Saturday, July 20, 2013

Functional imaging (fMRI) of allodynia in CRPS

Brain cells are one thing an fMRI can't hone in on.         Purestock/Getty Images

This article dates from 2006 and yet I've not heard much mention of people with CRPS having access or using functional MRI to assess allodynia.  Most likely, it offers little real information that can be put to use within treatment, but may open doors and minds within the research community. Should it become part of the diagnostic protocol?  


Functional imaging of allodynia in complex regional pain syndrome

  1. Frank Birklein, MD, PhD
  1. Address correspondence and reprint requests to Dr. C. Maihöfner, Department of Neurology/Institute for Physiology and Experimental Pathophysiology, University of Erlangen–Nuremberg, Universitätsstrasse 17, D-91054 Erlangen, Germany;
  1. doi: 10.1212/01.wnl.0000200961.49114.39Neurologyvol. 66 no. 5 711-717

Objective: To investigate cerebral activations underlying touch-evoked pain (dynamic–mechanical allodynia) in patients with neuropathic pain.
Methods: fMRI was used in 12 patients with complex regional pain syndromes (CRPSs). Allodynia was elicited by gently brushing the affected CRPS hand. Elicited pain ratings were recorded online to obtain pain-weighted predictors. Both activations and deactivations of blood oxygenation level–dependent signals were investigated.
Results: Nonpainful stimulation on the nonaffected hand activated contralateral primary somatosensory cortex (S1), bilateral insula, and secondary somatosensory cortices (S2). In contrast, allodynia led to widespread cerebral activations, including contralateral S1 and motor cortex (M1), parietal association cortices (PA), bilateral S2, insula, frontal cortices, and both anterior and posterior parts of the cingulate cortex (aACC and pACC). Deactivations were detected in the visual, vestibular, and temporal cortices. When rating-weighted predictors were implemented, only few activations remained (S1/PA cortex, bilateral S2/insular cortices, pACC).
Conclusions: Allodynic stimulation recruits a complex cortical network. Activations include not only nociceptive but also motor and cognitive processing. Using a covariance approach (i.e., implementation of rating-weighted predictors) facilitates the detection of a neuronal matrix involved in the encoding of allodynia. The pattern of cortical deactivation during allodynia may hint at a shift of activation from tonically active sensory systems, like visual and vestibular cortices, into somatosensory-related brain areas.


There were, following publication, letters that pointed out both the study's strengths and one considerable weakness:

Functional imaging of allodynia in complex regional pain syndromeRon Kupers, PET Unit & Dept. Surgical Pathophysiology, Rigshospitalet
KF 3892, Blegdamsvej 9, 2100 Copenhagen, Denmark
Maihofner et al [1] describe fMRI data of allodynia in complex regional pain syndrome (CRPS). The authors are to be congratulated for a very carefully designed study. Of the 12 patients, 11 were suffering from pain and sensory abnormalities in the right hand. This homogeneity in the anatomical distribution of the pain complaints may explain why the authors obtained allodynia-induced activation of SI whereas other brain imaging studies failed/ [2]
Maihofner's study is also important because their pain-related activations are predominantly contralateral to the stimulated body area, conform with findings in acute, experimental pain studies. This contrasts with reports of bilateral responses in the pain matrix, often with a preponderence of responses in the hemisphere ipsilateral to stimulation. [2,3] Whereas these latter studies investigated neuropathic pain patients with minor [2] or major [3] lesions to the nervous system, Maihofner et al used CRPS-type I patients, a neuropathic pain condition characterized by an absence of lesion to the peripheral nervous system.
Taken together, this suggests that the ipsilateral activations are not driven by pain but may reflect central reorganization as a result of deafferentation. However, alternative interpretations cannot be excluded. For instance, the average duration of pain complaints in Maihofner's study is significantly shorter than in the two other reports (< 0.5 years compared to > 2 and > 5 years). [2,3]
Maihofner also reported a deactivation of the ipsilateral primary somatosensory cortex during non-painful brushing. They argue that this has never been reported in healthy subjects and and therefore they relate this finding to the chronic pain condition. We strongly disagree with this interpretation. Drevets et al [4] reported that anticipation of a painful stimulus causes a decrease in regional brain activity in parts of the somatosensory cortex ipsilateral to the location of the expected pain stimulus.
We showed that activity in ipsilateral SI in normal subjects decreases not only during the anticipation of a stimulus but also during actual somatosensory stimulation. [5] In another recent study in healthy volunteers, we found strong evidence for ipsilateral deactivations in SI (Figure 1). Taken together, the ipsilateral deactivation following allodynic brushing is unlikely to be linked to the chronic pain state. The most parsimonious explanation is that it reflects top-down anticipatory modulation elicited by attention to the expected stimulus.
1. Maihofner C, Handwerker HO, Birklein F. Functional imaging of allodynia in complex regional pain syndrome. Neurology 2006; 66: 711-7.
2. Witting N, Kupers RC, Svensson P, Jensen TS. A PET activation study of brush-evoked allodynia in patients with nerve injury pain. Pain 2006; 120: 145-54.
3. Peyron R, Schneider F, Faillenot I, Convers P, Barral FG, Garcia- Larrea L, Laurent B. An fMRI study of cortical representation of mechanical allodynia in patients with neuropathic pain. Neurology 2004; 63: 1838-46.
4. Drevets WC, Burton H, Videen TO, Snyder AZ, Simpson JR Jr, Raichle ME. Blood flow changes in human somatosensory cortex during anticipated stimulation. Nature 1995; 373: 249-52.
5. Kupers R, Svensson S, Jensen TS. Central representation of muscle pain and mechanical hyperesthesia in the orofacial region: a positron emission tomography study. Pain 2004, 108: 284-93.
Disclosure: The author reports no conflicts of interest.

The authors replied:

Christian Maihöfner, Department of Neurology, University of Erlangen Frank Birklein; Department of Neurology; University of Mainz; Germany
Schwabachanlage 6, 91054 Erlangen, Germany
We thank Dr. Kupers for his comments on our article. [1] The patients investigated in our study had no skin nerve lesions and had a moderate time in pain. Furthermore, we agree that one potential advantage of our study is that our patient group was homogenous with allodynia in one body region – hands. Dr. Kupers et al [2] and Dr. Peyron et al [3] investigated patients who complained of allodynia in very different body regions. In Peyron´s study [3], a significant proportion of patients even had pain from central origin (stroke). For stroke, significant central reorganization is obvious, but whether peripheral nerve lesions indeed affect encoding of allodynia in a way so that it occurs primarily in the ipsilateral brain hemisphere is speculative.
We also found bilateral responses after allodynic brushing in the medial affective pain system, as has been recently reported. [6] It seems reasonable that the major afferent pathways of touching, regardless of pain project in the lateral somatosensory discriminative system on the contralateral side as has been found in a previous PET- study of Dr. Witting and Dr. Kupers in experimental allodynia. [7] This confirms recent fMRI studies of our group. [8]
Regarding Dr. Kupers second point, we did not observe ipsilateral S1 deactivation after allodynic brushing. We observed ipsilateral S1 deactivation only after pleasant and non-painful brushing the healthy limb. We observed no ipsilateral deactivation during painful allodynia brushing when anticipation of the pain should be more intense than during pleasant touch. We continue to assume that ipsilateral S1 deactivation could be related to tonic activation of this brain region in unilateral chronic pain. Possibly tonic pre- activation also underlies the inconstant activation of the contralateral brain region as discussed above.
The increase of regional cerebral blood flow during brain activation (underlying BOLD effect and PET activation) will not be endless; there must be some asymptotic approach to a ceiling. We do agree that during somatosensory stimulation other leading sensory systems like visual or vestibular systems might become deactivated. This was one result of our study (see figure (E) F2). The underlying mechanisms and significance of BOLD deactivations are controversial. It is unclear what deactivations of the BOLD signal really mean (e.g. neuronal deactivation and or shift of attention). Further studies are needed to investigate the causes of ipsilateral S1 deactivation.

6. Schweinhardt P, Glynn C, Brooks J, McQuay H, Jack T, Chessell I et al. An fMRI study of cerebral processing of brush-evoked allodynia in neuropathic pain patients. Neuroimage 2006.
7. Witting N, Kupers RC, Svensson P, Arendt-Nielsen L, Gjedde A, Jensen TS. Experimental brush-evoked allodynia activates posterior parietal cortex. Neurology 2001;57:1817-1824.
8. Maihofner C, Schmelz M, Forster C, Neundorfer B, Handwerker HO. Neural activation during experimental allodynia: a functional magnetic resonance imaging study. Eur J Neurosci 2004;19:3211-3218.
Disclosure: The authors report no conflicts of interest.

© 2013 L. Ryan

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