Recognizing J. Purdon Martin's Contribution to Our Understanding of Locomotion and Basal Ganglia

Martin JP, Hurwitz LJ. Locomotion and the basal ganglia. Brain 1962;85:261–276. Early observations of Parkinson's disease (PD) during the prelevodopa era often included descriptions of akinesia also involving gait.1 Many of these observations are consistent with the phenomenon recognized today as freezing of gait (FOG).1, 2 In the years just before the development of levodopa, Dr. James Purdon Martin was a neurologist at the forefront of research on locomotion in the PD population. Martin had already contributed notable works such as linking hemiballismus to lesions of the Body of Luys (subthalamus) in 19273 and describing Fragile X syndrome (Martin-Bell syndrome) for the first time in 1943.4 However, we draw our attention to his innovative clinical approach in discerning the role of the basal ganglia in the control of locomotion and FOG. His work in this area can be exemplified with his 1962 publication titled “Locomotion and the Basal Ganglia.”5 Next, we consider this notable contribution in light of contemporary findings in the years leading up to the levodopa era. The mid-1960s development of levodopa represented a major turning point in the treatment of PD. To this day, it remains the pharmacological gold standard for controlling the hallmark motor impairments of PD.6 However, it was soon discovered that chronic use of levodopa could elicit dyskinesia7 and was associated with motor fluctuations.8 In addition, after the large-scale adoption of levodopa, researchers started to report paradoxical akinetic effects on locomotion, which became known as FOG.9 FOG describes the temporary inability to effectively generate stepping and can be characterized by knee trembling, shuffling, and akinesia.10 Early reports, such as the study by Andrews in 1973, described “freezing” (or “blocking”) as well as shuffling movements resulting from long-term use of levodopa in parkinsonian gait.11 Further clinical descriptions of FOG from long-term levodopa use can be attributed to researchers such as Barbeau in 1971 and Ambani and Van Woert in 1973, who also described the sensation of the feet being “stuck to the floor”12 and difficulties with start hesitation.12, 13 Today, it is generally accepted that levodopa improves FOG seen during the off state, but does indeed play a role in inducing FOG in rare cases.9, 14, 15 It is, however, believed that FOG was less common before levodopa became the main therapy for PD,1 although we are lacking evidence from prospective cohorts of untreated patients. This is a very important reason to look back to the prelevodopa era. Before the advent of levodopa, clinical practice and research in PD often employed medications, such as anticholinergics (eg, Cogentin, Benadryl), and nonpharmacological treatments, such as ablative neurosurgery16 and physiotherapy, to alleviate the common motor issues of PD.17 Even under these regimens, descriptions of FOG can be found.16 One of the earliest mentions can be traced back to Doshay in 1956,18 who subsequently differentiated PD from “senile tremor” on the basis of the occurrence of akinesia, which could manifest as a “freezing” of the legs to the ground.19 In addition, Schwab and Zieper reported in 1965 the effects of mood, motivation, and stress on a form of akinesia they also termed “freezing.”20 It is currently recognized that, in addition to motor problems, executive dysfunction and external stressors can play major roles in FOG pathophysiology. We also know that these mechanisms are closely related to basal ganglia dysfunction, which, as we will see, was not apparent from the beginning. One of the earliest reports to clearly describe FOG in the prelevodopa era and the role of the basal ganglia was by Martin and Hurwitz in their 1962 publication in Brain titled “Locomotion and the Basal Ganglia.”5 In this landmark paper, the authors presented a series of 8 case studies detailing the phenomenology of gait and posture disorders caused by parkinsonism. Most of the cases presented were a form of parkinsonism associated with encephalitis lethargica.21 The authors first provided a convenient framework for the requirements of locomotion, which would be used to discern whether the observed signs of parkinsonian gait were either attributed to the stepping mechanism or as a consequence of the inadequate control of locomotion. They specifically outlined the following 4 principal requirements that play a role in producing locomotion: antigravity, stepping, equilibrium, and generating propulsion. Maintaining equilibrium during locomotion requires restricting the center of gravity (COG) within the lateral limits of a narrow alternating base. The torso sways laterally toward the weight-bearing foot, providing a counterpoise for the swing of the contralateral foot generating propulsion in the process. Consequently, the COG shifts as the body propels obliquely forward and downward. This effectively creates a controlled and rhythmic mechanism, where a subsequent step forward must then be taken to avoid falling, ultimately driving the individual forward in locomotion.5 Running and crawling were also described as locomotion strategies. Little attention has been given to the importance of these and other compensation strategies in PD until recent times.22 In light of this framework, the report described the phenomenology of 8 individuals highlighting different gait abnormalities, which today we could consider presentations of FOG. For example, the authors made reference to several observed cases where the initiation of gait was not possible unless the individual was gently leaned forward and tilted side-to-side, at which point the individual was able to walk fairly normally. Similarly, another patient demonstrated start hesitation and stopping. Normal stepping was generated only when the COG was brought forward over the base of support. This was achieved by having the individual hold up a chair (Fig. 1A), thus enabling the individual to lean forward and displace the COG-initiating locomotion. The authors presented another individual who exhibited a festinating gait, which accelerated into running, after a series of steps while walking and holding up a chair. In this case, the individual needed to set the chair down to come to a full stop. One other patient needed an external push to one side to enable a counterbalance for the opposite foot to swing forward. In the rest of the cases, individuals were reported to experience various levels of immobility requiring the side-to-side sway necessary to initiate the swing phase. The result was shuffling and stopping as feet were “stuck” to the ground. The observations made by Martin and Hurwitz were significant early attempts of identifying the pathophysiological mechanisms identified as the clinical presentations of FOG today. Notably, these observations were reported during the prelevodopa era when such descriptions of FOG were far less common. Collectively, the case studies described make reference to the difficulty in initiating gait by bringing the COG sufficiently forward, festination of gait as a result of shortened faster steps as described by the sequence effect,24 and a difficulty in shifting laterally on the floor as needed in turning.5 Based on their observations, Martin and Hurwitz concluded that the ability to walk was present in these individuals despite the evidence of disordered gait initiation, festination, and various degrees of hypokinesia. They postulated that if a step can be produced then it is not the stepping mechanism itself that is inadequate. Rather, the problem likely resides in the “physiologically higher function by which stepping is initiated and controlled.”5 Martin condensed this idea 15 years later with: “postural activity should be regarded as a function in its own right and not merely as a component of movement.”25 The mechanical framework of locomotion Martin and Hurwitz presented, together with the manner in which locomotion was facilitated in patients, underscored the basal ganglia's central role in initiating and controlling gait (ie, by also controlling the COG) rather than acting as a motor center for stepping. The authors asserted that the basal ganglia regulate locomotion given their central role in maintaining postural adjustments. Consequently, lesions within the basal ganglia result in the difficulty in maintaining the proper postural control needed to initiate and maintain locomotion.5 For example, individuals with PD can exhibit difficulties in keeping the COG within a stable base under the conditions of propulsion.5 Indeed, these findings closely corroborate with current findings, which suggest that the severity of FOG relates closely with the ability of an individual with PD to maintain postural control. For example, it was reported that the ability to lean the body and shift the center of pressure forward in the anterior–posterior orientation can be impaired for individuals with PD exhibiting FOG.26 The phenomenology of basal ganglia disorders also stems from a variety of compensatory mechanisms, which in turn can become maladaptive phenomena. A typical example is festination of gait, which was also reported in Martin and Hurwitz. Festination can arise from a compensatory increase of cadence resulting in progressively smaller steps, which may also be a contributing factor leading to FOG,27 although in the case reported by Martin and Hurwitz, the COG was brought forward and movement was stopped by a physical barrier, such as a chair.5 However, this may explain only the motor pathophysiological mechanism related to spatiotemporal parameters driving locomotion. Delving further into the role of the basal ganglia, the models of FOG developed in the past decade also involve motor, cognitive, and limbic factors.28, 29 Indeed, it was suggested even during the prelevodopa era that negative emotional stimuli (eg, stress) could elicit FOG, whereas positive emotional stimuli (eg, motivation or incentive) could reduce it.20 Martin and Hurwitz are the first researchers to incorporate a framework of locomotion intended to ascertain the motor and higher level gait and postural control associated with the basal ganglia in the absence of the confounding role played by levodopa. The paper featured, along with subsequent works by Martin,30 can be recognized as some of the earliest works that contribute significantly to our current understanding of the basal ganglia's role in the clinical manifestations of FOG in parkinsonian gait. In the following years, Martin explored the effect of visual cueing and kinesia paradoxa,31 features that were decades later adopted for rehabilitation trials.32 Interestingly, in one such work the role of the caudate as a controlling gait center was hypothesized,30 as confirmed decades later with neuroimaging studies of patients with FOG.33 In conclusion, Martin (1893–1984), the neurologist who moved from Northern Ireland to London and dedicated more than half a century of work at the National Hospital in Queen Square, can be recognized as an important figure in modern clinical neurology.34 Among his important achievements, he has greatly contributed to our understanding of the role of the basal ganglia in human locomotion (Fig. 1). This contribution can be recognized for having advanced our understanding of parkinsonian gait. Informed consent and the approval of an institutional review board was not required for this work. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. The authors report no relevant conflicts. This study was funded by the University of Toronto and University Health Network Chair in Neuromodulation and Multidisciplinary Care to A.F. G.U.S. has nothing to declare. A.F. received honoraria from AbbVie, Abbott, Boston Scientific, Ceregate, Ipsen, Medtronic, and UCB and research support from AbbVie, Boston Scientific, and Medtronic.

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