5.3 Basal ganglia and movement disorders

The basal ganglia, a group of brain structures, play a crucial role in movement control and decision-making. These interconnected nuclei work together to modulate motor cortex activity, influencing the initiation and execution of voluntary movements through complex neural pathways.

Parkinson's disease, a common movement disorder, results from the loss of dopamine-producing neurons in the basal ganglia. This leads to an imbalance in motor control pathways, causing tremors, rigidity, and slow movement. Treatment focuses on restoring dopamine levels and managing symptoms.

Basal ganglia structures and connections

Main structures of the basal ganglia

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• The basal ganglia consist of a group of subcortical nuclei in the brain that are essential for motor control, learning, and decision-making
• Key structures of the basal ganglia include:
  • Striatum, which is composed of the caudate nucleus and putamen
  • Globus pallidus, divided into internal and external segments
  • Substantia nigra, containing the pars compacta and pars reticulata
  • Subthalamic nucleus

Connections within the basal ganglia

• The striatum serves as the main input structure, receiving projections from the cerebral cortex, thalamus, and substantia nigra pars compacta
  • It then projects to the globus pallidus and substantia nigra pars reticulata
• The globus pallidus and substantia nigra pars reticulata function as the output nuclei of the basal ganglia
  • They send projections to the thalamus and brainstem, influencing motor output
• The subthalamic nucleus receives input from the cerebral cortex and sends excitatory projections to the globus pallidus and substantia nigra pars reticulata
  • This allows it to modulate the activity of the basal ganglia output nuclei

Basal ganglia role in movement

Modulation of motor cortex activity

• The basal ganglia play a crucial role in the selection, initiation, and execution of voluntary movements through their connections with the cerebral cortex and motor areas of the brain
• They modulate the activity of the motor cortex through a balance of excitatory and inhibitory pathways known as the direct and indirect pathways
  • The direct pathway facilitates movement by disinhibiting the thalamus, allowing it to activate the motor cortex
  • The indirect pathway suppresses unwanted movements by inhibiting the thalamus

Dopamine signaling in movement control

• Dopamine, released by neurons in the substantia nigra pars compacta, is a key neurotransmitter in the basal ganglia
• It modulates the activity of the direct and indirect pathways, promoting movement initiation and control
  • Increased dopamine signaling enhances the activity of the direct pathway and reduces the activity of the indirect pathway, facilitating movement
  • Decreased dopamine signaling has the opposite effect, leading to reduced movement and motor symptoms
• Disruptions in the basal ganglia circuitry or dopamine signaling can result in various movement disorders, such as Parkinson's disease (characterized by dopamine depletion), Huntington's disease, and dystonia

Parkinson's disease pathophysiology

Dopaminergic neuron loss

• Parkinson's disease is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta
• The exact cause of dopaminergic neuron loss is not fully understood but is thought to involve a combination of factors:
  • Genetic susceptibility, with mutations in genes such as SNCA (encoding alpha-synuclein), LRRK2, and Parkin
  • Environmental factors, such as exposure to pesticides and heavy metals
  • Accumulation of abnormal proteins, particularly alpha-synuclein, which forms aggregates called Lewy bodies in the affected neurons

Basal ganglia dysfunction and symptoms

• The loss of dopamine in Parkinson's disease leads to an imbalance between the direct and indirect pathways of the basal ganglia
  • This results in increased inhibition of the thalamus and reduced activation of the motor cortex
• The cardinal motor symptoms of Parkinson's disease include:
  • Tremor, which is an involuntary shaking of the limbs, most commonly the hands and fingers
  • Rigidity, characterized by stiffness and increased resistance in the muscles
  • Bradykinesia, which refers to the slowness of movement and difficulty initiating movements
  • Postural instability, leading to impaired balance and an increased risk of falls
• Non-motor symptoms of Parkinson's disease may include cognitive impairment, depression, anxiety, sleep disturbances (such as REM sleep behavior disorder), and autonomic dysfunction (e.g., constipation, urinary problems, and orthostatic hypotension)

Parkinson's disease treatment mechanisms

Dopamine replacement therapy

• The primary treatment for Parkinson's disease is dopamine replacement therapy, which aims to restore the balance between the direct and indirect pathways in the basal ganglia
• Levodopa (L-DOPA) is the most commonly used dopamine replacement medication
  • It is a precursor to dopamine that can cross the blood-brain barrier and is converted to dopamine in the brain
  • Levodopa is usually administered in combination with a decarboxylase inhibitor (carbidopa or benserazide) to prevent its peripheral conversion to dopamine and minimize side effects
• Dopamine agonists, such as pramipexole, ropinirole, and rotigotine, directly stimulate dopamine receptors in the brain
  • They can be used as an alternative or adjunct to levodopa, particularly in the early stages of the disease

Adjunctive medications

• Monoamine oxidase B (MAO-B) inhibitors, such as selegiline and rasagiline, block the enzyme that breaks down dopamine in the brain
  • This prolongs the effects of dopamine and can be used as an adjunct to levodopa or as monotherapy in early Parkinson's disease
• Catechol-O-methyltransferase (COMT) inhibitors, such as entacapone and tolcapone, inhibit the enzyme that degrades levodopa
  • By increasing the bioavailability and duration of action of levodopa, COMT inhibitors can help manage motor fluctuations and wearing-off effects in advanced Parkinson's disease

Surgical and non-pharmacological treatments

• Deep brain stimulation (DBS) is a surgical treatment option for advanced Parkinson's disease that involves the implantation of electrodes in specific regions of the basal ganglia
  • The most common targets for DBS are the subthalamic nucleus and the globus pallidus interna
  • By delivering high-frequency electrical stimulation, DBS can modulate abnormal neural activity and improve motor symptoms in patients who no longer respond adequately to medication
• Non-pharmacological treatments play an important role in managing the motor and non-motor symptoms of Parkinson's disease and improving quality of life
  • Physical therapy focuses on maintaining mobility, strength, and balance through exercises and gait training
  • Occupational therapy helps patients adapt to daily living activities and maintain independence
  • Speech therapy addresses speech and swallowing difficulties, which are common in Parkinson's disease