Introduction 

Neuromuscular disorders (NMDs) are any conditions that affect nerve cells(neurons) or voluntary muscles and sensory communication occasionally.¹ Despite prominent muscle weakness and wasting (atrophy), fatigue is also a commonly reported symptom. There are two distinct types of classified fatigue among people with NMD: central and peripheral. Central fatigue involves the brain and spinal cord’s inability to activate and coordinate muscle groups; peripheral fatigue solely impairs muscle function.² Understanding their differences is essential for effective treatment and quality of life improvement for individuals with NMD This article will get you through the characteristics and implications of central and peripheral fatigue in the context of neuromuscular disorders.

Neuromuscular disorders 

Neuromuscular disorders are any conditions affecting the structure and/or function of any components of the neuromuscular system. Ranging from the anterior horn cells, dorsal or ventral nerve roots, plexus, peripheral nerves, neuromuscular junctions, and muscle fibres.³

Common neuromuscular disorders  

Some well-known NMDs include Amyotrophic lateral sclerosis (ALS), a progressive motor neuron degeneration; Charcot-Marie-Tooth disease (CMT), a hereditary condition causing peripheral nerve damage; Myasthenia gravis (MG), an autoimmune-induced impairment to neuromuscular junction; Peripheral neuropathy, the damage or dysfunction of peripheral nerves; and muscular dystrophy, a group of genetic disorders that causes progressive muscle weakness and degeneration. Despite their diverse underlying mechanisms and differing symptoms experienced from person to person, they all affect the neuromuscular system, resulting in muscle weakness and impaired movement.^1,3 

Role of the nervous system in muscle control 

The nervous system (brain and spinal cord) plays a crucial role in muscle activation and coordination. Though the underlying neural mechanism differs among diseases, the disrupted nerve-muscle communication impairs muscle contraction and relaxation signalling. The resulting weakness, involuntary contractions (spasms and cramps), coordination and fine movement impairment could challenge individuals with NMDs during physical activity.  

Impact on muscle function and fatigue 

Caused by dysfunctional muscle contraction signalling, neuromuscular disorders can induce significant muscle function impairments. This can result in muscle weakness, involuntary contractions, and coordination difficulties, adding additional strain to the already weakened muscles for decreased strength compensation. Notwithstanding it causes a faster energy expenditure and depletion (intensified fatigue) further exacerbates the overall fatigue among individuals with NMDs. 

Central fatigue 

What is central fatigue?

Central fatigue is the temporary decrease in neural drive and voluntary muscle activation, resulting in difficulty sustaining physical activities and/or impaired cognitive functioning due to CNS pathology.^2,4

Contributing factors 

Motor neuron dysfunction

Neuromuscular disorders often involve motor neuron dysfunction or degeneration. The limitations to motor unit activation and recruitment would inhibit motor pathways among CNS and disrupt motor signalling and activation to voluntary muscles. Hence resulting in reduced muscle force production and easy fatigue.²

Neurotransmitter imbalances 

Neurotransmitter imbalances, such as serotonin, dopamine, and gamma-aminobutyric acid (GABA), within the brain and spinal cord, can affect the neural circuits' excitability and functioning. These circuits regulate mood, motivation, motor control, and energy metabolism. Thereby contributing to central fatigue among NMDs.² 

Neuroinflammation

Inflammatory processes among the brain and spinal cord can occur in some NMDs. The release of cytokines from the activated immune system could pass through the blood-brain barrier, modify the neurotransmitter and neuroendocrine systems, disrupt neural signalling, and impair energy metabolism. Thereby leading to central fatigue.^2,5 

Signs and symptoms 

Generalised weakness

Central fatigue can induce a pervasive sense of weakness throughout the body, involving both voluntary and involuntary muscles, resulting in daily activities difficulties (e.g., walking, lifting objects, maintaining posture).⁵ 

Reduced endurance

Central fatigue may cause stamina and endurance reduction, making it challenging to sustain physical activities or engage in prolonged tasks without feeling excessively tired.⁵

Cognitive fatigue and decreased motivation

Central fatigue can trigger cognitive (mental) fatigue. Resulting in concentration, memory, and mental processing speed difficulties, making it harder to engage in complex cognitive tasks or maintain focus for extended periods. Individuals may also experience a lack of motivation to participate in daily tasks/activities due to overwhelming fatigue.⁵

Neuromuscular disorders associated with central fatigue 

• Amyotrophic Lateral Sclerosis (ALS) 
• Multiple Sclerosis (MS)
• Parkinson’s Disease (PD)

Assessment and measurement 

• Fatigue severity scale for subjective fatigue experience measurement⁴ 
• Neuropsychological tests, and psychomotor vigilance task (PVT) 
• Transcranial magnetic stimulation (motor-evoked potential via EMG)⁶
• Cervicomedullary region electrical stimulation (corticomedullary motor-evoked potential via EMG)⁶

Peripheral fatigue 

What is peripheral fatigue?

Peripheral fatigue is the temporary muscle performance decline and impaired muscle contraction mechanisms, usually occurring among nerve endings, neuromuscular junctions, and muscles.^2,5

Contributing factors 

Energy depletion

Energy depletion is a prominent contributor to peripheral fatigue among NMDs. Caused by impaired energy production and utilisation processes, such as mitochondrial dysfunction, metabolic disturbances, and adenosine triphosphate (ATP) reduction among muscles. This leads to decreased muscle contractability and fatigue during physical activities among the population with NMDs.²  

Ionic imbalances

Ionic imbalances are significant in contributing to peripheral fatigue among NMD. Changes in potassium, calcium, and magnesium levels can disrupt excitation-contraction coupling and impair neuromuscular transmission, thus leading to decreased force production, thereby exacerbating peripheral fatigue among individuals with NMD.²

Neuromuscular transmission impairment

Impaired neuromuscular transmission is a significant trigger of peripheral fatigue in NMD. Dysfunctional neuromuscular communications, such as reduced acetylcholine release and impaired receptor sensitivity, hinder proper muscle activation. Hence leading to decreased force production, compromised muscle performance, and increased fatigability among the NMD population.²

Signs and symptoms

Muscle weakness 

There is usually a notable decline in muscle strength and force-generating ability. Either generalised or localised to specific muscles, it often leads to decreased endurance and coordination, resulting in daily activities, physical tasks, and mobility difficulties.

Muscle fatigability

There could be a failure to keep up with muscle contraction force over time, as well as rapid strength and endurance decline along with minimal exertion. This can lead to limitations upon sustained activities. Fatigability could be disproportionate to the exertion and persistent despite extended rest periods.⁴    

Muscle pain and discomfort 

Muscle pain, aching, twitching, cramps or spasms (involuntary painful contractions) can be triggered and exacerbated by peripheral fatigue due to muscular metabolic byproduct accumulation. While commonly affecting leg muscles, they might disrupt daily activities, sleep, and quality of life. 

Neuromuscular disorders associated with peripheral fatigue 

• Muscular dystrophy (MD)
• Peripheral neuropathies
• Myasthenia gravis (MG)

Assessment and measurement

• Borg rating of perceived exertion (RPE) scale
• Electromyography (EMG)
• Maximal voluntary contraction (MVC) 
• Muscle endurance tests 

Central vs peripheral fatigue 

Table of differences among central and peripheral fatigue 

How do they interact and influence each other?

Central and peripheral fatigue interact and influence each other through complex mechanisms among NMDs. 

Feedback loop

CNS alterations in central fatigue can reduce motor output and subsequently reduce muscles’ ability to generate force, triggering peripheral fatigue. Peripheral fatigue caused by impaired neuromuscular transmission can send signals back to the CNS, exacerbating central fatigue.²

Altered motor control 

Central fatigue can affect motor control and coordination, leading to altered muscle recruitment patterns, which can in turn contribute to increased peripheral fatigue by placing additional strain on specific muscles, resulting in inefficient movement patterns.²

Energy metabolism 

Central fatigue influences energy regulation and utilisation, affecting energy substrate availability for muscle contraction. Peripheral fatigue, with muscle function impairment, can further disrupt energy metabolism, worsening central fatigue.²

Sensory feedback

While muscle weakness in peripheral fatigue can provide sensory feedback to the CNS, its perception of effort can intensify central fatigue. In turn, central fatigue can influence sensory processing and one’s perception, thus provoking peripheral fatigue.²

Importance of distinguishing the two in NMD 

Proper differentiation between central and peripheral fatigue is crucial for accurate diagnosis and effective management of NMD. Understanding their distinct mechanisms and symptoms can help tailor treatment approaches, targeting the corresponding causes and improving prognostic outcomes. This also guides the targeting interventions, rehabilitation strategies, and personalised fatigue management development. 

Implications and management

Treatment approaches

While central fatigue may require medical interventions towards the neuromuscular disorders itself, psychological interventions (e.g., cognitive-behavioural therapy) can also help reduce associated cognitive fatigue and emotional distress. Treatment of peripheral fatigue, on the other hand, focuses on improving muscle functions with physical therapy, personalised exercise programmes, or medications targeting muscle contractility. 

Rehabilitation strategies to address fatigue in NMD

Rehabilitation strategies are crucial in addressing fatigue among NMD. They should be tailored to the individual’s needs and limitations, focusing on pacing activities, energy conservation techniques, and optimising lifestyle. Adaptive devices, strategies, and rest intervals can facilitate both central and peripheral fatigue management while avoiding exacerbation or overload.  

Potential impact on quality of life and daily activities 

Fatigue can significantly affect daily activities, work, social interactions, and the overall well-being of individuals with NMD. Accurately differentiating between central and peripheral fatigue will ensure appropriate management interventions are made and can help individuals with NMD in regaining a sense of control and enhance their quality of life. 

Summary 

This article has explored the differences between central and peripheral fatigue among neuromuscular disorders. Central fatigue involves impairments in the central nervous system processing that reduce muscle activation and performance. Peripheral fatigue involves muscle fibre failure in sustaining or generating force. Though the prognosis of neuromuscular disorders varies, individuals can still manage fatigue by daily activity modifications, prioritising rest, and optimal physical activity engagements to prevent potential overload. Don’t lose hope in seeking support from healthcare professionals when needed while staying informed about advancements and treatment options in fatigue management for neuromuscular disorders.