Effects of Direct Transcranial Current Stimulation on Central Neural Pain Processing in Fibromyalgia

1. BACKGROUND AND SIGNIFICANCE:

2. Fibromyalgia (FM):

*Fibromyalgia is the second most common rheumatologic disorder, behind osteoarthritis, afflicting 2-4% of the population of industrialized countries.(Jacobsen and Bredkjaer, 1992; Wolfe et al., 1990) To fulfill the criteria for FM established by the American College of Rheumatology in 1990, an individual must have both chronic widespread pain involving all four quadrants of the body (and the axial skeleton), and the presence of 11 of 18 pre-defined "tender points" on examination. A positive tender point is identified when an individual complains of pain when approximately four kilograms of pressure is applied to one of these points by an examiner. FM is the prototypical "central" or "non-nociceptive" pain syndrome. Research performed within the past decade has clarified a number of important issues regarding this condition. Multiple studies suggest neurological dysfunction as a hallmark of this disease (Clauw and Crofford, 2003), and this is supported by a number of objective functional neuroimaging abnormalities. (Gracely et al., 2002; Harris et al., 2007; Mountz et al., 1995) Overall the data suggest that the primary abnormality in FM is a generalized disturbance in central nervous system pain processing, leading individuals to sense pain throughout the body in the absence of inflammatory or patho-anatomic damage. (Clauw and Chrousos, 1997; Yunus, 1992) Most FM neuroimaging studies to date have examined brain responses to a painful stimulus, as the imaging of endogenous chronic pain is notoriously difficult. (Baliki et al., 2007). However few studies have examined the modulation of specific brain regions and how this impacts neurotransmitter levels, network connectivity, and structural changes such as cortical thickness within the same subjects. 2. Transcranial Direct Current Stimulation (tDCS):

*Therapies that directly modulate brain activity in specific neural networks might be particularly suited to relieve chronic pain in individuals with FM. Ultimately, this underlies the interest in neurostimulation approaches, which are being explored at multiple levels of the neuroaxis, including the peripheral nerves, spinal cord, deep brain structures, and cortex.(Lefaucheur, 2004) Among the methods of central neurostimulation, two of them, repetitive transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), are particularly appealing as they can change brain activity in a non-invasive, painless and safe way. TMS is a method of brain stimulation that was developed in 1985 (Barker et al., 1985). It is based on a time-varying magnetic field that generates an electric current inside the skull where it can be focused and restricted to small brain areas by appropriate stimulation coil geometry and size.(Pascual-Leone et al., 1999). This current, if applied repetitively, repetitive TMS (rTMS), induces a cortical modulation that lasts beyond the time of stimulation.(Pascual-Leone et al., 1999) Although tDCS has different mechanisms of action, it induces similar modulatory effects. Several animal studies in the 1960s showed that this technique changes brain activity reliably (Nitsche et al., 2003a, 2003b). tDCS is based on the application of a weak direct current to the scalp that flows between two relatively large electrodes-anode and cathode. Some studies have shown that the efficacy of tDCS depends critically on parameters such as electrode position and current strength.(Nitsche et al., 2003a, 2003b) In fact, application of tDCS for 13 min to the motor cortex can modulate cortical excitability for several hours.(Nitsche and Paulus, 2000; Nitsche and Paulus, 2001) In addition, this technique can be used to obtain clinical gains in neuropsychiatric disorders such as stroke and epilepsy.(Fregni and Pascual-Leone, 2007) In this study we will investigate the modulatory effect of 5 daily tDCS sessions on biochemical, functional, and structural systems and its association with the clinical output in FM. 3. Proton Magnetic Resonance Spectroscopy (H-MRS) in FM:

*H-MRS neuroimaging obtains chemical spectra from multiple volume-image elements, or voxels, within the human brain using radiofrequencies that excite protons. (Ross and Sachdev, 2004) Specific molecules are identified by their characteristic resonance frequency in the spectrum. Once acquired, spectra are analyzed to determine the relative concentrations of different molecules or central nervous system metabolites within the voxel or region of interest. Typical metabolites identified are: glutamate (Glu), N-acetyl-aspartate (NAA), creatine (Cr), choline (Cho), lactate, lipid, myoinositol, gamma-aminobutyric acid (GABA), and glutamine (Gln). Glu and GABA are of particular importance to brain neurophysiology as they are components of excitatory and inhibitory neurotransmission, respectively. Glu binds to both ionotropic and metabotropic receptors located on postsynaptic neurons and causes excitability (i.e. depolarization). Moreover changes in the strength of Glu neurotransmission are typically indicative of synaptic plasticity, a process proposed to be involved in chronic pain.(Zhuo, 2008) H-MRS methods display multiple features which are amenable to longitudinal studies. High-resolution anatomical scans can be used to isolate identical brain regions on successive sessions that are even weeks apart. Measurement of metabolites within the central nervous system has been largely understudied in the field of pain. Grachev et al. has reported that the level of NAA, a marker for neuronal viability and also function (Nakano et al., 1998; Sager et al., 2001), is lower within the dorsolateral prefrontal cortex of individuals with chronic low back pain as compared to healthy controls.(Grachev et al., 2000) In addition, a recent investigation has begun to implement H-MRS technology to assess functional changes in the concentrations of Glu in response to evoked pain stimuli.(Mullins et al., 2005) Mullins et al. have observed that Glu levels increase by as much as 10% in the anterior cingulate in response to cold pain applied to the foot. Glu in the central nervous system may play a role in FM pathophysiology. A study by Peres et al. found that cerebrospinal fluid levels of Glu were elevated in FM patients possibly having consequences for glutamatergic neurotransmission.(Peres et al., 2004) Administration of ketamine, a glutamate channel blocker, has been found to reduce experimental pain (Graven-Nielsen et al., 2000) and clinical pain (Cohen et al., 2006) in FM. Moreover our group recently demonstrated that long-term treatment of FM patients with acupuncture can lead to changes in Glu levels within the posterior insula and that these changes are highly correlated with changes in pain: greater reductions in Glu are associated with greater reductions in both experimental and clinical pain (Harris et al., 2008). In addition, we have recently compared posterior insula Glu and combined Glu + Gln (Glx) between FM patients and matched controls and have demonstrated that the patients have elevated Glx (and Glu) levels. (Harris et al., 2009). 4. Resting state networks (RSNs) in FM: