Basal ganglia - Anatomy, Neurochemistry, Connections, Disorders

Dr. Rahul Kumar, Senior Resident, Department of Neurology, M S Ramaiah Medical College and Hospitals

What are the basal ganglia?

Depends on target audience Anatomical: Non-cortical nuclei in the

forebrain Caudate nucleus, putamen, nucleus

accumbens, amygdala, septal nuclei, globus pallidus

Functional: Richly interconnected set of nuclei in the forebrain and midbrain

Outline for the Session

History and evolution of knowledge base Gross and microscopic anatomy of basal ganglia Connections of basal ganglia – input and output Neurochemistry Functional Subsystems in basal ganglia Processing of information Skeletomotor Circuit Other important circuits Mathematical Models of Basal Ganglia functioning

Time Permitting ….

Introduction to Basal Ganglia Diseases In Vivo assessment of disorders of basal

ganglia – fMRI and PET Recent advances in the

neuropharmacology and interventional therapies in basal ganglia disorders



The first anatomical identification of distinct subcortical structures, at the "base" of the brain, was carried out by Thomas Willis (1621 –1675) in his Cerebri Anatomi, published in 1664 and translated into English in 1681 as Anatomy of the Brain and Nerves.

The term Corpus Striatum was used for the first time by Raymond de Vieussens (1641 – 1716) in his Neurographia Universalis, published in 1690, to describe the striped appearance which a section of its anterior part presents.

http://upload.wikimedia.org/wikipedia/commons/b/ba/Thomas_Willis.jpg

http://images.google.it/imgres?imgurl=http://www.amuseum.de/medizin/CibaZeitung/images/cz103720.jpg&imgrefurl=http://www.amuseum.de/medizin/CibaZeitung/okt37.htm&h=350&w=265&sz=14&hl=it&start=2&um=1&tbnid=2S8I5pVL-ka9xM:&tbnh=120&tbnw=91&prev=/images?q=%22Raymond+de++Vieussens%22&svnum=10&um=1&hl=it&rls=GGLJ,GGLJ:2006-40,GGLJ:it&sa=N

For many years the Basal Ganglia were considered formed by two structures:

the caudate nucleus (Nucleus Caudatus), so called for the long characteristic tail, and

the lenticular nucleus (or Nucleus Lenticularis).

The first systematic description of the Basal Ganglia was performed by the French anatomist and neurologist Joseph Jules Dejerine (1849-1917) in his Anatomie des Centres Nerveux, published in Paris in 1895.In this book there is the first use of the term Globus Pallidus to indicate the ventral part of the Nucleus Lenticularis which was separated by Dejerine from the Putamen, considered part of the Striatum.

MAIN STRUCTURES BELONGING TO THE BASAL GANGLIA:CLASSIC VISION

MAIN STRUCTURES BELONGING TO THE BASAL GANGLIA:MODERN VISION

THE EVOLUTION OF TELENCEPHALON

During the phylogenesis the prefrontal cortex presents a disproportioned increase with respect to the other cerebral areas.

The prefrontal cortex, in the homo sapiens, represents about 1/3 of the entire neocortical surface.

Blinkov S.M., Glazer I.I., The human brain: a quantitative handbook. New York, Plenum Press, 1968.

Evolutionary conservatism

“The basal ganglia in modern mammals, birds and reptiles (i.e. modern amniotes) are very similar in connections and neurotransmitters, suggesting that the evolution of the basal ganglia in amniotes has been very conservative.”

Medina, L and Reiner, A.

Neurotransmitter organization and connectivity of the basal ganglia in vertebrates: Implications for the evolution of basal ganglia. Brain Behaviour and Evolution (1995) 46, 235-258

Rat

Human

The basal ganglia may have be conserved

…. unlike cerebral cortex and cerebellum the basal ganglia have not increased in relative size with brain development



Spiny I Spiny I neuronneuron

Spiny II Spiny II neuronneuron

Aspiny I Aspiny I neuronneuron

Aspiny II Aspiny II neuronneuron

Aspiny III Aspiny III neuronneuron

Neurogliform Neurogliform cellcell

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

From Holt et al., 1997, JCN

Basal Ganglia Components Basal Ganglia Components Basal Ganglia Components Basal Ganglia Components



Input Portion Input Portion

STRIATUM STRIATUM

(Caudate Nucleus and Putamen)(Caudate Nucleus and Putamen)

Output PortionOutput Portion

1. 1. PALLIDUM PALLIDUM (Globus Pallidus)(Globus Pallidus)

2. 2. SNr SNr (Substantia Nigra, Pars Reticulata)(Substantia Nigra, Pars Reticulata)

Basal Ganglia ConnectionsBasal Ganglia Connections

habenularhabenularnucleusnucleus

habenularhabenularnucleusnucleus

tectumtectum(superior colliculus)(superior colliculus)

tectumtectum(superior colliculus)(superior colliculus)

PPNPPN(pedunculopontine nucleus)(pedunculopontine nucleus)

PPNPPN(pedunculopontine nucleus)(pedunculopontine nucleus)

amygdaloid bodyamygdaloid bodyamygdaloid bodyamygdaloid body

rapherapherapheraphe

CerebralCerebralCortexCortex

CerebralCerebralCortexCortex

STNSTNSTNSTN

PallidumPallidum

SNrSNr

PallidumPallidum

SNrSNr

STRIATUMSTRIATUMSTRIATUMSTRIATUM

Connections of the Basal GangliaConnections of the Basal GangliaConnections of the Basal GangliaConnections of the Basal Ganglia

SNcSNcSNcSNcThalamusThalamusThalamusThalamus



glutaminergic

glutaminergic serotonergic

dopaminergic

gabanergic

Gpe – enkephalin, neurotensin Gpi - substance P, Dynorphin

Gpi and SNpr - GABA

Stn – Only excitatory output, Glutaminergic



Functions of the Basal Ganglia

Recurrent loops

Motor loop sensorimotor areas 1,2,3,4,5,6 -> putamen -> GP -> VA -

>SMA Oculomotor loop

prefrontal cortex & ppc 9,12, 7 -> caudate -> GP -> VA -> frontal eye fields & SC

Cognitive loop prefrontal cortical areas 9,12 -> caudate -> GP -> VA ->

prefrontal cortex Limbic loop

cingulate -> caudate (striosomes)-> GP -> MD -> ant. cingulate.

Topography is maintained within each loop!



From Graybiel et al., The basal ganglia and adaptive motor control, Science, 265: 1826, 1994

Cortex

Neostriatum

Gpi/SNpr

“divergent-reconvergent processing”

Movement control via disnhibition

From Chevalier and Deniau, TINS 13:277, 1990



Initiation and control of voluntary movement

Motor loop

Somatotopic subdivisions of the input remain segregated throughout the circuit.

Adapted from Rothwell, 1994; from Alexander and Crutcher, 1990

Basal ganglia circuitry

two circuits important in regulation of movement direct pathway indirect pathway

direct pathway decreases inhibitory basal ganglia output

indirect pathway increases inhibitory basal ganglia output

balance of these two circuits underlies regulation of movements

VA/VL

cortex

putamen

GPe

STN GPi/SNr

Direct pathway

VA/VL

cortex

putamen

GPe

STN GPi/SNr

Glutamate (+)

GABA (-)

Direct pathway

DBStion of direct pathway reduces inhibitory output of basal ganglia

Consequence is to promote movement

Indirect pathway

VA/VL

cortex

putamen

GPe

STN GPi/SNr

Glutamate (+)

GABA (-)

Indirect pathway

DBStion of indirect pathway increases inhibitory output of basal ganglia

Consequence is inhibition of movement

SN’s effects on direct and indirect pathways

VA/VL

cortex

putamen

GPe

STN GPi/SNr

Glutamate (+)

GABA (-)

SNpc

Dopamine’s effects on direct and indirect pathways

Dopamine release by SNpc DBStes direct pathway via D1 receptor

Dopamine release by SNpc inhibits indirect pathway via D2 receptor

Dopamine promotes movement

Direct vs. indirect pathways

From Graybiel, A. Neural Networks, Am J Psychiatry 158:21, January 2001

•Different populations of spiny neurons

•Neuromodulators/co-transmitters

•Striosomes vs. matrix

•Dopamine receptor subtypes



Dorso-lateral prefrontal circuit

“Executive functions”: attention, concentration, multi-tasking, set-shifting, problem solving, planning and organisation of tasks

Orbito-frontal circuit

Irritability, emotional lability, failure to respond to social cues, lack of empathy,

obsessive-compulsive behaviours

“Limbic” circuit

Input also from hippocampus, amygdala and entorhinal cortexMotivation and emotional behaviour

Oculomotor Loop

Dr. Rahul Kumar, Senior Resident, Department of Neurology, M S Ramaiah Medical College and Hospitals

To Recapitulate……

Subcortical structures and circuits No direct projections, act via pyramidal

pathways

Control movements, cognition, emotions, eye movements

Work on the Disinhibition Model

Circuits work in parallel, not in isolation



General Thoughts on Mathematical Modeling

What is being modeled – Math at the mercy of the biology Anatomy and neurochemsitry does not reveal

dynamics, rather leads to misconceptions Radically different concept of the BG-Th-Ctx

network

Serial Selection in the Basal Ganglia

Striatum

Inputs (Cortex/Thalamus)

Output Nuclei

Up-state/down-state filtering

1) Up-down states of medium spiny neurones

Local inhibitory circuits

2) Local inhibition in striatum

Local recurrent circuits4) Recurrent inhibition in output nuclei

Subthalamus

3) Diffuse/focused projection onto output nuclei

Focused inhibition

Diffuse excitation

Resonance Effect

Time = cycle (0) Time = cycle (1/2) Time = cycle (1)

Multiple Circuits of Different Resonant Frequencies

Motor Cortex

Putamen

GPi

VL Thalamus

GPe

STN

SMA

thalamus

SN

IO

Cortex

BasalGanglia

Cerebellum

target+

-

? Inbuilt vs reward

outputinput

Basal Ganglia: TD vs Reinforcement Learning

output

Specialization by Learning Algorithms

(Doya, 2009)

Temporal Dispersion Model of Basal Ganglia(Houk et al. 1995, Montague et al. 1996, Schultz et al. 2007,...)

evaluation

action selection

state representation

action output

sensory input

TD signal

Cerebral cortex

Striatum

Dopamine neurons

reward SNr, GP

Thalamus

V(s)

DA neurons: TD error

a

SNr/GPi: action selection: Q(s,a) a

NA?

Ach?

5-HT?

Dopamine Neurons and TD Error(t) = r(t) +

V(s(t+1)) - V(s(t))

before learning

after learning

omit reward

(Schultz et al. 2007)

RL Model of Basal Ganglia(…, Doya 2000) Striatum: value functions V(s) and Q(s,a)

Dopamine neurons: TD error

r

evaluation

action selection

state representation

action output

sensory input

TD signal

Cerebral cortex

Striatum

Dopamine neurons

reward SNr, GP

Thalamus

s

V(s) Q(s,a)

SNr/GPi: action selection: Q(s,a) a

Enhancement of response by dopamine

Probably 3 factors in striatum

pre

post

Glu

depolarizeNMDA LTP

dopamine rewardconsolidates

Likely learning rule in the striatum



ganglia – fMRI and PET Recent advances in the interventional

therapies in basal ganglia disorders

SMA

Putamen

-Globus

Pallidus (GPi)

-

SubstantiaNigra

+

VLo

SubthalamicNucleus

+

Cortex

+X

Parkinson’s Disease+

SMA

Putamen

-

-

+

VLo

SubthalamicNucleus

+X

Huntington’s Disease

GPiGPe

-

+

SMA

Striatum

- GlobusPallidus

-

+

VLo

SubthalamicNucleus

+

X

Hyperkinesia(e.g. ballism)





Healthy subject PD patient – Hoehn-Yahr Stage 1

Functional Imaging with ß-CIT: Dopamine Transporter

Longitudinal DAT Imaging in PD



ganglia – fMRI and PET Neuroimaging in Diseases of Basal

Ganglia Recent advances in the interventional






Approved Indications

DBS Therapy is approved for the treatment of symptoms due to: Essential Tremor

FDA approved in 1997 Parkinson’s disease

FDA approved in 2002 Dystonia

FDA approved (HDE*) in 2003

Target Sites for DBS Therapy

Vim Thalamus: Essential Tremor

Subthalamic Nucleus: Parkinson’s disease

and Dystonia

Globus Pallidus: Parkinson’s disease

and Dystonia

DBS Therapy: Implantable Components

Lead Extension Neurostimulator

(implantable pulse generator)

Soletra™

Single Channel OutputKinetra®

Dual Channel Output

Parkinson’s Disease Treatment: Continuum of Interventions

Modified from Giroux, ML and Farris, SF. Cleveland Clinic Foundation 2005Cleveland Clinic FoundationCenter for Neurological Restoration

Signs of levodopa“wearing-off”

Dyskinesia, “On-Off”

Motor Fluctuations

Postural Instability, Freezing, Falls, Dementia

DBS

Mild Moderate Severe

Treatment

Patient Symptoms

Disease Severity

Efficacy: Benefits of DBS TherapyImpact on MobilityDyskinesia

“On” Time

“Off” Time

Before

After

Additional Benefits of DBS

Bilateral, reversible, and adjustable Non-destructive versus ablative

procedures Can be non-invasively fine-tuned to

each patient’s individual needs

DBS Therapy: PotentialComplications and Risks

Surgery related Hemorrhage (inherent in any stereotactic

procedure); may be silent or symptomatic

Transient confusion Infection (typically occurs at neurostimulator site

in chest when it does occur) Stimulation related

Usually can be minimized or eliminated by adjusting stimulation settings

Reversible paresthesia, dysarthria, muscle contraction

Surgical Technique

Stereotactic frame placement or frameless stereotaxy

Targeting Imaging Stereotactic targeting Physiologic targeting

(microelectrode recording and stimulation)

Electrode placement Pulse generator

implantation

Surgical Technique: Targeting

Sophisticated imaging and software enables precise targeting for optimal outcomes and minimal risk

Microelectrode recording (MER) offers additional levels of verification of lead location

Surgical Technique: Microelectrode Recording

STN

Border/SN

10sec

10sec

80ms

80ms

80ms

Sagittal Section Through the Thalamus Border

Surgical Technique: DBS Lead Placement

Leads placed in motor territory of nucleus

Leads have four electrodes

Multiple electrode configurations possible during post-operative programming

Target Sites for DBS Therapy

Vim Thalamus: Essential Tremor

Subthalamic Nucleus: Parkinson’s disease

and Dystonia

Globus Pallidus: Parkinson’s disease

and Dystonia

Surgical Technique: Neurostimulator Placement

Can be done immediately or days/weeks later

Typically placed below clavicle

Connected to lead using extension

To Summarize …….

Mathematical models antedate the major discoveries in basal ganglia circuitry

Neuroimaging abnormalities are being described, functional neuroimaging possible but little discriminatory value

DBS promising, replicates tonic activity.

Health & Medicine

Basal ganglia - Anatomy, Neurochemistry, Connections, Disorders