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

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):

a.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

The inclusion criteria are:

1. Women who have met American College of Rheumatology (1990) criteria for the diagnosis
of FM (Wolfe, Smythe et al. 1990) for at least 1 year. 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

2. Continued presence of pain more than 50% of days

3. Willingness to limit the introduction of any new medications or treatment modalities
for control of FM symptoms during the study

4. Being over 18 and under 65 years of age

5. BMI of 36 or less (because we use the MRI machine)

6. Capability of giving written informed consent

The exclusion criteria are:

1. Presence of concurrent autoimmune or inflammatory disease; such as, rheumatoid
arthritis, systemic lupus erythematous, inflammatory bowel disease, etc. that causes
pain

2. Routine daily use of narcotic analgesics or history of substance abuse

3. Concurrent participation in other therapeutic trials

4. Pregnant and nursing mothers (verification of pregnancy status will be determined via
a urine test)

5. Severe psychiatric illnesses (current schizophrenia, major depression with suicidal
ideation, substance abuse within two years)

6. Contraindications to fMRI, or H-MRS methods

7. Any impairment, activity or situation that in the judgment of the Study Coordinator or
PI would prevent satisfactory completion of the study protocol