What is the cerebral physiological basis for fatigue


Weakness is one of the most common reasons patients are presented to primary care. Weakness is understood as the loss of muscle strength; However, many patients also speak of weakness when they generally feel tired or have functional limitations (e.g. due to pain or limited joint mobility) even though the muscle strength is normal.

Weakness can affect a few or many muscles and develop suddenly or gradually. Depending on the cause, there may be other symptoms. Weakness in certain muscle groups can also cause eye movement disorders, dysarthria, dysphagia, or respiratory weakness.


Voluntary movements are triggered in the motor cortex, which is located on the posterior edge of the frontal lobe. The neurons involved (upper motor neurons or neurons of the pyramidal tract) form synapses with neurons of the spinal cord (lower motor neurons or anterior horn cells). The lower motor neurons transmit impulses to the neuromuscular endplate and trigger muscle contraction.

General mechanisms of weakness thus include the dysfunction of

  • Upper motor neurons (lesions of the pyramidal tract and corticobulbar tract)

  • Lower motor neurons (e.g. due to peripheral polyneuropathies or cell damage in the anterior horn)

  • Neuromuscular endplate

  • Muscle (e.g. due to myopathies)

The location of certain lesions correlates with the physical findings:

  • A Upper motor neuron dysfunction leads to disinhibition of the lower motor neurons, which leads to increased muscle tone (spasticity) and increased muscle stretching reflexes (hyperreflexia). Babinski's sign is specific to pyramidal tract dysfunction. However, upper motor neuron dysfunction can decrease tone and reflexes if the motor paralysis occurs suddenly and is severe (e.g., if the spinal cord is transected, where the tone initially decreases and then gradually increases over days and weeks) or if the motor lesion is motor Damage to the cortex in the area of ​​the precentral gyrus alone and not to the neighboring motor association areas.

  • Lower motor neuron dysfunction interrupts reflex arcs with the result of hyporeflexia and reduced muscle tone (slackness) and can lead to fasciculations; over time the muscles atrophy.

  • Peripheral polyneuropathies are usually most noticeable in the longest nerves (i.e., weakness is more pronounced in the distal extremity than in the proximal extremity, and more pronounced in the legs than in the arms); they produce signs of lower motor neuron dysfunction (e.g., reflexes and decreased muscle tone).

  • The most frequent Neuromuscular endplate disease- Myasthenia gravis - typically causes a fluctuating weakness that worsens with activity and improves at rest.

  • Diffuse muscle dysfunction (e.g. in myopathies) are usually most clearly recognizable in the largest muscle groups (proximal muscles).


The many causes of muscle weakness are categorized according to the location of the lesion (see Causes of Muscle Weakness table). Usually, lesions in a specific location manifest in similar clinical findings. However, some diseases have lesion features in more than one localization. For example, patients with amyotrophic lateral sclerosis (ALS) may have dysfunction in both upper and lower motor neurons. Spinal cord disease can affect cords from the upper, lower motor neurons (anterior horn cells), or both.

Common causes for focal weakness are

Temporary focal weakness can occur as part of post-ictal (Todd) paralysis, which usually resolves over several hours, or it can be the result of a transient ischemic attack (TIA) or hypoglycemia; with treatment, the hypoglycaemia and the resulting weakness recede.

The most common causes of generalized weakness are

  • Degradation due to inactivity (inactivity atrophy) due to illness or frailty, especially in the elderly

  • Generalized muscle wasting due to prolonged immobilization in an intensive care unit (critical illness myopathy)

  • Cricital Illness Polyneuropathy (Critical Illness Neuropathy)

  • Common myopathies (e.g., alcoholic myopathy, hypokalaemia, corticosteroid myopathy)

  • Use of paralytic drugs in intensive care patients

Causes of Muscle Weakness

Upper motor neuron lesions in the brain

Increased muscle tone, hyperreflexia, Babinski's sign

Possibly more stiffness and loss of fine motor skills (dexterity) than weakness (hand grip)

Imaging of the brain with CT or MRI

For multiple sclerosis: MRI of the brain and the cervical and thoracic spinal cord (not CT); sometimes lumbar puncture

Myelopathies (include dysfunction of upper and / or lower motor neurons)

Spinocerebellar ataxias

Subacute combined degeneration

Upper and / or lower motor neuron dysfunction

Common erectile dysfunction, bowel and bladder incontinence or retention, lack of sphincter reflexes (e.g. anal reflex, bulbocavernosus reflex)

Progressive limb weakness and fatigue, clumsiness, spasticity (legs first, then arms, with gradual compression of the spinal cord)

Classic dermatome height sensitivity deficit

MRI and / or CT myelography of the spinal cord

Somatosensory evoked potentials

Tests to clarify the cause may include: Possibly including CSF analysis (e.g. protein, VDRL, IgG index, oligoclonal band, viral titers, PCR), vitamin B12 levels, HIV test, ANA, RPR, NMO-IgG autoantibodies (anti-aquaporin 4 antibodies), HTLV-1 or VDRL, genetic tests, serum copper and ceruloplasmin