Transcranial Alternating Current Stimulation (tACS) as a novel treatment option: a proof of concept study in Adult Classic Galactosemia

The brain is one of the major target organs affected in classic galactosemia
(CG). Patients suffer from speech and motor problems among others. These
problems are related to observed changes in functional and anatomical brain
networks compared to healthy controls. Cognitive and motor functions are driven
by neuronal oscillation in certain frequency bands, with language
syllables-theta (5-8 Hz) and motor-beta (15-30Hz) rhythm. In this proof of
concept study, we propose to (1) investigate for the first time which frequency
bands are affected in adult CG compared to healthy controls. We also propose to
(2) apply one form of non-invasive brain stimulation (NIBS), namely
transcranial alternating current stimulation (tACS) which can entrain brain
oscillations in individual and relevant frequencies such that they result in
behavioral improvement. NIBS has shown to have therapeutic efficacy in various
neurological and psychiatric disorders. It has not yet been applied in CG. TACS
is our method of choice as it*s possible to change oscillations during a longer
period of time, compared to TMS and tDCS.
We compare brain oscillation and tACS efficiency of CG adults and matched
healthy controls. 25 participants per group will have three sessions, two with
real stimulation, one with sham. Sham stimulation is used to assess the
efficacy of active stimulation and placebo effects. Each session consists of
three elements referred to as pre, during, and post stimulation. In the pre
stimulation part of the session, we quantify behavior (speed and accuracy) and
electroencephalography (EEG) oscillation profiles per individual. With regard
to behavior we measure reaction times and accuracy for selected language tasks.
With regard to brain oscillation, we acquire EEG at rest as well as during the
execution of the active language task. For each individual, we decompose the
obtained EEG signal into frequency bands and compare the frequency power
spectrum of CG and healthy controls. This benchmarking procedure allows us to
define *relevant frequencies*. Frequencies are *relevant* when their power
clearly differ between CG and controls or when they clearly modulate during an
active task. During the stimulation, participants perform the same task as in
the pre session while we simultaneously apply tACS or sham in the relevant
frequency and record behavioral performance. TACS should now entrain the
cortical brain oscillation network relevant for that task and should lead to
behavioral improvement. During post stimulation, behavior and EEG will again be
quantified immediately after stimulation, again for resting state and active
tasks.
To investigate whether tailored stimulation driven entrainment results in
optimization of behavior we analyze tACS induced behavioral change by comparing
pre, during and post tACS stimulation performance within and across groups. We
also quantify tACS induced pre-post changes in the EEG frequency power spectrum
within and across groups. In addition, we correlate behavioral and EEG change
to investigate their relation. The proof of concept study contributes to a
first understanding of brain oscillation in CG and to tACS as treatment in CG.
The proposed research requires and provides interdisciplinary expertise from
the medical and cognitive neuroscience point of view.

Main objective:
We propose a proof of concept study to apply noninvasive brain stimulation,
specifically tACS, for the first time to adult CG patients with the aim to find
stimulation protocols that improve their motor and language performance by
positively influencing their brain oscillatory profiles. Thereby we hypothesize
that tACS can entrain oscillations in individual and relevant frequencies such
that they result in improvements of their motor and language performance.

Secondary objectives:
1) Benchmark group and individual brain oscillations in CG for the first time
and compare them to those of healthy controls. Hopefully, this can give us more
insight into the impact of CG on the brain function and information transfer.
2) We apply these individualized frequencies with tACS to entrain the relevant
brain oscillation. In addition, we apply in a separate session a sham
stimulation to test for placebo effects.
3) We compare EEG and behavior pre and post stimulation to quantify the effect
and efficiency of tACS in CG.

We propose a pre/during/post stimulation mixed design in CG and healthy
controls. Control participants will be matched for age and gender. All
participants have two sessions **real stimulation** and one with a **sham
stimulation**. The patients will have an extra session to conduct
neuropsychological tests.

The intervention consists of tACS at beta and theta frequency to hopefully
ameliorate the motor and speech problems in patients with CG.

TACS is an extremely well tolerated treatment form of NIBS with a very small
risk of side effects. Mild side effects include headache, fatigue and prickling
and burning sensations during the tACS. Patients will receive a sham and real
stimulation and will perform language tasks.
We expect that the burden of participating in this study will be low, because
the EEG and tACS are accompanied by a very small risk of side effects. During
the sessions, they receive good guidance. Concerning discomforts, a conductive
paste is applied to the tACS and EEG electrodes to stick them to the scalp of
the patient. After the session has ended the patient
will be given the opportunity to wash his/her hair. Moreover, the only
difference between the study and control group is the first session, in which
the patients will be tested with neuropsychological tests and the healthy
controls won*t. However, there is no difference in the burden between the study
and control group, since the interventions are the same.
Personal benefits are not expected, but results pointing to normalization of
the EEG frequencies with improvement in the motor/language task, favors the use
of this technique as potential treatment in classic galactosemia patients with
motor and language problems.