Basal ganglia - Anatomy, Neurochemistry, Connections, Disorders
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Transcript of 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
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
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.
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
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
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
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
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
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
glutaminergic
glutaminergic serotonergic
dopaminergic
gabanergic
Gpe – enkephalin, neurotensin Gpi - substance P, Dynorphin
Gpi and SNpr - GABA
Stn – Only excitatory output, Glutaminergic
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
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!
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
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
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
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
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
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
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
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
Outline for the Session
Introduction to Basal Ganglia Diseases In Vivo assessment of disorders of basal
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)
Outline for the Session
Introduction to Basal Ganglia Diseases In Vivo assessment of disorders of basal
ganglia – fMRI and PET Recent advances in the interventional
therapies in basal ganglia disorders
Healthy subject PD patient – Hoehn-Yahr Stage 1
Functional Imaging with ß-CIT: Dopamine Transporter
Longitudinal DAT Imaging in PD
Outline for the Session
Introduction to Basal Ganglia Diseases In Vivo assessment of disorders of basal
ganglia – fMRI and PET Neuroimaging in Diseases of Basal
Ganglia Recent advances in the interventional
therapies in basal ganglia disorders
Outline for the Session
Introduction to Basal Ganglia Diseases In Vivo assessment of disorders of basal
ganglia – fMRI and PET Recent advances in the interventional
therapies in basal ganglia disorders
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.