This post is in the ‘Dementia’ part of my blog, but please note that not all patients with Parkinson’s disease have dementia. Some patients, however, do.

Parkinson’s disease is easily identifiable to the medical doctor in the UK, it is hoped, because the obvious ‘mask-life’ face of a patient, difficulties in walking (the shuffling gait), a tremor at rest, and stiffness of arms and legs. A particularly intriguing symptom of patients for decades undoubtedly in the research field has been the “freezing of gait” (FOG), which is typically a transient episode – lasting less than a minute, in which gait is halted and the patient complains that his/her feet are glued to the ground. When the patient overcomes the block, walking can be performed relatively smoothly. The most common form of FOG is ‘start hesitation’ (this is what happens when the patient wants to start walking) followed in frequency by ‘turning hesitation’. How or why this happens remains a mystery, but I bet during my lifetime some in-roads will be made into this by academic neurologists (not practising physicians). It is highly relevant as one-day a strategy involving offering cues in the environment may be of use in overcoming FOG problems. This video is for example a remarkable example of this.

As for my own interest in this incredibly interesting phenomenon, I once did at a questionnaire study as a post-doctoral research fellow with Prof Marjan Jahanshahi at Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology and the National Hospital for Neurology and Neurosurgery, University College London. This questionnaire at the factors which cause FOG, as perceived by patients attending the movement disorders clinic of the National. Hospital. This study examined the factors that induce FOG, and identified the cues and strategies that help overcome it through a postal survey of 130 PD patients. 72% reported FoG. The factors that commonly induced FOG, I found, were turning, fatigue, confined spaces and stressful situations, in addition to emotional factors. FOG was also ameliorated by various attentional and external cueing strategies. I feel that one day these results will be enormously useful in patients designing strategies for overcoming FOG, a very real and troublesome phenomenon for patients with Parkinson’s disease. I believe, personally, that it is these trigger factors which help us to understand the phenomenon of FOG, and it is these which my academic colleagues should invest their energies into discovering.

However, in many of the studies, there has been an emergent consensus to identify the factors which can cause patients to ‘unfreeze’ through the phenomenon known as ‘paradoxical kinesia‘. In an academic discussion on the subject, Dr. Friedrich Asmus and colleagues (2009) from the University of Tübingen, Germany, offered that, on the basis of the freezing study above, that, “in this context, visual cueing has a pivotal role, as shown by the report of a patient with PD during the war who was paradoxically able to run by following the footsteps of his wife in front of him. Smilar and reproducible effects of patterned movements like running stairs have been described in the context of paradoxical kinesis“. Another finding from the freezing study was that patients with Parkinson’s disease reported that turning difficulties appeared to be associated with freezing, but the problem was that only limited studies had been conducted to characterize these difficulties. In a formal analysis, the laboratory of Prof. Alice Nieuwboer at the University of Leuven in Belgium indeed this report to be borne out in formal gait analysis, and further found that, during turning, non-freezers and controls decreased their cadence whereas freezers increased it, which may be related to freezing-of-gait.

A major obstruction in this research is the observation that the underlying brain pathology underlying FOG remains largely unknown. Behavioural studies have helpfully identified several gait alterations in patients with Parkinson’s disease with FOG, even when the patient is not experiencing an actual FOG episode. These can be discovered when people with Parkinson’s disease are walking on a treadmill. Alterations include premature timing of muscle activations, increased variability of gait, increased temporal gait asymmetry and faulty generation of postural adjustments before step initiation. Recently, it was suggested that FOG may be caused by a failure to generate adequate amplitudes for the intended movement.

As an advance in the research from Snijders and colleagues published in Brain on 1^st December 2010, a study was reported, which looked at gait planning in patients with freezing of gait, using motor imagery of walking in combination with brain scanning. They included 24 patients with Parkinson’s disease: 12 patients with freezing of gait, 12 matched patients without freezing of gait and 21 matched healthy controls. Subjects performed two previously validated tasks—motor imagery of gait and a visual imagery control task. During motor imagery of gait, patients with freezing of gait showed more activity than patients without freezing of gait in the mesencephalic locomotor region.

And what does this brain area do? Well, on deeper examination, it seems that – as usual – no-one precisely knows, and the situation is undoubtedly complicated by the fact that defining this region in the human brain has been troublesome, in relation to our non-human counterparts. Based on biologically hypothesized connections of the central pattern generator in the salamander, it is now a widely held belief that this part of the brain indeed represents some sort of a robotic system which acts as a generator of simple movements. For example, electrical measurement studies from Steeves and Jordan back in 1984 have shown that stimulation of the mesencephalic locomotor region (MLR) located in the brain of the salamander produce different gaits, swimming or walking, depending on intensity level.

So where is this part of the brain exactly? Well, they describe:

Ascending projections were observed to the subthalamic nucleus, caudal hypothalamic nuclei, the centrum medianum nucleus of the thalamus, the ventral tegmental area of Tsai, the superior colliculus, and the periaqueductal gray region. The ascending projections were also ipsilateral, with sparse contralateral labeling confined to areas which received ipsilateral projections. Projections to the contralateral cuneiform nucleus were also consistently observed. The results, when compared to those of another study, suggest that the classical MLR is anatomically distinct from the more medial sites in the mesencephalon which can also induce locomotion.

In all honesty, this leaves me pretty clueless, and I doubt whether a human neurosurgeon would feel particularly comfortable with this working definition, either. But that brings one onto a really interesting point – can knowing the abnormal part of the brain is help with precise neurosurgery into a part of the brain, called ‘stereotactic surgery’? Well – maybe no, if “patients with freezing of gait also tended to have decreased responses in mesial frontal and posterior parietal regions“.

Is what they’ve done useful then? Yeah, but it is also the case they’ve found brain areas which correlate with this abnormal behaviour, rather than necessarily causing it. I remember the classic Psychology finals question from Cambridge from the early 1980s which provided, “If we subtract the brain areas activated by Christian saying the Lord’s Prayer from those activated by atheists saying the same prayer, would we have found the neural substrate of Christianity?” The paper in my sense falls into this classic problem of brain scanning, but what choice did the investigators really have because they couldn’t have got them into a scanner, freeze, and then unfreeze? That would in a sense be the ideal experiment, and it indeed might be possible if there were a convincing animal model of FOG and freezing-of-gait, but this surely is a long-way off.

Interesting further reading

Anke H. Snijders, Inge Leunissen, Maaike Bakker, Sebastiaan Overeem, Rick C. Helmich, Bastiaan R. Bloem, and Ivan Toni. Gait-related cerebral alterations in patients with Parkinson’s disease with freezing of gait Brain first published online December 1, 2010 doi:10.1093/brain/awq324

Steeves JV, Jordan, LM.  Autoradiographic demonstration of the projections from the mesencephalic locomotor region. Brain Res. 1984 Jul 30;307(1-2):263-76. http://www.ncbi.nlm.nih.gov/pubmed/6466996

Rahman, S, Griffin, HJ, Quinn, NP, Janahshahi, M.  The factors that induce or overcome freezing of gait in Parkinson’s disease. Behav Neurol 2008;19(3):127-36.