Ch 2. Cellular Mechanisms of Action of Therapeutic Brain Stimulation

Sungjun Kwon [email protected]

Special thanks to Jeong Heo Introduction

• DBS(Deep Brain Stimulation) has revolutionized the treatment for movement disorders

– e.g., Parkinson Disease, Dystonia(근긴장 이상증), Tremor Structure

Terms

• DBS: Deep Brain Stimulation

• firing: emitting an from a neuron

• : a change in a cell's , making it more positive, or less negative. Enough depolarization may result in an action potential.

• hyperpolarization: the opposite of depolarization, and inhibits the rise of an action potential.

• afferent: conveying towards the brain

• EPSP(excitatory postsynaptic potential): a temporary depolarization of postsynaptic membrane potential caused by the flow of positively charged ions into the postsynaptic cell as a result of opening of ligand-sensitive channels In This Chapter…

• how DBS works • the effects of DBS on neuronal functioning within the stimulated nucleus • reviews the crinical use of DBS in thalamus – explain fundamental effects of DBS based on cellular models DBS for Essential Tremor Essential Tremor

• 3-to-8 Hz tremor

• result from dysfunction in the olivo-cerebellar(소뇌) pathway – In olivo-cerebellar pathway, Purkinje cell secretes GABA, inhibitory DBS for Essential Tremor

• Electrical Stimulation to VL thalamus – projections from the deep cerebellar nuclei – projections to the primary motor cortex

Features of thalamic DBS for tremor(1/4)

• There is no evidence that chronic stimulation damages surrounding brain tissue

• The effects of stimulation are reversible

• Incorrect electrode placement will result in poor outcome Features of thalamic DBS for tremor(2/4)

• Immediate benefit on tremor – within seconds of turned on, tremor disappears completely or significantly suppressed – when the stimulator is turned off, the tremor returns immediately –  no after-effect

Features of thalamic DBS for tremor(3/4)

• Frequency Dependency of Stimulation – High Freq(>100 Hz)  clinical benefit – Low Freq may worsen movements • 5Hz  induce tremor (Hassler et al., 1960) • 15Hz  induce myoclonus(간대성 근경련, Bejjani et al., 2000) • 20Hz with higher amplitudes  significant tremor worsening – Pulse duration and amplitude determine whether a neural element will be brought to threshold – Frequency has a bigger role for somatic excitation Features of thalamic DBS for tremor(4/4)

• no involuntary movements or motor disruption with prolonged DBS

• When stimulation was applied directly to sensory thalamic relay, sensory perception was not disturbed Mechanisms of Action

Local Effects of DBS Local Effects of DBS

• from Human Studies • from Animal Studies • from Slice Preparations • from Modeling Studies Human Studies(1/2)

• is the neural element responsible for tremor suppression – from measurement of times • chronaxie: property of neural elements that is related to threshold for activation

• Thalamic were inhibited during high-freqeuncy stimulation – from microstimulation on nearby neurons using microelectrode

Human Studies(2/2)

• DBS increased blood flow in thalamus, suggesting increased neuronal activity – Using imaging techniques, such as PET, fMRI – Haslinger et al.(2003) found relationship between stimulation properties and thalamic blood flow • frequency – blood flow: U-shape • amplitude – blood flow: linear Animal Studies

• STN-DBS produced inhibition within STN and reducing firing at its projection sites

• High-frequency stimulation in the GP reduced the firing frequency of neighboring neurons

• However, efferent outflow from the stimulated nucleus incleased during DBS Slice Preparations(1/5)

• DBS on VL thalamic neurons using intracellular techniques(in vitro) Slice Preparations(2/5)

• high-frequency stimulation produced depolarization of thalamic neurons in slice

• the effects were stimulation frequency and amplitude dependent Slice Preparations(3/5)

• Neuronal responses to high-freq stimulation • Type 1: Depolarization occurred only at the onset of the stimulus train – Functional Deafferentation – the loss of synaptic input to postsynaptic thalamocortical neurons Slice Preparations(4/5)

• Type 2: Depolarization sustained throughout the train – Functional Inactivation – where depolarization was followed by repetitive spikes, while the cell remained depolarized, and which disrupted the rhythmic pattern of the outgoing signal Slice Preparations(5/5)

• The suppression of tremor activity was specific to the stimulated pathway and did not spill over to another pathway – DBS to different pathway – 5-Hz tremor-like input and 125-Hz DBS • to same pathway  DBS blocked the 5-Hz tremor-like input • to independant pathway  DBS didn’t blocked

Modeling Studies(1/2)

• focused on the immediate responses of local neural elements to extra-cellular stimulation.

• Responses to DBS were determined by – electrode position – stimulus intensity – wave-form duration – polarity – the proportion of inhibitory and excitatory terminals within the structure Modeling Studies(2/2)

• of passage were the targets of DBS • Where the cell body could be inhibited from firing action potentials, yet the axon that has a lower threshold for activation would fire independently – The axon that has a lower threshold than cell

• Regular high-frequency stimulation applied to the output of STN would normalize pathologic rhythmic activity in pallidum, thalamus, and cortex •  consider the effects of DBS at its downstream projection sites

Mechanisms of Action

Distant Effects of DBS Distant Effects of DBS

• The downstream projection sites from the nucleus may be more relevant to the mechanism of action than the local effects.

• from Human Studies • from Animal Studies • from Slice Preparation

from Human Studies

• Effects of thalamic DBS on EMG – single stimuli  sudden short lapses of posture in contracting muscles – The effects on EMG was transient even during prolonged DBS and only occurred with simulation of the cerebellar- receiving thalamus, not other basal ganglia structures

from Human Studies

• Effects of thalamic DBS on cortical function – using transcranial magnetic stimulation – patients with thalamic DBS had significantly larger motor- amplitudes – cerebello-thalamocortical pathway was facilitated in the ON stimulation state from Human Studies

• Effects of thalamic DBS on cortical function – measuring regional cerebral blood flow using functional imaging – During Parkinsonian tremor, activity in the sensorimotor cortex was increased – reduction in cerebellar activity with 135-180 Hz DBS – the effects of varying amplitude and frequency on the cortical blood flow • Stimulation amplitude ↑  nonlinear increase • Stimulation frequency ↑  linear increase • thalamic DBS results in activation rather than inhibition of thalamic projections from Human Studies

• Effects of thalamic DBS on cortical function – no behavioral correlate for motor cortex activation clinically – High-frequency stimulation produces no adverse motor effects • Aside from 2-3s, 1-2Hz stimulation produced EMG excitation or inhibition depending on the intensity • perhaps, cortical blood flow changes may be an epiphenomenon of thalamic DBS from Animal Studies

• The effects of VL thalamic DBS on primary motor cortex

• DBS to other basal ganglia nuclei and recorded activity at the projection site – DBS to the globus pallidus pars interna and recorded spontaneous activity in pallidal-receiving thalamus – High-frequency stimulation to the STN and recorded spontaneous activity in the globus pallidus

• DBS interrupted abnormal patterns of thalamic and basal ganglia activity

from Slice Preparations

• examined the ability of thalamocortical and corticaothalamic neurons to follow stimuli

• thalamocortical and corticothalamic fibers did not follow high-frequency stimulation faithfully • but complete conduction block did not occur from Slice Preparations

• Motor cortical neurons depolarized in response to subcortical external capsule stimulation – current clamp traces at resting membrane potential from Slice Preparations

• At 10Hz and 20Hz, synaptic transmission could be maintained throughtout the 30-sec train • freq. > 50Hz, temporal summation of EPSPs at the onset of stimulation • After this initial response, stimulation could no longer evoke a postsynaptic response • Amp. of initial depolarization incleases up to 100 Hz from Slice Preparations

• Synaptic depression was responsible for the lack of sustained depolarization in response to high-frequency stimulation • There was a marked depression of EPSP/Cs after the DBS train, and its time course depended on the stimulus train length. Summary and Functional Implications

• Neurons are functionally deafferentated, unable to fire action potentials due to synaptic depression – Tremor cells are unable to propagate EPSPs or action potentials and thereby the tremor signal does not make it to the motor output level

• The effects are specific to the pathway stimulated – functional deafferentation can limit propagation of tremor signals without disrupting information from other pathways.

• Thalamic stimulation, despite seemingly activating thalamocortical axons projecting to the motor cortex, does not disrupt motor control.

• Synaptic depression and axonal filtering prevent remote cortical excitation during high-frequency subcortical DBS. Summary and Functional Implications

• Spontaneous cortical firing is not altered, as the synaptic depression is specific to the stimulated pathway, alone.

• Functional deafferentation occurs immediately upon application of DBS and is rapidly reversible.

• The cellular effects of stimulation are frequency dependent – high frequencies (>60 Hz) required for tremor suppression.

• no involuntary movements or motor disruption with prolonged DBS – Axonal filtering at the level of thalamocortical axons and synaptic depression in the motor cortex prevent such disruption.

Potential of DBS Therapy

• In thalamic and subcortical white-matter DBS, there are some important principles that can be broadly applied to many forms of electrical stimulation

• Electrical stimulation is able to overcome the limitation of medication – Medication • works indiscriminately at all similar nervous system • timed to work only when symptoms require • produce multiple and unacceptable side effects – DBS • capability to selectively alter neurotransmitter release in a specific pathway • in a controlled manner, as required by symptoms • The costs of electrical stimulation are inexpensive, in comparison Q&A