Effects of Direct Transcranial Current Stimulation on Central Neural Pain Processing in Fibromyalgia
Condition: Fibromyalgia
MeSH terms: Fibromyalgia; Myofascial Pain Syndromes
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      The main goal of this Collaborative Proposal is to investigate biochemical, functional, and
      structural neuroimaging changes following non-invasive brain stimulation in patients with
      chronic widespread pain: fibromyalgia (FM). The fact that multiple therapeutic modalities
      which focus on central mechanisms provide modest relief for these patients raises the
      possibility that the cause for the chronicity of this debilitating disorder may lie within
      the brain itself. We propose that changes in the cortical milieu may result from prolonged
      experience of pain and suffering. Our previous results suggest changes in excitatory
      neurotransmitter levels, connectivity between multiple brain networks, and cortical thickness
      coincide within central neural loci related to pain perception and modulation in FM.
      Interestingly, modulation of cortical activity can be achieved noninvasively by a novel tool,
      transcranial direct current stimulation (tDCS), which has been reported to produce lasting
      therapeutic effects in chronic pain, especially FM. We propose to study the long-term effects
      of tDCS application on multiple levels of the central nervous system in FM patients. This
      project has significant clinical relevance and has the support of collaborators from
      University of Michigan and Harvard University
    

Detailed description: 
      1. BACKGROUND AND SIGNIFICANCE:

             1. 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:

                  -  Previous studies have found that in a task-free state (i.e. rest scan),
                     multiple distributed brain areas demonstrate temporal correlation of the fMRI
                     signal or "functional connectivity" in low frequency ranges.(Biswal et al.,
                     1995; Fransson, 2005) In one of the first such studies, Biswal et al. found a
                     significant correlation in resting fMRI signal from sensorimotor cortices of
                     opposite hemispheres.(Biswal et al., 1995) This resting state network (RSN)
                     has been referred to as the sensorimotor network, or SMN. (Beckmann et al.,
                     2005) FM pain is somatic in localization (usually soft tissue), hence resting
                     connectivity in the SMN may demonstrate increased connectivity to the pain
                     processing regions. Other RSNs have also been described, including one
                     anatomically consistent with the Default Mode Network (DMN) (Greicius et al.,
                     2003) [for review see (Buckner and Vincent, 2007; Vincent et al., 2007)]. This
                     network involves brain regions putatively engaged in self-referential
                     cognition that is "deactivated" (more active at rest than during a task state)
                     during a variety of externally focused task conditions. Typically, the DMN
                     (Figure 1) includes the inferior parietal lobule (IPL) (~BA 40, 39), the
                     posterior cingulate cortex (~BA 40, 39), the posterior cingulate cortex (~BA
                     30, 23, 31) and precuneus (~BA 7), areas of the inferior, medial and superior
                     frontal gyri (~BA 8, 9, 10, 47), the hippocampal formation, and the lateral
                     temporal cortex (~BA 21)(Buckner and Vincent, 2007). Resting fluctuations in
                     the DMN have demonstrated decreased connectivity in Alzheimer's disease
                     (Greicius et al., 2003) and increased connectivity in depression (Greicius et
                     al., 2004), compared to healthy controls. Interestingly, resting state
                     connectivity in the DMN has also been shown to change in response to an
                     intervention or task.(Waites et al., 2005) Waites et al. found increased
                     connectivity between the middle frontal gyrus and posterior cingulate (a
                     component of the DMN) in resting fMRI data following an active (cognitive)
                     task. While the functional significance of spontaneous fluctuations in the DMN
                     remains controversial, Fox and Raichle suggest that resting connectivity in
                     the DMN is fundamental to balancing excitatory and inhibitory inputs to
                     multiple brain networks, thereby setting the "gain" for future task-related
                     response. (Fox and Raichle, 2007) Positive correlations in fMRI signal refer
                     to putatively excitatory connections whereas negative correlations imply
                     putative inhibitory connectivity. We propose that application of tDCS with
                     decrease connectivity in the pain matrix regions that may result in a change
                     within the gain set by the DMN for brain processing within the pain matrix.

             5. White (WM) and Gray Matter (GM) Plasticity in Fibromyalgia:

                *The cortical mantle is a highly specialized, folded structure composed of a thin
                layer of GM. Abnormal variations in the thickness of the cortical mantle might
                reflect pathophysiological changes of intrinsic structure and integrity of the
                cortical laminae. Recently, some studies have shown this correlation in chronic
                pain diseases such as back pain (Apkarian et al., 2004), migraine (DaSilva et al.,
                2007b; Granziera et al., 2006) and trigeminal neuropathic pain (see preliminary
                data). The implications of an alteration in these diseases are either degenerative
                processes or neuroplasticassociated mechanisms. Apkarian and colleagues (Apkarian
                et al., 2004) found reduction in the gray matter of DLPFC of chronic back pain
                patients when compared to healthy controls using a volumetric based approach. More
                recently, such GM volume reduction was also found in the parahippocampus, and
                cingulate cortex of patients with fibromyalgia when compared to healthy controls.
                However, it seems that similar changes observed in the GM of fibromyalgia patients
                may be more related to comorbid affective disorders than the pain endurance (Peres
                et al., 2004; Wood et al., 2009). Using more sensitive and reliable neuroimaging
                tools in trigeminal neuropathic pain patients our group found cortical thickness
                changes that were spatially co-localized with functional allodynic (brush induced
                pain) activation. In addition, this pattern of concurrent structural and functional
                changes in chronic pain patients is influenced by somatotopic localization
                (sensorimotor cortex), known functionality of the specific region
                (sensory-discriminative and affective-motivational), underline
                activation/deactivation following allodynic stimulation and the duration of the
                disorder (see preliminary data). In another study of migraine patients, we found
                increased cortical thickness of caudal sensorimotor cortex in migraineurs compared
                to controls (DaSilva et al., 2007a). In the cortical mantle, the thickness changes
                in the sensory cortex could be due to the chronic sensory stimulation provoked by
                chronic pain. This is in line with a recent study that showed cortical thickening
                after sustained stimulation of the motor system (Draganski et al., 2004). In this
                study, volunteers who have learned to juggle showed transient and selective
                thickening of the motor cortex, as well as the motion-visual areas (MT/V5), as
                compared to the pre-learned phase. This suggests that overstimulation of the
                sensory-discriminative and affective-motivational neuronal systems in chronic pain
                may induce structural alterations in the cortex that is co-localized with
                inefficient pain modulation by the opioidergic system at a molecular level.

             6. Evaluation of Diffuse Noxious Inhibitory Controls (DNIC):

                  -  There is a body of evidence that suggests that the spontaneous pain and
                     hyperalgesia associated with CMI is due to a dysregulation of intrinsic
                     analgesic systems. The most well known intrinsic analgesic system is the
                     endogenous opioid system, which appears to function normally in CMI. Another
                     system, termed DNIC (Diffuse Noxious Inhibitory Controls), is characterized by
                     widespread analgesia evoked by a noxious stimulus applied to anywhere on the
                     body, such as tourniquet ischemia, or immersion of in painfully hot or cold
                     water. The widespread nature of the DNIC effect, involving convergent second
                     order neurons and a spinal-brain loop, is consistent with the diffuse
                     widespread pain of CMI disorders such as FM. The results of several studies
                     suggest that DNIC may be altered in CMI. Lautenbacher and Rollman observed
                     that DNIC evoked by hot water immersion decreased the sensitivity to painful
                     electrical stimuli in healthy control subjects but had no effect in patients
                     with FM. Marchand [unpublished observations] has reported a similar effect
                     using immersion of an arm in painfully hot water as both the conditioning and
                     pain stimulus. This method shows an effect of DNIC on pain ratings in healthy
                     controls but no effect in FM. Kosek and Hansson found that the DNIC
                     manipulation of tourniquet ischemia decreased the sensitivity to painful
                     pressure in control subjects but not in patients with FM.

                  -  Together, these results are consistent with the hypothesis that the pain and
                     tenderness in FM may be due to tonically inactive DNIC analgesic systems.
                     These results, however, do not specify causality and could also represent a
                     mechanism in which DNIC is tonically activated in CMI in response to the
                     widespread ongoing pain of the disease. These alternative mechanisms cannot be
                     separated using conventional psychophysical tests. Performing the tests in the
                     fMRI scanner will differentiate these mechanisms because in one case the DNIC
                     system remains "OFF" in the patient populations, in the other case the DNIC
                     system is constantly "ON." fMRI analysis of activity in brainstem regions
                     (e.g., caudal medulla) implicated in intrinsic DNIC analgesia will provide
                     evidence for tonic ON or OFF activity in these regions, and in addition
                     further specify the neuroanatomical locus of this abnormal pain processing.
                     The fMRI analysis will provide crucial evidence of whether FM results from a
                     DNIC defect or whether the DNIC abnormality is simply one of the signs of the
                     disease.

        2. RATIONALE (proposed research, and potential benefits to patients and/or society):

             1. There is not much information about FM disease and treatment options available.
                This study seeks to gain a better, more wholesome understanding about Fibromyalgia.
                People who suffer from this disease experience constant, chronic pain; which
                ultimately results in absence from school, work, etc. If a feasible treatment is
                available for Fibromyalgia sufferers, they will have an increase in life
                satisfaction and the bio-power (people able to work and perform more tasks) will
                increase.

        3. SPECIFIC AIMS (Research Objectives):

           a.The main goal of this Collaborative Proposal is to investigate biochemical,
           functional, and structural neuroimaging changes following non-invasive brain stimulation
           in patients with chronic widespread pain: fibromyalgia (FM). Additionally, we aim to:

           *Determine the effects of tDCS on the excitatory neurotransmitter glutamate (Glu) within
           the insula (posterior and anterior) and thalamus in individuals with FM. Glu levels
           within the insula and thalamus will be reduced following tDCS, reflecting a down
           regulation of excitatory neurotransmission in these pain regions.

             -  Investigate whether long-term therapy with tDCS normalizes gray matter thickness in
                target and cortical areas associated with pain perception and modulation in FM.
                Cortical thickness in FM patients, will return to comparable age- and sex-matched
                pain-free control participant levels following tDCS. These effects will be
                specifically detected in pain modulatory regions (e.g. dorsal lateral prefrontal
                cortex) of FM patients.

             -  Explore the effects of long-term tDCS on intrinsic connectivity between pain
                processing and modulatory regions and other brain networks (e.g. default mode
                network, sensory motor network) in FM. Our preliminary data suggest that FM
                patients display enhanced connectivity between various pain processing regions and
                the default mode network, a specific brain network that is active during periods of
                inactivity. We propose that tDCS will decrease connectivity between pain modulatory
                regions and other networks such as the default mode network thus resulting in a
                reduction in pain symptoms.

        4. RECRUITMENT METHODS:

           a.Potential subjects will be recruited by public advertisement in the School of
           Dentistry clinics, including MCOHR, and the Chronic Pain and Fatigue Research Center in
           addition to other University of Michigan clinics. They will also be recruited via
           UMClinicalStudies.org, the DaSilva lab webpage (with a flyer for the study listed under
           current research), ClinicalTrials.gov, and the U.S. National Institutes of Health. In
           addition, subjects may be recruited by the PI or study staff in a private setting. The
           potential subject's healthcare providers will be able to suggest the availability of the
           study and inform them of a place where they will be able to find more information about
           participating in the study.

        5. STUDY PROCEDURES:

             1. This study requires a total of 15 visits, broken down by the following: 1 baseline
                visit, 3 MRI visits, 10 tDCS testing visits, and 1 final follow-up/debriefing
                visit. Patient participant will last for a total of 5 consecutive weeks. During
                this time, we will be collecting clinical and psycophysical evaluation: the MRI
                photo imaging, DNIC/MAST pain tolerance data (computerized), and pain
                questionnaires (verbal), Quantitative Sensory Test (QST).

             2. No drugs will be administered during this study

             3. Devices used will include: MRI, tDCS, MAST/DNIC

        6. RISKS/DISCOMFORT:

             1. While these therapies are non-invasive, study participants may experience
                unpleasantness from the constant stimulus from the MAST/DNIC procedures; however,
                the pressure is not enough to cause any damage to the nail bed. The study
                participant is encouraged to inform the researchers of any discomfort/side effects
                they experience during any point of the study as the priorities of the research
                team is to keep the study participant safe. With regards to the tDCS testing, the
                participant may experience a temporary tingling sensation and minor skin
                irritation/redness as a result of the brain stimulation pads
    

Intervention name(s): Transcranial Direct Current Stimulation (tDCS)
Intervention type(s): Procedure
Intervention description(s): tDCS is based on the application of a weak direct current to the scalp that flows between two relatively large electrodes-anode and cathode. We will be using this device to investigate fibromyalgia.
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Diagnostic
Keywords: Fibromyalgia