Research Review By Dr. Ceara Higgins©

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Date Posted:

January 2017

Study Title:

Brain mechanisms of pain relief by transcutaneous electrical nerve stimulation: A functional magnetic resonance imaging study

Authors:

Choi JC, Kim J, Kang E, et al.

Author's Affiliations:

Yonsei University Wonju College of Medicine, South Korea; Kangwon National University, Chuncheon, South Korea; Julie English Institute, Wonju, South Korea; Yonsei University, Seoul, Korea.

Publication Information:

European Journal of Pain 2016; 20: 92–105.

Background Information:

Transcutaneous electrical nerve stimulation (TENS) reduces acute and chronic pain by delivering electronic current through the skin and has been shown to be effective in pressure pain, intense experimental pain, and thermal pain models (3). Maximum pain relief has been found from TENS delivered at a strong, yet non-painful intensity (8). While the exact mechanism is unknown, it is thought that TENS impulses interrupt nociceptive signals at the dorsal horn of the spinal cord (11).

Functional magnetic resonance imaging (fMRI) has been used extensively to study pain pathophysiology (9), which suggests that it may be useful for identifying the brain mechanisms associated with pain relief from the use of TENS.

The authors began this study with four hypotheses:
  1. Pain and brain responses to noxious stimuli are modulated by TENS.
  2. Increasing TENS intensity in proportion to pain duration would prevent temporal summation from noxious stimulation (temporal summation was defined as the increase in perceived pain when noxious heat is applied to the skin) (12).
  3. Temporal summation, pain, and brain responses to noxious stimuli during TENS would differ between men and women.
  4. The functional connectivity of the periaqueductal grey (PAG), which integrates top-down and bottom-up influences to modulate pain perception, with other brain areas is modulated by hormones and TENS.

Pertinent Results:

In the pain+TENS condition, periaqueductal gray (PAG) functional connectivity with the lateral prefrontal cortex increased, likely activating the descending pain-inhibitory pathway. As well, the superior parietal lobe, right postcentral cortex (S1), bilateral parietal operculum (S2), supramarginal cortex, and right ventrolateral prefrontal cortex (VLPFC) were all significantly activated in the pain+TENS condition when compared to the pain-only condition. This may indicate the stimulation of large-diameter A-beta fibers, leading to reduced pain.

In the pain-only condition, the left anteroventral thalamus, bilateral rACC (rostral anterior cingulate cortex), and right hippocampal cortex were more highly activated. The anterior thalamic nuclei have many projections to the ACC (10), which has been shown to process the affective-motivational dimension of pain (2). The hippocampal cortex activates in response to noxious stimulation and may contribute to negative affect associated with pain (1). Left PAG functional connectivity with the left, but not the right, lateral prefrontal cortex (PFC) significantly increased as the TENS effect increased in the pain+TENS condition. Both the lateral PFC and PAG are implicated in endogenous pain inhibition (2). Thus, the increase in TENS effect may activate the descending pain-inhibitory pathway.

In the pain+TENS condition, the right temporoparietal junction (TPJ) was more activated in women than in men. The TPJ works to direct attention to salient events and detect behaviourally relevant stimuli (4). This may indicate that women attend more strongly to noxious stimuli than men. In male participants, higher testosterone levels were associated with increased activation of the left precentral, right superior frontal (premotor area) and bilateral supramarginal cortices in the pain+TENS condition. Testosterone modulates opioid analgesia (5), and has anti-anxiety and analgesic effects (6). Increased TENS effect also decreased right PAG functional connectivity with the cerebellum, rACC, orbitofrontal cortex (OFC), and S1 in men in the pain+TENS condition.

Women showed increased PAG functional connectivity with the cerebellum and right PAG functional connectivity with the OFC. Women also had higher pain ratings in the pain+TENS condition. OFC activity has been correlated with pain (7), so the TENS effect may decrease pain perception by decreasing right PAG functional connectivity with the cerebellum, rACC, OFC, and S1.

The participants reported lower perceived pain (49.63 vs 75.75) and pain-related unpleasantness (47.13 vs 74.00) in the pain+TENS condition compared to the pain-only condition.

Clinical Application & Conclusions:

S1, S2, and parietal cortices were activated by non-painful TENS. TENS also increased PAG functional connectivity with the lateral prefrontal cortex. This would likely result in activation of the descending pain-inhibitory pathway to produce pain relief. Increasing TENS intensity in a step-wise fashion effectively prevented temporal summation. This study suggests that TENS application is effective for pain reduction. This mirrors what many see in clinical practice. Whether this effect is physiological, or represents some degree of a placebo effect, helping our patients reduce pain levels remains the most important outcome!

Study Methods:

12 men and 12 women were selected for this study. Exclusion criteria included peripheral and central nervous system diseases, significant clinical conditions, and medication use that could affect sensory perception, including neuropsychotropics or analgesics.

All participants had two channel TENS applied to their lower left leg skin with one cathode electrode over the fibular neck and the anode electrode from the same channel applied to the skin directly above the lateral malleolus. The other cathode electrode applied to the skin on the posterior left leg at the level of the fibular head, with the anode electrode from that second channel applied at the posterior left ankle. This allowed one channel to stimulate the common fibular (peroneal) nerve and the other to stimulate the tibial nerve. Noxious thermal stimuli at 45C were applied to the left lower leg skin through a thermode applied midway between the cathodes (fibular head level) and anodes (ankle level) with a Velcro strap. A duration of 15 seconds was selected for the study intervention because pain perception has been shown to increase over the first 10 seconds and then remain roughly constant (12). Subjects were placed in the MRI and individual TENS levels that were perceived as strong, but not painful, were identified for each participant (all under 80 Hz and 60 ms pulse duration).

Each participant received the same painful stimuli in both the pain and pain+TENS conditions. This began with temperatures of 32C at baseline, which were increased to 45C at a rate of 25C/sec. The target temperature of 45C was then maintained for 15 seconds and then returned to baseline at the same rate. Ten repetitions of noxious stimuli were included in each session. In the pain+TENS condition, the participants also received TENS for 15 seconds, which was increased in a step-wise manner to overcome any habituation effect. Participants in the pain+TENS condition began with a comfortable TENS intensity (CTI) for 5 seconds, then received CTI plus 1 mA for the second 5 second period, and then CTI plus 2 mA for the third 5 second period.

Six men and six women received the pain-only condition followed by the pain+TENS condition. The other six men and six women received the pain+TENS condition first followed by the pain-only condition. All participants remained in the MRI scanner for the duration of the study. At the end of each condition participants were asked to rate the average pain and unpleasantness experienced during the 15 second noxious stimulation period, as well as the pain experienced during the first, second, and third 5 second intervals. All ratings were performed using a numerical rating scale with 0 being no pain or unpleasantness and 100 being maximum pain or unpleasantness. Venous blood samples were drawn before fMRI scanning to assess testosterone and cortisol levels. Participants were instructed not to eat for 2 hours before the blood sampling.

Participants were instructed to stay awake and refrain from moving as much as possible during the scans. The participants’ heads were immobilized with padded earmuffs and a foam headrest and a plastic bar was placed across the bridge of the nose. MRI imaging slices were acquired at a thickness of 4mm to cover the entire brain volume.

Study Strengths / Weaknesses:

Strengths:
  • The authors controlled for any between group variation as a result of TENS interference with the fMRI by applying TENS to a rolled pig skin positioned between the participants lower legs in the pain only condition.
  • To minimize habituation or sensitization from the pain stimulus, the thermode was moved slightly to an adjacent area of skin between sessions.
Weaknesses:
  • No TENS-only control group was included in the study. That may have allowed the brain regions activated by TENS to be more clearly identified.

Additional References:

  1. Apkarian AV, Bushnell MC, Treede RD, et al. Human brain mechanisms of pain perception and regulation in health and disease. Eur J Pain 2005; 9: 463-484.
  2. Apkarian AV, Bushnell MC, Schweinhardt P. Representation of pain in the brain. In Wall & Melzacks Textbook of Pain, 6th Edition, SB McMahon, M Koltzenburg, I Tracey, DC, Turks, eds. (Philadelphia: Elevier Saunders) 2013: 111-128.
  3. Claydon LS, Chesterton LS, Barlas P, et al. Dose-specific effects of transcutaneous electrical nerve stimulation (TENS) on experimental pain: A systematic review. Clin J Pain 2011; 27: 635-647.
  4. Corbetta M, Shulman GL. Control of goal-directed and stimuluis-driven attention in the brain. Nat Rev Neuosci 2002; 3: 201-215.
  5. Craft RM, Mogil JS, Aloisi AM. Sex differences in pain and analgesia: The role of gonadal hormones. Eur J Pain 2004; 8: 397-411.
  6. Edinger KL, Frye CA. Testosterone’s anti-anxiety and analgesic effects may be due in part to actions of its 5alpha-reduced metabolites in the hippocampus. Psychoneuroendocrinology 2005; 30: 418-430.
  7. Lorenz J, Minoshima S, Casey KL. Keeping pain out of mind: The role of the dorsolateral prefrontal cortex in pain modulation. Brain 2003; 126: 1079-1091.
  8. Moran F, Leonard T, Hawthorne S, et al. Hypoalgesia in response to transcutaneous electrical nerve stimulation (TENS) depends on stimulation intensity. J Pain 2011; 12: 929-935.
  9. Peyron R, Laurent B, Garcia-Larrea L. Functional imaging of brain responses to pain. A review and meta-analysis. Neurophysiol Clin 2000; 30: 263-288.
  10. Shibata H, Naito J. Organization of anterior cingulate and frontal cortical projections to the anterior and laterodorsal thalamic nuclei in the rat. Brain Res 2005; 1059: 93-103.
  11. Tashani ), Johnson M. Transcutaneous electrical nerve stimulation (TENS). A possible aid for pain relief in developing countries? Libyan J Med 2009; 4: 62-65.
  12. Tran TD, Wand H, Tandon A, et al. Temporal summation of heat pain in humans: Evidence supporting thalamocortical modulation. Pain 2010; 150: 93-102.