Functional organisation of basal ganglia and possible mechanisms of DBS action Maja Kojović
Functional organisation of basal
ganglia and possible mechanisms
of DBS action
Maja Kojović
Overview of the talk
• Functional organisation of BG motor circuits in the healthy state
• Whats goes wrong in PD?
• Possible mechanism of the therapeutic benefit of DBS
Motor cortex sends excitatory output to BG; BG inhibits thalamus; thalamus excites motor cortex
Motor cortex
Thalamus
BASAL GANGLIA
Motor cortex
striatum
Motor cortex send excitatory ( Glut) input to stiatum ( Nc.caudatus and putamen)
Thalamus
Motor cortex
striatum
BG send the inhibitory (GABA) output through GPi( Gpi and SNrc) to thalamus
GPi Thalamus
BG tonically inhibits motor cortex The state of final inhibitory BG output depends on the balance between 2
intrinsic patways :direct and indirect pathway
Motirična skorja
Talamus
STN
GPe
GPi
striatum
t
Motor cortex
Thalamus
STN
GPe
GPi
striatum
DIRECT PATHWAY
Motor cortex
STN
GPe
GPi
striatum
Direct pathway promotes the movement:”go” pathway
Thalamus
Motor cortex
Thalamus
STN
GPe
GPi
striatum
INDIRECT PATHWAY
Indirect pathway restricts the movement: “no go” pathway
HYPERDIRECT PATHWAY IS THE FAST PATHWAY THAT INHIBITS THE MOVEMENTS -“HOLD YOUR HORSES“!
HYPERDIRECT PATHWAY: MOTOR CORTEX-STN
Motirična skorja
Talamus
STN
GPe
GPi
striatum
Motor cortex
STN
GPe
GPi
striatum
Thalamus
Motor cortex
ddopamin
Thalamus
STN
GPe
GPi
striatum
SNc
D2 D1
FINALLY THE DOPAMIN!!!
How BG normally control movements? Simplified view
Motor cortex
STN
GPe
GPi
striatum
MOVEMENT EXECUTION: DIRECT PATHWAY
DIRECT PATHWAY PROMOTES THE MOVEMENT = “GO PATHWAY”
Thalamus
Motor cortex
STN
GPe
GPi
striatum
MOVEMENT EXECUTION: DIRECT PATHWAY
DIRECT PATHWAY PROMOTES THE MOVEMENT = “GO PATHWAY”
Thalamus
Motor cortex
STN
GPe
GPi
striatum
MOVEMENT EXECUTION: DIRECT PATHWAY
DIRECT PATHWAY PROMOTES THE MOVEMENT = “GO PATHWAY”
Thalamus
Motor cortex
STN
GPe
GPi
striatum
Inhibition withdrawal
DIRECT PATHWAY
DIRECT PATHWAY PROMOTES THE MOVEMENT = “GO PATHWAY”
Thalamus
Motor cortex
Thalamus
STN
GPe
GPi
striatum
DIRECT PATHWAY
DIRECT PATHWAY PROMOTES THE MOVEMENT = “GO PATHWAY”
Inhibition withdrawal
Motor cortex
Thalamus
STN
GPe
GPi
striatum
MOVEMENT TERMINATION: INDIRECT PATHWAY
INDIRECT PATHWAY INHIBITS THE MOVEMENT: “NO GO” PATHWAY
Motor cortex
STN
GPe
GPi
striatum
MOVEMENT TERMINATION: INDIRECT PATHWAY
INDIRECT PATHWAY INHIBITS THE MOVEMENT: “NO GO” PATHWAY
Thalamus
Motor cortex
STN
GPe
GPi
striatum
MOVEMENT TERMINATION: INDIRECT PATHWAY
INDIRECT PATHWAY INHIBITS THE MOVEMENT: “NO GO” PATHWAY
Thalamus
Motor cortex
Thalamus
STN
GPe
GPi
striatum
MOVEMENT TERMINATION: INDIRECT PATHWAY
INDIRECT PATHWAY INHIBITS THE MOVEMENT: “NO GO” PATHWAY
Motor cortex
Thalamus
STN
GPe
GPi
striatum
MOVEMENT TERMINATION: INDIRECT PATHWAY
INDIRECT PATHWAY INHIBITS THE MOVEMENT: “NO GO” PATHWAY
Motor cortex
Thalamus
STN
GPe
GPi
striatum
MOVEMENT TERMINATION: INDIRECT PATHWAY
More inhibition
INDIRECT PATHWAY INHIBITS THE MOVEMENT: “NO GO” PATHWAY
Motor cortex
STN
GPe
GPi
striatum
MOVEMENT TERMINATION: INDIRECT PATHWAY
Thalamus
INDIRECT PATHWAY INHIBITS THE MOVEMENT: “NO GO” PATHWAY
More inhibition
HYPERDIRECT PATHWAY IS THE FAST PATHWAY THAT INHIBITS THE MOVEMENTS -“HOLD YOUR HORSES“!
HYPERDIRECT PATHWAY: MOTOR CORTEX-STN-GPi-THALAMUS-MOTOR CORTEX
Motirična skorja
Talamus
STN
GPe
GPi
striatum
Motor cortex
STN
GPe
GPi
striatum
Thalamus
Motirična skorja
Talamus
STN
GPe
GPi
striatum
Motor cortex
STN
GPe
GPi
striatum
HYPERDIRECT PATHWAY
HYPERDIRECT PATHWAY IS THE FAST PATHWAY THAT INHIBITS THE MOVEMENTS -“HOLD YOUR HORSES“!
Thalamus
Motirična skorja
Talamus
STN
GPe
GPi
striatum
Motor cortex
STN
GPe
GPi
striatum
HYPERDIRECT PATHWAY
HYPERDIRECT PATHWAY IS THE FAST PATHWAY THAT INHIBITS THE MOVEMENTS -“HOLD YOUR HORSES“!
Thalamus
Motirična skorja
Talamus
STN
GPe
GPi
striatum
Motor cortex
Thalamus
STN
GPe
GPi
striatum
HYPERDIRECT PATHWAY
HYPERDIRECT PATHWAY IS THE FAST PATHWAY THAT INHIBITS THE MOVEMENTS -“HOLD YOUR HORSES“!
More inhibition
Motirična skorja
Talamus
STN
GPe
GPi
striatum
Motor cortex
STN
GPe
GPi
striatum
HYPERDIRECT PATHWAY
HYPERDIRECT PATHWAY IS THE FAST PATHWAY THAT INHIBITS THE MOVEMENTS -“HOLD YOUR HORSES“!
More inhibition
Thalamus
What is happening in PD?
Motor cortex
Thalamus
STN
GPe
GPi
striatum
SNc
•DIRECT PATHWAY IS “GO” PATHWAY •INDIRECT PATHWAY IS “NO-GO” PATHWAY
DOPAMIN STIMULATES DIRECT PATHWAY (D1) AND INHIBITS INDIRECT PATHWAY (D2)
D2 D1
Motor cortex
Thalamus
STN
GPe
GPi
striatum
SNc
D2 D1
Bradyhypokinesis- hypoactivation of direct pathway hyperactivation of indirect pathway
•DOPAMIN FACILITATES DIRECT PATHWAY (D1) AND INHIBITS INDIRECT PATHWAY (D2) •LOSS OF DOPAMINE HYPOACTIVATION OF DIRECT PATHWAY AND HYPERACTIVATION OF INDIRECT PATHWAYBRADYHYPOKINESIS
PD : STN LESION
Thalamus
STN
GPe
GPi
striatum
SNc
D2 D1
Motor cortex
PD : STN LESION
Thalamus
STN
GPe
GPi
striatum
SNc
D2 D1
Motor cortex
PD : STN LESION
Thalamus
STN
GPe
GPi
striatum
SNc
D2 D1
Motor cortex
PD : STN LESION
Thalamus
STN
GPe
GPi
striatum
SNc
D2 D1
Motor cortex
PD : GPi LESION
Thalamus
STN
GPe
GPi
striatum
SNc
D2 D1
Motor cortex
PD : GPi LESION
Thalamus
STN
GPe
GPi
striatum
SNc
D2 D1
Motor cortex
Paradox of BG rate model
Parkinsonism is caused by increased Gpi inhibitory outputdecreased thalamocortical facilitation
But, thalamic lesions never cause parkinsonism!
Hyperkinesias are caused by decreased palidal inhibitory output increased thalamocortical facilitation
Gpi lesion rarely cause dystonia or chorea. Moreover, lesioning or DBS of Gpi DBS treat dystonia or hemibalism
Motor cortex
Thalamus
STN
GPe
GPi
striatum
SNc
Motor cortex
Thalamus
STN
GPe
GPi
striatum
SNc
•Changes in firing rates are not the only predictor of parkinsonian or hyperkinetic states
•Patholophysiological role of the changes in firing patterns
•Bursting in BG is rare in health but increased in PD
•Bursting means a series of firings at short periods of time followed by silence
•If bursting activity repeats periodically, it becomes oscillatory activity
•If many neurons oscillate at the same we call it synchronised oscillations
•BG activity in PD is more oscillatory and more synchronous than in normal individuals
Changes in firing patterns and pathological oscillations in PD
Burtsing
Regular
firing Synchoronised
oscillation
Role of pathological oscillatory activity in the basal ganglia
• Oscillations in the beta range ( cca 20 Hz) disrupt processing of movement-related information and may generate bradyhypokinesia
• Beta ocillation in the STN and GPi are very prominent in the OFF state (Brown et al., 2001; Levy et al., 2002) and reduced in the ON state after treatment with levodopa (Brown et al., 2001) or DBS (Giannicola et al., 2010) in parallel with improvement in parkinsonian motor signs.
• Pathological oscillations cause tremor
• Dyskinesias associated with prominent oscillations in theta/alpha range ( 4-10 Hz)
How does the HFS work to improve parkinsonian symptoms?
• By changing the firing rates of BG nuclei
• By change the abnormal firing patterns, i.e. bursting
• By removing pathological oscilatory activity
• Two major and nonexclusive explanations are proposed:
1. HFS silences stimulated neurons : inhibitory hypothesis
2. HFS excites stimulated neurons and thus introduces a new activity in the network
INHIBITORY HYPOTHESIS: DBS INHIBITS LOCAL NEURONAL ELEMENTS
• DBS has similar clinical effects on motor symptoms as lesion therapy or pharmacological blockade of the target nuclei.
• Thus, DBS must inhibit local neurons in the stimulated nucleus decrease its output
• Indeed, experimental evidence that STN-DBS and GPi-DBS are associated with reduction of the firing rates of the nearby neurons
Mechanisms of inhibition of the target nucleus during DBS
1. Depolarization block
2. Activation of inhibitory GABA afferents
STN
GPe
The inhibition hypothesis fits well with the firing rate model of PD
But….Evidence show excitatory effect of DBS
• In parkinsonian monkeys Gpi showed increased firing rates during STN HFS ( Hashimoto, 2003)
• Reduction of thalamic firing rates during GPi HFS ( Montgomery et al. 2006)
• PET studies :increased blood flow in GPi during STN HFS (Hershey et al., 2003)
• fMRI study : Increase in the BOLD signal in GPi during STN HFS (Jech et al., 2001)
Fundamentals of electrical stimulation
• Primary result of electrical stimulation in the CNS is to generate action potentials (APs) (Ranck, 1976)
• Axons have a lower thresholds for AP generation than soma
• DBS is much more likely to excite axons than somas
• Action potential initiation is yes or no phenomenon - once the stimulus amplitude is greater than the threshold for that individual axon,axon is often capable to follow stimulus frequencies up to and over 100 Hz with very high fidelity (Bucher and Goaillard, 2011)
Excitatatory Hypothesis
• HFS , by exciting axons, introduce the new activity in the network (time-locked to stimulation spikes)
• HFS overrides pathological activity
• Downstream nuclei become trapped in the HFS signal
How does HFS override pathological signal?
• No DBS
Information x Information y Information z Information n
HFS caused informational lesion
HFS
• HFS imposes regular repetitive pattern
• The signal that doesnt change in time lacks any meaningful information – its not a signal but a noise!
• The lack of information in the signal is called “informational lesion”, termed coined by Grill et al. (2004)
HFS: No information
HFS CAUSE MEANINGLESS SIGNAL, BUT LEAKAGE OF THE ABNORMAL SIGNALS MUST BE PREVENTED FROM ENTERING
THE CIRCUIT -THERE MUST BE A LOSS OF PATHOLOGICAL INFORMATION IN THE SYSTEM
1. Collision
2. Disruption may occur at the level of soma due to co-activation of excitatory and inhibitory afferents by HFS
3. Resetting of firing probability at stimulation-induced time-locked spikes.
HFS
UNRESOLVED QUESTION WITH EXCITATORY HYPOTHESIS AND INFORMATIONAL LESION
• How come that BG , which is in the case of DBS transmits the noise rather than the movement related information are still able to contribute to relatively normal movement control and execution?
DBS control different motor symptoms by different mechanisms?
• Different time course of DBS effect on different symptoms : Removal of pathological signal vs. changes in brain plasticity ( Agnesi et al..2013)
Immidiate reduction of tremor amplitude
with STN DBS turned on. Blahak et al., 2009
DBS induced changes in plasticity
•DBS can have effect on synaptic
plasticity at a network level , i.e.
sensorimotor cortex (Tisch et al.,
2007, Ruge 2011)
• Thank you for your attention
A role of DBS in neuroprotection?
• DBS in early PD may slow rest tremor progression; Hacker et al. 2018
A role of DBS in neuroprotection?
• STN lesion or STN DBS in parkinsonian rats or parkinsonian monkey caused sparing of dopaminergic neurons of SN
• Evidence in humans are lacking
PD-STN DBS
Thalamus
STN
GPe
GPi
striatum
SNc
D2 D1
Motor cortex
DBS effect of L-dopa induced dyskinesias
1. Reduction of L-dopa dose
2. Direct stimulation of lenticular fasciculus, which is part of Gpi output to thalamus
3. Dyskinesias are related to pathological oscillation in delta/alpha range and DBS may simply override/ attenutae this oscillations