Tryptophan Depletion in PD Patients Treated With STN DBS

Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor symptoms such as tremor, rigidity and slowness of movement. In later stages of the disease, when pharmacological treatment becomes less efficient, deep brain stimulation (DBS) of the subthalamic nucleus (STN) becomes a treatment option. Although motor symptoms improve significantly by DBS, a number of operated patients experience severe side effects, mostly related to mood, cognition or behavior. These adverse effects are most likely mediated through the serotonin (5-HT) system. Additionally, a dysfunction of the 5-HT system is implied in the pathophysiology of PD. PD patients are therefore regarded as 'vulnerable' to experiencing mood, cognitive and emotional problems due to changes in 5-HT activity.

To elucidate whether STN DBS is indeed the trigger for psychiatric and cognitive problems to arise in the PD patient, the 5-HT levels in PD patients implanted with STN DBS will be manipulated. In order to do this, the investigators will make use of the tryptophan (TRP) depletion method, an established research paradigm. In TRP depletion, the brain is depleted of TRP, the precursor of 5-HT, which consequently leads to lowered 5-HT levels. In both the normal and 5-HT depleted condition, mood- and cognitive parameters of the PD patients both with the STN stimulation on (ON) and off (OFF) will be assessed.

The goal is to get more insight into the effects of STN DBS in PD patients with a 5-HT vulnerabililty and the effects on 5-HT related mood and cognitive behaviour. This way, possible risk factors for and mechanisms underlying psychiatric side effects of STN DBS can be identified. The study is an intervention study with a placebo controlled, randomized cross-over design.

• Tryptophan (TRP) depletion (Dietary supplement), also known as TRP depleted: TRP depletion will be accomplished by administering a TRP-low amino acid protein drink containing 100 g of gelatin powder. The protein mixture consists of 18 amino acids. According to Dutch law, TRP is considered a food supplement and is not registered as a medicine.
• Placebo (Dietary supplement): The placebo treatment will consist of an identical amino acid protein drink containing 100 g of gelatin powder to which 1.21g TRP is added.
• Stimulator ON (Device): Participants will be tested while their stimulator is turned ON
• Stimulator OFF (Device): Participans will be tested while their stimulator is turned OFF

Primary outcomes

• Mood [There will be 6 measurements spread over 2 testing days with a wash-out period of min. 1 weak. baseline measure, 3.5 hours after intake of the amino acid mixture, and 5.5 hours after intake of the amino acid mixture]: as assessed through the Profile of Mood States

Secondary outcomes

• Motor scores [There will be 6 measurements spread over 2 testing days with a wash-out period of min. 1 weak. baseline measure, 3.5 hours after intake of the amino-acid mixture, and 5.5 hours after intake of the amino-acid mixture]: as assessed through the MDS-UPDRS
• Impulsivity [There will be 6 measurements spread over 2 testing days with a wash-out period of min. 1 weak. baseline measure, 3.5 hours after intake of the amino-acid mixture, and 5.5 hours after intake of the amino-acid mixture]: as assessed through a reaction time task
• Emotional Responsiveness [There will be 4 measurements spread over 2 testing days with a wash-out period of min. 1 weak. baseline measure, 3.5 hours after intake of the amino-acid mixture]: as assessed through the emotional responsiveness task

Sex: All

Inclusion Criteria:

* subjects must be mentally competent
* subjects must have undergone STN DBS surgery for PD symptomatology

Exclusion Criteria:

* head injury
* stroke
* currentl malignancy or infection
* neurological disorders other than PD
* psychoactive medication: specifically antidepressants and antipsychotics ( a stable dose of benzodiazepines will be allowed)
* clinically relevant cognitive decline, operationalized as a MMSE score < 24
* current psychiatric syptomatology, operationalized as a Hamilton Depression scale score > 16 or a score >2 on one of the MDS-UPDRS section I, items 1-6

• Yasin Temel, MD, PhD, Principal investigator, Maastricht University Medical Center