Elsevier

The Lancet

Volume 384, Issue 9942, 9–15 August 2014, Pages 523-531
The Lancet

Series
The expanding universe of disorders of the basal ganglia

https://doi.org/10.1016/S0140-6736(13)62418-6Get rights and content

Summary

The basal ganglia were originally thought to be associated purely with motor control. However, dysfunction and pathology of different regions and circuits are now known to give rise to many clinical manifestations beyond the association of basal ganglia dysfunction with movement disorders. Moreover, disorders that were thought to be caused by dysfunction of the basal ganglia only, such as Parkinson's disease and Huntington's disease, have diverse abnormalities distributed not only in the brain but also in the peripheral and autonomic nervous systems; this knowledge poses new questions and challenges. We discuss advances and the unanswered questions, and ways in which progress might be made.

Introduction

In modern clinical practice, the basal ganglia refers mainly to the striatum, the internal and external globus pallidus, the subthalamic nucleus, and the substantia nigra pars compacta and pars reticulata because of their close anatomical connectivity and pathophysiological implications (figure 1). The basal ganglia were implicated in the origin of movement disorders by Wilson's observations 100 years ago that lesions of the lenticular nucleus were associated with dystonia and parkinsonism1 and that focal lesions of the subthalamic nucleus and substantia nigra pars compacta caused hemichorea-ballism2 and parkinsonism,3 respectively. In his seminal Croonian lecture in 1925,4 Wilson stated: “I have found no reason to modify in any important respect…that the main features of disease of the corpus striatum consist of disorders of muscle tone regulation and the appearance of involuntary movements”. The recognition that Parkinson's disease arises as a consequence of degeneration of the substantia nigra pars compacta and loss of striatal dopamine5 reinforced this idea. Marsden6 subsequently concluded that “on the basis of the motor deficits observed in patients with Parkinson's disease, the basal ganglia normally are responsible for the automatic execution of learned motor plans”. In the mid-1980s, the emergence of a basal ganglia model7, 8, 9, 10(figure 2), which focused on the pathophysiology of parkinsonism and dyskinesias, further strengthened the association between the basal ganglia and abnormal movements. During the past two decades, robust evidence has accumulated that the basal ganglia are intimately connected with the cortex through several segregated but parallel loops (figure 1), which have been subdivided into motor, associative (cognitive), and limbic (emotional) domains.11 They deal, respectively, with the control of movement, behaviour and cognition, and reward and emotions. These features have also been documented for the striatum and subthalamic nucleus by MRI in people.12, 13 Accordingly, dysfunction in any one of these circuits can give rise to movement disorders, behavioural and cognitive abnormalities, and mood changes.

Section snippets

Movement disorders

Two fundamental disorders of muscle activation in the absence of paralysis or weakness are linked to disorders of the basal ganglia (videos 1–3). First, the parkinsonian syndrome is characterised by poverty and slowness of movement (akinesia or bradykinesia) and typically associated with increased muscle tone (rigidity), giving rise to the akinetic-rigid or parkinsonian syndrome, which can also be accompanied by tremor at rest. Second, dyskinesias and hyperkinesias are movements characterised

Anatamo-functional basis

Just as parkinsonism and dyskinesia represent opposite ends of the movement disorder spectrum and dysfunction of the motor circuit, impairments in the associative/limbic cortico-basal ganglia loop (figure 1) can give rise to reduced or excessive appetite and impulses (apathy and impulsivity). Whether a particular action is pertinent is controlled by the prefrontal cortex and the anterior striatum, which are typically engaged in executive functions such as sequential learning, decision making,

The role of dopamine

The basal ganglia and the dopaminergic projections (mesostriatal, mesolimbic, mesocortical) are involved in several cognitive functions, such as decision making, task switching, and dual tasking, which are typically associated with the frontal lobe but also with time estimation mechanisms and speech, and which engage large neuronal networks. The role of dopamine and the ventral striatum in the control of mood, pleasure, reward, and motivation in people is now well documented. A reasonable

Initial discoveries

The development and expansion of the study of movement disorders has been mainly driven by and based on the recognition of clinical patterns (phenomenology of movement disorders, associated neuropsychiatric conditions) and pathophysiological mechanisms. However, as in all disciplines of medicine, genetics is now having an extraordinary effect in revealing new perspectives on old clinical conditions and in providing a better understanding of aetiopathogenesis and pathophysiology. Genetic studies

Beyond movement disorders

Dysfunction and pathology of different regions and circuits are now known to give rise to many clinical manifestations that contradict the classic concept equating dysfunction of the basal ganglia with movement disorders. Additionally, typical diseases associated with the basal ganglia have diverse pathologies distributed not only in the brain but also in the peripheral and autonomic nervous systems. This knowledge has substantially expanded investigation and also posed new challenges. Although

Search strategy and selection criteria

We reviewed only articles published in English. We identified references through searching PubMed using the terms “movement disorders”, “Parkinson's disease”, “Huntington's disease”, “dystonia”, “executive dysfunctions”, “cognitive impairment-Parkinson's disease”, “psychiatric complications”, “genetics”, and “levodopa and dopamine agonists” as main keywords between January, 1970, and October, 2013. The reference list shows the main work published in the specialty according with our

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