Deep Brain Stimulation-Induced Mania in Parkinson's Disease

Official title

Understanding Deep Brain Stimulation-induced Mania: Finding Potential Predictors to Optimize Treatment

Overview

Parkinson's Disease (PD) is a common and debilitating neurodegenerative disease. While medication can alleviate its symptoms, not all patients will adequately respond to medical therapy. For these cases, deep brain stimulation (DBS) has been used to improve symptoms and quality of life. Nevertheless, this approach is, in some cases, associated with incapacitating neuropsychiatric side-effects, including mood disturbances, such as DBS-induced mania. While this condition has important functional short- and long-term consequences for quality of life and prognosis, its pathophysiology is still poorly understood. In this project the investigators propose to conduct a retrospective and naturalistic study in PD patients in whom DBS stimulation resulted in mania or mixed state episode, to clarify if specific sociodemographic and clinical predictors, namely stimulation parameters and target locations, might be associated to the occurrence of this neuropsychiatric adverse event. Additionally, the investigators aim to clarify if the occurrence of DBS-induced mania results from the impact of specific stimulation parameters and/or target locations in functional connectivity networks. To explore this question, the investigators will use different neuroimaging analysis methods termed lesion topography analysis and lesion network mapping, in order to compute maps of the stimulated regions topography and the functional networks that are associated with DBS-mania, respectively. The data that will be analyzed in this project, including neuroimages, will be obtained retrospectively, by different Movement Disorders and Functional Surgery Groups in the context of Deep Brain Stimulation, and that has been collected according to their usual clinical practice.

Detailed description

Parkinson's Disease is the second most common neurodegenerative disorder, characterized by very debilitating motor and non-motor symptoms. While medication can alleviate the impact of this disease in patient's daily life, not all patients will respond adequately to treatment, its benefits may not be long-lasting and/or incapacitating side-effects may result. For these cases, DBS has been used to improve symptoms and quality of life. Nevertheless, this approach may have clinically significant side-effects. In fact, important neuropsychiatric adverse events can occur as a result of DBS stimulation, including DBS-induced mania. This is a debilitating mood disorder, frequently associated to a decrease in DBS efficacy due to the need to change/alter stimulation parameters or switch off the device entirely with the patient losing the benefits and the improving quality of life associated with the amelioration of his motor (but also non-motor) symptoms provided by DBS-stimulation. However, reliable predictors for its occurrence are lacking and its pathophysiology is still poorly understood. In this project, the investigators aim to clarify if there are specific DBS electrode locations and/or stimulation parameters associated to development of DBS-induced Mania while additionally determining other potential sociodemographic and clinical predictors. The investigators also aim to further explore if DBS-induced mania results from the impact of specific stimulation parameters and/or target locations in functional connectivity networks.

The investigators hypothesize that specific stimulation parameters and treatment targets associated with DBS-induced mania stimulation will impact particular subcortical brain regions, alongside other clinical and sociodemographic predictors. Additionally, the investigators hypothesize that such specific pattern of stimulation will be associated to specific dysfunctional brain connectivity networks. To address these hypotheses, the investigators propose three specific aims:

1. To determine if there are specific DBS electrode location and/or stimulation parameters associated to development of DBS-induced Mania; 2. To determine if there are specific sociodemographic and/or clinical predictors for the emergence of DBS-induced Mania; 3. To explore if specific functional connectivity networks are associated to the DBS target location and/or stimulation parameters associated with Mania.

Interventions

• Other No Intervention / Exposure
  No intervention / exposure since this is an observational study

Primary outcome measures

• Topographic localization of volume of tissue activation (VTA) in DBS-induced mania [Time frame: From DBS parametres change until the date of first documented manic symptoms, assessed up to 24 months]

Secondary outcome measures (2)

• Sociodemographic and/or clinical predictors of DBS-induced mania [Time frame: From DBS parametres change until the date of first documented manic symptoms, assessed up to 24 months]
• Connectivity profile of volume of tissue activation (VTA) in DBS-induced mania [Time frame: From DBS parametres change until the date of first documented manic symptoms, assessed up to 24 months]

Eligibility criteria

DBS-induced mania cohort:

Inclusion criteria

• Age≥18-years-old;
• Patients diagnosed with PD who were submitted to DBS surgery irrespective of its target;
• Manic episode or mixed affective state diagnosed after surgery and associated to DBS modulation, i.e., after switching on the device or changing modulation parameters.

Exclusion criteria

• Patients diagnosed with bipolar disorder, or manic episode, or mixed affective state before the age of 18
• Patients diagnosed with bipolar disorder, or manic episode, or mixed affective state, before DBS surgery.

DBS Control Cohort:

A control cohort will also be collected. These patients will also meet the aforementioned inclusion and exclusion criteria with the exception of not having presented a manic episode or mixed affective state diagnosed after surgery and associated to DBS modulation.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Case-control

Study locations

Portugal · 1 center

• Champalimaud Foundation — Lisbon

Publications

• Mhyre TR, Boyd JT, Hamill RW, Maguire-Zeiss KA. Parkinson's disease. Subcell Biochem. 2012;65:389-455. doi: 10.1007/978-94-007-5416-4_16. PMID 23225012
• Nutt JG, Wooten GF. Clinical practice. Diagnosis and initial management of Parkinson's disease. N Engl J Med. 2005 Sep 8;353(10):1021-7. doi: 10.1056/NEJMcp043908. No abstract available. PMID 16148287
• Benabid AL, Pollak P, Louveau A, Henry S, de Rougemont J. Combined (thalamotomy and stimulation) stereotactic surgery of the VIM thalamic nucleus for bilateral Parkinson disease. Appl Neurophysiol. 1987;50(1-6):344-6. doi: 10.1159/000100803. PMID 3329873
• Siegfried J, Lippitz B. Bilateral chronic electrostimulation of ventroposterolateral pallidum: a new therapeutic approach for alleviating all parkinsonian symptoms. Neurosurgery. 1994 Dec;35(6):1126-9; discussion 1129-30. doi: 10.1227/00006123-199412000-00016. PMID 7885558
• Pollak P, Benabid AL, Gross C, Gao DM, Laurent A, Benazzouz A, Hoffmann D, Gentil M, Perret J. [Effects of the stimulation of the subthalamic nucleus in Parkinson disease]. Rev Neurol (Paris). 1993;149(3):175-6. French. PMID 8235208
• Deep-Brain Stimulation for Parkinson's Disease Study Group; Obeso JA, Olanow CW, Rodriguez-Oroz MC, Krack P, Kumar R, Lang AE. Deep-brain stimulation of the subthalamic nucleus or the pars interna of the globus pallidus in Parkinson's disease. N Engl J Med. 2001 Sep 27;345(13):956-63. doi: 10.1056/NEJMoa000827. PMID 11575287
• Mosley PE, Marsh R. The psychiatric and neuropsychiatric symptoms after subthalamic stimulation for Parkinson's disease. J Neuropsychiatry Clin Neurosci. 2015 Winter;27(1):19-26. doi: 10.1176/appi.neuropsych.14040069. PMID 25716484
• Accolla EA, Pollo C. Mood Effects After Deep Brain Stimulation for Parkinson's Disease: An Update. Front Neurol. 2019 Jun 14;10:617. doi: 10.3389/fneur.2019.00617. eCollection 2019. PMID 31258509

Identifiers

NCT: NCT05444907 · BPD_DBS

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗