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Freezing of gait is a common debilitating symptom described as a sudden inability to generate effective forward stepping, despite the intention to do so (Nutt et al., 2011), and

has a major impact on a patient’s independence, risk of falls and quality of life (Gray et al., 2000; Walton et al., 2015; see Box 1). The freezing phenomenon is associated with impairments in executive functioning (Amboni et al., 2008; Muller et al., 2014; Naismith et al., 2010a), visuospatial processing (Ehgoetz Martens et al., 2014a; Matar et al., 2013) and anxiety (Ehgoetz Martens et al., 2014b; Lieberman, 2006). Environmental triggers, such as obstacles or doorways (Cowie et al., 2012), dual-tasking (de Souza Fortaleza et al., 2017; Spildooren et al., 2010) and stress (Giladi et al., 2006)can all trigger freezing of gait, whilst patients can sometimes use cueing strategies to alleviate this symptom (Rahman et al., 2008). Freezing is not restricted to the lower limbs but can also occur in the upper limbs (Nieuwboer et al., 2009) and speech (Ackermann et al., 1993), suggesting that the neural network underlying the phenomenon extends beyond the motor control of gait (Rahman et al., 2008). These observations have led to the proposal that freezing cannot be summarized by just a gait disturbance but might be the result of ineffective information processing across multiple circuits, leading to dysfunction in a common final pathway (Lewis & Barker, 2009; Lewis & Shine, 2016). In brief, it is proposed that due to an ineffective segregation of the motor, cognitive and limbic pathways, a variety of

stimuli and conditions can cause an overwhelming response when conflict arises. This overwhelming response leads to an increased firing of the STN, which is part of the inhibitory hyper-direct pathway of the basal ganglia. In turn, overactivity in the STN leads to paroxysmal activity in the GPi, subsequently inhibiting the activity of the basal ganglia output nuclei to the locomotor region in the brainstem, disrupting the effective motor plans (Lewis & Shine, 2016). Evidence for this hypothesis comes from a number of functional MRI studies that have shown alterations within frontal and parietal cortical, cerebellar and brainstem locomotor networks in Parkinson’s disease patients with freezing of gait. For example, during motor arrests provoked by a virtual reality paradigm, alterations in BOLD responses were observed within frontoparietal and insular cortices as well as sensorimotor regions, basal ganglia, thalamus and mesencephalic locomotor regions (Shine et al., 2013b). Furthermore, a functional decoupling between the bilateral cognitive control network and the basal ganglia during freezing behaviour was also evident (Shine, 2013a). Altered task-free (‘resting state’) functional connectivity has also been shown to be associated with the severity of freezing behaviour, specifically within the cognitive control network, visual networks and locomotor regions including

Box 1: Evidence for the impact of freezing of gait on a patient’s quality of life Walton, C. C., Shine, J. M., Hall, J. M., O’Callaghan, C., Mowszowski, L., Gilat, M., Szeto, J. Y. Y., Naismith, S. L., Lewis, S. J. G. The major impact of freezing of gait on quality of life in Parkinson's disease. Journal of Neurology, 2015.

This study performed a regression analysis including factors that are known to impact a patient’s well-being. The model included cognition, motor severity, sleep and mood disturbances and freezing of gait. After controlling for disease duration and current dopaminergic treatment, the significant predictors to a patient’s quality of life were self-reported sleep-wake and mood disturbances and freezing of gait. Importantly, freezing of gait accounted for the highest amount of unique variance to a patient’s quality of life. We hypothesized that this finding is due to a loss of independence and fear of injury.

the supplementary motor cortex, mesencephalic and cerebellar motor regions (Fling et al., 2014; Tessitore et al., 2012). Together, these results confirm the involvement of both higher order cortical and locomotor regions in the manifestation of freezing of gait.

Other models of freezing exist that have aimed to describe freezing behaviour in Parkinson’s disease. Plotnik and colleagues (2012) hypothesized that freezing of gait results from poor control of one or more gait disturbances associated with freezing: deterioration in bilateral coordination, gait symmetry and rhythmicity, dynamic postural control and/or step scaling (Plotnik et al., 2012). When the overall gait performance can no longer be maintained above a certain threshold, a freezing episode takes place. Additionally, freezing of gait is often accompanied by a trembling of the knee and it was found that anticipatory postural adjustments coexist with knee trembling during automatically triggered stepping responses to platform perturbations. This observation gave rise to the suggestion that freezing results from a decoupling between pre-planned motor programs, such as anticipatory postural adjustment during step initiation and the release of an inherent stepping movement (Jacobs et al., 2009). The mechanisms in both models indicate involvement of the pedunculopontine nucleus (PPN), a collection of cholinergic and glutamatergic neurons located in the brainstem that is involved in voluntary limb movements, the planning of movement, posture as well as attention and arousal (Garcia-Rill et al., 2015; Tsang et al., 2010). Furthermore, the PPN provides sensory feedback to the cerebral cortex (Li et al., 2015). These models are supported by research into deep brain stimulation of the PPN, which can sometimes improve postural instability and gait disorders (Wang et al., 2016). However, these models do not account for the symptoms that often accompany freezing, such as executive dysfunction and anxiety (Hall et al., 2014). In contrast, Vandenbossche et al. (2013) suggest that the interplay between decreased gait automaticity and impairments in cognitive control play a key role in the occurrence of freezing of gait. Parkinson’s disease patients suffer from motor automaticity as a result of subcortical impairments and therefore rely more heavily on attentional resources. During challenging or ambiguous task requirements, freezing episodes can occur as a result of a breakdown in stepping motion. This hypothesis also incorporates the amelioration of freezing by using cueing strategies. Visual or auditory

cues force patients to utilize attentional control to maintain a stepping motion, presumably by circumventing the impaired subcortical structures (Bella et al., 2017; Ghai et al., 2018; Nieuwboer, 2008).

Evidently, more research into the associations and underlying mechanisms of this prevalent symptom is highly necessary. Chapter 3 of this thesis aimed to explore the epidemiology of freezing, as well as associated symptoms in different clinical stages of Parkinson’s disease. Subsequently, Chapter 4 assessed changes in the structural network topology of patients with freezing of gait, to explore whether this symptom can be described as a result of a more general network dysfunction due to ineffective information processing.