iTBS Methods and Motor Cortex Excitability

rTMS is a method of non-invasive neuromodulation. Although TMS (transcranial magnetic
stimulation) has widely been used as a research method to better understand brain
neurophysiology, rTMS protocols have been shown to be clinically beneficial to patients
suffering from neurological disorders such as Parkinson's Disease and stroke as well as
psychiatric diseases such as major depression. In October of 2008 the FDA approved 10 Hertz
(Hz) dorsolateral prefrontal cortex (DLPFC) stimulation for patients with medication
resistant depression. The typical duration of a single rTMS treatment for depression lasts
for about 30 minutes, but must be repeated daily over several weeks. The decision to use
DLPFC stimulation was due in part to imaging studies, which suggested depressed patients had
decreased activity in the region. Thus, rTMS could be used to reverse those behavioral
effects of depression by increasing activity in the DLPFC. Traditionally 5 Hertz (Hz)
stimulation and upward has been shown to be excitatory while stimulation of 0.2-1 Hertz (Hz)
has been shown to have inhibitory effects on the cortex. Although these parameters appear to
be efficacious the development of new rTMS methods are still being explored.

Theta burst stimulation (TBS) is a method with the potential of providing excitatory or
inhibitory effects on the cortex, which are as powerful as traditional rTMS methods yet more
efficient in duration and intensity required. Evidence from previous studies looking at theta
burst as a treatment for depression has highlighted the importance of the method's
development. One study indicated that theta-burst stimulation over the dorsomedial prefrontal
cortex (DMPFC) for a duration of just 6 minutes can produce comparable anti-depressant
effects to traditional 10Hz stimulation over 30 minutes. Theta burst stimulation effects were
first empirically tested on the human motor cortex by Huang et al. 2005. The effects of
stimulation (80% of active motor threshold) over the motor cortex were measured pre and post
treatment with electromyography (EMG) recordings of motor evoked potentials (MEPs) on a small
contralateral hand muscle in response to single pulses of TMS. Two protocols showed changes
in excitability of the corticospinal tract, including cTBS defined as three burst stimuli at
50 Hz with 20ms between stimuli repeated every 200ms at 5Hz and iTBS defined as a 2s train of
TBS repeated every 10 seconds. Although both protocols deliver a total of 600 pulses, the
cTBS protocols lasts for 40 seconds while the iTBS protocol lasts for 190 seconds. Huang et
al. 2005 determined that cTBS over motor cortex decreased excitability while iTBS increased
excitability which were present an hour following treatment.

The excitability of the motor cortex may be modulated differently depending on the type of
theta burst stimulation protocol utilized. iTBS was originally described by Huang et al. 2005
resulting in an excitatory effects (LTP like) on the cortex. Gamboa et al. 2010 later
confirmed this finding but showed that there was a decrease in excitability (LTD-like) when
the protocol is doubled. Both of these protocols are to be replicated and in addition 2 new
protocols. In order to investigate how cortical excitability changes as a function of
protocol, MEPs will be recorded using EMG on the hand muscle contralateral to the stimulated
cortex. Baseline MEPs will be obtained pretreatment, followed by one of the four theta burst
protocols, or a sham treatment. Theta burst protocols are to be administered to each
participant in randomized order. After theta burst is administered 20 MEPs will be collected
at 0, 10, 20, 30, 40, 50 and 60 minutes.

Specific Aim 1: To determine the long-term potentiation (LTP) like and long-term depression
(LTD) like effects of four different theta burst stimulation protocols on motor cortex
excitability.

Inclusion Criteria:

- Healthy adults (18 - 65 years of age)

- Able to read and understand questionnaires and informed consent

Exclusion Criteria:

- Pregnancy, females of child bearing age must undergo a pregnancy test to confirm
eligibility;

- History of seizure disorder or post-stroke seizure;

- Implanted medical devices or metal in head (except braces);

- Preexisting scalp lesion or wound or bone defect or hemicraniectomy;

- Left-hand dominance