We found a statistically significant pattern of an increase in thalamic glucose metabolism contralateral to the painful body region. Furthermore, there was a moderate correlation between quality of life and the ratio of thalamic glucose metabolism in patients with increased metabolism contralateral to their painful body side. A similar slight, but statistically insignificant, correlation, was found with regard to change in VAS back and leg pain.
Only a very limited amount of literature exists on changes in cerebral glucose metabolism as a result of pain perception and, therefore, direct comparisons to previous published results were not an option. As there is no standard protocol for using PET/CT to quantify changes in brain metabolism due to painful stimuli, we chose to use the European Association of Nuclear Medicine procedure guidelines for tumor imaging in the acquisition of SUV metrics 7. This was done to apply known methods for quantifying metabolism and to facilitate an easier reproduction of the techniques applied.
In order to analyze and quantify lateralization in the thalamus of each hemisphere we tested for and found no signs of general cerebral diaschisis as previously described by Segtnan et al. 6. Both the median and range of the SUV metrics for the cerebral hemispheres were compared with previously reported findings of a median cerebral hemisphere ratio of 0.95, ranging between 0.65-1.00 in healthy individuals. The present findings with a median of 0.98, ranging 0.89-1.00 are clearly within what is considered normal and, thus, were an indication of absence of cerebral hemispheric diaschisis.
We hypothesized that unilateral pain would lead to an increased glucose metabolism of the contralateral thalamus as a result of the afferent synapse in the somatosensory pathway. The results in Table 3 show the cSUVmean indicated a contralateral relationship between pain and increase in thalamic activity. The significance of this finding was a result of partial volume correction which, due to the limited spatial resolution of whole-body PET scanners, is necessary for proper quantification of tracer uptake in small structures as the thalamus 8. The reason for using the ratio between the two hemispheres, as opposed to the nominal values, was to make the individual patients serve as their own controls to adjust for inter-scan differences, which might otherwise skew the results.
As far as we know, these findings are the first quantitative cerebral glucose metabolism results reported in surgical candidates with LDH. A previous study by Newberg et al. found significant asymmetry in thalamic blood flow using SPECT in patients with chronic pain syndrome 4. Their observations indicated a significantly higher degree of lateralization in patients with pain compared to healthy controls. Despite being measures of cerebral blood flow and not metabolism, one would expect those two parameters to present some collinearity. Similar results were reported by Guillot et al., who found significantly increased thalamic activity in cats with osteoarthritis-associated pain 9, whereas Iadarola et al., using 15O-water bolus PET, reported a decrease in contralateral thalamic blood flow in four patients with chronic post-traumatic neuropathic pain in one lower limb and one patient with post-herpetic facial neuralgia 10. Decreases were maximally 15% compared to 8% higher uptake in two of our patients, 20% higher in five and 36% higher in the remaining 18 patients. As cause of the unexpected decreases, the authors suggested neurodegeneration known to accompany pathological increases in neural activity, excessive inhibition of thalamic activity to over-compensate for excessive excitatory nociceptive inputs, “learning” in that chronic pain may be transmitted with less activity within the thalamus as times go by, and uncoupling of blood flow from metabolism in the thalamus. The authors had no convincing arguments for any possibility. Nonetheless, it appears that decreased contralateral flow may be influenced by the duration of pain, which was ≥ 2–2½ years in four of their five patients compared to less than a year in 22 of our 26 patients, so that "learning" might in fact play a certain role. However, in view of the extreme versatility of measured regional cerebral flow [19, 20], vast heterogeneity among chronic pain patients, and the authors’ use of parametric instead of nonparametric statistics in such a small material make it is difficult accept these results at face value.
Correlations between quantitative measurements of glucose metabolism in the thalamus and clinical measures (VAS, disability and quality of life) were found to be moderate at best, and only when excluding patients not conforming with the abovementioned hypothesis of increased activity contralateral to the symptomatic side, did we find statistically significant correlations. This may lead to speculations on whether a correlation actually exists, as the coefficients were only moderate, and scatterplots of the observations did not indicate a convincing pattern (data not shown). The correlation with EQ-5D were the most consistent and indicated a worse quality of life at baseline when a higher ratio between the two thalami was measured. Likewise, a higher change in EQ-5D was observed at 1-year when the ratio had increased. This harmonizes well with the hypothesis that increased lateralization is indicative of a chronic pain condition and subsequently decreased physical and phycological well-being. When correlating the glucose metabolism ratio with pain perception measured by VAS leg- and back pain, the results were more diverse, and, therefore, less likely to be consistent in a larger cohort.
We acknowledge that our relatively small cohort is a limitation, as any observation will need to produce a relatively uniform and large signal for this to come out significant. This also means that any outliers will skew the results towards a type II error. A further limitation of unknown proportion is the patients’ use of pain medication, which was not recorded. Despite being asked not to take pain medication in five times the half-life of each drug before the PET/CT scan, the actual compliance with this instruction was unknown. Furthermore, the described method of quantifying glucose metabolism was only partly standardized and, therefore, probably somewhat observer dependent.
The current study sustains the hypothesis that unilateral pain of LDH patient is associated with an increase in the metabolism of the thalamus of the contralateral hemisphere in line with the suggestion that thalamus may operate as some sort of a “relay station” in pain perception. Whether there is a nominal relation between metabolism ratio and subjective pain perception is unclear, however, our data seem to suggest that quality of life is negatively affected by a higher degree of thalamic imbalance. Further research is needed, preferably using high resolution scanners and MRI segmentation, to confirm if our preliminary findings hold water and can serve as a basis for optimized post-surgery pain management in LDH.