Functional organisation of basal ganglia and possible ... · MOVEMENTS -“HOLD YOUR HORSES“!...

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

Inhibition withdrawal

DIRECT PATHWAY


Thalamus

Motor cortex

Thalamus

STN

GPe

GPi

striatum

DIRECT 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



Thalamus

Motor cortex

Thalamus

STN

GPe

GPi

striatum



Motor cortex

Thalamus

STN

GPe

GPi

striatum


More inhibition


Motor cortex

STN

GPe

GPi

striatum


Thalamus


More inhibition


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


Thalamus

Motirična skorja

Talamus

STN

GPe

GPi

striatum

Motor cortex

Thalamus

STN

GPe

GPi

striatum

HYPERDIRECT PATHWAY


More inhibition

Motirična skorja

Talamus

STN

GPe

GPi

striatum

Motor cortex

STN

GPe

GPi

striatum

HYPERDIRECT PATHWAY


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 : 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

Functional organisation of basal ganglia and possible ... · MOVEMENTS -“HOLD YOUR HORSES“!...

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Transcript of Functional organisation of basal ganglia and possible ... · MOVEMENTS -“HOLD YOUR HORSES“!...