Cortico-basal ganglia-thalamo-cortical loop

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Cortico-basal ganglia-thalamo-cortical loop
Basal ganglia circuits.svg
Connections of the basal ganglia.
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Anatomical terms of neuroanatomy

The cortico-basal ganglia-thalamo-cortical loop (CBGTC 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, [1] as well as to mental disorders of control, such as attention deficit hyperactivity disorder (ADHD), [2] obsessive–compulsive disorder (OCD), [3] and Tourette syndrome. [4]

Contents

The CBGTC loop primarily consists of modulatory dopaminergic projections from the pars compacta of the substantia nigra, and ventral tegmental area as well as excitatory glutamatergic projections from the cortex to the striatum, where these projections form synapses with excitatory and inhibitory pathways that relay back to the cortex. The loop was originally proposed as a part of a model of the basal ganglia called the parallel processing model, which has been criticized and modified into another model called the center surround model. [5]

Current organization schemes characterize cortico-basal ganglia interactions as segregated parallel processing, meaning there is little convergence of distinct cortical areas in the basal ganglia. This is thought to explain the topographically organized functionality of the striatum. [4] The striatum is organized on a rostro-caudal axis, with the rostral putamen and caudate serving associative and cognitive functions and the caudal areas serving sensorimotor function. [6] Sometimes when the striatum is the expressed target the loop is referred to as the cortico-striatal-thalamic-cortical loop. [7]

Neuroanatomy

Indirect and direct pathways. Some neuroanatomy is excluded for simplicity. CBGTC.svg
Indirect and direct pathways. Some neuroanatomy is excluded for simplicity.

The two major input structures of the circuit are the striatum and the subthalamic nucleus (STN). The striatum receives inputs from both the cortex and the pars compacta of the substantia nigra (SNc), while the STN only receives cortical inputs.

Two pathways emerge from the striatum. One pathway is called the indirect (or NoGo) pathway and is inhibitory. This projects to and inhibits the globus pallidus externus (GPe), resulting in the disinhibition of the globus pallidus internus (GPi), leading to inhibition of the thalamus. This pathway also, as a result of inhibiting the GPe, disinhibits the subthalamic nucleus, which results in excitation of the GPi, and therefore inhibition of the thalamus.

The second pathway, is called the direct (or Go) pathway and is excitatory. This pathway inhibits the GPi, resulting in the disinhibition of the thalamus. The direct pathway mostly consists of monosynaptic connections driven by dopamine receptor D1, adenosine A1 receptor, and muscarinic acetylcholine receptor M4, while the indirect pathway relies on connections driven by dopamine receptor D2, adenosine A2A receptor, and muscarinic acetylcholine receptor M1. [1] [8]

The parallel CBGTC loops have been segregated according to the functions of associated cortical regions. One scheme involves the division into limbic and motor loops, with the motor loops containing indirect and direct pathways, which are in turn interconnected with the limbic loop that projects into the ventral striatum. [9] The loop has also been divided into limbic, associative, oculomotor, and motor circuits [4] to explain the role of dopamine in the basal ganglia on motivational states. [10] A five loop division based on primary cortical targets has been described as follows: [11]

A problem identified with the current anatomy of the circuit is that the time delay between the direct and indirect pathways should result in this circuit not working. To overcome this, the center surround hypothesis posits a hyperdirect pathway from the cortex would inhibit other inputs besides one focused cortical input. However, the timing of basal ganglia activity and limb moment, as well as lesion studies do not support this hypothesis [12]

Function

Two models have been proposed to explain how actions are selected in the basal ganglia. The actor-critic model suggests that actions are generated and evaluated by a "critic" in the ventral striatum, while the actions are carried out by an "actor" in the dorsal striatum. Another model proposes the basal ganglia acts as a selection mechanism, where actions are generated in the cortex and are selected based on context by the basal ganglia. [13] The CBGTC loop is also involved in reward discounting, with firing increasing with an unexpected or greater than expected reward. [2] One review supported the idea that the cortex was involved in learning actions regardless of their outcome, while the basal ganglia was involved in selecting appropriate actions based on associative reward based trial and error learning. [14]

Role in disease

The CBGTC loop has been implicated in many diseases. For example, in Parkinson's disease, degeneration of dopaminergic neurons leading to decreased activity of the excitatory pathway is thought to result in hypokinesia, [15] and in Huntington's disease, degeneration of GABAergic neurons driving the inhibitory pathway is thought to result in the jerky body movements. [2] The co-degeneration of limbic projections along with motor projections may result in many of the psychiatric symptoms of these primarily motor illnesses. [9] In OCD, the loop may be dysfunctional, with an imbalance between the indirect and direct pathways resulting in unwanted thoughts, getting "stuck". [3] In ADHD, decreased tonic dopaminergic signaling resulting in excessive discounting of delayed rewards is thought to result in decreased attention. [2]

Research

The CBGTC loop has been studied in relation to consciousness, action selection, in relation to other circuits, and in the context of memory and cognition. [16] [17] The CBGTC loop model has been criticized as oversimplified and too rigidly applied, given evidence of anatomical and functional overlap and interactions between the direct and indirect pathways. [18] The loop has also been researched in the context of deep brain stimulation. [16] As of 2013 there was intense debate with regards to division of the circuit, pathway interactions, number of pathways and general anatomy. [17]

Related Research Articles

<span class="mw-page-title-main">Putamen</span> Round structure at the base of the forebrain

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.

<span class="mw-page-title-main">Striatum</span> Nucleus in the basal ganglia of the brain

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.

<span class="mw-page-title-main">Substantia nigra</span> Structure in the basal ganglia of the brain

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.

<span class="mw-page-title-main">Basal ganglia</span> Group of subcortical nuclei involved in the motor and reward systems

The basal ganglia (BG), or basal nuclei, are a group of subcortical nuclei, of varied origin, in the brains of vertebrates. In humans, and some primates, there are some differences, mainly in the division of the globus pallidus into an external and internal region, and in the division of the striatum. The basal ganglia are situated at the base of the forebrain and top of the midbrain. Basal ganglia are strongly interconnected with the cerebral cortex, thalamus, and brainstem, as well as several other brain areas. The basal ganglia are associated with a variety of functions, including control of voluntary motor movements, procedural learning, habit learning, conditional learning, eye movements, cognition, and emotion.

<span class="mw-page-title-main">Caudate nucleus</span> Structure of the striatum in the basal ganglia of the brain

The caudate nucleus is one of the structures that make up the corpus striatum, which is a component of the basal ganglia in the human brain. While the caudate nucleus has long been associated with motor processes due to its role in Parkinson's disease, it plays important roles in various other nonmotor functions as well, including procedural learning, associative learning and inhibitory control of action, among other functions. The caudate is also one of the brain structures which compose the reward system and functions as part of the cortico–basal ganglia–thalamic loop.

<span class="mw-page-title-main">Nucleus accumbens</span> Region of the basal forebrain

The nucleus accumbens is a region in the basal forebrain rostral to the preoptic area of the hypothalamus. The nucleus accumbens and the olfactory tubercle collectively form the ventral striatum. The ventral striatum and dorsal striatum collectively form the striatum, which is the main component of the basal ganglia. The dopaminergic neurons of the mesolimbic pathway project onto the GABAergic medium spiny neurons of the nucleus accumbens and olfactory tubercle. Each cerebral hemisphere has its own nucleus accumbens, which can be divided into two structures: the nucleus accumbens core and the nucleus accumbens shell. These substructures have different morphology and functions.

<span class="mw-page-title-main">Neural pathway</span> Connection formed between neurons that allows neurotransmission

In neuroanatomy, a neural pathway is the connection formed by axons that project from neurons to make synapses onto neurons in another location, to enable neurotransmission. Neurons are connected by a single axon, or by a bundle of axons known as a nerve tract, or fasciculus. Shorter neural pathways are found within grey matter in the brain, whereas longer projections, made up of myelinated axons, constitute white matter.

<span class="mw-page-title-main">Dopaminergic pathways</span> Projection neurons in the brain that synthesize and release dopamine

Dopaminergic pathways in the human brain are involved in both physiological and behavioral processes including movement, cognition, executive functions, reward, motivation, and neuroendocrine control. Each pathway is a set of projection neurons, consisting of individual dopaminergic neurons.

<span class="mw-page-title-main">Nigrostriatal pathway</span>

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.

<span class="mw-page-title-main">Direct pathway</span> Neural pathway that executes voluntary movements

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.

<span class="mw-page-title-main">Indirect pathway</span> Neuronal circuit that suppresses unwanted movements

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. It operates in conjunction with the direct pathway.

<span class="mw-page-title-main">Primate basal ganglia</span>

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.

<span class="mw-page-title-main">Medium spiny neuron</span> Type of GABAergic neuron in the striatum

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.

<span class="mw-page-title-main">Reward system</span> Group of neural structures responsible for motivation and desire

The reward system is a group of neural structures responsible for incentive salience, associative learning, and positively-valenced emotions, particularly ones involving pleasure as a core component. Reward is the attractive and motivational property of a stimulus that induces appetitive behavior, also known as approach behavior, and consummatory behavior. A rewarding stimulus has been described as "any stimulus, object, event, activity, or situation that has the potential to make us approach and consume it is by definition a reward". In operant conditioning, rewarding stimuli function as positive reinforcers; however, the converse statement also holds true: positive reinforcers are rewarding.

<span class="mw-page-title-main">External globus pallidus</span> Part of the globus pallidus

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.

<span class="mw-page-title-main">Internal globus pallidus</span>

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.

<span class="mw-page-title-main">Basal ganglia disease</span> Group of physical problems resulting from basal ganglia dysfunction

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.

<span class="mw-page-title-main">Blocq's disease</span> Loss of memory of specialized movements causing the inability to maintain an upright posture

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 biology of obsessive–compulsive disorder (OCD) refers biologically based theories about the mechanism of OCD. Cognitive models generally fall into the category of executive dysfunction or modulatory control. Neuroanatomically, functional and structural neuroimaging studies implicate the prefrontal cortex (PFC), basal ganglia (BG), insula, and posterior cingulate cortex (PCC). Genetic and neurochemical studies implicate glutamate and monoamine neurotransmitters, especially serotonin and dopamine.

The cause of obsessive–compulsive disorder is understood mainly through identifying biological risk factors that lead to obsessive–compulsive disorder (OCD) symptomology. The leading hypotheses propose the involvement of the orbitofrontal cortex, basal ganglia, and/or the limbic system, with discoveries being made in the fields of neuroanatomy, neurochemistry, neuroimmunology, neurogenetics, and neuroethology.

References

  1. 1 2 Silkis, I. (1 January 2001). "The cortico-basal ganglia-thalamocortical circuit with synaptic plasticity. II. Mechanism of synergistic modulation of thalamic activity via the direct and indirect pathways through the basal ganglia". Bio Systems. 59 (1): 7–14. doi:10.1016/S0303-2647(00)00135-0. ISSN   0303-2647. PMID   11226622.
  2. 1 2 3 4 Maia, Tiago V.; Frank, Michael J. (15 January 2017). "From Reinforcement Learning Models of the Basal Ganglia to the Pathophysiology of Psychiatric and Neurological Disorders". Nature Neuroscience. 14 (2): 154–162. doi:10.1038/nn.2723. ISSN   1097-6256. PMC   4408000 . PMID   21270784.
  3. 1 2 Maia, Tiago V.; Cooney, Rebecca E.; Peterson, Bradley S. (1 January 2008). "The Neural Bases of Obsessive-Compulsive Disorder in Children and Adults". Development and Psychopathology. 20 (4): 1251–1283. doi:10.1017/S0954579408000606. ISSN   0954-5794. PMC   3079445 . PMID   18838041.
  4. 1 2 3 DeLong, Mahlon; Wichmann, Thomas (15 January 2017). "Changing Views of Basal Ganglia Circuits and Circuit Disorders". Clinical EEG and Neuroscience. 41 (2): 61–67. doi:10.1177/155005941004100204. ISSN   1550-0594. PMC   4305332 . PMID   20521487.
  5. ↑ Utter, Amy A.; Basso, Michele A. (1 January 2008). "The basal ganglia: an overview of circuits and function". Neuroscience and Biobehavioral Reviews. 32 (3): 333–342. doi:10.1016/j.neubiorev.2006.11.003. ISSN   0149-7634. PMID   17202023. S2CID   810947.
  6. ↑ Kim, HF; Hikosaka, O (July 2015). "Parallel basal ganglia circuits for voluntary and automatic behaviour to reach rewards". Brain: A Journal of Neurology. 138 (Pt 7): 1776–800. doi:10.1093/brain/awv134. PMC   4492412 . PMID   25981958.
  7. ↑ Fettes, P.; Schulze, L.; Downar, J. (2017). "Cortico-Striatal-Thalamic Loop Circuits of the Orbitofrontal Cortex: Promising Therapeutic Targets in Psychiatric Illness". Frontiers in Systems Neuroscience. 11: 25. doi: 10.3389/fnsys.2017.00025 . PMC   5406748 . PMID   28496402.
  8. ↑ Parent, A.; Hazrati, L. N. (1 January 1995). "Functional anatomy of the basal ganglia. I. The cortico-basal ganglia-thalamo-cortical loop". Brain Research. Brain Research Reviews. 20 (1): 91–127. doi:10.1016/0165-0173(94)00007-C. PMID   7711769. S2CID   28252990.
  9. 1 2 NF, Mehrabi; Malvindar, Singh-Bains; Henry, Waldvogel; Richard, Faull (21 July 2016). "Cortico-Basal Ganglia Interactions in Huntington's Disease".{{cite journal}}: Cite journal requires |journal= (help)
  10. ↑ Ikemoto, Satoshi; Yang, Chen; Tan, Aaron (1 September 2015). "Basal ganglia circuit loops, dopamine and motivation: A review and enquiry". Behavioural Brain Research. 290: 17–31. doi:10.1016/j.bbr.2015.04.018. PMC   4447603 . PMID   25907747.
  11. ↑ Squire, Larry (2013). Fundamental neuroscience (4th. ed.). Amsterdam: Elsevier/Academic Press. p. 728. ISBN   9780123858702.
  12. ↑ DeLong, Mahlon; Wichmann, Thomas (15 January 2017). "Update on models of basal ganglia function and dysfunction". Parkinsonism & Related Disorders. 15 (Suppl 3): S237–S240. doi:10.1016/S1353-8020(09)70822-3. ISSN   1353-8020. PMC   4275124 . PMID   20082999.
  13. ↑ Redgrave, P.; Prescott, T.J.; Gurney, K. (April 1999). "The Basal Ganglia: A Vertebrate Solution to the Selection Problem?". Neuroscience. 89 (4): 1009–1023. CiteSeerX   10.1.1.32.4792 . doi:10.1016/S0306-4522(98)00319-4. PMID   10362291. S2CID   3187928.
  14. ↑ Hélie, Sébastien; Ell, Shawn W.; Ashby, F. Gregory (1 March 2015). "Learning robust cortico-cortical associations with the basal ganglia: an integrative review". Cortex. 64: 123–135. doi:10.1016/j.cortex.2014.10.011. ISSN   1973-8102. PMID   25461713. S2CID   17994331.
  15. ↑ Lanciego, José L.; Luquin, Natasha; Obeso, José A. (15 January 2017). "Functional Neuroanatomy of the Basal Ganglia". Cold Spring Harbor Perspectives in Medicine. 2 (12): a009621. doi:10.1101/cshperspect.a009621. ISSN   2157-1422. PMC   3543080 . PMID   23071379.
  16. 1 2 Brittain, JS; Sharott, A; Brown, P (June 2014). "The highs and lows of beta activity in cortico-basal ganglia loops". The European Journal of Neuroscience. 39 (11): 1951–9. doi:10.1111/ejn.12574. PMC   4285950 . PMID   24890470.
  17. 1 2 Schroll, Henning; Hamker, Fred H. (30 December 2013). "Computational models of basal-ganglia pathway functions: focus on functional neuroanatomy". Frontiers in Systems Neuroscience. 7: 122. doi: 10.3389/fnsys.2013.00122 . PMC   3874581 . PMID   24416002.
  18. ↑ Calabresi, Paolo; Picconi, Barbara; Tozzi, Alessandro; Ghiglieri, Veronica; Filippo, Massimiliano Di (1 August 2014). "Direct and indirect pathways of basal ganglia: a critical reappraisal". Nature Neuroscience. 17 (8): 1022–1030. doi:10.1038/nn.3743. PMID   25065439. S2CID   8983260.
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