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Second Beijing Forum
on Parkinson’s disease and Movement Disorders
September 14-17, 2012
Introduction to
Basal Ganglia Anatomy, Physiology, Physiopathology
Bernard Pidoux, MD, PhD
Fédération de Neurophysiologie Clinique, La Pitié-Salpêtrière
Laboratoire de Physiologie, Faculté de Médecine Pierre et Marie Curie
Sorbonne Université,
Paris, France
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Fig 71.- Coupe frontale passant par le tiers antérieur du noyau rouge
(Foix et Nicolesco, Masson 1925)
STN RN
3rd
ic
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Fig 135.- Coupe Sagittale région sous optique, colliculus du noyau
caudé; locus niger, centre médian de Luys (Foix et Nicolesco, Masson
1925).
SN
STN
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Swfp70
Schaltenbrand
& Wahren atlas Frontal view
AC-PC plane
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Swfp50
Schaltenbrand
& Wahren atlas
Frontal view
AC-PC plane
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Swfp40
Frontal view
AC-PC plane
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Swfp30
Frontal view
AC-PC plane
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Swfp15
Frontal view
AC-PC plane
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Functional
H8G345 H8G54 H8G164 H8G555
H8G69 H8G179 H8G579 H8G319
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ATLAS/MRI Registration
Patient
T1 T2 T1
post-op.
Atlas T1 T2
Histology
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Patient MRIs deformed in atlas space
(spatial normalisation)
T
Atlas Patient
T-1
Report atlas structures
on the patient
Atlas : deformation
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Accumbens, caudate nucleus, putamen
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GPe
GPi
Globus pallidus
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THRPT
CP
STN H2
RU ZI
SN
Sub Thalamic Nucleus, Substantia Nigra, red nucleus RU
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Thalamus
VIM
VPI PF/CM
VL
MD
VIM
VPE
VL
MD
VA
PU
VL
VIM
PU
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Functional territories
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Functions of basal ganglia from J.M. DENIAU
Cerebral Cortex
Thalamus
iln
Hippocampus
Amygdala
Basal
Ganglia
Sensorimotor, cognitive,
emotional, motivational,
memory
Environmental contextual analysis and organisation of a
contextually adaptated behavior
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Cortex
STN
Striatum
GPi / SNR
GPe / VPl
Reticular pathways brainstem,
medulla
Non specific
Thalamus
Amygdala
Caudate, Putamen, N. Acc. « core »
Prefrontal, cingular,
motor
N.Acc
« Shell »
hippocampus
Distinct output pathway
Ventral Pallidum (VPm)
SNc (DA)
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instruction action signal
mvt
start reward
Movement execution
Movement initiation
Movement preparation
Somatosensoy response
Visual response
Auditory response
Short term memory
Work memory
Prediction, waiting
Waiting for a reward
Reward
Striatum is active along all key phases of behavior organisation
From W. Schultz
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Basal ganglia
modulate
prefrontal cortical areas, premotor, motor
temporal and parietal cortex
via thalamic projections of
Substantia Nigra and Globus Pallidus
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VA pc
MD pc
VA mc
MD mc
DL
PF
LOF
MD pm
AC
VA
mc
MD pl
CL
Area 8
VA pc,
Vlo,
CM, VLm
PM
VA pc, Vlo,
VLm, MD
dc
AMS Vlo, CM,
VLm, AM
VA mc,
MD pl,
CM, CL
IPL
VA
mc
IT
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Informations originating from cortical areas are transmitted to
output structures of basal ganglia through three
main pathways:
• A direct trans-striatal circuit,
• An indirect trans-striatal circuit,
• A direct trans-subthalamic circuit
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Cortex
Striatum
GPi / SNR
Direct trans-striatal circuit activates target pathways of basal
ganglia via a disinhibition mechanism
Thalamus
Brainstem
+ Glutamate
- Gaba
- Gaba
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Striatal
activation
Output
neurons
inhibition
Activation of
target pathways
by disinhibition
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cortex
striatum
SNR/GPi
Cortical areas
fonctionnally
associated
Striatal
sub territories
Segregated
output pathways
Modular parallel architecture and convergence of direct trans-striatal
pathway
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Trans-subthalamic pathways perform a temporal and
spatial configuration of the striatal disinhibiting signal
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Cortical stimulation evoques a triphasic response (excitation-inhibition-excitation) in
SNR neurones. Early excitation results from the activation of direct trans-
subthalamic pathway, inhibition results from the activation of direct trans-striatal
circuit and late activation from indirect striato-pallido-subthalamo-nigral pathway.
Recording
Stimulation
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Functionnally associated
cortical areas
SNR/GPi
Direct
subthalamic
circuit
+ +
Direct striatal
circuit Indirect
circuit
_ Calibration of disinhibiting
striatal signal duration
Temporal calibration within a chanel
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Spatial selection : interaction between channels
Channel 1
Associated cortical areas
SNR/GPi
+
direct striatal
pathway
_
Channel 2
Associated cortical areas
SNR/GPi
+
Calibrated disinhibition of channel 1
target structures
inhibition of channel 2
target structures
trans subthalamic
pathway direct striatal
pathway
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cortico-striato-pallido-thalamo-
cortical loop circuits
Alexander & Delong
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Striatal medium spiny neuron
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Striatal output neurones afferents
Medium spiny neurons
dopamine
modulates
messages from
cerebral cortex
Adapted from Squire, 2003
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Globus Pallidus neurons
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Cerebral cortex
GPe
Striatum
STN
GPi / SNr
D1 D2
SNc
VTA
RR
DA DA + _
Physiopathological models are based on the hypothesis of a distinct neuronal origine of direct and
indirect trans-striatal pathways and on a differential control by dopamine on these two sub
populations of striatal neurones.
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Hypokinetic disorders
• Parkinson’s disease
• neuroleptics parkinsonian syndrom
• MPTP monkey parkinsonism model
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Parkinson’s disease
PHYSIOPATHOLOGY
• Death of Substantia Nigra dopaminergic neurons.
• Less dopamine in target structure : Striatum (caudate
nucleus and pallidum);
• When 50-60 % DA neurons have died, PD clinical signs
begin.
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Loss of dopaminergic neurons, DA
• Human mesencephalon
• Parkinson’s disease : DA neurons contain neuromelanine (black
pigment)
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Dopaminergic loss location
Possible role of calbindin afferents
Calbindin : calcium binding protein
neuroprotective effect by inhibiting free radical formation ?
• Ventral DA neurons have less calbindin => less protected => more neuronal loss.
• Dorsal DA neurons have numerous calbindin afferents.
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Cerebral cortex
Thalamus
VA
VL
Midbrain
Spinal chord
indirect inhibiting pathway
FR, NPP, CS, TQA
Caudate/Putamen
NST
GPe
SNc
Gpi/SNr direct excitatory pathway 1
1
2
2
Excitation (Glu)
Inhibition (GABA)
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Parkinson’s disease
• Resting tremor (4-6 Hz) : trembling in the
hands, arms, legs, jaw and face
• Rigidity: stiffness of the limbs and trunk
• Bradykinesia: slowness of movements
• Akinesia: difficulty in initiating movement
• Postural instability: impaired balance
• and depression…
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Cerebral cortex
Thalamus
VA
VL
midbrain
spinal chord
Indirecte inhibiting pathway
FR, NPP, CS, TQA
Caudate/Putamen
STN
GPe
SNc
Gpi/SNr Directe excitarory pathway 1
1
2
2
Excitaion (Glu)
Inhibition (GABA)
AKINESIA / PARKINSON
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D. Albe – Fessard, 1967
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Parkinson’s disease tremor cells
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rythmic activity induced by hyperpolarisation of
thalamic neurons
• In Parkinson’s disease, Gpi is hyperactive
• Gpi neurotransmitter GABA creates post synaptic hyperpolarisation
• hyperpolarized thalamic neurones change from tonic to rythmic activity
Thalamus Gpi
- GABA)
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Neuronal pace-maker
Somatic Na
potential
KCa
Calcium
dendrites
potential
Calcium potential
somatic rebound
AHP
Phenomenon facilitated by hyperpolarisation
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Tremor
Central pace maker ?
Peripheral reflex loop
Central loops
- transcerebellum
- transcortical
-motoneurone
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Cerebral cortex
Thalamus
VA
VL
midbrain
spinal chord
Indirecte inhibiting pathway
FR, NPP, CS, TQA
Caudate/Putamen
STN
GPe
SNc
Gpi/SNr Directe excitatory pathway 1
1
2
2
Excitation (Glu)
Inhibition (GABA)
AKINESIA / NEUROLEPTICS
D1 D2
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Vidéo projection
Parkinson’s disease
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Hyperkinétic disorders
- Huntingtons’ chorea
- Ballism
- L-dopa induced dyskinesia
- Neuroleptic dyskinesia
- Gilles de la Tourette syndrome
- Obsessive Compulsive Disorders
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Chorea
• Huntington’s chorea – abnormal hungtingtin gene coding for protein : cell death (apoptosis)
– Loss of enkephalinergic « medium spiny neurons »
– Progressively neurodegenerative
– Hereditary
– Chorea, depression, cognitive troubles
• Other causes
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Two sub-population of striatal
« medium spiny neurons »
From Squire, 2003
Substance P / Dynorphine, D1 recept
Enkephalines, D2 receptors
Direct pathway Indirect pathway
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Cerebral cortex
Thalamus
VA
VL
Midbrain
Spinal chord
Indirect inhibiting pathway
FR, NPP, CS, TQA
Caudate/Putamen
STN
GPe
SNc
Gpi/SNr direct excitatory pathway 1
1
2
2
Excitation (Glu)
Inhibition (GABA)
HUNTINGTON’s CHOREA
Enk SP D1 D2
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Ballism (violent and large amplitude movements)
bicucculine STN perfusion
(L Tremblay & D Grabli, U679, Paris, France)
Focal lesion of right
STN (cerebral toxoplasmosis )
Bicucculine: GABA-A antagonist
Depolarisation bloc with high dosage
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Cerebral cortex
Thalamus
VA
VL
Midbrain
Spinal chord
indirect inhibiting pathway
FR, NPP, CS, TQA
Caudate/Putamen
STN
GPe
SNc
Gpi/SNr direct excitatory pathway 1
1
2
2
Excitation (Glu)
Inhibition (GABA)
HEMIBALLISM
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Gilles de la Tourette syndrome (Tourette’s disease)
• Multiple physical motor tics
• Vocal tics, simple or complexe (coprolalia).
• Sometime associated with Obsessive
Compulsive Disorders (OCD)
« Urge to move » and rebound after volontary control
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Case reports
Tourette’s syndrome and DBS – Houeto et al. 2005 JNNP
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Gilles de la Tourette syndrome (Tourette’s disease)
Vidéo projection
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Bicucculine injected into « limbic »
GPe
• stereotypical
movements
• Licking
• « Touching »
Bicucculine: GABA-A post synaptic receptor antagonist
Inducing GABA-A inhibition (moderate dosage)
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Cerebral cortex
Thalamus
VA
VL
Midbrain
Spinal chord
indirect inhibiting pathway
FR, NPP, CS, TQA
Caudate/Putamen
STN
Limbic
Gpe
SNc
Gpi/SNr direct excitatory pathway 1
1
2
2
Excitation (Glu)
Inhibition (GABA)
EXPERIMENTAL STEREOTYPES
Bicucculine
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Micro Electrode Recording &
stimulation during
neurosurgery
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1989, the year of DBS birth in Grenoble, France :
A.L. Benabid & P. Pollak
high frequency chronic stimulation of thalamus Vim for
the treatment of Parkinson’s disease tremor
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Hutchinson et al., Annals of Neurol., 1998, 622-627
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Lozano et al, J. Neurosurg. 84:194-202, 1996
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Somatotopic arrangement of STN neurones responding to passive or active movements in a
patient with Parkinson's disease.
Rodriguez-Oroz M C et al. Brain 2001;124:1777-1790
© Oxford University Press 2001
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Fig. 2 Schematic representation of the intrinsic organization of the subthalamic nucleus (STN)
according to the tripartite functional subdivision of the basal ganglia.
Hamani C et al. Brain 2004;127:4-20
The Guarantors of Brain 2003
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30 sec
3 sec
0,3 sec
microelectrode réticular thalamic nucleus recording
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Parkinson : Subthalamic Nucleus - STN
0,6 sec
6 sec
Microelectrode single cell recording
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Parkinson : Substantia Nigra recording
2 sec
0,2 sec
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DBS HFS of GPi improves
Levo-DOPA Induced Dyskinesia and Dystonia
Possible mechanisms :
DBS may induce GABA release in GPi
(Dostrovksy et al, J. Neurophysiol 2000)
HFS may introduce more regular pattern in GPi output
cancelling abnormal movements
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Effects of Pallidal HFS
Effect of increasing stimulation frequency
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Inhibition by release of GABA neurotransmitter ?
Effects of Pallidal HFS
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12 patients : 80 % of good match between electrophysiology and atlas Mean errors = 1 mm
STN electrophysiology merged into 3D normalized Atlas
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1 mm
3D Atlas fusion with per op MER electrophysiology
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STN Inhibition by STN HFS trains
Filali M, Hutchison WD, Palter VN, Lozano AM, Dostrovsky JO
Stimulation-induced inhibition of neuronal firing in human subthalamic nucleus.
Exp Brain Res. 2004 Jun;156(3):274-81.
STN HFS removes rigidity, akinesia and tremor
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Pralong E, Debatisse D, Maeder M, Vingerhoets F, Ghika J, Villemure JG.
Effect of deep brain stimulation of GPI on neuronal activity of the thalamic
nucleus ventralis oralis in a dystonic patient.
Neurophysiol Clin. 2003 Sep;33(4):169-73.
Effect of HFS of GPi on Thalamus activity
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STN HF stimulation
Inhibitory and excitatory effects on the same SNr cell
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Hamani C, Saint-Cyr JA, Fraser J, Kaplitt M, Lozano AM.
The subthalamic nucleus in the context of movement disorders.
Brain. 2004 Jan;127(Pt 1):4-20. Epub 2003 Nov 7. Review.
Basal Ganglia : a complex circuitry connecting many nuclei
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Ashby P, Kim YJ, Kumar R, Lang AE, Lozano AM.
Neurophysiological effects of stimulation through electrodes in the human subthalamic nucleus.
Brain. 1999 Oct;122 ( Pt 10):1919-31.
GPe, GPi, STN, Thalamus projections
O GLU * GABA
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Orthodromic
Antidromic
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Conclusion
• Fundamental research on basal ganglia contributes
to improve our knowledge on the physiopathology
of a number of neuro-psychiatric diseases.
• Models of basal ganglia help understanding
normal and abnormal organization of neuronal
networks.
• However, neurophysiological and clinical
exploration of basal ganglia during neurosurgical
procedures show much more complexe features as
will be illustrated by following vidéos.
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Fédération de Neurophysiologie Clinique
Laboratoire de Physiologie
http://www.physio.chups.jussieu.fr