Defining the microstructural basis of tremor in vivo to identify novel therapeutic targets

Tremor, a shaking or trembling in part the body that cannot be controlled, is a common and disabling condition that affects many people. Common causes of tremor include Essential Tremor Syndrome (ET), Parkinson's disease (PD) and a rarer condition called dystonia. It can significantly impact day to day activities and quality of life, and is highly variable between sufferers, posing a challenge both with diagnosis and treatment. Half of all tremor patients do not respond to any of the medication currently available. In these individuals, more invasive treatments are often considered such as deep brain stimulation (DBS) or focused ultrasound, that interrupt the brain circuits that carry the abnormal tremor signals, often targeting a deep region known as ventralis intermedius nucleus of the thalamus (Vim). However, there are many other bran areas and networks involved in the generation and propagation of tremor. A better understanding of these could allow non-invasive "neuromodulation" treatments in the future, using targeted electrical stimulation to dampen the abnormal brain signals.

To develop better treatments for tremor, a greater understanding of the neural circuits that underpin tremor in humans is required. This requires mapping how focal brain regions, and the connections between these, are altered in tremor sufferers, to better understand how different patterns of damage to these structures modify tremor properties such as body regions affected, severity or response to treatment.

Some parts of the brain known to be affected in tremor, such as Vim, cannot be seen on routine MRI. Advanced MRI techniques, using quantitative MRI (qMRI), not only allow these areas to be defined but also provide measurements that reflect different properties of brain tissue and allow the connections between region to be mapped. Furthermore, it is now possible to use openly available "big data" resources, such as the UK Biobank, to link ("annotate") focal changes in brain regions to the genes that are related to these brain structures, and in doing so allow us to identify possible biochemical pathways that may represent avenues for future treatments. This study will focus on ET and PD, the most common causes of tremor with the following objectives
1. To map the changes in brain tissue associated with different tremor properties using qMRI
2. To map connections between regional brain changes and identify genes associated with these brain structures
3. To use these maps to identify potential treatment options, using either neuromodulation or drugs, that are targeted to specific tremor subtypes/properties

The study will run over three years and use data from 40 people with PD tremor and 70 normal people, from an existing study led by Dr Lambert(Quantitative MRI for Anatomical Phenotyping in Parkinson's disease (qMAP-PD). We will add 40 additional participants with tremor who will undergo the same assessments as qMAP-PD study. We will characterize the tremor using standardized scales and advanced video recording of tremors with a smart watch like device to generate detailed tremor recordings. Detailed qMRI of will allow us to identify and map the structures and networks that give rise to the different tremor characteristics. Once we have identified brain regions, we will link these to genes based on an existing resource (UK biobank). In this process we will mark or annotate these genes on brain regions (gene annotation). Using existing knowledge, we will identify factors that influence function in these regions. This will allow identification of potential new medical treatment options from existing knowledge resources.

This combined approach will deliver three key outputs with wide applications to direct precision therapies for tremor: (1) Maps of the brain regions that underpin tremor characteristics (2) Potential targets for modulation through electrical stimulation or focused ultrasound and (3) New treatment options for tremor

Background and objective
Tremor is common, significantly impacts quality of life, and is often difficult to treat with up to 50% classed as "medically intractable". Even in the most common tremor disorders, Parkinson's Disease(PD) and Essential Tremor Syndrome(ET), how damage to different brain circuits cause, and modify, tremor remains poorly understood. In this study we aim to map the microstructural and network changes in brain using quantitative MRI(qMRI) in people with tremor due to ET or PD.

Methods
We will include three groups of patients PD, ET, and controls. Data from early-stage PD (Mixed rest-postural tremor n= 40; Postural only n= 36; Rest only n= 8; No tremor n= 16) and control (n= 74), from an existing study led by Dr Lambert (Quantitative MRI for Anatomical Phenotyping in Parkinson's disease (qMAP-PD). We will acquire additional data for 40 additional participants with ET who will undergo the same assessments as qMAP-PD study. Clinical assessment of tremor will use standardised tremor rating scales, augmented using video capture paired with high frequency accelerometers (GENEactiv)) to generate "tremograms". All patients will have a qMRI including diffusion study and resting state fMRI. Voxel based morphometry and quantification will be used to compare tremor subtypes. We will map the structures that give rise to the different tremor properties and identify linked clinical-anatomical networks. From these maps UK biobank data will be used to identify genetic-structural correlates for genetic annotation. We will further screen and annotate these results with drugs that can potentially target strategic locations within the network that may be suited for future trials.

Outcomes
a. Quantitative methodology to map tremor subtypes based on anatomical patterns
b. Anatomical tremor-subtype networks - Providing potential targets for neuromodulation in targeted individuals
c. Precision therapies targeting aetiologically segregated tremor syndomes