Basal Ganglia


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Firstly, we have to be clear about the term basal ganglia, this term is a misnomer, and should actually be called basal nuclei. Let’s discuss the basic important structures.


Ganglia:

Ganglia are the collection of neuronal cell bodies outside the CNS.


Nuclei:

Nuclei are collection of neuronal cell bodies surrounded by white matter within the CNS.


Caudate Nucleus:

Caudate Nucleus is C-shaped mass of grey matter present anatomically in relation with lentiform nucleus and thalamus, having following parts, caput, corpus and cauda.


Internal Capsule:

Different types of axon bundles going up and down passing through a structure called internal capsule. Internal capsule have two limbs, anterior and posterior and Genu. Anterior limb is present between the head of caudate nucleus and lentiform nucleus. Posterior limb is present between the thalamus and lentiform nucleus. Genu is located between anterior and posterior limbs.


Lentiform Nucleus:

Lens shaped mass of grey matter present lateral to internal capsule, consist of two parts, Putamen and globus pallidus.


Substantia Nigra:

This nucleus is located in mid brain, also consist of two parts.

*The posterior part of substantia nigra is dense grey matter and called Pars compacta. It contains dopaminergic neurons.

*Anterior part of substantia nigra is less dense and called pars reticularis. This part contain (GABA)- ergic neurons.

Amygdala:

Beside the tail end of caudate nucleus there is collection of grey matter placed under the lentiform nucleus and is known as amygdale


Classification of Basal Ganglia.

Term basal ganglia are used for the nuclear masses (grey matter) at the base of cerebral hemisphere. Basal ganglia are classified in two ways:

Traditional Classification:

These following structures consider the traditional basal ganlia.

a) Lentiform nucleus

b) Caudate nucleus

c) Amygdala

d) Claustrum

Clinical classification:

Modern or clinical classification describes lentiform nucleus and caudate nucleus having special connections with subthalamic nucleus and substantia nigra. The neurologists consider this classification more useful in clinics.


Globus Pallidum.

Globus pallidus is the medial part of lentiform nucleus, which is further divided into medial and lateral devisions collectively called pallidus striatum.

Globus pallidus externus (lateral divisions).

Globus pallidus internus (medial divisons).


Corpus Striatum:

Caudate nucleus, Putamen nucleus and globus pallidus are collectively called corpus striatum.


Neo-striatum:

Caudate nucleus with putamen nucleus is called neo-striatum. Caudate nucleus and putamen nucleus have similar connections, neurotransmitters, embryological derivation and are structurally and functionally similar.


Connections of Basal Ganglia

Corticonuclear fibers:

The fibers which are going from cerebral cortex to the motor nuclei of brain stem.

Coprticospinal fibers:

The fibers which are going from cerebral cortex to motor nuclei in spinal Cord, functionally corticonuclear and cortico-spinal fibers are same.


How movement occurs?

It is interesting to know that basal ganglia have electrical activity before you even start a movement. First pre-frontal cortex thinks an idea of movement, then this idea goes to premotor area and supplementary motor area, they should consult with basal ganglia and basal ganglia will refine the movement and give special signal, through thalamus this information will go back to motor cortex and from there fibers will descend as croticonuclear and corticospinal fibers to carry out movement by the muscle. When there is need to perform a movement, cortex consults with basal ganglia through direct and indirect pathways.


Direct Pathway

It is formed by corticostriatal fibers connecting with striato-pallidus internus fibers connected with pallido-thalamic fibers and in thalamus they connect with thalamo-cortical fibers. Here corticostriatal and thalamocortical fibers are glutamatergic neurons; and pallido-thalamic and striato-pallidus internus fibers are dopaminergic neurons. –When you are not doing movement, motor cortex is inhibited.


How motor cortex is inhibited?

When someone is at rest; globus pallidus internus is actively firing and pallido-thalamic fibers are very active, these fibers keep releasing lot of GABA in ventro-anterior, ventro-lateral and dorso-medial nucleus of thalamus, so due to inhibitory action of GABA, thalamo-cortical fibers are inhibited, hence thalamo-cortical fibers will not stimulate motor-cortex.


Role of direct pathway in Movement.

When someone thinks of a movement, in cortex cortico-striatal fibers will get stimulated and will release glutamate; as glutamate is stimulatory neurotransmitter, it will stimulate striato-pallidus internus fibers release of GABA in pallidus internus which will inhibit pallido-thalamic fibers and as pallido-thalamic fibers are inhibited; thalamo-cortical fibers are free from pallidal inhibition causing stimulation of motor cortex and muscle contracts. Here thalamus is acting as relay station.


Indirect Pathway:

To carry out any movement, agonists muscle should be stimulated and antagonist muscle should be inhibited. So another pathway is also working. Striatum is influencing the activity of globus pallidus internus indirectly via a loop involving sub- thalamus. When someone plans a movement cortico-striatal fibers (glutamatergic) stimulated. They stimulates neurons in putamen to globus pallidus externus. When these neurons are stimulated they release GABA which will inhibit neuronal connection between Globus Pallidus externus and sub-thalamus, resulting in insufficient release of GABA on neurons that connect subthalamus to globus pallidus internus and these fibers subthalamo-globus pallidus internus are disinhibited, they will release a great amount of glutamate in globus-pallidus internus; hence, neurons of globus-pallidus internus to thalamus gets stimulated, and their nerve endings will release more GABA in thalamus to inhibit those certain thalamo-cortical fibers which are connected with cerebral cortex.

Direct Pathway:

1- Shorter pathway that doesn’t involve subthalamus.

2- Direct pathway followed by stimulation of thalamo-cortical fibers.

Indirect Pathway:

1- Longer pathway that involves subthalamus.

2- Indirect pathway when stimulated, eventually they will inhibit thalamo-cortical fibers.


Role of dopamine and substantia Nigra:

In substantia nigra pars compacta there are dopaminergic neurons, these neurons go up and release dopamine in both direct and indirect pathway. So these nigro-striatal fibers influence both direct and indirect pathways. These dopaminergic fibers help initiate and facilitate the movements.


D1 and D2 Receptors:

There are D1 and D2 receptors in the striatum where striato-pallidus internus fibers of direct pathway start. There are D2 receptors in the striatum where striato-pallidum externus fibers of indirect pathway start. Dopamine released and stimulate direct pathway. When dopamine binds with D1 receptors, neurons are stimulated. Dopamine released and stimulate indirect pathway. When dopamine binds with D2 receptors neurons are inhibited. Dopamine released by nigro-striatal fibers is facilitating the movement, it should stimulate direct pathway, increased firing of thalamo-cortical fibers occurs and UMN of corticospinal tract gets stimulated, at the same time they inhibit striato-pallidus externus fibers of indirect pathway and these inhibited striato-pallidus externus fibers will release less GABA, so pallidus externus subthalamic fibers will be less inhibited and their nerve endings will release more GABA, this increased GABA will inhibit subthalamo-pallidus internus fibers releasing insufficient glutamate. Pallidus internus-thalamic fibers will be inhibited and their nerve endings will release less GABA with less inhibitory action on thalamo- cortical fibers of indirect pathway, so it will also get out of inhibitory action and will stimulate motor cortex. So basically dopamine firing on both pathways stimulate motor cortex.


Crotico-nigral fibers:

Crotico-nigral fibers are responsible for bringing information from cortex to substantia nigra.


Brief review of Pathways:

Neurons in striatum are under glutamatergic effect from cortico-striatal pathways and are under dopaminergic effect from nigro-striatal pathway. But neurons which are directed to globus pallidus internus have D1 receptors and neurons in the striatum which are directed to globus pallidus externus have D2 receptors. When nigro-striatal fibers fire, they have stimulatory action on the direct pathway and enhance the movement and at the same time they have inhibitory action on the indirect pathway that also enhance the movement.


GABA inhibitory mechanism:

GABA has two mechanisms to keep the neurons inhibited either by loading the neurons with anions or helping the cations to escape so neurons remain electro negative.


Substantia nigra Pars reticualris:

Pars reticualris is just displaced grey matter from the globus pallidus internus.


Cholinergic Effect:

Dopaminergic effect on both direct and indirect pathways is counterbalanced by cholinergic neurons with in the striatum. It inhibits direct pathway and stimulates indirect pathway.


Dysfunctions of these Pathways:

Actually when these circuits are disturbed, motor movements become abnormal. Basal ganglia lesions can cause hypokinesia, hyperkinesia or dyskinesia. Basal ganglia initiate the movement and program the movement.


Injury to direct pathway:

Classical example of direct pathway under functioning is Parkinson. In Parkinson there are:

i) Hypokinesia.

ii) Rigidity.

iii) Tremors.

Why hypokinesia occurs?


Effect on direct pathway:

Primary problem of Parkinson is degeneration of neurons in pars compacta of substantia nigra, insufficient release of dopamine leads to hypo-stimulation of D1 receptors, then these striato-pallidus internus fibers are not competent enough to initiate the movement. When these fibers are inhibited, they release less dopamine in pallidus internus, pallidal neurons are disinhibited and pallidus internus-thalamic fibers will slightly over fire and they secrete more GABA in thalamus, which cause inhibition of thalamo-cortical neurons, so thalamo-cortical activity decreases, resulting in less stimulation of motor cortex, it is difficult to start a movement which is also called as hypokinesia.


Effect on indirect pathway:

In Parkinson disease, nigro-striatal pathway degenerates, it decreases dopamine in direct pathway as well as in indirect pathway at D2 receptors, causing little inhibition of striato-pallidus externus neurons, they will over fire and more GABA will release, cause less “gabaminergic” in pallidus externus- subthalamic neurons, so decreased GABA in subthalamus results in over firing of “glutamatergic” subthalamo-pallidus internus fibers. It will lead to stronger stimulation of pallidus internus-thalamic neurons and they will release more GABA in thalamus, now thalamo-cortical neurons are also inhibited. “So when both direct and indirect pathways have loss of dopaminergic activity, they will lead to hypo stimulation of motor cortex, making difficult to initiate the movement and lead to hypokinesia or akinesia.”


Masked Face in Parkinson:

Due to hypokinesia of facial muscles, it becomes difficult to change facial expressions and this is known as masked face of Parkinson disease.


Rigidity:

Cortico-reticular and reticulo-spinal fibers are responsible to maintain the tone of the muscles. Cortico-reticular neurons have inhibitory effect over reticulo-spinal fibers in normal persons. When cortex is inhibited in Parkinson disease, cortico-reticular neurons are also inhibited, hence reticulo-spinal neurons over fire and increase the tone of muscles. For example, when muscle tone is increased in flexors and extensors, movement of arm becomes very difficult and limb resembles rigid lead pipe, so it is called lead pipe rigidity.


Tremors:

There are cholinergic fibers in striatum which have opposite action to dopaminergic fibers. For normal motor function, there should be balance in cholinergic and dopaminergic activity in striatum. When dopaminergic activity decreases (e.g., Parkinson), relative cholinergic activity increases. There are some neurons within the lentiform nucleus which are making “reverberatory circuits” (responsible for maintaining tone in flexors and extensors), when dopamine is less and acetylcholine is unchecked, these reverberatory cirucuits become fast, so it results that even in resting conditions agonists and antagonists are working in alternate fashion, and it will produce tremors and here they are known as resting tremors of Parkinson.


MPTP associated Parkinsonism:

In California some young people started presenting Parkinson symptoms and all of them were street heroin addicted which later was found to be contaminated with methyl-phenyl- tetra pyridine, this can damage nigro-striatal neurons and patients can develop Parkinson like disease even in very young age.


Anti-psychotic associated Parkinsonism.

Parkinson like conditions also occur when patient is using dopamine receptor blocker-antipsychotic drugs block D1 and D2 receptors and functionally its like loosing nigro-striatal pathway, after sometime patient can complain of new problems of shaky palsy and unable to move around. This is a drug induced Parkinsonism. Always remember that basal ganglia lesions don’t produce paralysis, either they reduce movement or produce abnormal movement.

-Direct pathway lesion can produce hypokinesia.

-Indirect pathway lesion can produce hyperkinesias.


Hyperkinesia/Dyskinesia:

If striato-pallidus externus (gabaminergic with enkephalin) is damaged, indirect pathway cannot work properly, and excessive unwanted movements are produced.


Types of Hyperkinesia:

1. Chorea: Huntington’s chorea and Sydenham chorea.

2. Wilson’s disease.

3. Athetosis.

4. Dystonia.

5. Ballismus/Hemiballismus.

6. Tardive dyskinesia.

In all these types, damage is in indirect pathway, so movement will be excessive.


1- Chorea:

Sudden, brisk, purposeless flying movements of limbs. When gabaminergic neurons in caudate nucleus (striatum) are damaged, indirect pathway is dysfunctional and many motor programs are abnormally released. If indirect pathway is disturbed and motor cortex is over stimulated it may cause inappropriate release of multiple motor programs. In chorea from CNS motor programs which are stored there; haphazardly their components are released and they result into sudden uncontrollable or involuntary purposeless movements.


i) Huntington’s chorea: It is inherited disorder on chromosome number 4, there is a special gene (Huntington’s gene), in this gene trinucleotide repeat CAG are amplified, that results in abnormal production of toxic protein which damage gabaminergic neurons of indirect pathway as well as cholinergic pathway so that dysfunction of basal ganglia occurs and choreoform movements will occur. These patients also develop dementia and depression. In Huntington’s disease, head of caudate nucleus degenerates and lateral ventricles appear as if it is abnormally widened.


ii) Sydenham chorea. It is transit chorea which occurs in rheumatic fever due to inflammation of caudate nucleus and is more common in girls. It is short term and transit. It gets resolved when rheumatic fever is resolved.


Charachteristics of trinucleotide diseases:

After every generation, trinucleotide repeat amplify, during gametogenesis trinucleotide genes are over copied, so children have more repeats than parents.

-Trinucleotide diseases progressively worsen generation after generation.

-Disease becomes more sever and appear at early age as compared to parents.


2. Wilson’s Disease:

It is an inherited disease of copper metabolism, progressive in character, related with chromosome number 13. Due to low level of ceruloplasmin in blood, copper starts accumulating in caudate nucleus, liver, lentiform nucleus and cornea. It is also called “Hepato-lenticular disease”.


Brief introduction of Rheumatic Fever:

Strepto B-hemolyticus, Lanzfield group A, rheumatogen strain, attack throat. Most of children form antibodies against these bacteria but 3% children’s immune system fires back against bacteria and also attacks on some of our own tissue which have antigenic similarities with bacterial antigen. These antibodies may cross react with cardiac tissue, synovial membrane, skin and caudate nucleus.


3. Athetosis:

These are slow, sinus and rhythmic movements. All diseases which can produce chorea can also produce athetosis. Some patients have both chorea and athetosis, and we call it choreo-athetosis.


Difference between Chorea and Athetosis:

If motor programs (motor commands) are haphazardly and rapidly occur, then that will cause chorea. If motor programs are released slowly and rhythmically, and one movement converts into other movement smoothly, it is called athetosis.


4. Dystonia:

It is a disorder characterized by sustained muscle contraction resulting in twisting movements and abnormal posture. Abnormal posture in Parkinson is due to dystonia in axial or truncal muscles and dystonia in cervical muscles may cause torticollis.


5. Bellismus/Hemibellismus:

“Excessive movements in ballistic fashion” If subthalamus is damaged, indirect pathway is gone and there are excessive movements of hip and shoulder girdle muscles. Subthalamus specially controls hip girdle and shoulder girdle muscles. If subthalamus of one side is damaged, clinical features will appear to contralateral side.

-If it is unilateral, it is called hemibellismus.

-If it is bilateral, it is called bellismus.


6. Tardive Dyskinesia:

In a psychotic patient who is taking dopamine receptor blockers for very long time , the dopamine receptors will up regulate in striatum, tissue becomes hypersensitive to dopamine and if too much dopamine is accumulated in indirect pathway, it will be excessively inhibited, and cause dyskinesias. 8 Mostly this problem occurs in female patients over 50 years of age using antipsychotics for very long time and they develop strange choreoathetosis type movements usually in jaw, lips, tongue and in facial muscles.


 

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