Point of viewA pathophysiological model of freezing of gait in Parkinson's disease
Introduction
Parkinson's disease (PD) is a common neurodegenerative condition affecting around 1% of people over the age of 60 years. The disease has a major impact on the quality of life of these patients, their families and carers carrying a significant socio-economic burden, which has been estimated in a recent UK study to involve an annual healthcare cost of over £5000 per patient [1].
In addition to its motor aspects, PD is known to have profound effects on both memory and mood [2], [3]. Quality of life is further impacted by a range of other complaints including pain, bowel dysfunction and disturbances of sleep [4].
Although symptomatic treatments are very helpful, particularly in the early stages of the disease, patients commonly develop specific late onset manifestations, which do not respond easily to medications. Disease progression is notably correlated with deterioration of gait and specifically the phenomenon of freezing of gait (FOG) where patients experience sudden unwanted arrests in their walking. During these freezing episodes, patients suddenly suffer an inability to move, often describing themselves as having been ‘stuck to the floor’. Patients suffering with FOG are significantly more likely to experience falls [5] and are consequently more likely to require admission to a nursing home [6].
The basis for FOG remains unknown as it responds poorly to l-dopa therapy [7]. Furthermore, other treatment strategies such as deep brain stimulation [8], the use of the psychostimulant medication methylphenidate [9] and environmental cueing devices [10] have shown at best modest benefits. In this review, we have therefore attempted to take the current understanding of basal ganglia circuitry and explain FOG in relation to it with the hope that this will lead to new, testable hypotheses.
Section snippets
Characterisation of freezing
Freezing of gait is not unique to PD as it has been reported in a number of other conditions such as progressive supranuclear palsy (PSP), normal pressure hydrocephalus and vascular parkinsonism [11]. This finding indicates that the phenomenon is not uniquely related to severe dopamine depletion and suggests that the interruption of common neural networks along differing points by a variety of pathological mechanisms may result in the same symptomatic end point.
In the case of PD, there is a
Therapeutic approaches
Attempts to treat FOG have varied. One approach attempted to use botulinum toxin A injected into the calf muscles on the basis that the problem in this condition is akin to that seen in dystonia. Whilst an initial open-label study showed some promising symptomatic benefits [20], a subsequent randomized double-blind placebo-controlled crossover study showed no such benefits [21].
Other strategies have involved using treatments that ameliorate the dopaminergic loss and its downstream effects
Basal ganglia circuits
As stated above, disturbances in basal ganglia circuitry play a central role in the pathology of PD. It is well described that co-ordinated neural activities are dependent on a series of parallel neuronal networks passing through the basal ganglia connecting and integrating functions between the basal ganglia nuclei, various regions of the cerebral cortex, the thalamus and brainstem [26], although more recent work showing the dense arborisation of connections between basal ganglia nuclei would
Mechanisms underlying freezing
We have suggested the anatomical pathway and the key structures in it, but how does FOG come about? Despite the predominance of motoric symptoms in PD both cognitive and limbic deficits are well recognised [2], [41], [42], [43], [44]. The observation that freezing symptoms in PD patients are responsive to external stimuli has long been recognised. Many patients and their carers are well aware of simple ‘tricks’ to alleviate their freezing attacks, such as stepping over a small obstacle (like a
The proposed model
In healthy subjects, the basal ganglia circuits operate through a series of parallel pathways that can integrate information from a wide range of diverse inputs and co-ordinate an efficient functional output such that, individual disease features can be attributed to deficits in specific pathways. Most notably with regard to FOG in PD, a breakdown in the normal operation of the motor loop results in an inhibition of the PPN, an area with descending connections to the spinal cord and presumed
Underlying pathogenesis
In the model of FOG proposed above, paroxysmal excessive inhibition of the thalamus and PPN could result from a specific and transient local unavailability of dopamine due to ‘competing’ functional circuits. How this ‘local shortfall’ in the circuitry is translated into the disruption of motor sequences remains unclear but one explanation would be to suggest that these transitory conditions could result in a non-sustained period of increased synchronicity triggering a freezing episode. In this
Previous research
Although attempts at understanding the processes underlying FOG in PD have focussed on neurophysiological [67], [68] and kinematic aspects [69], some limited attempts to look at this with functional imaging have been undertaken. Two studies have been performed in patients with FOG utilising the technique of single photon emission computed tomography (SPECT) to assess cortical perfusion. Although no significant deficits were recorded in one of these experiments [70], the other did demonstrate
Conclusion
Whilst the proposed model attempts to account for our current understanding of the phenomenon of freezing, it is clearly simplistic and generalised. Testing this hypothesis of FOG is now required. It is anticipated that directed studies in which cognitive and limbic load might be manipulated within behavioural, neurophysiological and functional neuroimaging approaches will help determine their measurable effect on freezing behaviour. It is hoped that such studies will ultimately be combined
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