EXTRAPYRAMIDAL PATHWAY: COMPONENTS, FUNCTION, ROUTE, DISEASES - ANATOMY AND PHYSIOLOGY - 2025

The notion of the extrapyramidal pathway or the extrapyramidal system (EPS) arose as a result of anatomical and physiological studies aimed at understanding the way in which the central nervous system controlled the activity of the skeletal muscles, with the aim that the body assumed the proper body posture and produce voluntary movements.

In this process, it was discovered that the control of muscular activity required the control of the motor neurons of the anterior horn of the spinal cord, the only connection between the central nervous system and skeletal muscle fibers, and that this control was exercised by nerve projections from brain centers. superiors.

Basal ganglia anatomy (Source: Beckie Port, adapted from original work by Jlienard, previously derived from work by Andrew Gillies', Mikael Häggström's and Patrick J. Lynch's via Wikimedia Commons)

Among these projections, an important pathway is formed by some axons that originate in the motor areas of the cerebral cortex and descend directly, that is, without scales, to the spinal cord, joining, as they pass through the medulla oblongata, in some prominences which, due to their shape, were called "pyramids".

This tract was called the “pyramidal tract” or “corticospinal tract” and it was involved in the control of the fine and skillful movements executed by the distal portions of the limbs, while the existence of structures with motor function but not included was recognized. in this way (extra).

The term “extrapyramidal motor system”, already obsolete from a physiological point of view, is still used in clinical jargon to refer to those structures of the brain and brainstem that collaborate in motor control, but are not part of the pyramidal system or direct corticospinal.

Anatomical components and function of the pyramidal pathway

The extrapyramidal pathway can be described as organized into two groups of components: one would be made up of a set of brain stem nuclei and their projections towards the spinal cord, and the other would be made up of the subcortical nuclei known as nuclei or basal ganglia.

- Brainstem nuclei

In the brain stem there are groups of neurons whose axons project into the gray matter of the spinal cord and which have been described as organized in two systems: one medial and the other lateral.

Medial system

The medial system is made up of the vestibulospinal, reticulospinal, and tectospinal tracts that descend through the ventral cords of the cord and exert control over the axial or trunk muscles, in addition to the proximal muscles of the extremities involved in body posture.

Lateral system

The most important component of the lateral system is the rubro-spinal tract, whose axons project from the red midbrain nucleus, descend through the lateral cord of the spinal cord and end up influencing the motor neurons that control the distal muscles of the extremities.

From the foregoing, it can be deduced that the medial system collaborates in the basic postural adjustments, necessary for voluntary motor activity, while the lateral system deals, together with the direct corticospinal route, with the movements of the extremities aimed at a purpose such as reaching and manipulate objects.

- Basal ganglia

The basal ganglia are subcortical neuronal structures that are involved in the processing of motor information such as planning and programming of complex skillful movements, and whose alterations give clinical manifestations that are grouped into syndromes known as “extrapyramidal”.

Ganglia include the striatum, which is made up of the putamen and the caudate nucleus; the pale globe, which has an external portion (GPe) and an internal portion (GPi); the substantia nigra, organized into a compact portion (SNc) and a reticulated portion (SNr), and the subthalamic or Lewis nucleus.

These structures work by receiving information mainly from different regions of the cerebral cortex; information that sets in motion internal circuits that affect an output neuronal activity that returns, via the motor portion of the thalamus, to the cerebral cortex.

- Connectivity, pathway and neurochemistry in the basal ganglia

Information about the ganglia enters through the striatum (caudate and putamen). From there, pathways begin that connect with the exit nuclei that are the GPi and the SNr, whose axons go to the ventroanterior and ventrolateral nuclei of the thalamus, which, in turn, project to the cortex.

The different stages of the circuit are covered by neurons that belong to a particular neurochemical system and that can have an inhibitory or excitatory effect. The cortico-striated connections, the thalamus-cortical and the subthalamic fibers release glutamate and are excitatory.

Neurons whose axons exit the striatum use gamma amino butyric acid (GABA) as the main neurotransmitter and are inhibitory. There are two subpopulations: one synthesizes substance P as a cotransmitter and the other enkephalin.

GABA neurons (+ Substitute P)

GABA (+ Sust. P) neurons have D1 dopamine receptors and are excited by dopamine (DA); they also establish a direct inhibitory connection with the basal ganglia outlets (GPi and SNr) that are also GABAergic but “+ dynorphin” and inhibit glutamatergic cells of thalamic-cortical projection.

GABA neurons (+ Encef.)

GABA (+ Enceph.) Neurons have D2 dopamine receptors and are inhibited by dopamine. They establish an indirect excitatory connection with the outputs (GPi and SNr), since they project to the GPe, inhibiting their GABAergic neurons, which inhibit the glutamatergic neurons of the subthalamic nucleus, whose function is to activate the outputs (GPi and SNr).

The compact part of the substantia nigra (SNc) has dopaminergic neurons (DA) that connect with the striatum making connections, as already mentioned, excitatory D1 on GABA cells (+ Sub. P) and inhibitory D2 on GABA cells (+ Encef.).

Then, and in accordance with the above, an activation of the direct pathway ends up inhibiting the outputs of the basal ganglia and releasing the activity in the thalamic-cortical connections, while the activation of the indirect pathway activates the outputs and reduces thalamic activity. -cortical.

Although the interactions and the exact joint functioning of the direct and indirect pathways just considered have not been clarified, the anatomical and neurochemical organization described helps us to understand, at least in part, some pathological conditions resulting from dysfunction of the basal ganglia.

Basal ganglia diseases

Although the pathological processes that settle in the basal ganglia are diverse in nature and affect not only certain motor functions but also cognitive, associative and emotional functions, in clinical pictures motor alterations occupy a prominent place and most of the research it has focused on them.

The movement disorders typical of basal ganglia dysfunction can be classified into one of three groups, namely:

- Hyperkinesias, such as Huntington's disease or chorea and hemibalism.

- Hypokinesias, such as Parkinson's disease.

- Dystonias, such as athetosis.

In general terms, it can be said that hyperkinetic disorders, characterized by excessive motor activity, present with a decrease in the inhibition that the outputs (GPi and SNr) exert on the thalamic-cortical projections, which become more active.

Hypokinetic disorders, on the other hand, are accompanied by an increase in this inhibition, with a reduction in thalamic-cortical activity.

Huntington's disease

It is a hyperkinetic disorder characterized by involuntary and spasmodic random jerking of the extremities and orofacial region, choreiform or "dance" movements that gradually increase and incapacitate the patient, speech disturbance and progressive development of dementia.

The disease is accompanied early by a degeneration of the GABA (+ Encef.) Striatal neurons of the indirect pathway.

As these neurons no longer inhibit GPe GABAergic neurons, they exaggeratedly inhibit the subthalamic nucleus, which stops exciting the inhibitory outputs (GPi and SNr) and the thalamic-cortical projections are disinhibited.

Hemibalism

It consists of the violent contractions of the proximal muscles of the limbs, which are projected with force in large-scale movements. The damage in this case is the degeneration of the subthalamic nucleus, which results in something similar to that described for chorea, although not by hyper inhibition, but by destruction of the subthalamic nucleus.

Parkinson's disease

It is characterized by difficulty and delay in the initiation of movements (akinesia), slowing of movements (hypokinesia), an expressionless face or facial expression in a mask, gait alteration with decreased associated movements of the limbs during movement and tremor Involuntary limbs at rest.

The damage, in this case, consists of the degeneration of the nigrostriatal system, which are the dopaminergic projections that start from the compact region of the substantia nigra (SNc) and connect with the striatal neurons that give rise to the direct and indirect pathways.

The suppression of the excitation that the dopaminergic fibers exert on the GABA (+ Sust. P) cells of the direct pathway, removes the inhibition that these exert on the GABAergic outlets (GPi and SNr) towards the thalamus, which is now more inhibited. intensity. It is then a disinhibition of the outputs.

On the other hand, the suppression of the inhibitory activity that dopamine exerts on the GABA cells (+ Encef.) Of the indirect pathway releases them and increases the inhibition they exert on the GABA cells of GPe, which disinhibits the neurons of the nucleus subthalamic, which then hyperactivates the outputs.

As can be seen, the final result of the effects of dopaminergic degeneration on the two internal pathways, direct and indirect, is the same, whether it is disinhibition or stimulation of the GABAergic outputs (GPi and SNr) that inhibit the nuclei thalamic and reduce their output into the cortex, which explains the hypokinesis

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