Basal Ganglia

Direct and Indirect Pathways and Connections

Mary K. Vaughan, Ph.D.

Basal Ganglia Game Plan

Neostriatum a.k.a. Striatum

Dorsal component of neostriatum
Caudate nucleus Putamen

Ventral component of striatum

Nucleus accumbens **Olfactory tubercle -

Important in Limbic Loop in phase 3

Somatotopy of Inputs to the Caudate and Putamen

Head of the caudate
Frontal eye fields and prefrontal cortex

Dorsal Putamen
Input from leg area of cortex

Ventral putamen
Input from face and hand area of cortex

Paleostriatum
Consists of two subnuclei
globus pallidus interna (Gpi) globus pallidus externa (Gpe)

GPe

GPi

Substantia nigra
Found in the mesencephalon Consists of two subnuclei substantia nigra pars compacta (SNpc) substantia nigra pars reticulata (SNpr)

Substantia nigra

Subthalamic nucleus

Subthalamic nucleus

Four Nuclei of Basal Ganglia

Caudate/putamen Globus pallidus GPi GPe Substantia nigra pars compacta (SNpc) pars reticulata (SNpr) Subthalamic nucleus

Ansa lenticularis
Ansa lenticularis exits from the globus pallidus interna (Gpi), comes around the internal capsule and joins other tracts of the thalamic fasciculus

Lenticular Fasciculus
Lenticular fasciculus exits from Gpi and forms part of the border of the subthalamic nucleus Joins other tracts in thalamic fasciculus

Thalamic Fasciculus
A collection of tracts that are destined for the VL and some for the VA as well. Composed of the:
Lenticular fasciculus Ansa lenticularis Nigrothalamic tract Dentatothalamic tract from cerebellum

Subthalamic Fasciculus
A loop connecting
GPe with STN via GABAergic pallido-subthalmic projections Subthalamic nucleus projects back to the GPi via subthalamopallidal excitatory glutaminergic projections

Output Thalamic Nuclei

Part of the basal ganglia output back to the cortex

Output thalamic nuclei

Part of thalamic output back to the cortex

Other output to nuclei of the brain stem

Pedunculopontine nuclei a nucleus of the old motor system in the locomotor area of the reticular formation Tectum, particularly superior colliculus

Parallel Circuits in Basal Ganglia

Information flow through the basal ganglia is separated into five distinct parallel circuits each with its own direct and indirect pathway.
Motor loop Today Oculomotor loop Dorsolateral prefrontal loop Lateral orbitofrontal loop Limbic loop Phase 3

Loops of the Basal Ganglia

Each loop
Starts from specific areas of cortex Passes through distinct regions of the basal ganglia Modulates different areas of the thalamus Returns to distinct cortical regions that requested the information

Motor Loop
Starts in supplementary motor cortex, primary motor and premotor cortices Projects mainly to putamen Projections to thalamus include
VLo VA CM
CM

DeLongs Direct and Indirect Pathways

He proposed that basal ganglia output can be grouped into two projection systems
Direct pathway Indirect pathway

It has been proposed that the basal ganglia are parallel processing information They appear to function in balanced opposition

Neurotransmitters
GABA inhibitory Glutamate Stimulatory Acetylcholine within neostriatum Neuropeptides co-localized with GABA
Enkephalin Substance P/dynorphin

Dopamine
D1 stimulates adenylate cyclase activity D2 inhibits adenylate cyclase activity

Striatal Cholinergic Interneurons

Cholinergic interneurons in the striatum are stimulatory particularly in the indirect pathway Centrally active anticholinergic, antiparkinsonian drugs act via muscarinic receptors and reduce activity of striatal cholinergic interneurons
Striatal cholinergic interneurons

Direct Pathway
Glu (Stimulation) GABA (Inhibition) GABA (Inhibition) Glu (Stimulation)

Indirect Pathway
Glu GABA GABA Glu GABA Glu

Parkinsons Disease
Bradykinesia Pill-rolling tremor Masked facies Micrographia Microphonia Marche de petit pas Postural Instability Autonomic dysfunction Festinating gait Seborrhea Cramps of feet or toes Decreased eyeblink

Signs and Symptoms

Bradykinesia
Slow and small steps Masked facies (little movement, staring) Small handwriting

Resting tremor (pill rolling tremor) Postural instability Rigidity

Pathology in Parkinsons Disease

Loss of dopamine containing neurons in the pars compacta of substantia nigra Depletion of dopamine in striatum which correlates with severity of dopamine cell loss in the SNpc at post-mortem

Progressive Stages

MPTP
N-methyl-2,3,4,6tetrahydropyridine is a dopamine neurotoxin that selectively destroys SNpc neurons Produces Parkinsons disease in man and primates Causes loss of dopamine in striatum

Drug-Induced Parkinsons Disease

Drugs that deplete brain dopamine e.g., reserpine Drugs that block dopamine receptors e.g., phenothiazine and butyrophenone antipsychotic drugs Reversible upon drug elimination

Huntingtons Disease
Dementia Hyperactivity

Huntingtons Disease
Autosomal dominant Caused by an abnormal CAG repeat
Normal 11-34 Abnormal 38-121

Caudate nucleus dies Progressive dementia Usually manifested in the 40s Genetic test now available

Hemiballism
Discrete unilateral lesion of the subthalamic nucleus Forceful, violent and persistent hyperkinetic movements Involves the contralateral limbs and mainly the proximal musculature

Wilsons disease Hepatolenticular degeneration

Autosomal recessive disorder of chromosome 13 Onset usually 13-25 years Accumulation of copper in liver Kayser-Fleischer rings in eye due to Cu Putamen degenerates

Sydenhams chorea
An autoimmune disease caused by rheumatic fever Chorea may last 3-6 weeks Usually seen in children Also called St. Vitus dance

Take home message

Alterations in output via the indirect striatal projection systems is the key to understanding the different basal ganglia disorders. Decrease activity of STN neurons
direct lesion - hemiballism increased inhibition - Huntingtons chorea

Increase activity of STN neurons

Increase activity of STN neurons - Parkinsons disease