Parkinson disease (PD) is a common neurodegenerative disorder affecting about 1% of the population over the age of 60 years [1]. PD is typically characterized by motor symptoms; however the clinical spectrum of the disease is more extensive, covering a wide range of nonmotor symptoms including cognitive and behavioral changes, sleep disorders, autonomic dysfunctions, sensory symptoms, and fatigue [2,3]. The surgical treatment of PD was reintroduced in the late 1990s with the advent of subthalamic deep brain stimulation (DBS) [4,5], and this is now an established treatment for PD patients [6-9].

Follow-up studies in PD show that after DBS surgery, motor function and performance during daily living activities improve for up to 5 to 10 years, although the initial benefit in part progressively deteriorates [10] and patients still experience clinical fluctuations that prevent them from performing simple daily activities [11]. In addition, immediately after surgery` PD patients face a highly fragile stabilization period, in which parameters are set and patients and families get used to the new situation introduced with DBS.

The long-term outcome of DBS depends on the development of unresponsive PD disturbances related to disease progression that should be properly monitored to allow early recognition and treatment [9].

Long-term PD disability involves motor and nonmotor symptoms that worsen in time. Cognitive impairment and dementia have a higher prevalence in older patients [12,13]. Dementia and hallucinations predict nursing home placement and seem to double the mortality risk especially in older PD patients [14]. Another common, bothersome nonmotor symptom is the onset of lower urinary tract symptoms [15]. Up to 68% of PD patients fall every year, with approximately 50% falling repeatedly [16]. Cognitive behavioral education and exercise training were suggested to be effective in reducing the risk of falls [17,18]. Pain affects 29% to 85% of PD patients who experience various types of pain that may fluctuate with motor symptoms as “nonmotor fluctuations” [19]; the pain improves after DBS [20].

PD progression often leads to hospitalization [21]. The most frequent causes for admission are falls, pneumonia, urinary tract infections, reduced mobility, psychiatric disorders, and mental status changes [22]. PD progression in DBS patients is monitored in scheduled follow-up clinical visits (once or twice a year) when the neurologist takes an instantaneous picture of the patient’s condition that cannot completely reflect the daily condition. At home, patients rely on a family caregiver, who is usually not trained to deal with PD progression and DBS. Often, the reference center is far from the patient's house.

Research carried out in the last 15 years shows that recordings of neuronal activity (local field potentials [LFPs]) from the implanted electrodes provide information related to the patient's state [23-34]. LFPs correlate with motor and nonmotor PD symptoms and were recently proposed as a feedback variable for new DBS systems able to adapt stimulation parameters to the patient’s state [11]. Provided that the new generation of DBS stimulators will allow LFP recordings during stimulation [11], it is likely that the analysis of neuronal activity in DBS patients can be integrated into monitoring systems to provide feedback and alarms.

These observations suggest that monitoring DBS patients more closely and continuously might be crucial to ensure a better quality of life. The use of telemedicine for monitoring PD patients has attracted a lot of attention [35-38], but no technology has been developed to support the continuous monitoring of DBS patients at home, including neurophysiological monitoring, together with an effective empowerment tool for caregivers.

To achieve the definition of the consensus care pathway for PD patients with DBS implant and establish a shared set of caregiver needs, we will analyze the current management practices by involving neurologists and psychologists (maximum 15) from the DBS Study Group of the Italian Neurological Society (Società Italiana di Neurologia) and organizing a focus group dedicated to homecare management of patients. The focus group will draft a consensus clinical care pathway that will be validated by a larger group of at least 30 PD experts.

We will then prepare structured interviews for patients and caregivers to establish their main needs while at home, and we will interview patients and caregivers recruited through the Associazione Italiana Parkinson and directly through the Movement Disorders Ambulatory of both the Borgoroma Hospital and the Fondazione IRCCS Ca’Granda Ospedale Maggiore Policlinico. The expected number of patients and caregivers to be interviewed is 50.

Finally, we will involve 10 to 15 patients, together with their caregivers and reference neurologists, in a focus group dedicated to the definition of the main needs and requirements for home monitoring support systems starting from the results of the interviews.

After having completed the needs analysis for both health care professionals and patients and families, we will model through a graphical language (Unified Modeling Language [UML]) the care pathway of the PD patients with DBS at home, according to the clinical care pathway and the patient and caregiver needs.

UML is a widely used visual language for specifying, visualizing, constructing, and documenting the artifacts of software systems, as well as for business modeling and other nonsoftware applications [39,40]. A UML model is composed of diagrams modeling the static and dynamic behaviors of the system/process. The UML modeling approach is based on the decomposition of a complex system into many different objects representing the subjects/objects related through hierarchical and functional relationships and specified through properties. The methods available to each object represent all the actions that the object exposes or receives. The methods available map all the existing interactions between objects in the system. This decomposed and simplified structure allows the introduction of a formal representation and supports the verification of its validity.

To define neurophysiological biomarkers (Table 1) providing feedback on the patient’s state, we will record LFPs from 30 patients affected by PD and implanted with subthalamic nucleus DBS electrodes through a new experimental system that records LFPs while DBS is ON [41] and transmits signals by radiofrequency to a recording system (Figure 1). Recordings will take place 2 to 3 days after the surgery for electrode implantation and will record continuously for 3 hours. All of the experimental sessions will be videorecorded to allow further offline reassessment of the patient’s state by an experienced neurologist in order to detect motor fluctuations and other symptoms that may require feedback to the caregiver or to the reference neurologist.

LFPs will be bipolarly recorded through DBS electrodes (Medtronic 3389) implanted in the subthalamic nucleus. The DBS electrode has four cylindrical contacts (0, 1, 2, and 3 beginning from the most caudal). Two contacts will be used for recording and one for DBS delivery. LFPs will be recorded through a new system (aDBS, Newronika srl) that allows LFP recording with DBS ON [41]; control of DBS parameters, manual and automatic, through ad hoc algorithms; and radiofrequency transmission of recorded signals.

LFP analysis will be conducted offline with ad hoc programs stored on the WebBioBank system for clinical data collection. These Matlab-based programs allow signal preprocessing and analysis and were previously used for other LFP analyses [25,26,28,33].

Because LFPs represent the activity of large populations of neurons, the analysis will be carried out in the frequency domain. Spectral analysis (power spectrum), cross-spectral analysis (coherence), parametric and nonparametric time-frequency analysis, and bispectral analysis (bicoherence) will be applied to extract biomarkers. Parametric and nonparametric tests will be used to evaluate the intrasubjective changes of LFP biomarkers in different conditions and during different tasks.

The implementation of the system architecture will be based on the extension of the already-existing WebBioBank system for the management of electronic health records (EHR) of PD patients with DBS electrode implants, integrated with signal analysis [42]. The system will be extended with a set of mobile apps to support the caregiver in managing and monitoring the patient at home.

The architecture will consist of two modules, Care Pathway and Caregiver Support, which are both connected to the WebBioBank Web-based platform (Figure 2). The Care Pathway module will be a part of the WebBioBank EHR system and will be devoted to supporting the continuous monitoring of the disease progression and updating of home treatments, customized for each patient. The Caregiver Support module will be designed to provide the tools and information the patient and caregiver need for the proper implementation of the Care Pathway, according to the needs and requirements defined in the first phase of the project. A set of mobile apps will be made available to patients and caregivers to support symptom interpretation, emergency management, and routine daily activities and allow information exchange with the reference neurologist. A mobile device, such as a tablet, will be provided to patients who do not have a personal one.

The system will be implemented and preliminary tested (alpha test) on the same patients involved in the focus groups previously described. System validation will be not part of this project.