The basal ganglia

Basal Ganglia
Consist of Four Nuclei
striatum caudate and putamen globus pallidus substantia nigra subthalamus

The basal ganglia are the principal subcortical components of a family of parallel circuits linking the thalamus with the cerebral cortex

Motor Function of the Basal Ganglia

control of complex patterns of motor activity using scissors throwing balls shoveling dirt

Function of the Basal Ganglia?

not much is known about the specific functions of each of these structures thought to function in timing and scaling of motion and in the initiation of motion most information comes from the result of damage to these structures and the resulting clinical abnormality

Caudate Circuit
Caudate extends into all lobes of the cortex and receives a large input from association areas of the cortex

Mostly projects to globus pallidus, no fibers to subthalamus or substantia nigra

Most motor actions occur as a result of a sequence of thoughts. Caudate circuit may play a role in the cognitive control of motor functions

Putamen Circuit

Mostly from premotor and supplemental motor cortex to putamen then back to motor cortex.

Neurotransmitters in the Basal Ganglia

Lesions of Basal Ganglia

globus pallidus athetosis - spontaneous writing movements of the hand, arm, neck, and face putamen chorea - flicking movements of the hands, face, and shoulders substantia nigra Parkinson's disease - rigidity, tremor and akinesia loss of dopaminergic input from substantia nigra to the caudate and putamen

Lesions of Basal Ganglia

subthalamus hemiballismus - sudden flailing movements of the entire limb caudate nucleus and putamen huntingtons chorea - loss of GABA containing neurons to globus pallidus and substantia nigra

Integration of Motor Control

spinal cord level preprogramming of patterns of movement of all muscles (i.e., withdrawal reflex, walking movements, etc.). brainstem level maintains equilibrium by adjusting axial tone cortical level issues commands to set into motion the patterns available in the spinal cord controls the intensity and modifies the timing

Integration of Motor Control (contd)

cerebellum function with all levels of control to adjust cord motor activity, equilibrium, and planning of motor activity basal ganglia functions to assist cortex in executing subconscious but learned patterns of movement, and to plan sequential patterns to accomplish a purposeful task

Overall scheme for integration of motor function

 History of Parkinsons disease (PD)

First described in 1817 by an English physician, James Parkinson, in An Essay on the Shaking Palsy.

The famous French neurologist, Charcot, further described the syndrome in the late 1800s.

Epidemiology of PD

The most common movement disorder affecting 1-2 % of the general population over the age of 65 years.

The second most common neurodegenerative disorder after Alzheimers disease (AD).

Incidence / 100 000

Incidence of PD

Age

Prevalence / 100 000

Prevalence of PD

Age

Epidemiology of PD
May be less prevalent in China and other Asian countries, and in African-Americans. Prevalence rates in men are slightly higher than in women; reason unknown, though a role for estrogen has been debated.

Risk factors of PD
Age - the most important risk factor Positive family history Male gender Environmental exposure: Herbicide and pesticide exposure, metals (manganese, iron), well water, farming, rural residence, wood pulp mills; and steel alloy industries Race Life experiences (trauma, emotional stress, personality traits such as shyness and depressiveness)? An inverse correlation between cigarette smoking and caffeine intake in case-control studies.

Clinical features of PD
Three cardinal features: resting tremor bradykinesia (generalized slowness of movements) muscle rigidity

Clinical features of PD

Resting tremor: Most common first symptom, usually asymmetric and most evident in one hand with the arm at rest.
Bradykinesia: Difficulty with daily activities such as writing, shaving, using a knife and fork, and opening buttons; decreased blinking, masked facies, slowed chewing and swallowing. Rigidity: Muscle tone increased in both flexor and extensor muscles providing a constant resistance to passive movements of the joints; stooped posture, anteroflexed head, and flexed knees and elbows.

Additional clinical features of PD

Postural instability: Due to loss of postural reflexes. Dysfunction of the autonomic nervous system: Impaired gastrointestinal motility, bladder dysfunction, sialorrhea, excessive head and neck sweating, and orthostatic hypotension. Depression: Mild to moderate depression in 50 % of patients. Cognitive impairment: Mild cognitive decline including impaired visual-spatial perception and attention, slowness in execution of motor tasks, and impaired concentration in most patients; at least 1/3 become demented during the course of the disease.

Neuropathology of PD

Eosinophilic, round intracytoplasmic inclusions called lewy bodies and Lewy neurites. First described in 1912 by a German neuropathologist - Friedrich Lewy. Inclusions particularly numerous in the substantia nigra pars compacta.

Lewy bodies

Neuropathology of PD: Lewy bodies

Not limited to substantia nigra only; also found in the locus coeruleus, motor nucleus of the vagus nerve, the hypothalamus, the nucleus basalis of Meynert, the cerebral cortex, the olfactory bulb and the autonomic nervous system.

Confined largely to neurons; glial cells only rarely affected.

Functional neuroanatomy of PD

Substantia nigra: The major origin of the dopaminergic innervation of the striatum.

Part of extrapyramidal system which processes information coming from the cortex to the striatum, returning it back to the cortex through the thalamus. One major function of the striatum is the regulation of posture and muscle tonus.

Neurochemistry of PD

Late 1950s: Dopamine (DA) present in mammalian brain, and the levels highest within the striatum.

1960, Ehringer and Hornykiewicz: The levels of DA severely reduced in the striatum of PD patients.
PD symptoms become manifest when about 50-60 % of the DA-containing neurons in the substantia nigra and 70-80 % of striatal DA are lost.

Dopamine synthesis

Dopamine pathways in human brain

Therapy of PD: levodopa

Late 1950s: L-dihydroxyphenylalanine (L-DOPA; levodopa), a precursor of DA that crosses the blood-brain barrier, could restore brain DA levels and motor functions in animals treated with catecholamine depleting drug (reserpine). First treatment attempts in PD patients with levodopa resulted in dramatic but short-term improvements; took years before it become an established and succesfull treatment. Still today, levodopa cornerstone of PD treatment; virtually all the patients benefit.

Therapy of PD: limitations of levodopa

Efficacy tends to decrease as the disease progresses.

Chronic treatment associated with adverse events (motor fluctuations, dyskinesias and neuropsychiatric problems).

Therapy of PD: limitations of levodopa

Does not prevent the continuous degeneration of nerve cells in the subtantia nigra, the treatment being therefore symptomatic.

Inhibition of peripheral COMT by entacapone increases the amount of L-DOPA and dopamine in the brain and improves the alleviation of PD symptoms.

Therapy of PD: Other treatments

DA receptor agonists (bromocriptine, pergolide, pramipexole, ropinirole, cabergoline) Amantadine Anticholinergics

Diagnosis of PD

History and clinical examination Positron Emission Tomography (PET) or Single-photon Emission Computed Tomography (SPECT) with dopaminergic radioligands Exclusion of several causes of secondary Parkinsonism

Summary

1-2 % of the general population over the age of 65 y Lewy bodies and Lewy neurites particularly in the substantia nigra pars compacta dopaminergic neurons projecting to striatum DA levels severely reduced in striatum. Resting tremor, bradykinesia, muscle rigidity Levodopa and other dopaminergic drugs No treatment which would prevent the continuous degeneration of nerve cells in the substantia nigra and resulting striatal DA loss

MCQs
Which circuit in the basal ganglia is thought to be involved in the cognitive control of motor functions? A.Caudate circuit B.Putamen circuit C.Papez circuit D.Nigropallidothalamic circuit ANS: A Chorea and choreiform movement is a sign of dysfunction in which brain region? A.Substantia nigra B.Caudate nucleus and putamen C.Subthalamic nucleus D.Thalamus ANS: B Parkinson's disease is the result of A.Disruption of the putamen circuit B.Loss of GABA input from caudate nucleus and putamen to the substantia nigra C.Loss of dopaminergic input from substantia nigra to the caudate nucleus and the putamen D.Loss of serotonin input from substantia nigra to the thalamus and subthalamus ANS: C

MCQs
Neurological disease associated with the globus pallidus produces which type of symptom? A.Rigidity B.Chorea C.Hemiballismus D.Athetosis ANS: D Which of the following structures is not considered to be part of the basal ganglia? A.Caudate nucleus B.Red nucleus C.Substantia nigra D.Putamen ANS: B Hemiballismus is associated with damage or dysfunction of which of the following structures? A.Thalamus B.Caudate nucleus C.Subthalamus D.Red nucleus ANS: C

Parkinsonism and Parkinsons disease

Problem based learning

Task
Read the case details Identify the keywords Define important terms

Home work

Management of the case

Use our knowledge of basic sciences to interpret the various abnormalities

Case Details
A 58-year-old male patient who was a univeristy professor by occupation, was seen by the neurologist He visited the neurologist because for the past 3 months, he was experiencing a recent onset of an intermittent shaking movement involving both his upper limbs that occurs primarily at rest. He also had difficulty in getting out of bed in the mornings But once he got up he carried on with his daily work He also complained of difficulty in turning his body rapidly when someone called him from the back

Key words
A 58-year-old male patient who was a univeristy professor by occupation, was seen by the neurologist He visited the neurologist because for the past 3 months, he was experiencing a recent onset of an intermittent shaking movement involving both his upper limbs that occurs primarily at rest. He also had difficulty in getting out of bed in the mornings But once he got up he carried on with his daily work He also complained of difficulty in turning his body rapidly when someone called him from the back

Questions
What are the presenting symptoms in this patient ? Why do you think he went to a neurologist ? Which parts of the CNS are involved in the control of movement ?

Case details
Neurologic evaluation reveals mild upper limb rigidity in addition to the resting tremor in the upper limbs. The doctor noticed that all the movement of the patient were slow. On further neurological examination, when the patient is asked to walk to and fro his arms do not sway and he finds it difficult to turn around. His blood pressure and vital signs are normal

Key words
Neurologic evaluation reveals mild upper limb rigidity in addition to the resting tremor in the upper limbs. The doctor noticed that all the movement of the patient were slow. On further neurological examination, when the patient is asked to walk to and fro his arms do not sway and he finds it difficult to turn around. His blood pressure and vital signs are normal

Questions
What is rigidity ? (Increased tone of the muscles due to a lesion of the extra pyramidal system) What do you mean by tremor ? What is the neurological term for slowness of movement ? What does the triad of tremor rigidity and bradykinesia suggest ?

Case details
After a detailed history and examination, the neurologist concludes that the patient has features of Parkinsonism.

Keywords
After a detailed history and examination, the neurologist concludes that the patient has features of Parkinsonism.

Questions
What is Parkinsonism ? Parkinsonism is a neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability Which part of the nervous system is involved with parkinsonism ? How does the body perform a smooth, controlled and coordinated movement?

Key aspects of a goal directed movement

An individual must first be aware of the surrounding environment and his position in space. This information is generated through somatosensory, proprioceptive, and visual sensory inputs to the posterior parietal cortex.

 The individual then decides what action is desired. This is accomplished via the parietal and anterior frontal lobes, which are extensively interconnected. These regions are thought to be important for abstract thought and decision making, and hence it is here that decisions about what actions to take are made and their likely outcomes are judged.

 A plan must then be constructed to determine how the actions will be carried out. This is performed in the premotor cortex (PMC) and supplemantary motor areas (SMA), where axons from the both the prefrontal and and parietal cortex converge. In this area the signals indicating what actions are desired are converted into signals that indicate how the actions will be perfomed.

 Finally, a command to begin the action must be issued and the plan must be implemented. This invloves the primary motor cortex, which, together with the PMC and SMA, contributes most of the axons to the descending corticospinal tract. From this region of the brain signals pass out to the muscles, converting the plan of action into an actual movement.

What are the structures in the brain that regulate and coordinate motor activity ?
Cerebellum Basal ganglia

Cerebellum

The main function of the cerebellum is the coordination of motor activities. Commands to initiate movement come from the somatomotor cerebral cortex, but the cerebellum fine-tunes motor control, giving smoothness of motion and exactness of positioning. The cerebellum makes comparisons of internal and external feedback signals to correct ongoing movements. Lesions of the cerebellum result in movements that are jerky and that overshoot or undershoot their intended mark. The cerebellum is the site to ensure well-timed and co-ordinated movements and sequences.

Basal Ganglia

The term basal ganglia relate to a set of nuclei that are located deep in the hemispheres. The basal ganglia are involved in the regulation of cortically initiated motor activity, which if disturbed leads to some form of movement disorder

 the basal ganglia receive inputs from the cerebral cortex , the inputs go onward to the various parts of the basal ganglia and then signals go back to the cerebral cortex via the thalamus. What could be the purpose of this loop? Evidently the basal ganglia function to maintain the muscle tone needed to stabilize joint position (as, for example, holding a glass of water while talking) or to inhibit muscle tone during the initiation of movement.

Interruption of the feedback loops of the basal ganglia by damage to one of its structures results in the uncontrollable oscillations manifested as tremors or as other movement disorders.

Home work
What are the parts of the basal ganglia ? What are the functions of basal ganglia ? What are the types of movement disorders ? What are the causes of Parkinsonism ? List the various clinical signs of parkinsonism. What is Levo Dopa ?