Parasitic Pathogens Affecting the CNS

Parasitic Pathogens Affecting the CNS
By:Mark F. Wiser
Department of Tropical Medicine
School of Public Health

Protozoa Affecting the CNS
Rare cases
Free-living ameba
Rare invasion of the brain
Entamoeba histolytica
Cerebral Malaria
Plasmodium falciparum
African Sleeping Sickness
African Trypanosomes
Associated with congenital defects and AIDS
Toxoplasma gondii
Disease

Protozoan
Amebas Affecting the CNS
* Entamoeba histolytica
o normally found in large intestine
o can become invasive (primarily liver)
* Free-living Amebas

GAE; skin or lung lesions
Balamuthia mandrillaris
GAE; skin or lung lesions; amebic keratitis
Acanthamoeba species
PAM

Naegleria fowleri
Diseases
Ameba

Toxoplasma gondii
* cosmopolitan distribution
* seropositive prevalence rates vary
o generally 20-75%
* generally causes very benign disease in immunocompetent adults
o congenital transmission
o AIDS associated
* tissue cyst forming coccidia
o predator-prey life cycle
o felines are definitive host
o infects wide range of birds and mammals (intermediate hosts)

Definitive Host
* adult forms
* sexual reproduction

Intermediate Host
* immature forms
* asexual reproduction

chronic stage = bradyzoites
acute stage = tachyzoites
* ingestion of sporulated oocysts (cat feces + incubation)
* ingestion of zoites (undercooked meat)
* congenital infection (only during acute stage)
* organ transplants
o chronic infection in donor
o immunosuppression
* blood transfusions (only during acute stage)

Human Transmission
Acquired Postnatal Toxoplasmosis
* 1-2 week incubation period
* acute parasitemia persists for several weeks until development of tissue cysts
o often asymptomatic (>80%)
o a common symptom is lymphadenopathy without fever
o occasionally mononucleosis-like (fever, headache, fatigue, myalgia)
* likely persists for life of patient
* immunosuppression can lead to reactivation (eg, organ transplants)

Congenital Toxoplasmosis
* 1o infection must occur during or shortly before pregnancy
o can only occur once
o 1/3 will pass infection to fetus
* incidence ~1 per 1000 births
* severity varies with age of fetus
o move severe early in pregnancy
o more frequent later in pregnancy
* infection can result in: spontaneous abortion, still birth, premature birth, or full-term ą overt disease
* typical disease manifestations include: retinochoroiditis, psychomotor disturbances, intracerebral calcification, hydrocephaly, microcephaly

Toxoplasmic Encephalitis
* common complication associated with AIDS during the 1980's
* recrudescence of latent infection
* multifocal disease associated with immunosuppression
* lesions detectable with CT or MRI
* little spread to other organs
* symptoms include: lethargy, apathy, incoordination, dementia
* progressive disease  convulsions
* usually fatal if untreated

Diagnosis
* various serological tests
* active (acute) vs chronic infection
o compare samples at 2 week intervals
o IgM > IgG; Ab titers
* seldom by direct parasite demonstration
o biopsy
o inoculation into mice or cell culture (only acute stage)
* CT scans or MRI for toxoplasmic encephalitis

Prevention
But dog contact is highly correlated with Toxoplasma transmission.
Several studies show no correlation between cat contact and Toxoplasma.

An Enigma
Some Helminths Affecting the CNS
Taenia solium and Cysticercosis
* adult tapeworm infects GI tract of humans
* larval stages infect tissues causing cysticercosis or neurocysticercycosis
* most common parasitic disease of the CNS
* endemic throughout much of the developing world
o especially prevalent in Central and South America, Sub-Saharan Africa, Southeast Asia and Central and Eastern Europe
* prevalence of 3.6% in some regions of Mexico
* greatest cause of acquired epilepsy worldwide

Cysticercosis in the United States
* has become an important parasitic disease, particularly in California
* estimated that 1000 new cases of neurocysticercosis will be diagnosed each year
* increasing prevalence attributed to the migration of large numbers of rural immigrants from developing countries
* also improvements in neuro-imaging leading to better diagnosis

http://www.dpd.cdc.gov/dpdx/
Disease States
* Taeniasis = adult tapeworm in small intestine
o Usually asymptomatic (eggs or proglottids in feces)
o Vague abdominal symptoms occasionally report
* Cysticercosis = T. solium larvae in human tissues (eg, muscle)
o Usually asymptomatic
o Painless subcutaneous nodules in arms and chest
* Neurocysticercosis (NCC) = cysts in the central nervous system
o Most severe manifestation

Pathogenesis of Cysticerci
* larva (cysticercal cysts) survive up to 5 years
* living larva produce little inflammation
* death of larva leads to inflammation and edema resulting in symptoms
* cellular reaction eventually destroys parasite and leaves a calcified nodule

Clinical Manifestations
* presentation is varied—depends on stage, number, size and location of cysts
* seizures/convulsions most common symptoms
* blocked circulation of CSF can lead to intracranial hypertension or hydrocephalus
* occasionally large cysts can mimic tumors
* can also cause a variety of mental and motor changes

Diagnosis
* onset of epileptic seizures
* person from endemic area
* CT scans and MRI are most useful
o 1-2 cm cystic lesions
o with or without edema and inflammation
* some serological tests available
o problems with sensitivity and specificity

Treatment
* symptomatic treatment (eg, antiepileptic drugs)
o spontaneous cures noted especially in children
* praziquantel and albendazole kill the cysts faster
o limited clinical benefit
o administer with corticosteroids (anti-inflammatory)
* surgical excision of cysts was previous treatment

Prevention and Control
* Enhanced personal hygiene
* Thorough cooking/ freezing of pork to kill cysticerci
* Enhanced environmental sanitation
o proper disposal of human feces
* Agricultural inspection of pork
* Vaccination of pigs?

Parasitic Pathogens Affecting the CNS.ppt

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Cysticcercosis

CYSTICERCOSIS
By:Palak Parikh

EPIDEMIOLOGY
* Found in approximately 50 million people worldwide (probably an underestimate)
* Endemic in several countries in Central and South America, sub-Saharan Africa, India, and Asia
* Prevalence in this country often higher in rural areas
* 221 deaths identified in the US from 1990-2002 (62% had emigrated from Mexico)

CYSTICERCOSIS TRANSMISSION
* Caused by the larval stage of Taenia solium, the pork tapeworm
* Humans develop by ingestion of T. solium eggs; they can spread infection by:
o Egg-containing feces contaminating water supplies in endemic areas
o Contaminating food directly, as eggs are sticky and can often be found under the fingernails of tapeworm carriers.

LIFE CYCLE
* Once eggs ingested, embryos are released in the small intestine and invade the bowel wall.
* They then disseminate hematogenously to other tissues and develop into cysticerci over 3 weeks to 2 months.
* Cysticerci – liquid-filled vesicles consisting of a membranous wall and a nodule containing the invaginated scolex.
* Scolex – head armed with suckers and hooks and a rudimentary body.

PATHOGENESIS
* Cysticerci initially viable but do not cause much inflammation in surrounding tissues – asymptomatic infection
* Host develops immune tolerance to cysticerci, which remain in this stage for several years.
o Postulated mechanisms of tolerance:
+ Taenia elaborate substances that inhibit or divert complement pathways away from parasite
+ Humoral antibodies do not kill mature taenia.
+ Poorly defined factors may interfere with lymphocyte proliferation and macrophage function, inhibiting normal cellular immune defenses.
* Clinical manifestations occur when inflammatory response develops around degenerating cysticercus.

SYMPTOMATIC DISEASE
* Divided into:
o Neurocysticercosis
o Extraneural cysticercosis

NEUROCYSTICERCOSIS
* 80% of infections are asymptomatic
* Symptoms mainly due to mass effect, inflammatory response, or obstruction of foramina and ventricular system of brain.
* Most common symptoms:
o Seizures
o Focal neurological signs
o Intracranial hypertension
* Peak estimated to occur 3-5 years after infection

NEUROCYSTICERCOSIS
* Increased risk of seizures with a single calcific granuloma.
* Risk of seizures highest when lesions are degenerating and are surrounded by inflammation.
* Encephalitis and diffuse brain edema most common in children and young females.
* 1-3% of cases involve the spinal cord, with thoracic lesions the most common.

NEUROCYSTICEROSIS IN ENDEMIC COUNTRIES
* Most common cause of adult-onset seizures
* Risk of seizures in seropositive individuals 2-3 times higher than seronegative controls.
* Punctate calcifications most frequent finding on neuroimaging of brain.

EXTRANEURAL CYSTICERCOSIS
* Typically involves:
o Eyes – in 1-3% of all infections
o Muscle
o Subcutaneous tissue – nodules most common in patients from Asia and Africa than from Latin America

DIAGNOSIS
* Serologic testing
* Peripheral eosinophilia only if cyst is leaking
* CT scan or MRI
o Pathognomonic Lesion: Scolex – mural nodule within a cyst
* Brain biopsy (only in symptomatic patients with equivocal serology and radiologic tests)

SEROLOGIC TESTING
* ELISA
* Complement fixation (CF)
* Radioimmunoassay
* Enzyme linked immunoelectrotransfer blot (EITB) assay – test of choice

EITB ASSAY
* Enzyme-linked immunoelectrotransfer blot assay
* Test of choice for detecting anticysticercal antibodies
* Uses affinity-purified glycoprotein antigens
* Higher sensitivity (83-100%) and specificity (93-98%) than ELISA
* Can be performed on serum or CSF but has a higher sensitivity on serum.
* Detected 94% of pathologically confirmed NCC with 2 or more lesions compared to only 28% with a single lesion in one study.

CT VS MRI
* MRI preferred since it is more sensitive in detecting:
o small lesions
o brainstem or intraventricular lesions
o perilesional edema around calcific lesions
o scolex
o degenerative changes in the parasite
* CT scan cheaper and better at detecting:
o small areas of calcifications.
o cysticercal infestation of extraocular muscles.

* Perform CT scan first followed by MRI in patients with inconclusive findings or in those with negative CT scans where strong clinical suspicion persists.

PERUVIAN STUDY
POTENTIAL TREATMENTS
* Albendazole (15 mg/kg/day) X 15 days + corticosteroids (30-40 mg prednisolone or 12-16 mg dexamethasone daily) – per UpToDate
* Praziquantel (50 mg/kg/day) X 15 days + corticosteroids (30-40 mg prednisolone or 12-16 mg dexamethasone daily) – per UpToDate
* Corticosteroids alone
* Anticonvulsants in patients who present with seizures or are at high risk for seizures
* Surgery

ALBENDAZOLE VS PRAZIQUANTEL
* Albendazole
o Destroys 75-90% of parenchymal brain cysts
o Does not interact with anticonvulsants
o Levels not adversely affected w/ co-administration of corticosteroids
* Praziquantel
o Destroys 60-70% of cysts 3 months after administration
o Decreased efficacy compared to Albendazole
o Available for oral administration
o Does not cross the blood-brain barrier well, so CSF levels only approx 20% of plasma levels.
o Involves cytochrome P-450 hepatic metabolism, which is induced by corticosteroids, phenytoin, and phenobarbital

* No blinded randomized controlled trials comparing albendazole to praziquantel.
Because of the above, praziquantel is generally considered second-line therapy.

TREATMENT
* One randomized, double-blind, placebo-controlled trial
o 120 pts with living cysticerci in the brain and seizures treated with antiepileptic drugs
+ Randomized to either albendazole (800 mg qd) and dexamethasone (6 mg qd X 10 days) or double placebo
+ Followed for 30 months or until they were seizure-free for 6 months after tapering of antiepileptic drugs
o Results:
+ Resolution of intracranial cystic lesions more common in treatment arm
+ Number of patients experiencing generalized seizures declined in the treatment arm
+ No significant change between the two groups in patients experiencing partial seizures

NEUROCYSTICERCOSIS
* Treatment in those with:
o 5-50 cysts (both antiparasitic and steroids)
o Steroids alone in patients w/ > 50 cysts
* No Treatment in those with:
o Asymptomatic nonviable neurocysticercosis
o Calcified cysts
o Single viable cysts
o Fewer than 5 cysts

ANTICONVULSANTS
* Recommended for patients who present with seizures
* Should be stopped if patient remains seizure-free during therapy to see if the patient remains asymptomatic
* Should be reinitiated chronically if the patient has recurrent seizures
* Should be considered in patients w/ multiple cysts who have no history of seizure activity

SURGICAL INTERVENTION
* Used in some patients with intracranial hypertension
* Shunting improves hydrocephalus, although recurrent blockages of shunts common
* Surgical intervention recommended for cysts:
o Located in the 4th ventricle
o Attached to middle cerebral artery
o Compressing the optic chiasm
o Located in the spine

TREATMENT OF EXTRANEURAL CYSTICERCOSIS
* None if pt asymptomatic
* Surgical excision for intraocular disease
* Medical therapy for involvement of extraocular muscles or optic nerve.
* NSAIDs for patients w/ symptomatic subcutaneous or intramuscular lesions.
* Excision of solitary lesions if NSAIDs fail or not tolerated.

BEFORE INITIATING MEDS…
* Apply PPD.
* Consider treating with a single dose of ivermectin before beginning corticosteroids, as many patients have risk factors for strongyloidiasis.
* Consult ophthalmology to rule out ocular cysticercosis.

PATIENT MONITORING
* Intermittent surveillance w/ imaging until cyst(s) resolve(s).
o Perhaps every 3-6 months if patient improving or earlier if patient symptomatic.
* Reimaging of brain 2 months after completion of treatment
* Consider antiparasitic therapy if cysts growing off therapy

POSSIBLE PREVENTION
* Human Tapeworm Infections
o Inspection of pork for cysticerci
o Freezing or adequately cooking meat to destroy cysticerci
o Administering antiparasitic agents to pigs
* Infection in Pigs
o Confining animals and not allowing them to roam freely
o Improved sanitary conditions
* Egg Transmission to Humans
o Good personal hygiene and hand washing prior to food preparation
o Identifying human carriers of tapeworms
o Mass community programs to treat tapeworm carriers.
* Possible Vaccine – porcine vaccine currently in the works

TAKE HOME POINTS
* Cysticercosis caused by the larval stage of Taenia solium, the pork tapeworm
* Pay special attention if pt from Central and South America, sub-Saharan Africa, India, and Asia, as neurocysticercosis is the most common cause of adult-onset seizures in these endemic areas.
* Order Head CT first to diagnose neurocysticercosis; if negative and suspicion still high, order Brain MRI.
* EITB test of choice for serology.
* Place PPD before starting treatment.
* Obtain Ophthalmology consult before starting treatment.
* Albendazole and Dexamethasone comprise first-line treatment for symptomatic cysticercosis. Consider concurrent anticonvulsants if pt presents with seizures.

REFERENCES
* aapredbook.aappublications.org
* UpToDate.
* www.dpd.cdc.gov
* www.e-radiology.net
* www.parasite-diagnosis.ch
* www.stanford.edu/class/cysticercosis/symptoms

CYSTICERCOSIS.ppt

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The Basal Ganglia

The Basal Ganglia

Outline
* Components of the basal ganglia
* Arrangement of basal ganglia components in the brain
* Architecture: cytology & neurochemistry
* Pathways & circuitry
* Function(s) of the basal ganglia
* Dysfunction and pathology
* Differences between human and rodent basal ganglia?

What are the Basal Ganglia?
The basal ganglia include…
* Neostriatum
o Caudate nucleus
o Putamen
o Nucleus Accumbens
* Globus Pallidus
o Internal segment
o External segment
o Ventral pallidum
* Subthalamic nucleus
* Substantia nigra
o Pars compacta
o Pars reticulata
* Pedunculopontine nucleus**
Subgroups of the basal ganglia
* Striatum
o Caudate nucleus
o Putamen
* Lenticular nuclei
o Globus pallidus
o Putamen
* Corpus striatum
o Caudate
o Lenticular nuclei

How are the basal ganglia arranged in the brain?
Caudate Nucleus
o C shaped structure
o Lateral wall of lateral ventricle
o Head, body and tail of caudate

Putamen and Globus Pallidus
* Putamen + Globus Pallidus = lentiform or lenticular nuclei
* Fills in space between the inferior horn and the anterior horn and body of the lateral ventricle.
* Gap between the lentiform nuclei and the lateral ventricle filled by the caudate nucleus.
* The posterior limb of the internal capsule separates the lentiform nuclei from the thalamus.

* Claustrum
* Septum pellucidum
* Insular cortex
* Corpus callosum
* Caudate nucleus
* Putamen
* Nucleus accumbens
* Internal capsule
* External capsule
* Extreme capsule
* Caudate nucleus
* Putamen
* Globus pallidus external (GPe)
* Globus pallidus internal (GPi)
* Ventral pallidum
* Anterior commissure
* Substantia innominata
* Internal capsule
* Lentiform nucleus**
* Caudate (Head, body, tail)
* Putamen
* GPe & GPi
* Lateral ventricle, anterior and temporal horn
* Internal capsule, anterior and posterior horn
* Caudate nucleus (body and tail)
* Putamen
* Globus pallidus
* Subthalamic nucleus
* Substantia nigra

- Pars compacta
- Pars reticulata
* Subthalamic nucleus
* Substantia nigra
* Globus pallidus external
* Subthalamic nucleus
* Substantia nigra
* Ventral tegmental area

Functions of the Basal Ganglia
* Extrapyramidal motor system
* Motor planning, sequencing and learning
* Striatal neuronal activity is not sufficiently explained by the stimuli presented or the movements performed
* Dependent on certain behavioral situations, certain conditions or particularly types of trials
+ -sensory stimuli but only when they elicit movements
+ -instruction cues (go-no go)
+ -memory related cues
+ -reward (especially ventral striatum)
+ -self-initiated moves
* Basal ganglia distinguished from cerebellum by connections with limbic system

Architecture of the basal ganglia: cellular and neurochemistry

Cytoarchitecture
* Main neurotransmitter in basal ganglia is GABA
* 95% of neurons in neostriatum are medium spiny neurons
o Contain GABA
o Principal neurons: project to globus pallidus and SNpr
o Subpopulations are distinguished by peptides, neurotransmitter receptors and connections
o Receive bulk of afferent input
* Several populations of interneurons
o aspiny
o ACh, somatostatin, GABA/parvalbumin
Neuronal circuitry of the basal ganglia
The Neostriatal Mosaic
* Neostriatum divided into two compartments:
patch (striosome) & matrix
* First described by Ann Graybiel in 1978 using AChE stain
* Not visible in Nissl stains (“hidden chemoarchitecture”)
* Define input/output architecture of neostriatum

Neostriatal Mosaic and Input/Output Organization
* Most inputs to the neostriatum terminate in a patchy fashion (“matrisomes”)
* Input from a given cortical region terminates over an extended anterior-posterior extent
* Functionally related cortical areas project to the same patches
* Output neurons to a given efferent subregion are also arranged in patches
* Neurons in patches project to both GPi/SNpr and GPe

Functional subdivisions
* Sensorimotor
o Putamen + globus pallidus/SNpr
o SNpc
* Association
o Caudate nucleus + globus pallidus/SNpr
o SNpc
* Limbic
o Nucleus accumbens + ventral pallidum
o VTA

Basal ganglia connections and pathways
Connections
* Afferents/inputs (neostriatum):
o Cerebral cortex (entire cortex)
o Thalamus (intralaminar and midline nuclei)
o Amygdala (basolateral nucleus)
o Raphe, substantia nigra pars compacta, VTA
* Efferents/output (GPi, VP, SNpr)
o Ventral tier nuclei of thalamus
o Subthalamic nucleus
o Superior colliculus
Organization of inputs to basal ganglia
Organization of basal ganglia outputs

All regions of cerebral cortex project to the basal ganglia, but output of basal ganglia is directed towards the frontal lobe, particularly pre-motor and supplementary motor cortex
Basic Circuit of Basal Ganglia

Neostriatum
GPi/SNpr
Cerebral Cortex
VA/VL thalamus
Direct vs. indirect pathways
* Different populations of spiny neurons
* Neuromodulators/co-transmitters
* Striosomes vs. matrix
* Dopamine receptor subtypes
Both

Recurrent loops
* Motor loop
o sensorimotor areas 1,2,3,4,5,6 -> putamen -> GP -> VA ->SMA
* Ocularmotor loop
o prefrontal cortex & ppc 9,12, 7 -> caudate -> GP -> VA -> frontal eye fields & SC
* Cognitive loop
o prefrontal cortical areas 9,12 -> caudate -> GP -> VA -> prefrontal cortex
* Limbic loop
o cingulate -> caudate (striosomes)-> GP -> MD -> ant. cingulate.
Topography is maintained within each loop!

Motor loop
Somatotopic subdivisions of the input remain segregated throughout the circuit.
Adapted from Rothwell, 1994; from Alexander and Crutcher, 1990
Processing in the basal ganglia
Huntington’s and Parkinson’s diseases
* Neurodegenerative diseases
* Motor dysfunction
* Brainwide pathology with focus on basal ganglia elements
* Genetic and/or environmental causes
Huntington’s Disease
Clinical symptoms
* Hyperkinetic & hemiballistic movements

Pathology hallmarks
* Striopallidal degeneration
* Decreased striatal volume
* Decrease in 5-HT1B receptors in ventral pallidum
Hyperkinetic hypothesis
* Reduced Glu (+) from STN to GPi, due either to STN lesions or reduced striatopallidal inhibitory influences along the in direct pathway lead to reduced inhibitory outflow from GPi/SNr and excessive disinhibition of the thalamus.
* Increased Glu (+) to cortical areas engaged by the motor circuit (SMA, PMC, MC) results in hyperkinetic movements.
Parkinson’s Disease
Clinical symptoms
* Hypokinetic movement
* Cogwheel rigidity

Pathology hallmarks
* Nigostriatal degeneration
* DA neuronal degeneration in SN
Hypokinetic hypothesis
* Inhibition of GPe within the indirect pathway leads to disinhibition of the STN
* Increased STN to the basal ganglia output nuclei (Gpi/SNr), leads to excessive thalamic inhibition.
* This is reinforced by reduced inhibitory input to Gpi/SNr through the direct pathway.
* Overall result is a reduction in reinforcing influence of the motor circuit upon cortically initiated movements.

PD Therapeutics: The approaches
* Pharmacology
o DA, mGluR, MAO(B) inhibitors, antioxidants, iron chelators
* Surgical
o Pallidal ablation
o DBS of globus pallidus or STN
* Transplantation
o Fibroblast cells
o Stem cells
* Vaccines
* RNA interference (RNAI)-based treatments

DBS: Deep Brain Stimulation of STN
Common themes in neurodegeneration
* Neurotoxicity
* Inflammation (glia)
* Apoptosis
* Abnormal protein aggregation
Thank you!
Notable differences between basal ganglia of human and rodents …..
There are differences in:
* Divisions & nomenclature
* Proportions
* Topography of afferent and efferent projections
Globus pallidus and entopeduncular nucleus (rodent)
vs.
Globus pallidus (external) and Globus pallidus (internal) (primate)
Regional proportion by volume
(% of total volume)
Spinal Cord

Major projection differences

* Neurons projecting to the motor and associative striatum
o Rats: reside in distinct regions
o Primates: arranged in interdigitating clusters.
* Terminal fields of projections arising from the motor and associative striatum
o rats: largely segregated
o Primates: not segregated
* Organization of patch- and matrix-projecting dopamine cells
o Rats: organized in spatially, morphologically, and histochemically distinct ventral and dorsal tiers,
o Primates: no (bi)division of the dopaminergic system that results in two areas which have all the characteristics of the two tiers in rats.

The Basal Ganglia.ppt
http://login.ncmir.ucsd.edThe Basal Ganglia

Outline
* Components of the basal ganglia
* Arrangement of basal ganglia components in the brain
* Architecture: cytology & neurochemistry
* Pathways & circuitry
* Function(s) of the basal ganglia
* Dysfunction and pathology
* Differences between human and rodent basal ganglia?

What are the Basal Ganglia?
The basal ganglia include…
* Neostriatum
o Caudate nucleus
o Putamen
o Nucleus Accumbens
* Globus Pallidus
o Internal segment
o External segment
o Ventral pallidum
* Subthalamic nucleus
* Substantia nigra
o Pars compacta
o Pars reticulata
* Pedunculopontine nucleus**
Subgroups of the basal ganglia
* Striatum
o Caudate nucleus
o Putamen
* Lenticular nuclei
o Globus pallidus
o Putamen
* Corpus striatum
o Caudate
o Lenticular nuclei

How are the basal ganglia arranged in the brain?
Caudate Nucleus
o C shaped structure
o Lateral wall of lateral ventricle
o Head, body and tail of caudate

Putamen and Globus Pallidus
* Putamen + Globus Pallidus = lentiform or lenticular nuclei
* Fills in space between the inferior horn and the anterior horn and body of the lateral ventricle.
* Gap between the lentiform nuclei and the lateral ventricle filled by the caudate nucleus.
* The posterior limb of the internal capsule separates the lentiform nuclei from the thalamus.

* Claustrum
* Septum pellucidum
* Insular cortex
* Corpus callosum
* Caudate nucleus
* Putamen
* Nucleus accumbens
* Internal capsule
* External capsule
* Extreme capsule
* Caudate nucleus
* Putamen
* Globus pallidus external (GPe)
* Globus pallidus internal (GPi)
* Ventral pallidum
* Anterior commissure
* Substantia innominata
* Internal capsule
* Lentiform nucleus**
* Caudate (Head, body, tail)
* Putamen
* GPe & GPi
* Lateral ventricle, anterior and temporal horn
* Internal capsule, anterior and posterior horn
* Caudate nucleus (body and tail)
* Putamen
* Globus pallidus
* Subthalamic nucleus
* Substantia nigra

- Pars compacta
- Pars reticulata
* Subthalamic nucleus
* Substantia nigra
* Globus pallidus external
* Subthalamic nucleus
* Substantia nigra
* Ventral tegmental area

Functions of the Basal Ganglia
* Extrapyramidal motor system
* Motor planning, sequencing and learning
* Striatal neuronal activity is not sufficiently explained by the stimuli presented or the movements performed
* Dependent on certain behavioral situations, certain conditions or particularly types of trials
+ -sensory stimuli but only when they elicit movements
+ -instruction cues (go-no go)
+ -memory related cues
+ -reward (especially ventral striatum)
+ -self-initiated moves
* Basal ganglia distinguished from cerebellum by connections with limbic system

Architecture of the basal ganglia: cellular and neurochemistry

Cytoarchitecture
* Main neurotransmitter in basal ganglia is GABA
* 95% of neurons in neostriatum are medium spiny neurons
o Contain GABA
o Principal neurons: project to globus pallidus and SNpr
o Subpopulations are distinguished by peptides, neurotransmitter receptors and connections
o Receive bulk of afferent input
* Several populations of interneurons
o aspiny
o ACh, somatostatin, GABA/parvalbumin
Neuronal circuitry of the basal ganglia
The Neostriatal Mosaic
* Neostriatum divided into two compartments:
patch (striosome) & matrix
* First described by Ann Graybiel in 1978 using AChE stain
* Not visible in Nissl stains (“hidden chemoarchitecture”)
* Define input/output architecture of neostriatum

Neostriatal Mosaic and Input/Output Organization
* Most inputs to the neostriatum terminate in a patchy fashion (“matrisomes”)
* Input from a given cortical region terminates over an extended anterior-posterior extent
* Functionally related cortical areas project to the same patches
* Output neurons to a given efferent subregion are also arranged in patches
* Neurons in patches project to both GPi/SNpr and GPe

Functional subdivisions
* Sensorimotor
o Putamen + globus pallidus/SNpr
o SNpc
* Association
o Caudate nucleus + globus pallidus/SNpr
o SNpc
* Limbic
o Nucleus accumbens + ventral pallidum
o VTA

Basal ganglia connections and pathways
Connections
* Afferents/inputs (neostriatum):
o Cerebral cortex (entire cortex)
o Thalamus (intralaminar and midline nuclei)
o Amygdala (basolateral nucleus)
o Raphe, substantia nigra pars compacta, VTA
* Efferents/output (GPi, VP, SNpr)
o Ventral tier nuclei of thalamus
o Subthalamic nucleus
o Superior colliculus
Organization of inputs to basal ganglia
Organization of basal ganglia outputs

All regions of cerebral cortex project to the basal ganglia, but output of basal ganglia is directed towards the frontal lobe, particularly pre-motor and supplementary motor cortex
Basic Circuit of Basal Ganglia

Neostriatum
GPi/SNpr
Cerebral Cortex
VA/VL thalamus
Direct vs. indirect pathways
* Different populations of spiny neurons
* Neuromodulators/co-transmitters
* Striosomes vs. matrix
* Dopamine receptor subtypes
Both

Recurrent loops
* Motor loop
o sensorimotor areas 1,2,3,4,5,6 -> putamen -> GP -> VA ->SMA
* Ocularmotor loop
o prefrontal cortex & ppc 9,12, 7 -> caudate -> GP -> VA -> frontal eye fields & SC
* Cognitive loop
o prefrontal cortical areas 9,12 -> caudate -> GP -> VA -> prefrontal cortex
* Limbic loop
o cingulate -> caudate (striosomes)-> GP -> MD -> ant. cingulate.
Topography is maintained within each loop!

Motor loop
Somatotopic subdivisions of the input remain segregated throughout the circuit.
Adapted from Rothwell, 1994; from Alexander and Crutcher, 1990
Processing in the basal ganglia
Huntington’s and Parkinson’s diseases
* Neurodegenerative diseases
* Motor dysfunction
* Brainwide pathology with focus on basal ganglia elements
* Genetic and/or environmental causes
Huntington’s Disease
Clinical symptoms
* Hyperkinetic & hemiballistic movements

Pathology hallmarks
* Striopallidal degeneration
* Decreased striatal volume
* Decrease in 5-HT1B receptors in ventral pallidum
Hyperkinetic hypothesis
* Reduced Glu (+) from STN to GPi, due either to STN lesions or reduced striatopallidal inhibitory influences along the in direct pathway lead to reduced inhibitory outflow from GPi/SNr and excessive disinhibition of the thalamus.
* Increased Glu (+) to cortical areas engaged by the motor circuit (SMA, PMC, MC) results in hyperkinetic movements.
Parkinson’s Disease
Clinical symptoms
* Hypokinetic movement
* Cogwheel rigidity

Pathology hallmarks
* Nigostriatal degeneration
* DA neuronal degeneration in SN
Hypokinetic hypothesis
* Inhibition of GPe within the indirect pathway leads to disinhibition of the STN
* Increased STN to the basal ganglia output nuclei (Gpi/SNr), leads to excessive thalamic inhibition.
* This is reinforced by reduced inhibitory input to Gpi/SNr through the direct pathway.
* Overall result is a reduction in reinforcing influence of the motor circuit upon cortically initiated movements.

PD Therapeutics: The approaches
* Pharmacology
o DA, mGluR, MAO(B) inhibitors, antioxidants, iron chelators
* Surgical
o Pallidal ablation
o DBS of globus pallidus or STN
* Transplantation
o Fibroblast cells
o Stem cells
* Vaccines
* RNA interference (RNAI)-based treatments

DBS: Deep Brain Stimulation of STN
Common themes in neurodegeneration
* Neurotoxicity
* Inflammation (glia)
* Apoptosis
* Abnormal protein aggregation
Thank you!
Notable differences between basal ganglia of human and rodents …..
There are differences in:
* Divisions & nomenclature
* Proportions
* Topography of afferent and efferent projections
Globus pallidus and entopeduncular nucleus (rodent)
vs.
Globus pallidus (external) and Globus pallidus (internal) (primate)
Regional proportion by volume
(% of total volume)
Spinal Cord

Major projection differences

* Neurons projecting to the motor and associative striatum
o Rats: reside in distinct regions
o Primates: arranged in interdigitating clusters.
* Terminal fields of projections arising from the motor and associative striatum
o rats: largely segregated
o Primates: not segregated
* Organization of patch- and matrix-projecting dopamine cells
o Rats: organized in spatially, morphologically, and histochemically distinct ventral and dorsal tiers,
o Primates: no (bi)division of the dopaminergic system that results in two areas which have all the characteristics of the two tiers in rats.

The Basal Ganglia.ppt

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