A wide range of human brain imaging techniques has provided the opportunity to explore in vivo the neurophysiological processes of the brain1,2. This neuroimaging research has shown neuronal plasticity, which refers to the possibility of the central nervous system including the brain to adapt but also to maladapt structure, function and organization3. Subsequently, the role of maladaptive brain alterations in the persistent complaints of various chronic pain conditions (e.g., fibromyalgia, chronic low back pain, temporomandibular disorders) has been gradually elucidated1-3. Emerging evidence indicates that different chronic pain conditions are each associated with distinct brain reorganization, which is referred to as the neural pain signature4. In addition, changes in resting state interactions between brain networks implicated in default states, salience, attention, and reward have been demonstrated in chronic pain patients2,4. The results of longitudinal imaging studies suggest that brain alterations are involved in the transition to chronic pain5. In particular, the corticolimbic circuitry, which is a key system for reward and motivated behavior, has been reported as a mediator for this transition6.
Although it can be hypothesized that brain alterations also play a role in the complex persistent complaints of patients with chronic whiplash-associated disorders (WAD), these changes remain poorly investigated. Therefore, the study of Vállez García and colleagues7, recently published in EBioMedicine, is of great scientific and clinical importance because they examined possible alterations in regional cerebral blood flow (rCBF) in female patients with chronic WAD (n= 12) compared to healthy pain-free women (n= 8) by using H215O positron emission tomography (PET). Brain function, which reflects the amount of ‘activity’ that the brain generates, can be measured via its blood perfusion and/or metabolism by using PET8 with intravenous injection of a radiopharmaceutical tracer such as H215O. Active brain regions have a higher need of oxygen and glucose, which is reflected in higher perfusion and/or metabolism.
Recently, we published a commentary article12 on the contribution of the study of Vállez García et al.7 to the literature. In this blog post I give a summary of this commentary article.
The case-control study of Vállez García et al.7 correctly raises our attention to the necessity of examining brain alterations in chronic WAD, which is a prominent gap in current literature. Nevertheless, reorganization of the brain is possibly the missing cornerstone for understanding the pathophysiology of chronic WAD and for advancing pain treatment. The authors hypothesized that the close interaction between the neck and midbrain structures through fibers originating from the C1-C3 spinal segments that project to the periaqueductal grey (PAG) and the thalamus7 could be the missing key. We believe this is indeed one possible piece of the puzzle for understanding chronic WAD, however, we want to alert that also alterations in (resting state) functional brain connectivity and activity, and structural alterations in cortical and subcortical grey matter regions and white matter tracts could contribute to chronic pain and associated complaints in these patients. In contrast to their hypothesis, Vállez García et al. could not detect significant alterations in rCBF in the PAG7, which is a midbrain structure believed to be involved in brain-orchestrated descending pain modulation3. Nevertheless, this hypothesis is plausible, as dysfunctional pain modulation is a key symptom of patients with chronic WAD. On the contrary, the authors demonstrated altered rCBF in limbic5 and corticolimbic6 brain regions and regions that are involved in various aspects of pain processing1,3. Previous brain imaging studies in other chronic musculoskeletal pain patients such as chronic low back pain and fibromyalgia have likewise observed functional but also structural alterations in these regions (e.g. thalamus, insula, precuneus, parahippocampal and posterior cingulate gyrus) compared to controls 1,3,11.
Furthermore, Vállez García et al. correlated the rCBF of the regions that presented significant perfusion differences with subjective scores on the Neck Disability Index (NDI), Hospital Anxiety and Depression Scale (HADS), Whiplash Disability Questionnaire (WDQ), and the electrical perception and pain thresholds measured at the second and sixth cervical spinal processes7. This is important as these measures represent subjective pain experience and are cost-effective in the context of clinical practice. The authors reported significant correlations between the rCBF in the right precuneus, right insula, and right superior temporal lobe, although to different extents, with the scores obtained from the NDI, HADS, WDQ and the electrical perceptions and pain thresholds (both positive and negative correlations) in the chronic WAD group. However, it is not clear from the manuscript if these are weak, moderate or strong correlations. Yet, the observed correlations are of clinical importance because they emphasize the existence of a relationship between clinical symptoms in chronic WAD patients and regional perfusion alterations in the brain. Additionally, we believe it would have been valuable to investigate the presence of disturbed conditioned pain modulation (CPM) or inefficient descending pain inhibition in the chronic WAD group compared to controls. Subsequently, the efficacy of CPM could have been correlated with the rCBF of regions critically involved in descending pain inhibition such as the PAG3. Knowledge on these relations is important to further unravel the mechanisms of persistent pain.
Alterations in brain perfusion in patients with chronic WAD compared to healthy controls using PET imaging have only been demonstrated by two other studies9,10. These studies included, in accordance to the present study, rather small sample sizes (n=18 and n=39). Linnman et al9 analyzed rCBF using 15O PET and found alterations in the parahippocampal and posterior cingulate gyrus, and thalamus in the chronic WAD group, which is according to the results of Vállez García et al. Otte et al. used FDG (18F) PET and only demonstrated hypometabolism in parieto-occipital regions in chronic WAD patients10. However, Otte et al. did not examine regional hyperperfusion. Interestingly, Vállez García et al.7 showed in a subanalysis also hypoperfusion in the posterior parietal occipital region.
Future research
The study by Vállez García et al.7 advances our understanding of chronic WAD and provides researchers and clinicians with innovative insights into the role of the brain in chronic WAD, however, only focused on alterations in rCBF. Because of the cross-sectional nature of the study, no conclusions can be drawn about the causal relationship between chronic pain and rCBF alterations. Consequently, there remain various critical questions that the field has yet to address regarding chronic pain in chronic WAD. What is the causal relationship between brain imaging results and the development and maintenance of persistent pain? Who is vulnerable to develop chronic pain and what underlies this vulnerability? To which structural and functional extent is the brain altered, measured with sophisticated MRI techniques, and what is the relation between brain alterations and various clinical measures? Besides the chicken and the egg discussion, it will be a challenge for researchers to explore the effectiveness of different therapy strategies for chronic WAD patients by analyzing the effects of specific interventions on brain alterations as well as on clinical measures by using a longitudinal design.
Key messages
The paper of Vállez García et al.7 provides innovative insights and confirmation of previously determined findings on the presence of rCBF alterations in brain regions involved in affective, motivational and cognitive processing of pain, and in regions part of the (cortico)limbic system in female patients with chronic WAD compared to healthy pain-free women. Furthermore, clinical important relations between rCBF alterations and pain intensity, pain perception, pain-related disability, anxiety and depression were revealed. These results should impart to both scientists and clinicians, the knowledge that brain alterations possibly play a role in the persistent complaints of patients with chronic WAD. However, further research is absolutely warranted to unravel the specific role of the brain with the ultimate endeavor to improve pain treatment and to decrease suffering from pain.
Iris Coppieters
2016 Pain in Motion
References and further reading:
1. Schmidt-Wilcke T. Neuroimaging of chronic pain. Best Pract Res Clin Rheumatol. 29:29-41, 2015.
http://www.ncbi.nlm.nih.gov/pubmed/26266997
2. Baliki MN, Apkarian AV. Nociception, Pain, Negative Moods, and Behavior Selection. Neuron. 87:474-91, 2015.
http://www.sciencedirect.com/science/article/pii/S0896627315005188
3. Davis KD, Moayedi M. Central Mechanisms of Pain Revealed Through Functional and Structural MRI. Journal of Neuroimmune Pharmacology. 8:518-534, 2013.
http://www.ncbi.nlm.nih.gov/pubmed/22825710
4. Kucyi A, Davis KD. The dynamic pain connectome. Trends Neurosci. 38:86-95, 2015.
http://www.ncbi.nlm.nih.gov/pubmed/25541287
5. Hashmi JA, Baliki MN, Huang L, Baria AT, Torbey S, Hermann KM, Schnitzer TJ, Apkarian AV. Shape shifting pain: chronification of back pain shifts brain representation from nociceptive to emotional circuits. Brain. 136:2751-68, 2013.
http://www.ncbi.nlm.nih.gov/pubmed/23983029
6. Vachon-Presseau E, Centeno MV, Ren W, Berger SE, Tetreault P, Ghantous M, Baria A, Farmer M, Baliki MN, Schnitzer TJ, Apkarian AV. The Emotional Brain as a Predictor and Amplifier of Chronic Pain. J Dent Res. 95:605-12, 2016. http://www.ncbi.nlm.nih.gov/pubmed/26965423
7. Vállez García D, Doorduin J, Willemsen AT, Dierckx RA, Otte A. Altered Regional Cerebral Blood Flow in Chronic Whiplash Associated Disorders. EBioMedicine. 2016. doi:10.1016/j.ebiom.2016.07.008.
http://www.sciencedirect.com/science/article/pii/S2352396416303139
8. Fox PT, Mintun MA, Raichle ME, Herscovitch P. A noninvasive approach to quantitative functional brain mapping with H2(15)O and positron emission tomography. J Cereb Blood Flow Metab. 4:329-33, 1984.
http://www.ncbi.nlm.nih.gov/pubmed/6470051
9. Linnman C, Appel L, Soderlund A, Frans O, Engler H, Furmark T, Gordh T, Langstrom B, Fredrikson M. Chronic whiplash symptoms are related to altered regional cerebral blood flow in the resting state. Eur J Pain. 13:65-70, 2009. http://www.ncbi.nlm.nih.gov/pubmed/18486506
10. Otte A, Ettlin TM, Nitzsche EU, Wachter K, Hoegerle S, Simon GH, Fierz L, Moser E, Mueller-Brand J. PET and SPECT in whiplash syndrome: a new approach to a forgotten brain? J Neurol Neurosurg Psychiatry. 63:368-72, 1997. http://www.ncbi.nlm.nih.gov/pubmed/9328255
11. Coppieters I, Meeus M, Kregel J, Caeyenberghs K, De Pauw R, Goubert D, Cagnie B. Relations between brain alterations and clinical pain measures in chronic musculoskeletal pain: a systematic review. Journal of Pain. 2016. doi: 10.1016/j.jpain.2016.04.005. [Epub ahead of print].
http://www.ncbi.nlm.nih.gov/pubmed/27263992
12. Coppieters I, Malfliet A. Chronic Whiplash-Associated Disorders: Reorganization of the brain? EBioMedicine. 2016. doi: 10.1016/j.ebiom.2016. 08.010
http://www.ncbi.nlm.nih.gov/pubmed/27539066
Free PDF available from:
http://dx.doi.org/10.1016/j.ebiom.2016.08.010
http://www.sciencedirect.com/science/article/pii/S2352396416303139
