Basal ganglia pathways
Each day we are doing thousands of movements, from walking to writing and so many more. Have you ever wondered which system is responsible for organizing and smoothening all these movements? The answer to that question lies within the structure called basal ganglia.
The basal ganglia are a collection of subcortical structures consisting of several connected nuclei located in the brain. They are called the caudate nucleus, putamen, globus pallidus, subthalamic nucleus, and substantia nigra (the last two are only functionally connected and related to this system).
Three major pathways emerge from the basal ganglia, which project onto various structures of the brain, communicating with them. They are called the direct (excitatory), indirect (inhibitory) and hyperdirect (inhibitory) pathways. The activity of the direct and indirect pathways are modulated by D1 and D2 dopamine receptors contained in the substantia nigra, pars compacta. The hyperdirect pathway bypasses the striatum and therefore the substantia nigra compacta does not play a role in its regulation.
This article will explain them, and also provide you with some relevant clinical aspects about them and the basal ganglia.
|Basal ganglia||Nuclei: Striatum, globus pallidus, subthalamic nucleus, substantia nigra
Function: movement modulation
|Direct pathway||Type: Excitatory
Pathway: cortex -> striatum -> globus pallidus, pars interna -> thalamus -> motor cortex -> spinal cord / brainstem
Function: movement initiation
|Indirect pathway||Type: Inhibitory
Pathway: cortex -> striatum -> globus pallidus, pars externa -> subthalamic nucleus -> globus pallidus, pars externa -> thalamus -> motor cortex -> spinal cord / brainstem
Function: movement termination
|Hyperdirect pathway||Type: inhibitory
Pathway: cortex -> subthalamic nucleus -> globus pallidus, pars externa -> thalamus -> cortex -> spinal cord / brainstem
Function: baseline inhibition, inhibition of extemporous movement
|Function modulation||Nigrostriatal and thalamostriatal pathways|
|Clinical aspects||Hypertonic-hypokinetic and hypotonic-hyperkinetic syndromes|
- Direct pathway
- Indirect pathway
- Hyperdirect pathway
- Modulation of the basal ganglia
- Clinical aspects
The “basal ganglia” or basal nuclei, refers to a group of nuclei situated deep within the cerebral hemispheres and form a major portion of the “extrapyramidal system”. This system receives inputs from wide areas of the cerebral cortex and returns it, via the thalamus, to the cortex and brainstem.
The major structures that compose the basal ganglia are:
- the striatum (Str), which includes the caudate nucleus and the putamen,
- the globus pallidus (GP) which is divided into two segments, the internal (GPi) and external parts (GPe),
- the subthalamic nucleus (STN)
- the substantia nigra (SN) which is also divided into two parts, the reticular part (SNr) and the compact part (SNc).
All these structures lay in the core of the cerebral hemispheres, wrapped around by the ventricular system and separated between them with an abundant network of descending and ascending pathways that connect the cerebral cortex and the brainstem.
The basal ganglia or nuclei are heavily interconnected and play an important role in motor planning and modulation. By choosing the intended movement, the basal ganglia use different pathways to initiate and terminate the motor program, by controlling the muscle tone, muscle length, speed, and strength of the movement by using the pyramidal system as the executor.
To make this possible, the basal ganglia use three pathways: the direct, indirect and hyperdirect pathway.
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The direct pathway starts from the cortex and projects to the striatum (caudate nucleus and putamen) with excitatory glutamatergic (glu) neurons. The neurons from the striatum, which are inhibitory GABAergic, send their axons to the medial (internal) globus pallidus and substantia nigra, pars reticulata (SNr).
The neurons from the internal globus pallidus and SNr send their axons to the thalamus, and they are also inhibitory. The fibers that travel from the pallidum to the thalamus, form two white matter fascicles called ansa lenticularis and lenticular fasciculus, that fuse into one pathway called thalamic fasciculus just before they enter the thalamus.
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From the thalamus, excitatory pathways go to the cortex (prefrontal, premotor and supplementary cortex) where they affect the planning of the movement by synapsing with the neurons of the corticospinal and corticobulbar tracts in the brainstem and spinal cord.
In summary, we have the following connections:
- Cortex - Striatum (glu)
- Striatum - GPi/SNr (GABA)
- GPi/SNr - Thalamus (GABA)
This entire system functions on the principle of positive feedback. Since the two of the inhibitory synapses are serially connected, that means that the first inhibitory neuron (striatum) suppresses the activity of the second inhibitory neuron (globus pallidus). The result of this is a reduction of the inhibitory influence that the globus pallidus has over the thalamus, so-called disinhibition of the thalamus, which is equivalent to the excitation of the motor cortex. So the final function of the direct pathway of the basal ganglia is to excite the motor cortex or to increase the motor activity.
This pathway begins (like the direct pathway) from the cortex, projecting to the striatum. Instead of sending axons directly to the GPi and SNr, they project to the external globus pallidus.
The neurons from the GPe send inhibitory fibers to the subthalamic nucleus instead of sending directly to the thalamus (hence its name “indirect”). From the subthalamic nucleus, neurons send their axons to the GPi/SNr and then continue as the direct pathway with GABAergic inhibitory neurons to the thalamus and glutamate excitatory efferents to the cortex.
So, functionally, the striatum inhibits the external globus pallidus, and that causes disinhibition of the subthalamus. For that reason, the neurons of the subthalamus become more active, and they excite the internal segment of the globus pallidus which in the end, inhibits the thalamic nuclei. The final result of this pathway is a decreased activity of the cortical motor neurons and consequential suppression of the extemporaneous movement.
The hyperdirect pathway consists of neurons projecting from the cortex directly to the subthalamic nucleus (STN). Those fibers convey strong excitatory signals to the GPi/SNr with shorter conduction time than the direct and indirect pathway, bypassing the striatum.
When receiving glutamatergic inputs from the cerebral cortex directly to the subthalamic nucleus, it then excites the GPi/SNr thus suppressing thalamic activity on the cerebral cortex and increasing inhibitory influences on the upper motor neurons. As a result, together with the indirect pathway, only the selected motor program is executed and other competing motor programs are canceled.
In summary, when a given motor pattern is computed by the cerebral cortex, it is first conveyed to the basal ganglia via glutamatergic projections to the striatum, with the purpose of releasing the intended movement and suppressing the unintended ones. The direct pathway funnels the information from the striatum to GPi/SNr via GABAergic inhibitory projections thus selectively reducing its activity and releasing firing from the thalamocortical neurons to initiate the movement.
Along with the initial signal to the striatum, the cerebral cortex suppresses competing motor programs by the indirect and hyperdirect pathways. When excited by the glutamatergic inputs of the cerebral cortex, striatum sends inhibitory signals to the GPe which normally exerts GABAergic inhibition on the STN. Therefore, the glutamatergic excitatory neurons of the STN can then excite the GPi/SNr thus suppressing thalamic activity on the cerebral cortex and increasing inhibitory influences on the upper motor neurons.
Modulation of the basal ganglia
The neuronal circuits that modulate the function of the basal ganglia are:
- The nigrostriatal pathway
- The thalamostriatal pathway
This pathway projects from the substantia nigra pars compacta to the striatum, and it utilizes the neurotransmitter dopamine. This pathway has a modulatory effect on the basal ganglia, with dopamine facilitating the motor loop in these two ways:
- It excites the direct pathway
- It inhibits the indirect pathway
The different effect on the direct and indirect pathway is explained by the activation of the different dopamine receptors that are located within the neurons of the striatum. There are two types of dopamine receptors, D1 and D2, which respond differently when stimulated with dopamine. Stimulation of D1 results with the excitation of the neuron, while the stimulation D2 results with inhibition.
D1 receptors are found on the striatal neurons that give rise to the direct pathway. On the other hand, D2 receptors are found on the neurons whose axons form the indirect pathway. So the final effect of the nigrostriatal pathway is the promotion of the direct pathway and at the same time the inhibition of the indirect pathway. The activity of the neurons within the pars compacta substantia nigra is related to the reward system and behavioral stimuli, so it is thought that they play a role in some forms of motor learning.
These fibers arise from the intralaminar nuclei of the thalamus and terminate primarily in the striatum. Besides that, some fibers terminate in the globus pallidus and in the subthalamic nucleus.
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Disorders of the basal ganglia are classified into two categories: hypertonic-hypokinetic and hypotonic-hyperkinetic.
Hypertonicity is an abnormal increase of the muscle tone in response to passive stretch. As we have learned so far, when the indirect pathway of the basal ganglia is stimulated, it sends signals to the motor cortex and brainstem, which ultimately inhibit muscle tone. Following a lesion of the basal ganglia, this inhibitory influence is lost and hypertonicity is manifested contralateral to the side of the lesion.
Dyskinesia is a presence of the unintentional purposeless movements. Dyskinesias are classified further as:
These disorders are caused by a disturbance of the indirect loop that causes a loss of the inhibition of the thalamic neurons, which ultimately results in excess cortical activity and movement. They are presented as:
- Tremor, that is a rhythmic, low amplitude movement that may be manifested as the nodding of the head, or in the hands and feet.
- Chorea is a sequence of rapid involuntary movements involving mostly the hands and feet, the tongue, and facial muscles.
- Hemiballismus is a condition where the patient exhibits involuntary ballistic (violent striking) movements on only one side of the body, that affect only the proximal muscles of a limb.
- Ballismus is the equivalent to the hemiballismus, with the difference that it affects the entire body. It is the most extreme type of dyskinesia.
- Huntington’s disease is a rare inherited condition that manifests with severe chorea and hemiballismus that develop over time. The neuropathological substrate of the disease is the degeneration of the striatal neurons that give rise to the indirect pathway.
- Tics are brief, stereotyped semi-voluntary movements, which means that unlike other movement disorders, they are partially suppressible. Tics can be either motor (motor tics) or sounds (vocal tics). They are common in children and can appear as the result of direct brain injury (ex. head trauma or encephalitis). However, most of them are idiopathic and are part of the spectrum of Gilles de la Tourette syndrome or another idiopathic tic disorder.
- Dystonia is characterized by involuntary, sustained muscle contraction that leads to abnormal postures of the neck, toes, hands, or other parts of the body.
- Myoclonus is a jerky, involuntary, and usually arrhythmic movement. To imagine how myoclonus looks like, think of body jerks as one is falling asleep, this is physiological myoclonus.
These disorders result from the degeneration of the neurons that form the direct pathway. Since this is the pathway that serves for the planning of the movement, the problems that patients will have been presented in two forms:
- Bradykinesia that is presented with slow movement
- Akinesia is presented with the inability to move at all because the individual is unable to plan or to direct a movement toward a desired position or target.
Parkinson’s disease is the most prevalent disorder associated with basal ganglia. It is the result of the degeneration of the dopaminergic neurons of the pars compacta of the substantia nigra. This is actually the place of origin of the nigrostriatal pathway that is essential for the promotion of the direct pathway of the basal ganglia. Because of its damage, the excitation of the supplementary motor area which is of key significance for the movement planning is lost.
Essential tremor (ET) is a medical condition characterized by symmetrical involuntary rhythmic contractions and relaxations of certain muscle groups. It usually affects the arms, hands, or fingers; but sometimes involves the head, vocal cords, or other body parts, and it intensifies when one tries to use the affected muscles during voluntary movements such as eating and writing.
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