Effects of deep brain stimulation on eye movements

Several different pathways in the brain are involved in the control of eye
movements. For instance, they are important to look quickly from one object of
interest to another (i.e. saccades), to follow slowly moving objects (i.e.
smooth pursuit) or to keep a stationary object of interest focused (i.e. gaze).
The pathways important for eye movements are located in close proximity to
pathways in the brain important for limb movements. For example, there are the
basal ganglia-thalamocortical pathways connecting the cortex with the basal
ganglia based on the classic concept by Alexander et al. (Ann. Rev. Neurosci
1986). In close proximity to the motor circuit, important for limb movements,
is the oculomotor circuit of the basal ganglia-thalamocortical pathways,
connecting the frontal eye field to the basal ganglia (incl. nucleus caudatus,
globus pallidus and substantia nigra) and projecting via the mediodorsal
thalamus back to the cortex. Diseases of the basal ganglia such as Parkinson*s
disease or Dystonia affect the functioning of several circuits (Pinkhard et al.
BMC Neurology 2012, Stell et al. JNNP 1990). Thus, limb motor and eye movement
deficits such as deficits with saccadic eye movements and smooth pursuit can be
found in patients with Parkinson*s disease. Another system important for limb
and eye movements is the cerebello-thalamo-cortical pathways (Macchi and Jones
et al. J. Neurosurg. 1997). These pathways originate in the cerebellar nuclei
and lead into the ventrolateral thalamus which is right lateral to the
mediodorsal thalamus. The ventrolateral thalamus projects predominantly to the
motor cortex, but also to the prefrontal and vestibular cortical areas. The
cerebello-thalamo-cortical pathways are also important for saccadic eye
movements and smooth pursuit. For instance vascular lesions of the
ventrolateral thalamus cause an impairment of saccades in the contralateral
direction and smooth pursuit deficits to the ipsilateral direction (Brigell et
al. Ann Neurol 1984; Rosseaux et al. Rev. Neur. 1985; Hirose et al. Neurology
1985). Furthermore, diseases such as essential tremor with its pathophysiology
being closley connected to a disturbance of cerebello-thalamo-cortical pathways
go along with smooth pursuit deficits (Helmchen et al. Brain 2003). A third
system important for controlling eye movements is the medial longitudinal
fasciculus connecting the midbrain with the brainstem. This fasciculus runs
close to the midline, that is medial to the mediodorsal nucleus, and is
important for gaze. For instance, patients with very medial thalamic lesions
cannot keep looking their eyes on one object (Deleu, Acta Neurol Scan 1997;
Joni and Gregory, Stroke 1995).
Some of these systems appear to have distinct functions while others share some
of their properties. However, direct comparisons of their functions (or
malfunctions as part of an underlying disease process) in eye movements have
not been studied in detail.
Deep Brain Stimulation targeting different subcortical structures such as the
subthalamic nucleus, Globus pallidus or ventrolateral thalamus is a well
established treatment for patients with movement disorders such as Parkinson*s
disease, essential tremor or Dystonia. Furthermore, reports on the effects of
DBS in patients with Tourette Syndrome as an experimental approach are
promising (Ackermans et al. Brain 2011). For Deep Brain Stimulation,
stimulation electrodes are implanted in the brain, which are connected to a
pacemaker implanted in the subclavian region. It is believed that Deep Brain
Stimulation reduces pathological over-activity in the neuronal network adjacent
to the targeted structure (McIntyre et al. Clin. Neurophysiol 2004). For
instance, this causes a clear cut improvement of bradykinesia and rigidity at
the limbs in Parkinsonian patients. The advantage of Deep Brain Stimulation
over lesioning the targeted structure comes from the adaptability of the
programming to maximize symptom control and to avoid side effects. Furthermore,
the effects of Deep Brain Stimulation are completely and immediately
reversible, as it can get switched *off* and *on* any time. In some cases the
patients do that themselves at night to save battery life time.

As pathways in the brain important for limb movement run in close proximity to
pathways involved in eye movements, one may expect that Deep Brain Stimulation
has an effect on both limb and eye movement. First reports from international
research groups and publications from the universities of Maastricht and Aachen
suggest that Deep Brain Stimulation does indeed effects eye movements as well.
For instance, Deep Brain Stimulation targeting the subthalamic nucleus improved
the latency of saccadic eye movements in Parkinsonian patients (Temel et al.,
Exp. Neurol. 2009), while it impaired the accuracy of saccades in patients with
essential tremor and Deep Brain Stimulation targeting ventrolateral thalamus
(Kronenbuerger et al., Brain Stimulation 2010) or caused a vertical gaze palsy
in a patient with Tourette Syndrome treated with Deep Brain Stimulation
targeting the very medial thalamic nuclei (Ackermans et al. Neurosurgery
2007).
The direct comparison of eye movement functioning with Deep Brain Stimulation
targeting different subcortical structures in patients with different diseases
and with stimulation switched *on* and *off* may be helpful to better
understand the role of subcortial pathways in the control of eye movements.

Thus we intend to study four patient populations: (1) patients with Parkinson*s
disease treated with Deep Brain Stimulation targeting the subthalamic nucleus
or Globus pallidus, (2) patients with essential tremor treated with Deep Brain
Stimulation targeting the ventrolateral thalamus, (3) patients with Dystonia
treated with Deep Brain Stimulation targeting the Globus pallidus internus and
(4) patients with Tourette Syndrome treated with Deep Brain Stimulation
targeting the medial thalamus or the Globus pallidus. The patients will be
studied twice: once with Deep Brain Stimulation switched *on* and once with
Deep Brain Stimulation *off* while performing different eye movement tasks
(i.e. tasks of saccades, smooth pursuit and gaze). We would like to assess 12
patients with Parkinson*s disease, 12 patients with essential tremor, 6
patients with Tourette Syndrome and 6 patients with Dystonia. All patients are
patients that have obtained Deep Brain Stimulation either at the University
Hospital in Maastricht or at the University Hospital in Aachen.
As Deep Brain Stimulation reduces pathological over-activity, we expect an
improvement of eye movement deficits as part of the disease process. In
contrast, we expect an impairment of eye movements with Deep Brain Stimulation
in tasks that are not affected by the disease.

For the literature citated , please refer to the reference section of the
Template Research Protocol on page 28.

Primary Objective:
Is there an effect of DBS on eye movements?

Secondary Objective:
Are there different effects of DBS on eye movements by targeting different
structures in the brain?

This study is a DBS-on versus DBS-off comparison (paired comparison). Thus eye
movement parameters will be assess and compared when DBS is switched on and
off. Additionally we will also compare the effects of DBS of different targets
in the brain on different eye movements. Therefore different patient
populations treated with DBS will be assessed and compared (comparison of
different groups).

The equipment of the oculomotor laboratory of the ear, nose and throat clinic
of the academisch ziekenhuis Maastricht are used for the eye movement
recording. This equipment is also used in the routine care. The eye movement
recording is done by attaching skin electrodes next to both eyes, which causes
no discomport. Additionally the patients are seated on a comfortable chair and
asked to look toward a screen where the light point is projected. This step up
allows the recording of eye movements with great precision but without
discomfort to the patients.
The examination of the eye movement will take about twice 30 minutes (once with
DBS switched on and once with DBS switched off). When stimulation is switched
off, the patients will have their symptoms similarly to the extent before the
DBS was started. Thus during the DBS-off test period they will have
bradykinesia, rigidity, tremor, dystonia or tics. This starts about 5 minutes
after the DBS is switched off and disappears within 5 minutes when DBS is again
switched on. Studying the patients when DBS is switched off is important to
assess the eye movements without DBS and to compare the above mentioned
parameter to the situation when DBS is switched on. Only with this approach we
can find out, if DBS has effects on eye movements.
The eye movement analysis will be performed on the days when the patients have
their regular outpatient control visits to the AZM. Thus the patient will not
spend too much extra time for participation in this study (time investment for
the patient for participation altogether: 80 minutes).
There are no medical risks involved by having the DBS turned off. However,
there will be discomfort when the DBS is turned off. This is by far the only
way to find out if DBS has an effect on the different eye movements. The
knowledge about the effects of DBS on eye movements is important to get a
deeper understanding of how the brain works and this may be the basis for new
or better treatment options for patients with movement disorders or eye
movement disorders. Furthermore, as DBS is increasingly applied for patients
with movement disorders and is presently under the investigation for the
treatment of psychiatric disorders, the knowledge about the effect of DBS in
eye movements is important. This is because if may help to identify additional
benefits of the DBS treatment or identifying side effect of DBS that may be
important for the care of patients.

Minors and incapacitated patients will not be included into this study.