The indirect pathway, sometimes known as the indirect pathway of movement, is a neuronal circuit through the basal ganglia and several associated nuclei within the central nervous system (CNS) which helps to prevent unwanted muscle contractions from competing with voluntary movements. [1] It operates in conjunction with the direct pathway.
The indirect pathway originates in the D2 subtype of the striatal medium spiny neuron [2] , which respond to the absence of continuous dopamine signal. The indirect pathway passes through the caudate, putamen, and globus pallidus, which are parts of the basal ganglia. [3] It traverses the subthalamic nucleus, a part of the diencephalon, and enters the substantia nigra, a part of the midbrain. In a resting individual, a specific region of the globus pallidus, known as the internus, and a portion of the substantia nigra, known as the pars reticulata, send spontaneous inhibitory signals to the ventrolateral nucleus (VL) of the thalamus, through the release of GABA, an inhibitory neurotransmitter. [4] Inhibition of the excitatory neurons within VL, which project to the motor regions of the cerebral cortices of the telencephalon, leads to a reduction of activity in the motor cortices, and a lack of muscular action. [5]
When the prefrontal cortex, which is generally involved in decision making and planning, determines that motor activity be executed, it sends activating signals to the motor cortices. The motor cortices send activating signals to the direct pathway through the basal ganglia, which stops inhibitory outflow from parts of the globus pallidus internus and the substantia nigra pars reticulata. The net effect is to allow the activation of the ventrolateral nucleus of the thalamus which, in turn, sends activating signals to the motor cortices. These events amplify motor cortical activity that will eventually drive muscle contractions.
Simultaneously, in the indirect pathway, the motor cortices send activating signals to the caudate and putamen. The cells of the indirect pathway in the caudate and putamen that receive these signals are inhibitory and, once activated, they send inhibitory signals to the globus pallidus externus, reducing the activity in that nucleus. The globus pallidus externus normally sends inhibitory signals to the subthalamic nucleus. On activation of the indirect pathway, these inhibitory signals are reduced, which allows more activation of the subthalamic nucleus. Subthalamic nucleus cells can then send more activating signals to some parts of the globus pallidus internus and substantia nigra pars reticulata. Thus, parts of these two nuclei are driven to send more inhibitory signals to the ventrolateral nucleus of the thalamus, which prevents the development of significant activity in the motor cerebral cortices. This behavior prevents the activation of motor cortical areas that would compete with the voluntary movement.
Interruption or dysfunction of the indirect pathway of movement results in hyperkinesia, or dyskinesias, which are, in general, diseases which lead to the production of additional involuntary muscle activity.
The putamen is a round structure located at the base of the forebrain (telencephalon). The putamen and caudate nucleus together form the dorsal striatum. It is also one of the structures that compose the basal nuclei. Through various pathways, the putamen is connected to the substantia nigra, the globus pallidus, the claustrum, and the thalamus, in addition to many regions of the cerebral cortex. A primary function of the putamen is to regulate movements at various stages and influence various types of learning. It employs GABA, acetylcholine, and enkephalin to perform its functions. The putamen also plays a role in degenerative neurological disorders, such as Parkinson's disease.
The striatum or corpus striatum is a nucleus in the subcortical basal ganglia of the forebrain. The striatum is a critical component of the motor and reward systems; receives glutamatergic and dopaminergic inputs from different sources; and serves as the primary input to the rest of the basal ganglia.
The substantia nigra (SN) is a basal ganglia structure located in the midbrain that plays an important role in reward and movement. Substantia nigra is Latin for "black substance", reflecting the fact that parts of the substantia nigra appear darker than neighboring areas due to high levels of neuromelanin in dopaminergic neurons. Parkinson's disease is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta.
The basal ganglia (BG) or basal nuclei are a group of subcortical nuclei found in the brains of vertebrates. In humans and other primates, differences exist, primarily in the division of the globus pallidus into external and internal regions, and in the division of the striatum. Positioned at the base of the forebrain and the top of the midbrain, they have strong connections with the cerebral cortex, thalamus, brainstem and other brain areas. The basal ganglia are associated with a variety of functions, including regulating voluntary motor movements, procedural learning, habit formation, conditional learning, eye movements, cognition, and emotion.
In neuroanatomy, a nucleus is a cluster of neurons in the central nervous system, located deep within the cerebral hemispheres and brainstem. The neurons in one nucleus usually have roughly similar connections and functions. Nuclei are connected to other nuclei by tracts, the bundles (fascicles) of axons extending from the cell bodies. A nucleus is one of the two most common forms of nerve cell organization, the other being layered structures such as the cerebral cortex or cerebellar cortex. In anatomical sections, a nucleus shows up as a region of gray matter, often bordered by white matter. The vertebrate brain contains hundreds of distinguishable nuclei, varying widely in shape and size. A nucleus may itself have a complex internal structure, with multiple types of neurons arranged in clumps (subnuclei) or layers.
The globus pallidus (GP), also known as paleostriatum or dorsal pallidum, is a subcortical structure of the brain. It consists of two adjacent segments, one external, known in rodents simply as the globus pallidus, and one internal, known in rodents as the entopeduncular nucleus. It is part of the telencephalon, but retains close functional ties with the subthalamus in the diencephalon – both of which are part of the extrapyramidal motor system. The globus pallidus is a major component of the basal ganglia, with principal inputs from the striatum, and principal direct outputs to the thalamus and the substantia nigra. The latter is made up of similar neuronal elements, has similar afferents from the striatum, similar projections to the thalamus, and has a similar synaptology. Neither receives direct cortical afferents, and both receive substantial additional inputs from the intralaminar thalamus.
The nigrostriatal pathway is a bilateral dopaminergic pathway in the brain that connects the substantia nigra pars compacta (SNc) in the midbrain with the dorsal striatum in the forebrain. It is one of the four major dopamine pathways in the brain, and is critical in the production of movement as part of a system called the basal ganglia motor loop. Dopaminergic neurons of this pathway release dopamine from axon terminals that synapse onto GABAergic medium spiny neurons (MSNs), also known as spiny projection neurons (SPNs), located in the striatum.
The direct pathway, sometimes known as the direct pathway of movement, is a neural pathway within the central nervous system (CNS) through the basal ganglia which facilitates the initiation and execution of voluntary movement. It works in conjunction with the indirect pathway. Both of these pathways are part of the cortico-basal ganglia-thalamo-cortical loop.
The subthalamic nucleus (STN) is a small lens-shaped nucleus in the brain where it is, from a functional point of view, part of the basal ganglia system. In terms of anatomy, it is the major part of the subthalamus. As suggested by its name, the subthalamic nucleus is located ventral to the thalamus. It is also dorsal to the substantia nigra and medial to the internal capsule. It was first described by Jules Bernard Luys in 1865, and the term corpus Luysi or Luys' body is still sometimes used.
Hypokinesia is one of the classifications of movement disorders, and refers to decreased bodily movement. Hypokinesia is characterized by a partial or complete loss of muscle movement due to a disruption in the basal ganglia. Hypokinesia is a symptom of Parkinson's disease shown as muscle rigidity and an inability to produce movement. It is also associated with mental health disorders and prolonged inactivity due to illness, amongst other diseases.
The pars reticulata (SNpr) is a portion of the substantia nigra and is located lateral to the pars compacta. Most of the neurons that project out of the pars reticulata are inhibitory GABAergic neurons.
The pedunculopontine nucleus (PPN) or pedunculopontine tegmental nucleus is a collection of neurons located in the upper pons in the brainstem. It is involved in voluntary movements, arousal, and provides sensory feedback to the cerebral cortex and one of the main components of the reticular activating system. It is a potential target for deep brain stimulation treatment for Parkinson's disease. It was first described in 1909 by Louis Jacobsohn-Lask, a German neuroanatomist.
The subthalamus or prethalamus is a part of the diencephalon. Its most prominent structure is the subthalamic nucleus. The subthalamus connects to the globus pallidus, a basal nucleus of the telencephalon.
The basal ganglia form a major brain system in all species of vertebrates, but in primates there are special features that justify a separate consideration. As in other vertebrates, the primate basal ganglia can be divided into striatal, pallidal, nigral, and subthalamic components. In primates, however, there are two pallidal subdivisions called the external globus pallidus (GPe) and internal globus pallidus (GPi). Also in primates, the dorsal striatum is divided by a large tract called the internal capsule into two masses named the caudate nucleus and the putamen—in most other species no such division exists, and only the striatum as a whole is recognized. Beyond this, there is a complex circuitry of connections between the striatum and cortex that is specific to primates. This complexity reflects the difference in functioning of different cortical areas in the primate brain.
Medium spiny neurons (MSNs), also known as spiny projection neurons (SPNs), are a special type of GABAergic inhibitory cell representing 95% of neurons within the human striatum, a basal ganglia structure. Medium spiny neurons have two primary phenotypes : D1-type MSNs of the direct pathway and D2-type MSNs of the indirect pathway. Most striatal MSNs contain only D1-type or D2-type dopamine receptors, but a subpopulation of MSNs exhibit both phenotypes.
The external globus pallidus combines with the internal globus pallidus (GPi) to form the globus pallidus, an anatomical subset of the basal ganglia. Globus pallidus means "pale globe" in Latin, indicating its appearance. The external globus pallidus is the segment of the globus pallidus that is relatively further (lateral) from the midline of the brain.
The internal globus pallidus and the external globus pallidus (GPe) make up the globus pallidus. The GPi is one of the output nuclei of the basal ganglia. The GABAergic neurons of the GPi send their axons to the ventral anterior nucleus (VA) and the ventral lateral nucleus (VL) in the dorsal thalamus, to the centromedian complex, and to the pedunculopontine complex.
Basal ganglia disease is a group of physical problems that occur when the group of nuclei in the brain known as the basal ganglia fail to properly suppress unwanted movements or to properly prime upper motor neuron circuits to initiate motor function. Research indicates that increased output of the basal ganglia inhibits thalamocortical projection neurons. Proper activation or deactivation of these neurons is an integral component for proper movement. If something causes too much basal ganglia output, then the ventral anterior (VA) and ventral lateral (VL) thalamocortical projection neurons become too inhibited, and one cannot initiate voluntary movement. These disorders are known as hypokinetic disorders. However, a disorder leading to abnormally low output of the basal ganglia leads to reduced inhibition, and thus excitation, of the thalamocortical projection neurons which synapse onto the cortex. This situation leads to an inability to suppress unwanted movements. These disorders are known as hyperkinetic disorders.
Blocq's disease was first considered by Paul Blocq (1860–1896), who described this phenomenon as the loss of memory of specialized movements causing the inability to maintain an upright posture, despite normal function of the legs in the bed. The patient is able to stand up, but as soon as the feet are on the ground, the patient cannot hold himself upright nor walk; however when lying down, the subject conserved the integrity of muscular force and the precision of movements of the lower limbs. The motivation of this study came when a fellow student Georges Marinesco (1864) and Paul published a case of parkinsonian tremor (1893) due to a tumor located in the substantia nigra.
The cortico-basal ganglia-thalamo-cortical loop is a system of neural circuits in the brain. The loop involves connections between the cortex, the basal ganglia, the thalamus, and back to the cortex. It is of particular relevance to hyperkinetic and hypokinetic movement disorders, such as Parkinson's disease and Huntington's disease, as well as to mental disorders of control, such as attention deficit hyperactivity disorder (ADHD), obsessive–compulsive disorder (OCD), and Tourette syndrome.