1. Cortical neurochemical correlates of neuropathic pain severity and impact after spinal cord injury. Eva Widerström-Noga, PradipPattany, YeniselCruz-Almeida, Elizabeth Felix,Alberto Martinez-Arizala, Diana Cardenas, Salomé Pérez

2. Störmer et al., 1997 (n=901) 66% chronic pain or distressing dysesthesia >7 on VAS (61%) Widerström-Noga et al., 1999 (n=430) 77% reported chronic pain >7 on NRS (50 %) Turner & Cardenas, 1999 (n=164) 80.5% reported chronic pain 62% high pain intensity Finnerup et al., 2001(n=330) 77% experienced chronic pain or dysesthesia Median VAS 41 Siddall et al., 2003 (5 year follow-up; n=73) 81% reported chronic pain of which 58% was rated as severe Rintala et al., 2005 (n=348) 75% reported having at least one pain problem Wollaars et al., 2007 (n=279) 77% reported chronic pain Dijkers et al., 2009 (review) 26-96% prevalence based on 42 studies De Miguel & Kraychete, 2009 (review) 64-82% prevalence

3. Chronic refractory pain superimposed over other impairments of SCI further decreases quality of life (Westgren & Levi, 1998) by impacting on independence and activities (Widerström-Noga et al., 2006; Kennedy et al., 2009). After SCI, spontaneous or treatment induced complete pain relief is rare. Over time new sources of pain, such as upper extremity pain, may develop (Siddall et al., 2003;Jensen et al., 2005; Cruz-Almeida et al., 2005).

4. MR Spectroscopy MRSis a non-invasive method to measure metabolites in the human brain.. MRSis based on the fact that different chemicals vibrate at different frequencies when stimulated by a magnet. MRSproduces a signature of the nature and amounts of chemicals that are present in the brain. Stability of signals is an advantage for longitudinal studies or clinical trials. Changes are reflective of long-term plasticity.

5. Metabolites of interest N-acetyl aspartate (NAA) is a free amino acid thought to be localized in neurons in the brain and commonly considered a neuronal marker and a decrease may be an indicator of neuronal dysfunction. Myo-inositol (Ins) is an organic osmolyte, with a major role in the volume and osmoregulation of astrocytes and is often considered a glial marker.

6. MRS in Pain and SCI 3.0 Tesla Imaging of the thalamus and the anterior cingulate region in order to increase the understanding of the metabolic processes in these areas and their relationships with neuropathic pain and psychosocial impact after in SCI. Anterior cingulate cortex has a role in the attentional and affective processing of pain. Subjects with SCI and neuropathic pain, no pain and able-bodied controls. Exclusion of known TBI, or cognitive deficits.

7. Anterior cingulate cortex

8. Test-retest reliability We repeated the MR scans after 2-4 weeks in 36 persons with SCI and neuropathic pain. The analysis shows ICCs indicating adequate test-retest reliability of metabolites (nmol) and ratios between the two test sessions (ICC > 0.6).

9. Test-retest reliability The Pain Severity subscale (PS), the Life Interference (LI), the Life Control (LC), and the Affective Distress (AD) of the Multidimensional Pain Inventory (MPI) exhibited excellent test-retest reliability between the two test sessions.

10. Relationship between pain severity and ACC NAA/Ins ratio The PS subscale and the NAA/Ins ratio were significantly (p=0.004) correlated r=-0.453), indicating that greater pain severity is related to a lower NAA/Ins ratio (lower levels of neuronal markers relative to greater level of glial markers). This finding supports our hypothesis that neuropathic pain is associated with a decline or dysfunction of neurons in combination with an increase in glia or glial activation.

11. Relationship between ACC NAA/Ins ratio and psychosocial impact of pain This finding supports our hypothesis that the psychosocial impact of neuropathic pain is also associated with a decline or dysfunction of neurons in combination with an increase in glia or glial activation.

12. Cluster analysis We hypothesized that a cluster analysis would yield two significantly different subgroups: (1) High psychosocial pain impact and lower NAA/Ins ratio and (2) Low psychosocial pain impact and higher NAA/Ins ratio. The cluster analysis was performed using an unbiased SPSS two-step cluster procedure. Results: (1) High Pain impact and low NAA/ML ratio (n=20; 52.6%), and (2) Low pain impact and greater NAA/ML ratio (n=18; 47.4%)

13. Cluster analysis

14. External validation of subgroups

15. Comparison among groups

16. Summary Metabolic concentrations in the ACC are stable over a period of 2- 4 weeks supporting the longitudinal usefulness of MRS. Severe neuropathic pain and pain impact is associated with biomarkers suggesting neuronal dysfunction paired with glial recruitment or activation. This is consistent with research showing a relationship between glial activation and persistent pain behavior in SCI rats (Zhao et al., 2007). Two SCI neuropathic pain subgroups: High pain impact and Low pain impact. These clusters were significantly different with respect to other pain measures, psychosocial measures and the NAA and Ins concentrations supporting their validity. Comparisons between SCI High pain impact, SCI no pain and able bodied controls show significant differences between controls and SCI high impact with respect to the NAA/Ins ratio and psychosocial measures.

17. Conclusion Research suggests that the experience of pain, affective distress, and cognitive control is anatomically and functionally integrated in the ACC (Shackman et al., 2011). Research also indicates that the ACC can suppress both sensory and affective qualities of pain via activation of µ-opioid receptors and via activation of the PAG (Zubieta et al., 2001). Thus, our results in consistent with hypothesis that greater pain severity and psychosocial impact are associated with metabolic concentrations in the ACC reflecting neuronal dysfunction possibly due to decreased pain modulatory function.

18. Special thanks to: Staff: Jim Adcock, MS Letitia Fisher Co-Investigators: PradipPattany, YeniselCruz-Almeida, Elizabeth Felix, Alberto Martinez-Arizala, Diana Cardenas, Salomé Pérez This project was funded by the VARR&D (Merit Review B5023R), and the Miami Project to Cure Paralysis.