Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT04606979 |
| Other study ID # |
B1432020000012 |
| Secondary ID |
|
| Status |
Active, not recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
October 11, 2020 |
| Est. completion date |
August 31, 2022 |
Study information
| Verified date |
April 2022 |
| Source |
Vrije Universiteit Brussel |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Implicit motor sequence learning (IMSL) is a form of cognitive function that is known to be
directly associated with impaired motor function in Parkinson's disease (PD). Research in
healthy young participants shows the potential for transcranial direct current stimulation
(tDCS), a non-invasive brain stimulation technique, over the primary motor cortex (M1) to
enhance IMSL. tDCS has direct effects on the underlying cortex, but also induces distant
(basal ganglia) network effects - hence its potential value in PD, a prime model of basal
ganglia dysfunction. To date, however, only null-effects have been reported in persons with
PD. In the present study, the investigators will investigate the potential of tDCS delivered
over M1 to enhance IMSL, as measured by the Serial Reaction Time task, in persons with PD.
The investigators will determine immediate effects that may occur concurrently with the
application of tDCS but also short-term (five minutes post-tDCS) and long-term (one week
post-tDCS) consolidation effects, as previous studies suggest that tDCS exerts its beneficial
effects on IMSL in a consolidation phase rather than in an acquisition phase. Establishing
possible consolidation effects is of a particular interest, as long-term effects are vital
for the successful functional rehabilitation of persons with PD.
Description:
STUDY DESIGN
The investigators will conduct a single-blind, sham-controlled, counterbalanced study to
investigate the effects of M1 tDCS on IMSL. As age-related effects may serve as an
explanation for the conflicting findings in healthy young adults and persons with PD, the
investigators will include a healthy control group, age-matched to the PD group. For the
sequence-specific aspect of IMSL (primary outcome), a mixed factorial repeated measures ANOVA
will be carried out with "group" (2 levels: PD, healthy) as between-subjects factor and
"stimulation" (2 levels: anodal, sham), "blocks" (2 levels: random block, mean of adjacent
blocks) and "time" (3 levels: during, post5min, post1week) as within-subjects factors.
Similarly, for general learning (secondary outcome), a mixed factorial repeated measures
ANOVA will be carried out with "group" (2 levels: PD, healthy) as between-subjects factor and
"stimulation" (2 levels: anodal, sham), "blocks" (7 levels: Blocks 1-6, Block 8) and "time"
(3 levels: during, post5min, post1week) as within-subjects factors. All participants will
receive both anodal (real) and sham (placebo) tDCS in a random order. Counterbalancing will
be done by an independent investigator using Microsoft Excel®. Baseline scores on the Scales
for Outcomes in Parkinson's disease COGnition (SCOPA-COG), Montreal Cognitive Assessment
(MoCA) and Hospital Anxiety and Depression Scale (HADS) questionnaires, as well as clinical
subtypes (akinetic-rigid subtype, tremor subtype) and sequence awareness scores will be taken
up as covariates.
RECRUITMENT STRATEGY
Persons with PD will be recruited via following instances and centres: the Flemish Parkinson
Liga (VPL); neurologists of the University Hospital of Brussels (UZ Brussel), University
Colleges Leuven-Limburg (UCLL) and RevArte rehabilitation centre (Antwerp); private
physiotherapy practitioners specialized in neurologic rehabilitation. Age-matched healthy
participants will be recruited via the PD candidates (partners of the patients), several
residential care homes in and around Brussels and by posting digital flyers on social media.
There are no restrictions or prohibitions for the subjects. Participants will continue to
take their medication during the trial period, and will perform the experimental procedure
during the ON-phase of their medication. This is in order to maximize feasibility to perform
the task and for the sake of uniformity with previous studies examining tDCS effects in PD.
MATERIALS
A 1x1 Low Intensity Direct Current Stimulator (Soterix Medical Inc, New York, USA) will be
used to generate and deliver tDCS through a pair of identical square rubber electrodes (size
35 cm2), placed in rectangular saline-soaked sponges. For the stimulation of M1, electrodes
will be placed over C3 or C4 according to the international 10-20 electroencephalogram
system, matching with the M1 contralateral to the performing hand. The reference electrode
will be positioned on F1 or F2, ipsilateral to the performing hand.
The current stimulation will be slowly ramped up from 0 milliampere (mA) to 2 mA in one
minute. For the anodal tDCS condition, this intensity will be maintained for the duration of
the SRT-task (approximately 20 minutes), which is well within evidence-based safety standards
for tDCS. This will result in a current density of 0,057 mA/cm2. For the sham tDCS condition
- unbeknown to the subject - stimulation will be gradually decreased towards 0 mA immediately
after the one-minute ramp-up. During the last block of the SRT-task, this gradual ramping-up
and -down of the current stimulation will be repeated to optimize the process of blinding of
participants. To control for blinding of the subjects, after the last session subjects will
be asked whether they were aware of the stimulation condition or not. Transient side-effects
will be inventoried by the experimenter during and two weeks after the tDCS protocol,
including a slight itching sensation under the electrode, redness of the skin under the
electrode, headache, nausea, fatigue or insomnia.
The Serial Reaction Time task (SRT-task) will be used to determine IMSL. The SRT- task will
be performed on a laptop using E-Prime® software (Psychology Software Tools, Inc.,
Pittsburgh, Pennsylvania, USA). Participants will be asked to press the horizontally aligned
response keys C, V, B, N of a standard azerty keyboard for a leftmost, left, right, rightmost
target, respectively. Responses will be given with the index finger of the least affected
hand in the case of the persons with PD and with the dominant hand in the case of the healthy
controls. If both hands are equally affected in the persons with PD, the dominant hand will
be used as well. The response keys C, V, B and N will be the only visible keys, all other
keys will be covered.
PROCEDURE
The experiment will take place at a laboratory of the Vrije Universiteit Brussel (VUB), in
the participants' home environment, or at a nearby community centre of their choosing, under
supervision of the investigator. The option to conduct the experiment outside of our
laboratory at the VUB is given as displacements are not always evident for these
participants.
The experimental procedure will be preceded by an in-person interview to collect general
clinical and demographic characteristics. A shortened, 3-block x 25 trials random SRT-task
will also be performed to assess whether participants have sufficient motor function to
complete the experiments. Following the interview, a neuropsychological assessment will be
done by means of three questionnaires:
- The Montreal Cognitive Assessment (MoCA) will be used to assess cognitive function
across 8 domains (executive functions, visuospatial skills, attention, concentration,
language, short term memory and orientation).
- The Scales for Outcomes in Parkinson's disease, COGnition part (SCOPA-COG) is a short,
reliable and valid instrument for the assessment of cognitive function in PD. It
consists of 10 items, divided over four domains: memory (4 items), executive function (3
items), attention (2 items) and visuospatial function (1 item). Scored 0-43, with lower
scores indicating more severe cognitive impairment.
- The Hospital Anxiety and Depression Scale (HADS) is a two-dimension scale developed to
identify depression and anxiety. It consists of 14 items, divided into two 7-item
subscales. Each item is rated on a 4-point scale ranging from 0 (absence) to 3 (extreme
presence).
Furthermore, participants' motor function will be assessed by means of:
• The Unified Parkinson's Disease Rating Scale, part III (UPDRS-III), one of the most widely
used clinical rating scales for PD, which consists of 4 parts. For the present study, only
part III will be used, which assesses motor function by means of 14 items.
Following the screening session (T0), all eligible participants will be seen four times
(T1-T4) over the course of minimally five to maximally eleven weeks. All four sessions (T1,
T2, T3, T4) will start with a practice block of the SRT-task consisting of 72 random trials,
followed by the actual experimental SRT-task of eight blocks of 72 trials. Blocks will be
separated by a thirty second break. In Blocks 1 through 6 and Block 8, the order of the
target (i.e. black dot) locations will follow a repeating sequence. This is unbeknown to the
participant. The rationale is that reaction times will decrease with repetition of the
sequence throughout blocks 1-6 and 8, denoting a general training effect (secondary outcome
measure IMSL). When the sequence suddenly changes to a random sequence in Block 7, reaction
time will increase in Block 7 and decrease once more in regularly sequenced Block 8, denoting
a sequence-specific learning effect (primary outcome measure IMSL). To control for possible
carry-over effects, the SRT-task will follow a different sequence in each stimulation
condition (e.g. 132342134142 in T1-T2 and 243413241213 in T3-T4). To make sure IMSL is
independent of a specific sequence, six different, structurally identical, sequences of 12
elements long will be counterbalanced between the participants.
The first interventional session (T1) will be planned at least 1 week after the screening
session (T0) and will consist of active (anodal) tDCS or sham (placebo) tDCS administered
during the SRT-task. Five minutes post-tDCS, subjects will be asked to carry out a short,
three-block version of the SRT-task without application of tDCS to investigate potential
short-term consolidation effects: Blocks 1 and 3 following the same regular sequence as
earlier; Block 2 following a random sequence.
The second session (T2) will be planned one week later. During this one-week post-tDCS
session the same, full version of the SRT-task from one week earlier will be performed, this
time without the application of tDCS, to determine potential long-term consolidation effects.
After T2, a washout period of at least three weeks will be planned to control for carry-over
effects between the two stimulation conditions (active/sham tDCS). Cross-over will take place
and the same procedure with the opposite stimulation condition will be repeated during the
third (T3) interventional and fourth (T4) follow-up session. Half of participants in each
group will have received active tDCS during T1 and sham tDCS during T3, while the other half
of participants will have received these conditions in reversed and randomized order.
Each session, the SRT-task will be started within 90 minutes after medication intake
("ON-phase of medication"). This is in order to maximize feasibility to perform the task and
for the sake of uniformity with previous studies examining tDCS effects in PD. A
post-SRT-task questionnaire will be completed after the last session (T4) to determine
whether participants became aware of the sequential nature of the task. If participants
indicate that they believe a specific sequence appeared, they will have to reproduce the
sequence of the last session as correct as possible. This sequential score (x/12, based on
the highest number of sequence elements they can reproduce in the correct order) will serve
as the outcome measure for explicit knowledge regarding the repeating sequences.
STATISTICAL ANALYSES
All statistical analyses will be carried out using International Business Machines (IBM)
Statistical Package for the Social Sciences (SPSS) Statistics version 26. The level of
significance will be set at α = 0.05. A trend towards significance will be defined as 0.05 ≤
α < 0.10. Bonferroni corrections for multiple comparisons will be made when necessary.
Cohen's f effect sizes will be reported, with values of .10, .25, and .40 representing small,
medium, and large effect sizes, respectively.
In the event of null-effects, the investigators will conclude that there is no evidence of a
difference between conditions. However, the investigators will also calculate post-hoc Bayes
factors for each group (PD, healthy controls) to assess whether a lack of difference in
sequence learning between the anodal and sham stimulation conditions could be interpreted as
evidence for the absence of an effect of tDCS on sequence learning.
For the PD group, patients will be classified as akinetic-rigid subtype or tremor subtype
based on UPDRS-III subscores in the "Off" medication state. This clinical subtype of the
persons with PD will be taken up as covariate, to assess whether this characteristic
influences IMSL or the treatment thereof via tDCS. A method similar to the one used by Xu et
al. (2018) will be used [70]. First, "tremor score" (sum of UPDRS items 20 and 21 divided by
7) and "non-tremor score" (sum of UPDRS items 18, 19, 22, 27, 28, 29, 30 and 31 divided by
12) will be calculated per patient. If the tremor score is at least twice the non-tremor
score, patients are classified as tremor subtype; if the non-tremor score is at least twice
the tremor score, patients are classified as akinetic-rigid subtype.
Correlation analyses, Bonferroni-corrected for multiple comparisons, will be performed to
investigate if the amount of IMSL correlates with demographical, neuropsychological and
clinical variables (including clinical subtypes of PD). If assumptions for parametrical
testing are violated, the non-parametric alternative Spearman's Rho will be calculated.
The analyses of the SRT-task performance will be based on median reaction time (RT) per block
instead of mean RT to minimize potential outlier effects. Practice trials, the first response
after each break, erroneous responses and responses following an error will be excluded from
the analyses. Median RTs per block will be analyzed to determine (1) a general learning
effect (secondary outcome measure) and (2) a sequence-specific learning effect (primary
outcome measure).
General learning effects during and one-week post-tDCS will be derived from a decline in
median RTs over the seven regularly sequenced blocks (i.e. Blocks 1-6 and Block 8). This will
not be applicable to the 5-minutes post-tDCS SRT-task as it is a short version with only
three blocks. A 2x2x2x7 repeated measures ANOVA will be carried out with group (PD, healthy
controls) as between-subjects factor and stimulation (active, sham), time (during, post1week)
and block (Blocks 1-6, Block 8) as within-subjects factors.
Sequence-specific learning effects during, 5 minutes and 1 week post-tDCS will be analyzed by
subtracting the mean of the median RTs of adjacent sequenced blocks (Blocks 6 and 8 during
stimulation and at 1 week post-tDCS; Blocks 1 and 3 at 5 minutes post-tDCS) from the median
RT of the random block (Block 7 during stimulation and at 1-week post-tDCS; Block 2 at
5-minutes post-tDCS). A 2x2x2x3 repeated measures ANOVA (or Friedman and Wilcoxon signed rank
tests as non-parametrical alternatives) will be carried out with group (PD, healthy controls)
as between-subjects factor and stimulation (active, sham), sequence (random block, mean of
adjacent sequenced blocks) and time (during, post5min, post1week) as within-subject factors.
In case assumptions of sphericity are violated, Greenhouse-Geisser or Huynh-Feldt corrections
will be reported. Bonferroni-corrected t-tests will be implemented to further analyze
significant main and interaction effects.
Error percentages in the SRT-task are generally small and thus, because of a limited number
of observations, less sensitive to IMSL. The percentage erroneous reactions per block will be
calculated for both stimulation conditions (anodal, sham) and for the three measurements over
time (concurrent, post5minutes, post1week). The Shapiro-Wilk test of residuals will be
carried out to evaluate normality of distribution.
The sequential score, as outcome measure for explicit knowledge, will be taken up as a
covariate in the analyses. An independent samples t-test (or non-parametrical alternative
Mann-Whitney U test) will be carried out to ascertain whether the sequential scores (x/12) of
the PD group are different from the healthy control group.
