The influence of deep brain stimulation on reward and attention in Parkinson*s disease

Parkinson*s disease is primarily a movement disorder stemming from a loss of
dopamine producing cells in the substantia nigra. Symptoms, such as tremor,
rigidity, postural instability and slowness of movements, arise when a large
fraction of these neurons is lost. However, as dopamine networks are widespread
throughout the brain, emotion and cognition also change as a function of
reduced dopamine signalling. Dopamine replacement therapy can ameliorate these
symptoms but may also lead to impulse control behaviors (ICBs), which have a
reward-oriented aspect, such as addiction to dopaminergic medication,
pathological gambling and increased sexual and eating desire. This is not
surprising as dopamine is involved in the circuits that control motivation
(Berridge 2007), reward-processing (Wise 1998; Kapogiannis, Campion et al.
2008; Cools, Frank et al. 2009; Buckholtz, Treadway et al. 2010), and attention
(Chamberlain, Robbins et al. 2007). The prevalence of ICBs is thought to be 6%
in patients not using dopamine replacement therapy and 17% in patients using
dopamine agonist treatment (Voon, Hassan et al. 2006; Weintraub, Siderowf et
al. 2006; Weintraub, Koester et al. 2010). Why certain patients develop ICBs is
not yet fully understood, although important leads have recently emerged
(Djamshidian, Averbeck et al. 2011). Some of these factors relate to premorbid
personality features (Djamshidian, O'Sullivan et al. 2011): while Parkinson*s
patients without ICBs are typically risk averse and anhedonic (Ishihara and
Brayne 2006), those who develop ICBs appear to be more novelty seeking (Voon,
Thomsen et al. 2007). Reducing ICBs requires a reduction in dopamine
replacement therapy, which is possible in combination with deep brain
stimulation (DBS), for instance of the subthalamic nucleus (STN). With this
technique, patients are implanted with an electrode that runs from a
subcutaneously placed pulse generator directly to a specific brain region such
as the STN. Patients with Parkinson*s disease can benefit greatly from
stimulation of the STN. Unfortunately, DBS of the STN may also result in
hypersexuality (Doshi and Bhargava 2008), mania (Kulisevsky, Berthier et al.
2002), and impulsivity (Frank, Samanta et al. 2007; Ballanger, van Eimeren et
al. 2009). This suggests that even when dopaminergic medication is reduced,
stimulation of a node in a dopaminergic pathway (e.g., STN) may result in
impulsive, reward-oriented behavior. Therefore, we wish to investigate the
effects of STN DBS on how rewards steer visual selective attention. While many
studies on Parkinson*s disease focus on alterations in higher order cognition
(Cools, Barker et al. 2001; Cools, Stefanova et al. 2002; Cools, Miyakawa et
al. 2010; Obeso, Wilkinson et al. 2011), only a few studies have examined
automatic (bottom-up) attention in Parkinson*s disease (Cools, Rogers et al.
2010). One of these studies (Cools, Rogers et al. 2010) showed that rigidity in
set-shifting tasks are accounted for by greater automatic capture of attention
by salient information. Although they interpreted this finding in terms of
reduced top-down control, the authors acknowledged that it might also argue for
a disproportionate influence of automatic bottom-up attention (Cools, Rogers et
al. 2010). In our study, the main focus will be on attentional processes that
are independent of strategic top-down control. In light of the reward-oriented
aspect of ICBs in Parkinson*s disease, we will focus on the interplay between
reward and selective attention. It was for instance recently shown that
previously rewarded stimuli capture attention more strongly (Hickey, Chelazzi
et al. 2010). This shows that rewards may act to change the salience of stimuli
at the level of the visual cortex (Hickey, Chelazzi et al. 2010; Anderson,
Laurent et al. 2011; Anderson, Laurent et al. 2013). This mechanism may account
for reward-driven behaviors associated with dopamine replacement therapy and
STN DBS in Parkinson*s patients. In turn, better understanding of the
mechanisms through which these behaviors arise may lead to better treatment and
patient care.

The main goal of this study is to investigate the side effects of deep brain
stimulation in Parkinson's disease. An important aspect of these side effects
is the reward-oriented behavior. For this reason, patients will be administered
psychological tests which will provide valuable information on the different
components of this reward-oriented behavior.

Patients with Parkinson's disease will be enrolled. Based on various test, a
cognitive profile of each individual patient will be made. This study involves
a within-subjects design, consisting a 4 parts with which it possible to see
the influence of the STN on different components of the learning reward
contingencies

please see protocol

For this research it is required that DBS is turned on or off during certain
blocks of the experiment. Patients will only be tested when they are in their
on-phase. In the on-phase patients respond well to medication resulting in few
symptoms (patients will remain on their prescribed medication). When patients
are in the on-phase, switching DBS off will result in few side-effects
(Odekerken, van Laar et al. 2013). We therefore anticipate a minimal burden for
patients. However, patients will be explicitly instructed to directly notify
the experimenter should any symptoms manifest.
One clear benefit will be a better understanding of the mechanisms through
which ICBs may manifest in patients with Parkinson*s disease. Secondly, the
role of the STN in reward-oriented behaviors in general, and in Parkinson*s
patients in particular will be clarified. Third, we will also look at effects
of stimulation of the ventral vs dorsal STN which will increase our
understanding of the effects of stimulation of subcomponents of the SNT (see
page 13 and 14 for further explication). In the future, this knowledge should
lead to better treatment for patients with Parkinson*s disease but also for
other patient groups in which reward-driven behaviors are present and DBS may
constitute a treatment option (e.g., addiction).