature that also lacks information about the encoding process of nociceptive st imuli in the cerebellum ( Helmchen et al., 2003 2004) While cerebellar WM volume changes have been clearly observed with age, cerebellar WM volume also appears to change with chronic pain in older individuals. Thus, our findings suggest that increased chronic pain may be associated with alterations in cerebellar WM structure, above and beyond the already reported age related changes.
Limitations These results are limited by several factors. First only correlations were examined between cerebellar WM and clinical pain in a cross sectional study thus causal inferences cannot be made This is often a limitation of clinical studies as we cannot establish whether chronic pain caused changes to the cerebellar WM, or pre existing WM structure caused increased pain intensity, or both v ariables were associated to a third variable Second the sample consisted of high functioning, community dwelling older adults For this reason, findings cannot be generalized to institutionalized older adults or individuals recruited from pain clinics who often experience more severe levels of pain along with higher rates of cognitive impairment and co morbidities Third, the lack of association in the male sample is likely due to the significantly smaller male sample size and lack of statistical power in this subgroup C linicians have consistently been tasked with relieving human suffering, and the quantitative approach to cl inical pain assessment has been developed more recently as a method to capture the cognitive component of pain Since chronic pain is a multidimensional phenomenon, pain intensity and pain related disability are important attributes of any chronic pain con dition ( von Korff et al. 1992). Chronic pain has been extensively measured using self rep orted, clinical pain scales, and i t is believed that clinical pain disability, in addition to pain intensity, is crucial to monitor and target for treatment purposes. While targeting a decrease in clinical pain intensity is sufficient for short term alleviation, it does not guarantee the i mprovement of quality of life. Therefore, w hile pain intensity remains a determi nant in any painful experience, this self report score has its limitations and other measures such as pain disability and experimental pain should also be considered for the devel opment of targeted therapeutic treatments For example, q uantitative sensory testin g (QST) can assess the integrity of the somatosensory system along various levels of the neural axis, from receptor to brain, complem enting clinical neurophysiological studies that only measure sensory large fiber function. W hile this experimental method do es not pro vide information about the exact source of somatosensory dysfunction, it can provide more inf ormation about central pathways originating from large myelinated A beta, thinly myelinated A delta, and small
unmyelinated C fibers In addition, QST has been shown to predict treatment response in a numbe r of pain conditions and it may be used to probe different pain m echanisms ( Cruz Almeida and Fillingim, 2014). Future Direction s Despite these limitations, the findings from this research show the need for further investigation into the impact of chronic pain on the brain during aging Longitudinal studies can further examine associations between cerebellar WM, pain intensity, and disability, while also examining how these associations may impact physical function performance Future research is needed to further delineate the role of the cerebellum in older individuals with chronic pain using l arger sam ples including more males. It i s important to recognize that there are regional differences within the cerebellum itse lf when it comes to aging. T otal cerebellar volume remains stable until about 50 years, following which volumes are negatively correlated with age. Regionally, however, the vermis shows clear structural differences across a larger age spectrum, while the lateral hemisphere is not imp acted by age at all (Luft et al., 1999). Therefore, examining changes in white matter volume within cerebellar regions previously known to remain constant with age can allow for larger sample sizes to be examined for neurobiological differences related to pain above and beyond aging A dditional measures of WM structure such as Mean Diffusivity (MD) and Fractional Anisotropy (FA) will help in answering the next key question about the specific role of white matter in human pain motor interactions. In the p resent analysis, all tool individually masked and labeled each structural MRI image. This has allowed for the development of scripts intended for use with TRACULA minimizing dependence on image normalization to the Montreal Neurological Institute ( MNI ) atlas for diffusion tensor image analysis Since normalization can remove the individual variation of white matter between subjects, utilizing the individual labels created by Freesurfer will now allow for closer examination of the white m atter tracts in certain regions of the brain such as the cerebellum. Examining cerebellar white matter
MD and FA values, in addition to WM volume, will further characterize WM integrity, contributing to literature that focuses on white matter in the contex t of pain, mobility, and aging. Conclusion There were significant negative associations between cerebellar WM volume and clinical pain intensity scores. Lower cerebellar white matter volume in participants, particularly older females, was associated with h igher clinical pain intensity but not disability An improved understanding of the cerebellar role in the experience of pain has implications for the discovery of new treatments for managing pain Few studies have discerned cerebellar function a s it relates to pain processing, which is a multi dimensiona l experience. Based on the evidence available, the cerebellum plays a role in affective pain processing, pain modulation, and sensorimotor processing (Moulton et al., 20 10 ). More research is required to define the role of the cerebellum, particularly its w hite matter, in human pain processing and its impact on physical function
Sources Apkarian AV, Baliki MN, Geha PY. Towards a theory of chronic pain. Prog Neurobiol 2009;87:81 97. Apkarian AV, Bushnell MC, Treede RD, Zubieta JK. Human brain mechanisms of pain perception and regulation in health and disease. Eur J Pain 2005;9:463 84. Apkarian AV, Hashmi JA, Baliki MN. Pain and the brain: specificity and plasticity of the brain in clinical chronic pain. PAIN 2011;152:s49 64. Andersen, B. B., G undersen, H. J. G., & Pakkenberg, B. (2003). Aging of the human cerebellum: a stereological study. The Journal of Comparative Neurology 466 (3), 356 365. https://doi.org/10.1002/cne.10884 Arndt, S., Cohen, G., Alliger, R. J., Swayze, V. W. 2nd, & Andreasen N. C. (1991). Problems with ratio and proportion measures of imaged cerebral structures. Psychiatry Research 40 (1), 79 89. Buckalew, N., Haut, M. W., Aizenstein, H., Rosano, C., Edelman, K. D., Perera, S., Weiner, D. (2013). White matter hyperintensity burden and disability in older adults: is chronic pain a contributor? PM & R : The Journal of Injury, Function, and Rehabilitation 5 (6), 471 80; quiz 480. https://doi.org/10.1016/j.pmrj .2013.03.004 Buckalew N, Haut MW, Morrow L, Weiner D. Chronic pain is associated with brain volume loss in older adults: preliminary evidence. Pain Medicine. 2008; 9 :240 248. doi: 10.1111/j.1526 4637.2008.00412.x. Coghill, R. C., Sang, C. N., Maisog, J. M., & Iadarola, M. J. (1999). Pain intensity processing within the human brain: a bilateral, distributed mechanism. Journal of Neurophysiology 82 (4), 1934 1943. https://doi.org/10.1152/jn.19184.108.40.2064 Cruz Almeida Y., Rosso, A., Marcum, Z., Harris, T., Newman, A. B., Nevitt, M., ... & Health ABC Study. (2017). Associations of musculoskeletal pain with mobility in older adults: potential cerebral mechanisms. Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences 72 (9), 1270 1276. Cruz Almeida, Y., & Fillingim, R. B. (2014). Can quantitative sensory testing move us closer to mechanism based pain management? Pain Medicine (Malden, Mass.) 15 (1), 61 72. https://doi.org/10.1111/pme.12230
Cruz Almeid Fillingim, R. B. (2014). Racial and ethnic differences in older adults with knee osteoarthritis. Arthritis & Rheumatology (Hoboken, N.J.) 66 (7), 1800 1810. https://do i.org/10.1002/art.38620 Ekerot, C. F., Gustavsson, P., Oscarsson, O., & Schouenborg, J. (1987). Climbing fibres projecting to cat cerebellar anterior lobe activated by cutaneous A and C fibres. The Journal of Physiology 386 529 538. Fischl, B., van der Kouwe, A., Destrieux, D., Halgren, E., Sgonne, F., Salat, D. H., Busa, E., Seidman, L. J., Goldstein, J., Kennedy, D., Caviness, V., Makris, N., Rosen, B., Dale, A. M. (2004). Automatically Parcellating the Human Cerebral Cortex, Cerebral Cortex Volume 1 4(1), 11 22, https://doi.org/10.1093/cercor/bhg087 Gagliese, L., & Melzack, R. (1997). Chronic pain in elderly people. Pain 70 (1), 3 14. https://doi.org/10.1016/S0304 3959(96)03266 6 Gereau, R. W., Sluka, K. A., Maixner, W., Savage, S. R., Price, T. J., M Fillingim, R. B. (2014). A Pain Research Agenda for the 21st Century. The Journal of 15(12), 1203 1214. http://doi.org/10.1016/j.jpain.2014.09.004 Horvath, S., Mah, V., Lu, A. T., Woo, J. S., Choi, O. The cerebellum ages slowly according to the epigenetic clock. Aging 7 (5), 294 306. Helmchen, C., Mohr, C., Erdmann, C., Petersen, D., & Nitschke, M. F. (2003 ). Differential cerebellar activation related to perceived pain intensity during noxious thermal stimulation in humans: A functional magnetic resonance imaging study. Neuroscience Letters, 335(3), 202 206. https://doi.org/10.1016/S0304 3940(02)01164 3 Helmchen, C., Mohr, C., Erdmann, C., & Binkofski, F. (2004). Cerebellar neural responses related to actively and passively applied noxious thermal stimulation in human subjects: A parametric fMRI st udy. Neuroscience Letters, 361(1 3), 237 240. https://doi.org/10.1016/j.neulet.2003.12.017 Institute of Medicine (US) Committee on Advancing Pain Research, Care, and Education. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Educa tion, and Research. Washington (DC): National Academies Press (US); 2011. Available from: https://www.ncbi.nlm.nih.gov/books/NBK91497/ doi: 10.17226/13172
Kelly, R. M., & Strick, P. L. (2003). Cerebellar loops with motor cortex and prefrontal cortex of a n onhuman primate. for Neuroscience 23 (23), 8432 8444. Patterns of age related shrinkage in cerebellum and brainstem observed in vivo using three dimensional MRI volumetry. 9 (7), 712 721. Mansour, A. R., Baliki, M. N., Huang, L., Torbey, S., Herrmann, K. M., Schnitzer, T. J., & Apkarian, A. V. (2013). Brain white matter structural properties predict transition to chronic pain. PAIN 154 (10), 2160 2168. https://doi.org/10.1016/J.P AIN .2013.06.044 Melzack, R. and Casey, K.L., Sensory, motivational and central control determinants of pain: a new conceptual model. In: D. Kenshalo (Ed.), The Skin Senses, Charles C. Thomas, Springfield, IL, 1968, pp. 423 439. Moulton, E. A., Schmahmann, J. D., Becerra, L., & Borsook, D. (2010). The cerebellum and pain: Passive integrator or active participator? Brain Research Reviews 65 (1), 14 27. https://doi.org/10.1016/j.brainresrev.2010.05.005 Patel, K. V, Guralnik, J. M., Dansie, E. J., & Turk, D. C. (2013). Prevalence and impact of pain among older adults in the United States: findings from the 2011 National Health and Aging Trends Study. Pain 154 (12), 2649 2657. https://doi.org/10.1016/j.pai n.2013.07.029 Phillips, N. (2017). yarrr: A Companion to the e Book "YaRrr!: The Pirate's Guide to R". R package version 0.1.5. https://CRAN.R project.org/package=yarrr Ossipov, M. H., Morimura, K., & Porreca, F. (2014). Descending pain modulation and chro nification of pain. Current Opinion in Supportive and Palliative Care 8 (2), 143 151. https://doi.org/10.1097/SPC.0000000000000055 Raz, N., Dupuis, J. H., Briggs, S. D., McGavran, C., & Acker, J. D. (1998). Differential effects of age and sex on the cerebe llar hemispheres and the vermis: a prospective MR study. AJNR. American Journal of Neuroradiology 19 (1), 65 71. Saab, C. Y., & Willis, W. D. (2003). The cerebellum: Organization, functions and its role in nociception. Brain Research Reviews 42 (1), 85 95. https://doi .org/10.1016/S0165 0173(03)00151 6
Schmahmann, J. D. (1991). An emerging concept. The cerebellar contribution to higher function. Archives of Neurology, 48(11), 1178 1187. Seminowicz, D. A., Wideman, T. H., Naso, L., Hatami Khorousha hi, Z., Fallatah, S., Ware, Stone, L. S. (2011). Effective treatment of chronic low back pain in humans reverses of the Society for Neuroscience, 31(20), 7540 7550. htt ps://doi.org/10.1523/JNEUROSCI.5280 10.2011 Sullivan, E. V, Adalsteinsson, E., Hedehus, M., Ju, C., Moseley, M., Lim, K. O., & Pfefferbaum, a. (2001). Equivalent disruption of regional white matter microstructure in ageing healthy men and women. Neuroreport 12 (1), 99 104. https://doi.org/10.1097/00001756 von Korff, M., & Keefe, F. J. (1992). Grading the severity of chronic pain. Pain 50 (2), 2 3. https://doi.org/10.1016/0304 3959(92)90154 4 Wickham, H. (2009). ggplot2: Elegant Graphics for Data Analysis. Springer Verlag New York Wilkie, R., Peat, G., Thomas, E., & Croft, P. (2007). Factors associated with restricted mobility outside the home in community dwelling adults ages fifty years and older with knee pain: an example of use of the Internati onal Classification of Functioning to investigate participation restriction. Arthritis and Rheumatism 57 (8), 1381 1389. https://doi.org/10.1002/art.23083