Deep brain stimulation (DBS) of the subthalamic nucleus or the globus pallidus is an established treatment for Parkinson’s disease (PD) that yields a marked and lasting improvement of motor symptoms. Yet, DBS benefit on gait disturbances in PD is still debated and can be a source of dissatisfaction and poor quality of life. Gait disturbances in PD encompass a variety of clinical manifestations and rely on different pathophysiological bases. While gait disturbances arising years after DBS surgery can be related to disease progression, early impairment of gait may be secondary to treatable causes and benefits from DBS reprogramming. In this review, we tackle the issue of gait disturbances in PD patients with DBS by discussing their neurophysiological basis, providing a detailed clinical characterization, and proposing a pragmatic programming approach to support their management.
Brain-wide neural circuits enable bi- and quadrupeds to express adaptive locomotor behaviors in a context- and state-dependent manner, e.g., in response to threats or rewards. These behaviors include dynamic transitions between initiation, maintenance and termination of locomotion. Advances within the last decade have revealed an intricate coordination of these individual locomotion phases by complex interaction of multiple brain circuits. This review provides an overview of the neural basis of state-dependent modulation of locomotion initiation, maintenance and termination, with a focus on insights from circuit-centered studies in rodents. The reviewed evidence indicates that a brain-wide network involving excitatory circuit elements connecting cortex, midbrain and medullary areas appears to be the common substrate for the initiation of locomotion across different higher-order states. Specific network elements within motor cortex and the mesencephalic locomotor region drive the initial postural adjustment and the initiation of locomotion. Microcircuits of the basal ganglia, by implementing action-selection computations, trigger goal-directed locomotion. The initiation of locomotion is regulated by neuromodulatory circuits residing in the basal forebrain, the hypothalamus, and medullary regions such as locus coeruleus. The maintenance of locomotion requires the interaction of an even larger neuronal network involving motor, sensory and associative cortical elements, as well as defined circuits within the superior colliculus, the cerebellum, the periaqueductal gray, the mesencephalic locomotor region and the medullary reticular formation. Finally, locomotor arrest as an important component of defensive emotional states, such as acute anxiety, is mediated via a network of survival circuits involving hypothalamus, amygdala, periaqueductal gray and medullary premotor centers. By moving beyond the organizational principle of functional brain regions, this review promotes a circuit-centered perspective of locomotor regulation by higher-order states, and emphasizes the importance of individual network elements such as cell types and projection pathways. The realization that dysfunction within smaller, identifiable circuit elements can affect the larger network function supports more mechanistic and targeted therapeutic intervention in the treatment of motor network disorders.
Virtual reality (VR) technology has emerged as a promising tool for studying and rehabilitating gait disturbances in different cohorts of patients (such as Parkinson's disease, post-stroke, or other neurological disorders) as it allows patients to be engaged in an immersive and artificial environment, which can be designed to address the particular needs of each individual. This review demonstrates the state of the art in applications of virtual walking techniques and related technologies for gait therapy and rehabilitation of people with movement disorders makes recommendations for future research and discusses the use of VR in the clinic. However, the potential for using these techniques in gait rehabilitation is to provide a more personalized approach by simulate the experience of natural walking, while patients with neurological disorders are maintained localized in the real world. The goal of our work is to investigate how the human nervous system controls movement in health and neurodegenerative disease.
Freezing of gait (FOG) is a common and challenging clinical symptom in Parkinson’s disease. In this review, we summarise the recent insights into freezing of gait and highlight the strategies that should be considered to improve future treatment. There is a need to develop individualised and on-demand therapies, through improved detection and wearable technologies. Whilst there already exist a number of pharmacological (e.g., dopaminergic and beyond dopamine), non-pharmacological (physiotherapy and cueing, cognitive training, and non-invasive brain stimulation) and surgical approaches to freezing (i.e., dual-site deep brain stimulation, closed-loop programming), an integrated collaborative approach to future research in this complex area will be necessary to systematically investigate new therapeutic avenues. A review of the literature suggests standardising how gait freezing is measured, enriching patient cohorts for preventative studies, and harnessing the power of existing data, could help lead to more effective treatments for freezing of gait and offer relief to many patients.
Anticipatory postural adjustments (APAs) are the coordinated muscular activities that precede the voluntary movements to counteract the associated postural perturbations. Many studies about gait initiation call APAs those activities that precede the heel-off of the leading foot, thus taking heel-off as the onset of voluntary movement. In particular, leg muscles drive the center of pressure (CoP) both laterally, to shift the body weight over the trailing foot and backward, to create a disequilibrium torque pushing forward the center of mass (CoM). However, since subjects want to propel their body rather than lift their foot, the onset of gait should be the CoM displacement, which starts with the backward CoP shift. If so, the leg muscles driving such a shift are the prime movers. Moreover, since the disequilibrium torque is mechanically equivalent to a forward force acting at the pelvis level, APAs should be required to link the body segments to the pelvis: distributing such concentrated force throughout the body would make all segments move homogeneously. In the aim of testing this hypothesis, we analyzed gait initiation in 15 right-footed healthy subjects, searching for activities in trunk muscles that precede the onset of the backward CoP shift. Subjects stood on a force plate for about 10 s and then started walking at their natural speed. A minimum of 10 trials were collected. A force plate measured the CoP position while wireless probes recorded the electromyographic activities. Recordings ascertained that at gait onset APAs develop in trunk muscles. On the right side, Rectus Abdominis and Obliquus Abdominis were activated in 11 and 13 subjects, respectively, starting on average 33 and 54 ms before the CoP shift; Erector Spinae (ES) at L2 and T3 levels was instead inhibited (9 and 7 subjects, 104 and 120 ms). On the contralateral side, the same muscles showed excitatory APAs (abdominals in 11 and 12 subjects, 27 and 82 ms; ES in 10 and 7 subjects, 75 and 32 ms). The results of this study provide a novel framework for distinguishing postural from voluntary actions, which may be relevant for the diagnosis and rehabilitation of gait disorders.
The striatum is a very heterogenous brain area, composed of different domains and compartments, albeit lacking visible anatomical demarcations. Two populations of striatal spiny projection neurons (SPNs) build the so-called direct and indirect pathway of the basal ganglia, whose coordinated activity is essential to control locomotion. Dysfunction of striatal SPNs is part of many movement disorders, such as Parkinson’s disease (PD) and L-DOPA-induced dyskinesia. In this mini review article, I will highlight recent studies utilizing single-cell RNA sequencing to investigate the transcriptional profiles of striatal neurons. These studies discover that SPNs carry a transcriptional signature, indicating both their anatomical location and compartmental identity. Furthermore, the transcriptional profiles reveal the existence of additional distinct neuronal populations and previously unknown SPN sub-populations. In a parallel development, studies in rodent models of PD and L-DOPA-induced dyskinesia (LID) report that direct pathway SPNs do not react uniformly to L-DOPA therapy, and that only a subset of these neurons is underlying the development of abnormal movements. Together, these studies demonstrate a new level of cellular complexity for striatal (dys-) function and locomotor control.