Anatomy and Physiology of the Basal Ganglia, Neuro-circuitry, Neurochemistry, Mathematical Models, Disorders, Deep Brain Stimulation

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

2. 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

4. 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

5. 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

6. 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

7. 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.

8. 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).

9. 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.

10. MAIN STRUCTURES BELONGING TO THE BASAL GANGLIA:
CLASSIC VISION

11. MAIN STRUCTURES BELONGING TO THE BASAL GANGLIA:
MODERN VISION

12. 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.

13. 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

14. The basal ganglia may have be conserved
Human
…. unlike cerebral cortex and
cerebellum the basal ganglia have
not increased in relative size with
brain development
Rat

15. 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

20. Spiny I
neuron
Spiny II
neuron
Aspiny I
neuron
Aspiny II
neuron
Aspiny III
neuron
Neurogliform
cell

21. 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

22. Basal Ganglia
Basal Ganglia
Components
Components

23. 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

24. Basal Ganglia
Basal Ganglia
Connections
Connections
Input Portion
STRIATUM
(Caudate Nucleus and Putamen)
Output Portion
1. PALLIDUM (Globus Pallidus)
2. SNr (Substantia Nigra, Pars Reticulata)

25. Connections of the Basal Ganglia
Connections of the Basal Ganglia
amygdaloid body
amygdaloid body
Cerebral
Cerebral
Cortex
Cortex
raphe
raphe
STRIATUM
STRIATUM
Thalamus
Thalamus
STN
STN
SNc
SNc
Pallidum
Pallidum
SNr
SNr
tectum
tectum
(superior colliculus)
(superior colliculus)
habenular
habenular
nucleus
nucleus
PPN
PPN
(pedunculopontine nucleus)
(pedunculopontine nucleus)

26. 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

27. glutaminergic
serotonergic
dopaminergic
glutaminergic

28. gabanergic
Gpe – enkephalin, neurotensin
Gpi - substance P, Dynorphin

29. Gpi and SNpr - GABA

30. Stn – Only excitatory output, Glutaminergic

31. 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

32. Functions of the Basal Ganglia

33. 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!

34. 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

35. Cortex
Neostriatum
Gpi/SNpr
“divergent-reconvergent
processing”
From Graybiel et al., The basal ganglia and adaptive motor control, Science, 265: 1826, 1994

36. Movement control via disnhibition
From Chevalier and Deniau, TINS 13:277, 1990

37. 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

38. Initiation and control of voluntary movement

39. Motor loop
Somatotopic subdivisions of the
input remain segregated
throughout the circuit.
Adapted from Rothwell, 1994; from Alexander and Crutcher, 1990

40. Basal ganglia circuitry
 two circuits important in
cortex
regulation of movement
 direct pathway
 indirect pathway
putamen
 direct pathway decreases
inhibitory basal ganglia output
 indirect pathway increases
inhibitory basal ganglia output
 balance of these two circuits
underlies regulation of
movements
GPe
STN
VA/VL
GPi/SNr

41. Direct pathway
cortex
putamen
GPe
VA/VL
Glutamate (+)
GABA (-)
STN
GPi/SNr

42. Direct pathway
 DBStion of direct pathway reduces inhibitory output of
basal ganglia
 Consequence is to promote movement

43. Indirect pathway
cortex
Glutamate (+)
putamen
GABA (-)
GPe
STN
VA/VL
GPi/SNr

44. Indirect pathway
 DBStion of indirect pathway increases inhibitory output
of basal ganglia
 Consequence is inhibition of movement

45. SN’s effects on direct and indirect pathways
cortex
putamen
SNpc
GPe
VA/VL
Glutamate (+)
GABA (-)
STN
GPi/SNr

46. 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

47. Direct vs. indirect pathways
•Different populations of spiny neurons
•Neuromodulators/co-transmitters
•Striosomes vs. matrix
•Dopamine receptor subtypes
From Graybiel, A. Neural
Networks, Am J Psychiatry
158:21, January 2001

48. 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

49. Dorso-lateral
prefrontal circuit
“Executive functions”: attention, concentration, multi-tasking, set-shifting,
problem solving, planning and organisation of tasks

50. Orbito-frontal circuit
Irritability, emotional lability, failure to respond to social cues,
lack of empathy,
obsessive-compulsive behaviours

51. “Limbic” circuit
Input also from hippocampus, amygdala and entorhinal cortex
Motivation and emotional behaviour

52. Oculomotor
Loop

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

54. 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

55. 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

56. 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

57. Serial Selection in the Basal Ganglia
Inputs
1) Up-down states
(Cortex/Thalamus)
of medium spiny
neurones
Striatum
2) Local inhibition
Up-state/down-state filtering
in striatum
3) Diffuse/focused
projection onto
output nuclei
4) Recurrent
inhibition in
output nuclei
Subthalamus
Local inhibitory
circuits
Focused
inhibition
Diffuse
excitation
Output Nuclei
Local recurrent circuits

58. Resonance Effect
Time = cycle (0)
Time = cycle (1/2)
Time = cycle (1)

59. Multiple Circuits of Different
Resonant Frequencies
SMA
Motor Cortex
Putamen
VL Thalamus
GPe
GPi
STN

60. Specialization by Learning
Algorithms
(Doya, 2009)
output
Cortex
Basal Ganglia: TD vs Reinforcement Learning
? Inbuilt vs reward
Basalthalamus
Ganglia
SN
IO
input
output
Cerebellum
target
+
-

61. Temporal Dispersion Model of
Basal Ganglia(Houk et al. 1995, Montague et
al. 1996, Schultz et al. 2007,...)
sensory
input
action
output
Cerebral cortex
state representation
Ach?
Striatum
evaluation
5-HT?
Thalamus
TD signal
a
V(s)
Dopamine neurons
reward
SNr, GP
action selection
DA neurons: TD error δ
SNr/GPi: action selection: Q(s,a) → a
NA?

62. before learning
after learning
omit reward
(Schultz et al.
2007)
Dopamine
Neurons
and TD
Error
δ(t) = r(t)
+
γV(s(t+1))
- V(s(t))

63. RL Model of Basal Ganglia
(…, Doya 2000)
 Striatum: value functions V(s) and Q(s,a)
sensory
input
Cerebral cortex
state representation
s
action
output
Striatum
evaluation
TD signal
δ
V(s)
Thalamus
Q(s,a)
Dopam ine neurons
r
reward
SNr, GP
action selection
Dopamine neurons: TD error δ
SNr/GPi: action selection: Q(s,a) → a

64. Enhancement of response by
dopamine

65. Likely learning rule in the
Probably 3 factors in striatum
striatum
pre
post
Glu
depolarize
dopamine
reward
NMDA
LTP
consolidates

66. 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

67. Cortex
+
+
Substantia
Nigra
+
Parkinson’s
Disease
Putamen
X
SMA
-
Globus
Pallidus
(GPi)
VLo
-
+
Subthalamic
Nucleus

68. +
SMA
Putamen
X-
Huntington’s
Disease
VLo
-
++
GPe GPi
-
Subthalamic
Nucleus

69. SMA
+
Hyperkinesia
(e.g. ballism)
Striatum
-
VLo
-
Globus
Pallidus
+
X
Subthalamic
Nucleus

70. 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

72. Functional Imaging with ß-CIT:
Dopamine Transporter
Healthy subject
PD patient – Hoehn-Yahr
Stage 1

73. Longitudinal DAT Imaging in PD

74. 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

83. 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

84. 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

85. Target Sites for DBS Therapy
Vim Thalamus:
Essential Tremor
Subthalamic Nucleus:
Parkinson’s disease
and Dystonia
Globus Pallidus:
Parkinson’s disease
and Dystonia

86. DBS Therapy: Implantable
Components
 Lead
 Extension
 Neurostimulator
(implantable pulse
generator)
Soletra™
Single Channel Output
Kinetra®
Dual Channel Output

87. Parkinson’s Disease Treatment:
Continuum of Interventions
Disease Severity
Patient Symptoms
Mild
Moderate
Signs of levodopa
“wearing-off”
Severe
Dyskinesia,
“On-Off”
Motor
Fluctuations
Treatment
DBS
Modified from Giroux, ML and Farris, SF. Cleveland Clinic Foundation 2005
Cleveland Clinic Foundation
Center for Neurological Restoration
Postural Instability,
Freezing, Falls, Dementia

88. Efficacy: Benefits of DBS Therapy
Impact on Mobility
Dyskinesia
Before
“On” Time
After
“Off” Time

89. 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

90. DBS Therapy: Potential
Complications 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

91. Surgical Technique
 Stereotactic frame placement or
frameless stereotaxy
 Targeting
 Imaging
 Stereotactic targeting
 Physiologic targeting
(microelectrode recording
and stimulation)
 Electrode placement
 Pulse generator implantation

92. 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

93. Surgical Technique:
Microelectrode Recording
Border
Sagittal Section Through the Thalamus
80ms
STN
10sec
80ms
Border/SN
10sec
80ms

95. Surgical Technique:
DBS Lead Placement
 Leads placed in motor
territory of nucleus
 Leads have four
electrodes
 Multiple electrode
configurations
possible during postoperative
programming

96. Target Sites for DBS Therapy
Vim Thalamus:
Essential Tremor
Subthalamic Nucleus:
Parkinson’s disease
and Dystonia
Globus Pallidus:
Parkinson’s disease
and Dystonia

97. Surgical Technique:
Neurostimulator Placement
 Can be done
immediately
or days/weeks later
 Typically placed
below clavicle
 Connected to lead
using extension

98. 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.