Review articleFatigue and basal ganglia
Introduction
Fatigue is a common symptom in neurological diseases. Fatigue is defined in the dictionary of the English language as “great tiredness; weakness or strain caused by use”. In basic physiology, fatigue is defined as a failure to sustain force output (e.g. fast-fatiguable muscle). Fatigue is not same as weakness: fatigue is a specific symptom and is rarely a complaint in a number of neuromuscular diseases that actually weaken muscles [1]. In this paper, we shall examine the role of basal ganglia in the mechanism of central-type of fatigue in neurological disorders.
Section snippets
Defining fatigue as a symptom: subtypes of fatigue
The physiological definition of fatigue, which is the inability to sustain a specified force output or work rate during exercise, has often been termed “objective fatigue” [2]. Neuromuscular disorders like myasthenia gravis and metabolic myopathies are best examples of this type of fatigue. Similar objective fatigue can also be experienced by patients with peripheral circulatory disorders, as in ischemic heart disease and left ventricular failure [3]. A more appropriate term for this type of
Is non-neuromuscular fatigue a psychiatric disorder?
Unlike peripheral fatigue, where the mechanism of fatigue is attributed to the failure of neuromuscular transmission, metabolic defects of the muscles or a peripheral circulatory failure, the mechanism of fatigue in PD, MS, PPFS or CFS is very poorly understood. Clinicians have often chosen to ignore fatigue in these patients as an important symptom or felt compelled to equate fatigue with depression, somnolence or disinclination, seeking to explain the mechanism of fatigue by paradigms based
Defining central-type fatigue
As a symptom, unqualified fatigue is non-specific and may be associated with a variety of neurological and non-neurological illnesses. To define a central-type fatigue, and to distinguish it from the fatigue of peripheral neuromuscular disorders, it is necessary to establish presence of both physical and mental fatigue.
What is, then, this central fatigue? Taking the analogy of peripheral neuromuscular fatigue, central fatigue may be defined as the failure to initiate and/or sustain attentional
Basal ganglia circuits are neural substrates of parallel information processing
The basal ganglia consist of six extensively interconnected nuclei: the caudate nucleus and putamen comprising the neostriatum that develops from the striate ridge of the telencephalic vesicle; globus pallidus or pallidum that is derived from the diencephalon and is divided into the internal and external segments; substantia nigra, the largest single mesencephalic nucleus; subthalamic nucleus (STN) and amygdala (archistriatum). Amygdala provides an important link between basal ganglia with the
Basal ganglia are involved in the limbic modification of cortical motor output
Basal ganglia were considered to be the centre for motor activity since the end of the 18th century. Carville and Duret demonstrated in 1875 that while undercutting the excitable cerebral cortex caused only transient paralysis, a section through basal ganglia and internal capsule on both sides made the animal powerless as well as prostate. In his experients, Ferrier observed that although in the rabbit and lower vertebrates righting and progressing by hopping can be effective without the basal
Basal ganglia and motivation
Basal ganglia appear to be capable of concurrent participation in a number of separate functions, i.e. motor, cognitive and limbic processing, due to the parallel structure of the individual basal ganglion circuitry. From Denny-Brown’s experimental work on caudate ablation in monkeys it became clear that damage to the caudate nuclei led to a condition in which animals had difficulty formulating internally driven responses. In a more recent experiment using a memory-guided saccade task with an
Neuropathology of central fatigue
Basal ganglia are exquisitely vulnerable to mutiple neurodegenerative processes, injury by hypoxia, direct invasion of viruses and pro-inflammatory cytokines [34]. Alterations of neurotransmitter balance in the absence of neuronal loss can also cause basal ganglia dysfunction that may be potentially reversible. Several observations in specific diseases stengthen the association between basal ganglia disease and the chronic fatigue of central-type. We discuss below only a few disorders
The putative abnormality in basal ganglia pathways that may cause fatigue
Based on the current models of basal ganglia circuitry, we posulate that the interruption of the associated loop of striatocortical fibres or a net change in the thalamic activity suppressing cortical activation via the striato-thalamo-cortical loop will predispose to the symptoms of central fatigue. Since thalamus is the final common pathway of the corticofugal projections from the basal ganglia, an increase in the net thalamic inhibition or a shift in the reciprocal state of activation
Testing the hypothesis
Magnetoencephalography (MEG) may provide a non-invasive method of measuring the thalamocortical rhythm in patients with central fatigue. Since the role of dopamine and also of serotonin may be important in modulating the activity of the pallido-thalamo-cortical loop, functional neuroimaging by the positron emission tomography (PET) scans specifically for the distribution and densities of the dopamine ( [11] C-raclopride PET scan) and serotonin ([carbonyl- [11] C]WAY-100635-PET scan) receptors
Objective measurement of central-type fatigue
Like pain, central fatigue is difficult to quantify and measure objectively. Currently, severity of fatigue is assessed by a variety of self-report instruments that are questionnaire-based and are essentially subjective, relying entirely on an individual’s own assessment of his/her functioning [40]. Based on our argument in this paper, we suggest that both the physical and mental fatigue should be assessed separately in a patient with central fatigue. While physical fatigue may be estimated by
Conclusion
The anatomical pathways and the chemical substrate for fatigue in CNS disorders are not fully understood. Although central fatigue is exceedingly common as a symptom in neurological practice, little is known about its precise mechanism in most diseases, even when the pathology of the underlying neurodegenerative and inflammatory processes are better understood. In this review, we have put forward a hypothesis suggesting that a failure of the nonmotor functions of basal ganglia may be relevant
Acknowledgements
We are indebted to the Barclay Trust and the George John Livanos Trust held at the University of Glasgow for supporting the study of chronic fatigue in neurological disorders. We are grateful to Peter G.E. Kennedy, Professor of Neurology and to W.M.H. Behan, Professor of Pathology, University of Glasgow, for their helpful comments and criticisms on the manuscript. We thank A.P. Payne, Professor of Anatomy, University of Glasgow, for inviting us for an oral presentation based partly on this
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