Expert View: The pathology of central fatigue in neurological disorders by Dr Abhijit Chaudhuri

October 13, 2021


In this Expert View, Dr Abhijit Chaudhuri discusses central fatigue in neurological disorders and proposes a model to help understand the cause of this type of fatigue and the development of new treatments.

Dr Chaudhuri advises the ME Association on clinical and research issues relating to the neurology of ME/CFS and assists with the preparation of the MEA Clinical and Research Guide (The Purple Book). He trained with Professor Peter Behan at the Institute of Neurological Sciences in Glasgow and worked with Professor Leslie Findley when he was at Queens Hospital in Romford.

Despite its shortcomings, this proposed model of central fatigue, basal ganglia and Parkinson’s disease remains a useful tool for understanding and evaluating new treatment options…

“A centrally active A2A receptor antagonist, in combination with a GABA-mimetic drug such as gabapentin and pregabalin, which may additionally help with the control of central pain frequently associated with chronic fatigue (9), would seem a possible way forward, but large-scale clinical trials are clearly needed.”


Dr Abhijit Chaudhuri, Queens Hospital, Romford.

The pathology of central fatigue in neurological disorders

Fatigue is a common yet poorly understood symptom in neurological disorders. Multiple sclerosis and Parkinsonian disorders are two common example of disorders of the central nervous system in which fatigue is frequently reported (1).

Fatigue is physical as well as cognitive, and cognitive fatigue is characterised by reduced speed of registration, retrieval, and processing of information.

The level of fatigue in a patient is never uniform; variability can be induced by changes in physical health, sleep, medications, mood, and pain level.

Chronic fatigue, like chronic pain, is a multimodal symptom, and is distinguishable from the focal or segmental fatigue of muscle or neuromuscular junction disorders which primarily involve a failure to sustain voluntary motor function.

Despite some overlap, a clear distinction should be made between ‘central’ and ‘peripheral’ fatigue (1).

The pathophysiological and neuroanatomical processes of central fatigue

Disruptions in the process of activation in the pathways interconnecting the basal ganglia, thalamus, limbic system, and higher cortical centre are implicated in the pathophysiological process of central fatigue (2).

A state of relative hypocortisolaemia might sensitise the hypothalamic-pituitary-adrenal axis to the development of persistent central fatigue after acute or prolonged stress, of which central fatigue in patients after viral infection (post-viral fatigue) or severe physical trauma (post-traumatic stress disorder) are possible examples (2).

Long COVID-19, estimated to affect 1.5% of UK population following exposure to the novel coronavirus (SARS CoV2) in the ongoing pandemic, bears close resemblance to the post-viral fatigue that the survivors had following the Spanish 1918 ‘flu pandemic’ (3).

The most severe of these cases were diagnosed as ‘encephalitis lethargica’. Sclerosis of the substantia nigra with occasional globus pallidus involvement was the pathological hallmark in post-mortem studies of these patients (4).

Despite an initial response to levodopa, the therapeutic benefit waned rapidly, and patients became severely dyskinetic on levodopa dose escalation.

Despite a wealth of neuroanatomical and neuropathological evidence supporting the notion of basal ganglia involvement in central fatigue, dopaminergic therapy – primarily targeting striatal dopaminergic receptors – has been less than rewarding (1).

More important, these have been few functional imaging studies mapping the dopaminergic system in the brains of patients with central fatigue and none yet planned for long COVID-19.

Cerebral dopamine transporter single-photon emission computed tomography (DAT-SPECT) scans are abnormal in Parkinson’s disease and Parkinson-plus syndromes, confirming a reduction of presynaptic dopamine receptor transporter protein (5).

These scans appear normal in post-encephalitic parkinsonism, and nearly normal in post-viral fatigue. Patients with post-viral fatigue may show abnormalities in proton (1H) magnetic resonance spectroscopy of the basal ganglia (6).

Anxiety and depression, which are common in patients with central fatigue have been the biggest confounders in the scientific interpretation of central fatigue. Antidepressants, such as selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors, do improve motivation, though antidepressants are not effective treatments for fatigue (1).

The development of lethargy and apathy after deep brain stimulation of the subthalamic nucleus can negate the benefits of motor improvement on the quality of life of patients with Parkinson’s disease (7).

Management of mood disorders, together with pain control, remains a key clinical strategy and therapeutic priority for symptomatic patients with central fatigue (8).

Adenosine receptors in the basal ganglia

Stimulation of the direct corticostriatal pathway in the basal ganglia results in motor activation, whereas activation of the indirect pathway produces motor inhibition (2). Dopamine, or dopamine agonists, will induce motor activation by activating the direct pathways via dopamine receptor 1 (D1) receptors.

The indirect pathway consists of gamma-aminobutyric acid (GABA)-ergic enkephalinergic neurons, which connect the striatum with GABAergic neurons in the external segment of the globus pallidus, that project to glutamatergic neurons in the subthalamic nucleus connecting to the output structures.

This indirect pathway has been implicated in motor fluctuations and dyskinesia in Parkinson’s disease (8).

Adenosine A2A receptors are selectively localised on medium spiny neurons of the indirect output pathway in the basal ganglia circuit, projecting from the striatum to the external globus pallidus.

Striatal A2A receptors are expressed on pre-synaptic glutamatergic terminals of cortico-limbic-striatal and thalamo-striatal pathways, co-localising with and antagonising dopaminergic D2 receptors, and are thus integral to the basal ganglia’s control of movement, motor learning, motivation, and reward (9).

Unlike dopamine, which is an extrinsic signal for neurons in nigrostriatal network, adenosine is an intrinsic signal locally produced from the activity of striatal circuits. Dephosphorylation of intracellular ATP generates adenosine, which is also released extracellularly from neurotransmitter synaptic vesicles and glial cells. A2A receptor antagonism improves motor function and fatigue (9).

Caffeine blocks adenosine receptors, which are the target of methylxanthines which also include theophylline. Since the late 1990s, it has been noted that using A2A antagonists with a preferential D2 agonist can improve motor function in Parkinson’s disease. Istradefylline, a selective A2A antagonist, has been shown to improve fatigue (10) and mood (11) in clinical studies of patients with Parkinson’s disease.

Take-home message

Despite its shortcomings, this proposed model of central fatigue, basal ganglia and Parkinson’s disease remains a useful tool for understanding and evaluating new treatment options.

In addition to dopamine and adenosine, striatal GABAergic neurotransmission will be a key area on which to focus future research since several non-motor symptoms of Parkinson’s disease are dopamine-independent and influenced by GABAergic neurotransmission. 

For instance, there is a reduction of GABAergic transmission in the frontostriatal circuit in Parkinson’s disease and patients experiencing visual hallucinations have reduced GABA levels in the visual cortex (12).

A centrally active A2A receptor antagonist, in combination with a GABA-mimetic drug such as gabapentin and pregabalin, which may additionally help with the control of central pain frequently associated with chronic fatigue (9), would seem a possible way forward, but large-scale clinical trials are clearly needed.

References

  1. Chaudhuri A, Behan PO. Fatigue in neurological disorders. Lancet 2004;363:978–88
  2. Chaudhuri A, Behan PO. Fatigue and basal ganglia. J Neurol Sci 2000;179:34–42.
  3. Prevalence of ongoing symptoms following coronavirus (COVID-19) infection in the UK. Office for National Statistics (ons.gov.uk). Last accessed on 30 September 2021 at: https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditionsanddiseases/bulletins/prevalenceofongoingsymptomsfollowingcoronaviruscovid19infectionintheuk/2september2021
  4. McAlpine D. The pathology of the Parkinsonian syndrome in epidemic encephalitis. J R Soc Med 1926;19:35–45.
  5. Bega D, Kuo PH, Chalkidou A, et al. Clinical utility of DaTscan in patients with suspected Parkinsonian syndrome: a systematic review and meta-analysis. npj Parkinsons Dis 2021;7:1–8
  6. Chaudhuri A, Condon BR, Gow JW, et al. Proton magnetic resonance spectroscopy of basal ganglia in chronic fatigue syndrome. Neuroreport 2003;14:225–8.
  7. Zoon TJC, van Roojen G, Balm GFAC, et al. Apathy induced by subthalamic nucleus deep brain stimulation in Parkinson’s disease: a meta-analysis. Mov Disord 2021;36:317–26.
  8. Calabresi P, Picconi B, Tozzi A, et al. Direct and indirect pathways of basal ganglia: a critical reappraisal. Nat Neurosci 2014;17:1022–30.
  9. Schiffman SN, Fisone G, Moresco R, et al. Adenosine A2A receptors and basal ganglia physiology. Prog Neurobiol 2007;83:277–292.
  10. Abe K, Fujita M, Yoshikawa H. Effectiveness of istradefylline for fatigue and quality of life in Parkinson’s disease patients’ and of their caregivers’. Advances in Parkinson’s Disease 2016;5:24–8.
  11. Nagayima H, Kano O, Murakami H, et al. J Neurol Sci 2019;396:78–83.
  12. Firbank MJ, Parikh J, Murphy N, et al. Reduced occipital GABA in Parkinson’s disease with visual hallucinations. Neurology 2018;91:e675–e685.
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