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Title: Neural and behavioral correlates underlying motor heterogeneity and freezing of gait in Parkinson's disease
Other Titles: Neurale- en gedragscorrelaten onderliggend aan motorische heterogeniteiten 'freezen' bij ziekte van Parkinson
Authors: Vervoort, Griet
Issue Date: 4-May-2016
Abstract: Parkinson’s disease (PD) is characterized by substantial heterogeneity in its symptomatology, which has led to the definition of subtypes. The most often used subtyping method is based on motor heterogeneity and makes the distinction between a tremor dominant (TD) subtype and one characterized by postural instability and gait disorder (PIGD). Previous studies have already investigated behavioral and neural alterations related to PD subtypes, but could not irrefutably confirm if PIGD and TD have a truly distinct disease development or rather represent disease progression. However, the confirmation of true subtype distinction is crucial to develop individualized treatment and allow early therapeutic intervention. Therefore, the research project presented in this doctoral thesis aimed to validate the PIGD and TD subtypes but also to unravel the pathophysiological mechanisms underlying them.
This was achieved in three complementary studies that respectively studied the behavioral, functional and structural neural correlates of PD subtypes. The first study used an extensive behavioral test battery to validate PIGD and TD subtypes and quantify the extent of motor and postural control impairment. This study revealed a more complex motor profile in PIGD than was previously assumed and indicated that PIGD was more strongly correlated with distal motor deficits than gait impairment. Given that the behavioral profile pointed to subtype-specific neural mechanisms, the second study applied a multi-level functional neuroimaging approach to investigate neural alterations in the PIGD and TD subtype. Therefore, functional connectivity patterns within the motor and cognitive control networks were investigated and correlated with the subtype discriminators identified in study 1. In addition, the brain-wide neural connectome in PIGD and TD patients was described by means of a structurally and functionally coherent whole-brain template. Confirming the hypothesis distilled from study 1, the results indeed indicated subtype-specific functional connectivity patterns in the striatal and fronto-parietal networks and showed an overall pattern of combined hypo-connectivity (65%) and hyper-connectivity (35%) in PIGD compared to TD. The neuro-anatomic basis for these functional connectivity alterations was further investigated in study 3. This study used probabilistic tractography to identify and evaluate white matter tracts between regions that showed altered functional connectivity in study 2. Moreover, brain-wide alterations in white matter integrity as well as site-specific shape alterations in the basal ganglia were investigated. The results indicated that structural deficits at least partially underlie functional connectivity alterations in PD subtypes and confirmed the crucial role of the striatum in PIGD pathophysiology.
Gaining insight into the PIGD subtype is of particular importance given its established relationship with freezing of gait (FOG). FOG is one of the most debilitating phenomena in PD and one of the major reasons for reduced quality of life. It is defined as a brief, episodic absence or marked reduction of forward progression of the feet despite the intention to walk. Mechanisms leading to FOG are currently still unclear although a lot of studies have investigated this topic. The current research project approached this matter from a novel point of view by focusing on the similarities between PIGD and FOG and investigating FOG conversion in a longitudinal manner to clarify the underlying mechanisms. Study 4 investigated this matter by concomitantly examining motor and cognitive control mechanisms using a dual-task gait paradigm in combination with resting-state functional MRI. This study revealed that similar regions than those involved in PIGD, are related to FOG suggesting an imbalance between the cognitive and motor control circuitry. The association between postural instability and FOG was confirmed in study 5. This study demonstrated that the emergence of FOG is associated with the progression of balance impairment, particularly in the dynamic postural control domain.
In summary, this doctoral thesis provided novel insights into behavioral and neural characteristics of PD subtypes and FOG. Overall, the findings support a shared pathophysiological mechanism between FOG and the PIGD subtype and extend the current knowledge base on the importance of postural instability and inadequate motor-cognitive control compensation as drivers for the development of PIGD and ultimately FOG.
Publication status: published
KU Leuven publication type: TH
Appears in Collections:Research Group for Neuromotor Rehabilitation
Laboratory for Parkinson Research

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