Cerebellar dysfunction and its compensation in presymptomatic carriers of dominant ataxia genes

The dominant spinocerebellar ataxias (SCAs) are a clinically and genetically
heterogeneous group of degenerative cerebellar diseases. There are family
members of SCA patients who have been tested positive for a gene mutation but
who do not yet have any symptoms, which they are however prone to develop at
some point as the mutations are fully penetrant. These so-called presymptomatic
carriers offer a unique opportunity to study the early, subclinical stages of
cerebellar dysfunction, as well as the consequences and the compensation
thereof within the motor system.

This project has three separate but complementary research objectives. First,
to find out whether there is indeed evidence of subclinical cerebellar
dysfunction in these subjects, by specifically focusing on cerebellar motor
learning. Second, to investigate whether the presumed latently defective
cerebellum has already led to altered functional and structural coupling
between the cerebellum and the motor cortex in these subjects. Third, to
explore the compensatory mechanisms in these individuals that allow them to
circumvent their latent cerebellar motor disturbance.

Cross-sectional, observational study with a strong neurophysiological and
neuroimaging emphasis.

For objective 1:
Two implicit motor learning tasks will be used: 1) the classic and
well-established eye blink conditioning, and 2) the adaptation to a rather
novel, highly demanding gait task on a splitbelt treadmill, which forces the
cerebellum to adapt to a different speed for left and right leg.

For objective 2:
The functional coupling will be studied by using transcranial magnetic
stimulation to search for changes in motor cortex excitability and the
cerebellar modulation thereof. The structural integrity of the
cerebello-thalamo-cortical pathway will be quantified by means of diffusion
tensor imaging (DTI) MRI.

For objective 3:
This issue will be tackled by using a functional MRI paradigm that involves
motor imagery of gait, which is able to show which cerebral networks are
differentially engaged in gait control.

The participants will undergo several experiments, with a combined duration of
approximately 12 hours, spread out over three days. None of the experiments are
painful or invasive.

There is a small risk of a seizure during the transcranial magnetic stimulation
session, but this has been proven to be almost negligibly low over the recent
years. The more relevant issue to mention here is the scenario that the SCA
mutation carrier thinks that he/she is still unaffected, but that the clinical
examination reveals subtle signs, indicating that the disease has started. The
potential participants will repeatedly be reminded of this before consent is
obtained and also before the actual clinical examination. If someone
unexpectedly turns out to be symtomatic, he/she is offered to be follow-up in
our Ataxia outpatient clinic.

Still, investigating these subjects is of great importance. The results of this
project will give us new and unique fundamental insight into the
characteristics of a very early-stage cerebellar defect and the consequences
this has for a central pathway within the motor system. Also, understanding the
mechanisms that compensate for a dysfunctional cerebellum is essential when
starting to think about potential targets for neuromodulatory interventions.