CORTICAL NEUROCHEMICAL

CORRELATES OF NEUROPATHIC PAIN

SEVERITY AND IMPACT AFTER SPINAL

CORD INJURY.

EVA WIDERSTRÖM-NOGA, PRADIP PATTANY, YENISEL

CRUZ-ALMEIDA, ELIZABETH FELIX, ALBERTO MARTINEZ-

ARIZALA, DIANA CARDENAS, SALOMÉ PÉREZ

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 dysesthesiaMedian 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

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).

MR Spectroscopy– MRS is a non-invasive method to measure

metabolites in the human brain..

– MRS is based on the fact that different

chemicals vibrate at different frequencies

when stimulated by a magnet.

– MRS produces 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.

Metabolites of interestN-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.

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.

Anterior cingulate cortex

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).

Measure Visit 1

Mean±SD

Visit 2

Mean±SD

ICC F, p-value

NAA 6.08±0.68 6.08±0.60 0.63 4.37, p<0.000

Cho 1.47±0.19 1.47±0.18 0.69 5.46, p<0.000

Cr 5.12±0.45 5.09±0.34 0.65 4.69, p<0.000

Ins 5.39±0.57 5.33±0.56 0.70 5.62, p<0.000

NAA/Ins 1.13±0.13 1.15±0.14 0.62 4.27, p<0.000

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.

Measure Visit 1

Mean±SD

Visit 2

Mean±SD

ICC F, p-value

MPI: PS 3.45±1.06 3.22±1.14 0.71 3.45, p<0.000

MPI: LI 1.72±1.37 1.53±1.43 0.94 16.26, p<0.000

MPI: LC 3.79±1.23 3.94±1.17 0.84 6.17, p<0.000

MPI: AD 1.71±1.42 1.67±1.39 0.83 6.01, p<0.000

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.

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.

Measure NAA/Ins ratio, r, p-value (n=38)

MPI: Life Interference -0.311, p=0.058

MPI: Life Control 0.479, p=0.002

MPI: Affective Distress -0.425, p=0.008

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%)

Measure High Pain

impact

(n=20)Mean±SD

Low pain

impact

(n=18)Mean±SD

T-value p-value

MPI:PS 3.85±0.9 2.79±0.74 3.931 .000

MPI: LI 2.40±1.36 1.02±1.06 3.511 .001

MPI:LC 3.22±1.20 4.52±0.66 -4.057 .000

MPI:AD 2.62±1.21 1.12±0.80 4.549 .000

NAA/ML 1.06±0.09 1.23±0.08 -6.137 .000

Cluster analysis

External validation of subgroupsMeasure High pain

impact

(n=20)

Mean±SD

Low pain

impact

(n=18)

Mean±SD

T-value p-value

NAA 5.87±0.57 6.33±0.47 -2.696 0.011

Ins 5.57±0.54 5.17±0.40 2.613 0.013

Measure High pain

impact

(n=20)Mean±SD

Low pain

impact

(n=18)Mean±SD

T-value p-value

BDI 13.7±8.76 4.69±3.78 4.032 0.000

STAI 40.28±10.50 27.86±5.25 4.526 0.000

VASm 4.74±1.94 2.94±2.00 2.812 0.008

SWLS 16.10±6.54 21.92±6.73 -2.697 0.011

Comparison among groups

Controls (n=24)

SCI no pain (n=18)

SCI High pain impact (n=20)

ANOVA F; p-value

NAA 6.21±.0.59 6.22±0.51 5.88±0.57 2.323; 0.108

Ins 5.37±0.43 5.65±0.55 5.57±0.54 1.507; 0.213

NAA/Ins 1.16±0.11 1.10±0.12 1.06±0.09 4.773; 0.012

Controls (n=24)

SCI no pain (n=18)

SCI High pain impact (n=20)

ANOVA F; p-value

VASm 0.20±0.47 0.54±.82 4.74±1.94 85.280; 0.000

BDI 1.12±1.36 4.72±4.68 13.70±8.76 28.089; 0.000

STAI 24.54±4.71 26.56±5.36 40.28±10.50 28.951; 0.000

SWLS 28.38±5.35 24.83±7.26 16.1±6.54 21.157; 0.000

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.

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.

Special thanks to:

Staff:Jim Adcock, MSLetitia Fisher

Co-Investigators: Pradip Pattany, Yenisel Cruz-Almeida, Elizabeth Felix, Alberto Martinez-Arizala, Diana Cardenas, Salomé Pérez

This project was funded by the VARR&D (Merit ReviewB5023R), and the Miami Project to Cure Paralysis.