Introduction

Cervical dystonia is characterised by irregular movements in the head and neck as a result of involuntary muscle contractions. This is often accompanied by pain and tremor.¹ The primary cause of this condition is dysfunction in a region of the brain known as the basal ganglia. However, other areas are known to be involved as well.² 

The basal ganglia regulate motor pathways that rely on multiple neurotransmitters, such as dopamine, glutamate, and GABA. Imbalances or abnormalities in the neurotransmitters within this network can lead to abnormal muscle contractions and disrupt normal muscle movement.³ 

Understanding these neuronal pathways and neurotransmitter roles is key to explaining the symptoms of cervical dystonia and informing more effective treatments.

Neurotransmitter dysregulation

Dopamine

An important neurotransmitter in the basal ganglia is dopamine. It is responsible for movement and cognition, but regulates other functions as well.⁴ It is heavily involved in the cortico-basal ganglia circuit, which will be discussed in more detail below. The projection of dopaminergic neurons between the cortex and basal ganglia within this circuit enables the initiation of intended motor movements while suppressing unwanted ones. The structures within the basal ganglia form two pathways that either promote movement or inhibit movement, depending on which pathway is activated by dopamine.⁵ 

A disruption in the level of dopamine in the brain is linked to impaired movement and inhibition. In the striatum, which is a major subregion of the basal ganglia, the imbalance between different dopaminergic receptors causes hyperexcitability within the cortico-basal ganglia circuit.⁶ This plays a key role in involuntary muscle contractions. Although very important in muscle control, dopamine is one of multiple neurotransmitters involved in this process.

GABA

GABA is the major inhibitory neurotransmitter within the central nervous system. Like dopamine, it is important in motor control and is present in the basal ganglia, acting within the cortico-basal ganglia circuit to regulate muscle tone activity. The GABAergic pathways within this circuit specifically help to maintain the balance between wanted and unwanted movements. It can be thought of as the regulatory neurotransmitter in the basal ganglia circuit. Similarly to dopamine, a disruption in the levels of GABA will lead to a lower control of muscle activity by the brain and therefore cause increased unwanted movements. These movements are linked to multiple conditions, such as cervical dystonia and Huntington’s disease.⁷ 

Understanding the function and role of this neurotransmitter in the brain and the way it affects movement is important for people affected by cervical dystonia. Benzodiazepines enhance the effects of GABA by binding to the same receptor sites, allowing more of this neurotransmitter to be released and act within the brain.⁸ This leads to increased inhibitory action of GABA and can help regulate the hyperexcitability of muscles in cervical dystonia.

Acetylcholine

Acetylcholine is another important neurotransmitter in the body involved in muscle contraction. It functions similarly to GABA in the basal ganglia by balancing dopamine activity to regulate wanted and unwanted movements. One reason supporting this is the significant use of anticholinergic drugs in most types of dystonia. Additionally, studies have shown that enhancing the effects of acetylcholine through acetylcholine agonists induces dystonia in humans.⁹ 

Acetylcholine mainly regulates motor output by acting on interneurons in the striatum. These interneurons act on nicotinic and muscarinic receptors and help to balance out pathways expressed by dopaminergic and GABAergic neurons, and help control the balance of wanted and unwanted movements through this.¹⁰ Having this in mind, it suggests that an increased level of striatal acetylcholine will lead to movement imbalances and involuntary muscle contractions.

Other neurotransmitters

Another key neurotransmitter involved in the basal ganglia is glutamate, the major excitatory neurotransmitter of the nervous system. Glutamate also serves an excitatory role in the basal ganglia, particularly within the cortico-basal ganglia circuit, where it contributes to generating motor output. It carries both information from the cortex and the thalamus to structures within the basal ganglia that lead to excitation and facilitation of the neuronal circuit.¹¹ Disruption in the levels of glutamate can lead to cervical dystonia through excessive excitation. In other words, there can be a higher level of excitation compared to inhibition that leads to abnormal muscle contractions.

While they are less important, we can’t ignore the other two neurotransmitters: serotonin and norepinephrine. Although not directly related to modulating motor movement in the basal ganglia, both noradrenergic and serotonergic neurons innervate the region in fine-tuning the circuits.^12,13

Motor circuitry involvement

Basal ganglia

Having discussed the key neurotransmitters that regulate muscle movement and how their dysregulation may contribute to cervical dystonia, we can now look at the basal ganglia in greater detail to place this in a broader context.

The main nuclei in the basal ganglia that are involved in the cortico-basal ganglia circuit are the striatum (formed by the caudate and putamen), globus pallidus externus (GPe), globus pallidus internus (GPi), subthalamic nucleus (STN), and the substantia nigra pars reticulata (SNr). The two main pathways involved in this circuit are called the direct and the indirect pathway.¹⁴

The first step of the direct pathway involves excitation of the striatum by glutamatergic neurons, which in turn inhibits the GPi and SNr. Under normal conditions, the GPi and SNr send inhibitory GABAergic projections to the thalamus, suppressing its activity. However, when activated, since GPi and SNr themselves become inhibited, the thalamus can excite the cortex and therefore action is promoted. This is called disinhibition.

The indirect pathway, in turn, works antagonistically to the direct pathway.¹⁴ It is called indirect as the projections from the striatum are not directly connected to the GPi and SNr, but rather go first through the GPe, then STN before reaching the GPi and SNr. The connections in this pathway are slightly more complicated, so let’s break them down step by step:

• The striatum sends inhibitory GABAergic projections to the GPe
• The GPe also sends inhibitory GABAergic projections to the STN
• STN, however, sends excitatory Glutaminergic projections to the GPi/SNr
• The pathway after this is the same as the direct pathway

When activated, the striatum causes disinhibition of the STN by inhibiting GPe and allows STN to send excitatory glutaminergic projections to the GPi/SNr. This causes inhibition of the thalamus, which therefore inhibits its output back to the cortex (excitatory).

Additionally, projection neurons from the striatum are referred to as medium-sized spiny neurons (MSNs), which express two different types of dopamine receptors: D1R and D2R. When dopamine binds to D1R receptors, the direct pathway is activated. However, when the D2R receptors are activated by dopamine, the indirect pathway is activated.¹⁵

Cerebral cortex

The cerebral cortex plays a key role in the cortico-basal ganglia circuit by being the main starting point and the final site of movement execution. The cortex sends glutaminergic projections to the striatum within the circuit. Meanwhile, the cerebral cortex is also the end point of the circuit, receiving its information from the thalamus, which leads to the execution of movement.¹⁵ Maladaptive plasticity changes within the cerebral cortex have been related to the incidence of cervical dystonia. Studies have shown that people affected by cervical dystonia show a higher plasticity in the motor cortex.¹⁶ 

Integration: linking neurotransmitters and circuit dysfunction

Now it’s time to bring everything together and link the circuit dysfunctions to neurotransmitter imbalances. We will start with dopamine, which acts within the basal ganglia on the D1R and D2R receptors. When there is an imbalance of dopamine, there are differences in the activation of D1R and D2R. This leads to an overreactivity of the direct pathway, causing muscle spasms that can be seen in cervical dystonia.

As for GABA and glutamate, projections within the cortico-basal ganglia circuits are formed both by GABAergic and glutaminergic neurons, making it easier to understand how an imbalance in the levels of neurotransmitters can lead to muscle contraction and spasms such as those in cervical dystonia. Enhanced excitatory input by glutamate or decreased inhibitory input by a decreased level of GABA may facilitate and increase the feedback from the basal ganglia to the cerebral cortex. 

Summary

Understanding the relationship between neurotransmitters and motor circuits is key to understanding the pathophysiology of cervical dystonia, but also important in targeting the condition pharmacologically. While there is no single cause, cervical dystonia is a result of a network disorder that involves both chemical and structural dysfunctions.

Current treatment for cervical dystonia includes botulinum toxin by means of intramuscular injections to block the release of acetylcholine. Benzodiazepines, baclofen, and other anticholinergic agents are used as adjuncts with botulinum toxin in treatment, showing how important the treatment of neurotransmitter imbalances is in people affected by cervical dystonia.¹⁷