Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02915848 |
| Other study ID # |
UHNToronto: 12-5452-B |
| Secondary ID |
|
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
September 9, 2016 |
| Est. completion date |
April 26, 2021 |
Study information
| Verified date |
April 2021 |
| Source |
University Health Network, Toronto |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Movement disorders such as Parkinson Disease, dystonia, and tremor are related to
abnormalities of part of the brain known as the basal ganglia. Recently, it has been
suggested that the basal ganglia works by oscillations (group of neurons cycle between
activation/deactivation when stimulated) of electrical signals. A treatment that involves
insertion of electrodes in the subthalamic nucleus (STN) for electrical stimulation, known as
deep brain stimulation (DBS), is an established treatment for advanced Parkinson's disease.
However its mechanism of action is still not completely understood. Currently, DBS utilizes
an "open loop" system whereby the stimulation settings are manually adjusted depending on the
patients' clinical response.
1. Determine whether the local field potential (LFP) recorded from the STN is stable over a
1.5 year period.
2. Address whether STN LFP is a suitable control signal, and how it should be used to
change DBS parameters
Description:
Study Design and Methods
Ten Parkinson's disease (PD) patients who are scheduled for bilateral STN DBS will be
recruited. DBS surgery will be performed at the Toronto Western Hospital as per standard
clinical care. The studies will be performed at two sites: Toronto Western Hospital and
London Mobility Laboratory at Western University. Recording of STN LFP using externalized DBS
leads, the effects DBS at different frequencies on PD motor symptoms will be studied at the
Toronto Western Hospital. Gait studies with full body kinematic measurements, recording of
LFP and effects of different stimulation frequencies will be studied at the London Mobility
Laboratory (LML) at Western University.
An outline of the study timeline is provided in Table (2, 3 and 4). Standardized tasks
performed are provided in Table 5.Ten PD patients with bilateral DBS in STN will be studied
for six visits to each site (TWH and LML). There will also be a presurgical baseline visit to
LML. Patients will first be studied 1-3 days after DBS electrode implantation and before the
implantation of the pulse generator. Local field potential (LFP) will be recorded from
bilateral STN DBS electrodes using externalized leads. Following internalization of the DBS
leads and insertion of the pulse generator (Activa PC+S, Medtronic), patients will be studied
within 7 days for a second visit. DBS programming will be performed as per usual clinical
practice. Patients will then be studied at 1, 2, 6, 12 and 18 months postoperatively.
Visits at the Toronto Western Hospital (TWH)
Visit 1 (TWH V1) This visit will obtain "acute" LFP recording for comparison to chronic
recordings. Patients will be studied 1-3 days after electrode insertion when the leads are
externalized. This is a two day visit, with one day in the off medication state (overnight
withdrawal) and one day in the on medication state in random order. For the on medication
state, 125% of the levodopa equivalent of the first morning preoperative dose will be
administered to increase the chance of recording levodopa-induced dyskinesia.
Stage 1: LFP will be recorded from bilateral STN DBS electrodes together with scalp EEG. Fig.
3 shows a schematic representation of the recording setup. Surface EMG and accelerometery
will be used to measure the tremor frequencies and levodopa-induced dyskinesias. mUPDRS and
the Rush dyskinesia rating scale (for on medication recordings) assessments will be
performed. Recordings will be made at rest and while the patients perform self-paced wrist
extension movements. The most prominent LFP frequencies in the θ, β and γ band oscillations
at rest and during voluntary movements in both on and off medication states (individualized
frequencies) as well as the electrode contact that shows the most prominent LFP oscillations
will be determined for each patient. This recording will take about one hour. The data
analysis will take one hour during which the patient will have a break.
Stage 2: This will involve stimulation. The DBS leads will be connected to an external
stimulator and a "filter DBS" device to record LFP during DBS. Four DBS conditions will be
studied in random order:
1) high frequency (185 Hz), 2) the individualized γ frequency that show maximum peak at rest
(γ rest, determined from stage 1), 3) the individualized γ frequency that show maximum
increase with voluntary movements (γ movement, determined from stage 1), and 4) no
stimulation. The contact will be selected based on location within the STN from postoperative
MRI using methods published by our group and maximum changes in the θ and β bands with
voluntary movements (Stage 1). The selected DBS contact will be the cathode (-ve) and anode
(+ve) will be a surface electrode placed on the chest wall (similar to contact -ve, case +ve
commonly used in therapeutic DBS). Pulse width will be set at100 μs and the current will be
the highest (maximum 5 mA) without inducing adverse effect. LFP will be recorded from the
electrode contacts adjacent to the one used for DBS using a bipolar montage to allow for
maximum cancellation of stimulus artifacts. For example, if contact 2 is used for DBS, LFP
will be recorded from contacts 1 and 3. For each condition, 15 min of DBS while resting will
be followed by mUPDRS assessment while DBS is maintained. Patients will be video recorded to
allow subsequent video scoring of mUPDRS and the Rush dyskinesia rating scale by blinded
raters. DBS for the right and left STN will be studied in random order, with one side in the
morning and one side in the afternoon. Investigators have performed more complex stimulation
protocols in PD patients with STN DBS.
The second day of study will occur the next day. The procedure will be the same as Day 1
except that the medication status (on or off medication) will alternate with Day 1 in random
order.
Visit 2 (TWH-V2) The purpose of this visit is to obtain early LFP recording from the Activa
PC+S device before DBS programming begins. This visit will be conducted within 4 weeks of
internalization of the DBS leads and insertion of the pulse generator (Activa PC+S), but
before the pulse generator is turned on for programming. The visit will be conducted over two
days, one day in the off medication state (overnight withdrawal) and one day in the on
medication state in random order as in Visit 1. The procedure is identical for Visit 1 with
recording of LFP at rest and during a self-paced wrist extension task, followed by testing of
4 different stimulation conditions. However, LFP will be recorded from the Activa PC+S device
using the real-time uplink mode to provide continuous recording rather than from externalized
leads. Since the device can only record LFP from one pair of contacts from each electrode
(right and left) at a time, for recordings in the resting state to examine the difference
between on and off medications, investigators will use the "montage sweep" mode that will
record alternately from all six possible combinations of bipolar contacts (0-1, 1-2, 2-3,
0-2, 0-3, 1-3) for each electrode. For the wrist extension movements, we will record from the
bipolar contact pair that produced the greatest change in γ oscillations with dopaminergic
medications and voluntary movements based on the results of Visit 1. In addition, we will
record from the adjacent contact pair. For example, if contact 1-2 was found to produce the
maximum γ peak, contacts 1-2 as well as contacts 0-1 and 2-3 will be studied. Each pair of
electrode contacts will be studied in separate runs. Following the LFP recording (stage 1),
the individual γ frequency peaks will be established. Stage 2 will study the effects of DBS
at high frequency, γ rest, γ movement and no stimulation assessed in random order with
recording of STN LFP during stimulation as in Visit 1. The same contact used for DBS in Visit
1 will be used with monopolar montage (contact -ve, case +ve). LFP with be recorded from the
adjacent contacts with bipolar montage as described in Visit 1 but the implanted Activa PC+S
device will be used for LFP recording
Visits 3- 6 (TWH-V3, V4, V5 and V6) After Visit 2, DBS programming will be performed as per
usual clinical practice and takes about 2-4 weeks to complete. Patients will then be studied
at 2, 6, 12, and 18 months after surgery. The assessment procedure will be identical to that
for Visit 2 except that the "high" frequency stimulation setting will be the setting normally
used by the patient for clinical benefit (130-185 Hz) instead of 185 Hz.
Visits at London Mobility Laboratory (Western University) Visit 1 will occur before surgery
to obtain baseline gait and kinematic measurements data in the on and off medication states.
For visits 2, 3 and 7, the TWH visits will occur 1-5 days before the London Mobility
Laboratory visits. The γ frequency stimulation to be used in the London Mobility Laboratory
visits will be the "γ movement" frequency determined from the corresponding TWH visit.
