Major depressive disorder (MDD) and chronic pain are highly comorbid, especially in
women. Pain symptoms can either precede or follow the onset of MDD, suggesting a
bidirectional relationship between MDD and chronic pain. Knee OA causes structural and
neural pain sensitization changes with segmental and central sensitivity, reduction of
pain threshold such as hyperalgesia inside and outside the already sensitized areas,
which can lead to generalized pain. Studies also have shown that rTMS can alleviate pain
symptoms of different etiologies including FM, headache, neuropathic pain, and complex
regional pain syndrome (CRPS). Several studies have highlighted the importance of the
interaction between pain and depression, suggesting that the therapeutic effects of rTMS
on pain and mood may be mediated by the joint modulation of pain pathways and social and
affective regions of the brain. The most effective fibromyalgia pain relief was observed
when targeting the primary motor cortex (M1), or the l-DLPFC. Direct comparison of the
stimulation of M1, l-DLPFC, and sham on outcome in FM and depressive symptoms and found
that while the pain intensity was decreased after M1 stimulation, better overall
functional improvement was achieved with rTMS to the l-DLPFC. Our preliminary data show
that rTMS treatment for MDD to left DLPFC reduced general pain symptoms in MDD patients,
possibly through top-down regulation of pain processing regions, however, rTMS to l-DLPFC
failed to improve severe chronic pain symptoms in those with MDD. We hypothesize that
targeting two nodes related to depression and pain processing will enhance rTMS treatment
outcome for comorbid knee OA and MDD.
We will perform a pilot feasibility trial of the Repetitive Transcranial Magnetic
Stimulation (rTMS) protocol for neuromodulation of treatment response to Tai Chi that
will compare 2 neuromodulation strategies in 30 subjects with OA knee arthritis pain and
comorbid depression. rTMS is a non-invasive treatment that can modulate activity of brain
circuits. rTMS most commonly has shown efficacy for relieving pain symptoms with an (M1)
site in the left primary motor cortex being the primary stimulation site. rTMS is
routinely used for treatment of depression with the stimulation to the left dorsolateral
prefrontal cortex (DLPFC), however stimulation at either sits can improve both symptoms
due to neuroplasticity of neurocircuits involved, as shown in our preliminary studies.
Pilot Study Research design 30 participants diagnosed with knee OA per parent study and
major depressive disorder (MDD, DSM-5R; BDI >20) will be randomized 1:1 into two
treatment conditions, using randomization scheme. All stimulation procedures will be
double-blinded. The two stimulation protocols consist of 24 sessions, with each session
including administration of: Group A) rTMS to M1-active/ l-DLPFC-active; Group B) rTMS to
M1-active/l-DLPFC-sham. We anticipate up to 6 (20%; 3 per group) dropouts.
Additional Inclusion/Exclusion criteria for the pilot project are:
- (1) serious medical or
psychiatric conditions other than MDD (DSM5); (2) the BDI score of >20 (moderate-severe
depression); (3) stable treatment regimen for pain and depression for at least 4 months;
(4) contraindications to TMS[69].
Randomization: We will assign participants 1:1 to group (l-DLPFC sham versus active)
randomly by a computer-generated, block-permutation scheme managed by a study team member
not involved in study assessments or treatment. For the total sample size of 30 (i.e.,~
15 per group) participants will be randomly assigned to the treatment condition (sham
versus active) using block randomization stratified on sex. A block size of 2 will be
used to ensure approximate equal balancing between the anticipated smaller group sizes.
Experimental blinding: The utilization of a specialized A/P treatment coil (MagVenture
Cool-B65 A/P coil) will allow for double blinding of the experimental condition for all
involved personnel including TMS technicians, TMS physicians, raters, and patients. The
symmetrical coil has no indication of active vs.#46; placebo sides but, internally, one side
has a magnetic shield that renders treatment ineffective. Sham stimulation mimics the
auditory TMS experience through a clicking noise. Additionally, scalp electrodes placed
on the left side of the forehand below the magnet deliver electrical stimulation to the
skin with each TMS train to mimic the sensory experience (i.e., tingling sensations
associated with receiving active TMS). Prior research suggests that treatment-naïve
participants are unable to distinguish sham from active TMS using this arrangement. The
study team member responsible for randomization will assign a participant to group A or B
using the randomization scheme above. They will then inform the TMS technicians of a
unique participant code that, when entered into the stimulator using its research
interface, will direct the technician to use one side or another of the A/P coil
- -
thereby determining whether the patient receives sham or active treatment.
Neither the
technicians nor the physicians delivering TMS, nor the raters will know which patient
corresponds to which treatment arm. The study team members will also write down whether
they believe study participants received sham or active treatment.
Neuronavigation: Neuroanatomic coil placement will be performed using the (Brainsight).
The stimulation coordinates for the anatomical locations of l-DLPFC and M1 will be
defined using the reliable targeting approach described in [78], based on a 3-dimensional
brain reconstruction provided by the ANT Visor2 system. Left DLPFC defined by this
algorithm corresponds to the junction between Brodmann Area (BA) 9 and BA 46, while the
M1 target corresponds to the posterior border of hand representation. Coil position and
angle will be maintained throughout and consistent across sessions.
rTMS treatments [70] will be performed with the MagVenture MagPro X100 stimulator
equipped with the Cool-B70 A/P for sham-controlled stimulation. The A/P coil supports
double-blinding of treatment. The coil has two sides, one of which is shielded so that no
energy is imparted to the brain when the shielded side is applied to the subject's head.
Small skin electrodes are applied to the scalp under the coil that impart a small
microcurrent to the scalp simulating the sensation of active treatment. The operator
receives a code from the device instructing them which side of the coil to use for each
subject, ensuring complete treatment blinding. Active treatment to l-DLPFC will consist
of 1800 pulses of intermittent theta burst stimulation (iTBS) at 120% MT. Active
treatment to M1 will consist of 1500 pulses of 10 Hz stimulation with 20 trains of 10-s
on and 30-s intertrain intervals at 100% MT. Intensity of active stimulation at both
targets will be ramped up to the target intensity over the first three treatment sessions
to increase tolerability.
Electric field modeling of TMS. Modeling will be performed to confirm that a therapeutic
level of stimulation is delivered to the correct neuroanatomical areas. We will utilize
simNIBS 3.0 (www.simnibs.org) to model current distributions with a finite element method
based upon the magnetic dipole model for the MagVenture A/P treatment coil positioned to
create a tangent with regard to brain structure. Electrical conductivities will be
assigned to different tissue types with assumed isotropic conductivity. The intensity was
set to 50% of maximum system output, a typical level needed to achieve 120% of MT. These
results indicate that the therapeutic level of stimulation is largely confined to the
target structures, and that the ratio of target to non-target activity is high. This
targeting technique will ensure accurate targeting the DLPFC and M1 sites.
Randomization allocation concealment and blinding. Participants will be randomly
allocated to either:
- (1) M1active/ l-DLPFCactive or (2) M1active/ l-DLPFCsham based on a
1:1 allocation ratio with the allocation list generated by the statistician.
Participants, study physicians, and the PI will be blinded to the type of rTMS they will
receive due to the coil. All participants will be given the same instructions and
information about the rTMS intervention. Researchers conducting laboratory-based outcome
assessment and will be blinded to group allocation. Unblinding will be allowed when an
adverse or unexpected event occurs.
Measures of feasibility and safety. Feasibility and safety of the rTMS and Tai Chi
intervention will be assessed using the following measures:
- (1) the number of sessions
attended by each participant (attendance rate >80% is considered feasible)[71]; (2) the
number of dropouts in each group (dropout rate <20% is considered feasible)[71]; (3) the
proportion of participants recruited from the total number screened; (4) willingness of
each participant to undergo interventions at baseline on an 11-point NRS with "not at all
willing" at 0 and "very willing" at 10 (80% of participants score 7 or more are
considered feasible); (5) the number of adverse events and the details of each event.
Each adverse event will be considered separately. One or more serious adverse events will
be considered unsafe.
Inflammatory markers: Inflammation is a characteristic feature of OA and depression, and
a panel of cytokine/chemokines will be obtained to characterize a pattern of inflammation
and to assess feasibility of using the panel to track changes in inflammation with TCC
intervention[72]. Whole blood will be centrifuged at 2000 rpm for 10 min and plasma will
be immediately stored at -80 0 C. We will use the Human 38-plex magnetic
cytokine/chemokine kits (EMD Millipore, HCYTMAG60K-PX38). T
