A multicenter double blind randomized crossover study comparing the impact of dorsal versus ventral subthalamic nucleus deep brain stimulation on apathy in Parkinson*s disease

Deep Brain Stimulation (DBS) of the subthalamic nucleus (STN) is part of the
standard care for advanced Parkinson*s Disease (PD) in developed countries.
Multiple studies have shown that STN DBS is able to reduce motor symptoms by on
average 50 percent (6,7). After implantation of the DBS-system, the stimulation
parameters are optimized for the best improvement of motor symptoms using the
Unified Parkinson*s Disease Rating Scale (UPDRS). This questionnaire is
primarily focused on motor symptoms and has only one item evaluating
behavioural changes, the effect of STN DBS on non-motor symptoms is therefore
less recognized. STN DBS is likely to have no negative effect on most mental
abilities (8,9), except for an increase in symptoms of apathy (1). Apathy is
best described as a loss of motivation with decreased initiative, interest and
energy and an emotional indifference with flat affect (10).

We found 16 studies that measured symptoms of apathy after STN DBS, of which 13
reported an increase of apathy despite motor improvement (1,2,11). Based on
nine studies using the proposed cut-off for apathy on scales, the point
prevalence of apathy was approximately 46%, ranging between 21% and 71%. These
studies suggest that apathy may be a common adverse effect of STN DBS and an
important trade-off for patients suffering from advanced PD and relying on this
treatment. Apathy in PD is associated with the lowest quality of life compared
to all other PD symptoms (12). A recent study showed that patients suffering
from apathy after STN DBS did not experience improved quality of life despite
improvement of motor symptoms (11).
One explanation for the occurrence of apathy after STN-DBS is the reduction of
dopaminergic medication after motor improvement by STN-DBS. However,
longitudinal studies show no correlation to the decreased LEDD and the
occurrence of apathy (11,13). Two recent neuroimaging studies suggest an
association between apathy after STN DBS and stimulation of the ventral part of
the STN, associated with non-motor limbic circuits involved in emotion
regulation and motivation. (2,14)
The STN is a relatively small brain structure with three regions that
separately connect to motor, limbic and cognitive circuits. As these neuronal
tracks are closely situated to each other and their projections partly overlap,
stimulating the motor region with STN DBS may also influence limbic and
cognitive circuits. The effect of STN DBS on motor symptoms is directly visible
during parameter optimization, while cognitive, affective and behavioural
effects may become apparent only after several months and may not be detected
during the optimization process. In the Academic Medical Center (AMC) in
Amsterdam, we have described at least three cases of post-operative apathy
after DBS, which improved after switching the parameters to activate a more
dorsal contact on the STN electrode (Zoon et al., in preparation).

In this study, we will test whether STN-DBS related apathy can be reversed by
switching stimulation to a more dorsal contact on the electrode.

This is a multicenter double blind randomized crossover placebo controlled
study. We will include 26 PD patients with apathy after six months of STN DBS,
i.e. a minimum score of 14 points on the Starkstein Apathy Scale (SAS). We will
compare a phase receiving dorsal stimulation versus a phase receiving original
stimulation in a double-blinded fashion

We will randomize patients into two arms, one receiving one month of dorsal STN
DBS first and then one month of regular DBS, the other arm will follow the
reversed order.

The burden of adjusting the DBS settings can include cognitive, affective,
behavioural and motor adverse effects. Severe adverse effects are unlikely and
all patients will be installed with the previously optimized settings intact
and professional care will be available 24 hours a day to instruct patients to
reverse the intervention settings when needed.
The experimental settings are closely situated to the original settings and
patients have already been stimulated at all contacts during the optimization
process of the DBS. The expected burden of the questionnaires is minor.
Patients included in this study will be offered the opportunity to receive DBS
with these settings. The outcome of this study could improve the quality of
life of a large group of patients relying on DBS for PD.