The Effects of Multi-focal tDCS on Motor-cognitive Dysfunctions in Parkinson's Disease

The current study aim to establish the therapeutic potential of tDCS for freezing of gait
(FOG) and motor-cognitive dysfunctions in Parkinson's Disease (PD). FOG phenomenon is often
unresponsive to pharmacological and other treatments, especially in the advanced stages of
the disease. While it is likely that Transcranial direct current stimulation (tDCS) will
provide symptomatic relief, we will also explore, via secondary outcomes, the potential for
tDCS to modify disease progression. Support for this possibility stems from the likely
mechanisms of action of tDCS.

Based on strong rationale and preliminary findings in previous works, the objectives of the
current proposal are to conduct a prospective multi-center, double-blinded, stratified
controlled randomized clinical trial, comparing real multifocal tDCS to sham stimulation. The
main aim:

- To demonstrate the "short-term" and the longer-term effects of tDCS on FOG severity and
frequency.

Participants: A total of 85 patients will be recruited (Hoehn and Yahr Stage 1-3.5) who
suffer from FOG, as measured by the new FOG questionnaire (NFOG-Q) and as demonstrated in
response to a FOG provoking protocol, who are on stable medications, who have no
contraindications to tDCS, and who are between the ages of 40-80. Patients with DBS will not
be included.

tDCS intervention: Subjects will be randomized to receive either a real or sham tDCS
intervention. Each intervention will consist of 10, 20-minute treatments completed over 2
consecutive weeks (i.e., 5 per week), following previously established protocols. A single,
weekly "maintenance" treatment will then be provided for the following 12 weeks (note: for
depression, maintenance tDCS is most often provided once every two weeks; we will take a more
conservative approach here in this first long-term study for FOG in PD).

Participants will continue taking their regular medications, and treatments will take place
in the "ON" medication state (approximately at the same time of day for each treatment). The
real tDCS intervention will simultaneously target both the M1 leg area and the the
dorsolateral prefrontal cortex (DLPFC), in the brain hemisphere contralateral to the more
affected side of the body, as determined by the summation of the motor symptoms on The
unified Parkinson's disease rating scale (UPDRS). Current will be applied using an array of 8
sponge electrodes and the StarStim tDCS device and software (Neuroelectrics, Inc). For this
protocol, the placement and current delivered through each electrode has been optimized using
the Neuroelectrics StimWeaver® Stimulation Optimization Service . In case of bilateral
symptom symmetry, tDCS will target the left M1 and DLPFC. For the sham intervention, the same
electrode placement and stimulation parameters will be used; however, current will only be
applied for the first 60 seconds of the stimulation session. This is a reliable control as
sensations arising from tDCS diminish considerably after the first minute of stimulation. At
the end of each treatment session, participants will complete a short questionnaire to assess
potential side-effects. At the end of the entire intervention, participants will be asked to
state if, in their opinion, they received the real or sham intervention.

Outcome measures: The primary outcome will be the number of FOG episodes measured in the lab
when subjects undergo a validated FOG-invoking protocol, after the initial 2-week
intervention and at the final study point, similar to that proposed by Ziegler et al.
Briefly, this protocol includes situations that have been shown to provoke FOG. Patients will
be asked to sit, to stand up and to walk to a a mark on the floor. They will perform two 360°
turns, clockwise and counter-clockwise. Then, the patients will be asked to open a door and
walk through it, turn outside, and come back to their chair. Secondary outcomes of FOG will
include FOG duration and the new FOG questionnaire (NFOG-Q). This FOG-provoking protocol will
take place in both the ON and OFF medication state and higher values (worse) of FOG will be
used as the primary outcome measure (in secondary analyses, we will examine ON and OFF FOG
separately).

Additional secondary measures will test the influence of tDCS on other motor, cognitive or
motor-cognitive functions related to PD and FOG. Secondary outcomes related to motor
function, which are likely to be affected by changes in M1 excitability, will include gait
speed (usual walking), Timed Up & Go scores, UPDRS motor scores, and level of activity over 7
days using portable, lightweight, water-proof sensors. Secondary measures of executive
function, which are hypothesized to be responsive to tDCS of the DLPFC, will include the
Trail Making test (TMT) parts A and B, and a previously validated computerized
neuropsychological battery that provides normalized scores for executive function and
attention (and memory). Dual-tasking gait speed (i.e., walking while performing a serial
subtraction test) will assess motor-cognitive interactions. Functional near infra-red
spectroscopy (available in Boston and Tel Aviv) will assess frontal activation during
dual-tasking walking; this reflects the subjects ability to handle cognitive loading and has
been associated with FOG. Finally, the PDQ-39 will evaluate quality of life.

Inclusion Criteria:

Inclusion criteria: patients diagnosed with PD, with Hoehn and Yahr Stage between 1-3.5,
who suffer from FOG, as measured at screening by the previously validated new FOG
questionnaire (NFOG-Q), whose medications have not changed within 1 month of the study and
are not anticipated to change during the study, are able to walk independently, and who are
between the ages of 40-80 inclusive.

Exclusion Criteria:

Subjects who show no FOG during testing in the lab in response to a FOG provoking protocol,
any diagnosed psychiatric or other neurological disorder, stroke, unbalanced and high blood
pressure, pregnancy, participation in any clinical trial in the last three months,
unwillingness to be randomized; implanted with deep brain stimulation, pacemakers,
intracranial electrodes, implanted defibrillators or any other prosthesis; or a perceived
inability to complete the study. Additional exclusion criteria related to tDCS safety will
include a personal or family history of epilepsy, the use of neuro-active drugs, or risk of
metal fragments in the eyes or head.