Mechanism of action
- Direct inhibition of neural activity
- High Fq trains (100Hz) produces inhibitory effects
- High fq of stimulation → action potentials propagate in both the orthodromic and antidromic directions to the axon terminals of the neuron → although the axons can manage the transmission at high fq, at the synaptic cleft the presynaptic neurotransmitter will be exhausted by this high fq stimulation; post synaptic receptors also become repress due to the high activation. (This phenomena is called synaptic filtering)
- This can lead to stopping the propagation of oscillatory activity patterns within brain networks
- Direct excitation of neural activity
- Low fq trains (10Hz) produces stimulatory effects
- Because they don't exhaust the synapse
- Biophysics of axonal responses to electrical stimulation
- Antidromic and/or postsynaptic recordings
- Information lesion (jamming)
- Extension of the ‘excitation mechanism’ → low fq
- Disruption of low-frequency oscillatory patterns
- At a constant low fq of stimulation → the DBS form an dis-informative oscillation throughout the whole network → this limits the propagation of informative oscillatory activity throughout the network (disruption of pathological oscillations to restore rhythmic activity and synchronization)
- Synaptic filtering
- Extension of the ‘excitation mechanism’
- Biophysics of high-frequency synaptic transmission
- ?? Improve neuronal plasticity
- Some DBS effect are delayed and progressive
- Possible that low fq stimulation can stimulate neuronal plasticity (think like constantly exercising that part of the brain) through remodelling astrocyte activity
- Example of mech of action in action
- Using High Fq DBS in PD at basal ganglia →
- Local neuronal inhibition
- But fq not low enough to bypass synaptic filtering so that information lesioning does not occur → Normal movement impulses at the basal ganglia does not get reduced.
Local direct electrical effects
- DBS generally excites action potentials in surrounding neuronal tissue.
- Effective DBS is reliant upon exciting sufficient action potentials in the desired target tissue while limiting spread of electric current to excite action potentials in unintended adjacent structures.
- Greater current intensity or volume improves outcome but increases likelihood of untoward side effects.
- Strategies to electrophysiologically tailor the DBS electrical field to each patient are therefore desirable.
- Variable stimulation parameters
- Current
- Axonal terminals have the lowest threshold, followed by axons, dendrites, and finally neuronal cell bodies
- Polarity
- Monopolar
- The distant pulse generator case acting as the anode
- Bipolar
- Over any combination of the four contacts of each electrode and multiple contacts can be specified as anodes or cathodes
- Neurons nearest the DBS cathode are more likely to be activated than those close to the anode, hence the designation of the pulse generator case as anode in monopolar DBS
- Voltage
- 0 to 10 V
- Frequency
- 2 to 300 Hz
- Width of the square wave pulse
- 60 up to 500 μs
- Larger axons respond more to narrower pulse widths of stimulation.
- Stimulation may be either continuous or cycled between on and off states each of at least 0.1 s duration.
- The orientation of the neuron relative to the DBS field is also relevant.
- Those oriented with the voltage gradient are more likely to reach threshold than those lying orthogonal to it.
- General principles: When considering which neurons are activated by DBS,
- Neurons further away from the brain electrode are less likely to be stimulated,
- Axons will be stimulated to give rise to an action potential at lower DBS amplitudes than neuronal cell bodies
- Larger axons will respond to lower stimulus amplitudes than will smaller axons
- Axons with branching processes will also be activated at lower stimulus amplitudes.
Risks
- 1% intracranial bleeding (<1% symptomatic bleeding)
- 2-5% infection or technical malfunction
Benefit
- 70-80% improvement
Indications
- Preclinical
- Obesity
- Tourette syndrome
- Consciousness
- Huntington disease
- Phase I
- Schizophrenia
- Tourette syndrome
- Addiction
- Tinnitus
- Huntington disease
- Anorexia
- Phase II
- Chronic pain
- Spasmodic dysphonia
- Alzheimer’s disease
- Epilepsy
- Anorexia
- Phase III
- Depression
- Alzheimer’s disease
- Epilepsy
- OCD
- Standard of care
- Parkinson’s disease
- Essential tremor
- Dystonia
- OCD
Surgery
- Early vs late
- Currently it is mostly done for late but perhaps earlier surgery is more beneficial
- Use neurophysiology
- Arguments for
- Imaging has limitations
- Functional mapping of target
- Test for adverse effects
- Reset course
- Arguments against
- Imaging is better
- Awake demands on patient
- If asleep GA interferes with recordings
- Slows you down
- Subjectivity
- Conflicting information
- Steerable DBS electrode
- Technical issues
- Awake
- Yes
- No
- Steps
- Procedure stages
- Microelectrode recording central tract
- Stimulation using microelectrode
- Ideal tract
- 4mm+ STN cells microelectrode recording
- Symptom reduction low currents ~1-2mA
- No side effects or at high currents 3mA+
- Impact effect
- Limited symptoms to assess
- Patient fatigue
- Effect on symtoms
- Side effects
- Decide whether to explore other tracts
- Implant DBS electrode best tract
- Surgical technique - implants
- Standard vs directional leads
- Electrode spacing
- Primary cell vs rechargeable IPG
- Remote programming
- Brain sensing
- Visualisation technology
- DBS hardware
- The most regularly used current DBS electrode is quadripolar, having four electrical contacts, each 1.5 mm long and separated by 0.5 mm of insulation.
- The DBS electrode is secured to the skull and connected to a lead that is tunnelled to the chest or abdomen where a pulse generator (pacemaker) containing the power source is implanted under the skin.
- Some pacemakers can be transcutaneously recharged.
- Surgical technique - workflow
- Imaging for planning (preop; intraop)
- Awake versus asleep
- Frame versus frameless
- Robot-assisted
- Microelectrode recording
- Intraop imaging (CT; O-arm; MRI)
- Staged versus “all-in-one”
- Surgical technique - Glasgow
- Preop MRI under GA; planning on Brainlab workstation
- Awake for selected PD and tremor; asleep for others
- Dexmedetomidine +/- remifentanil; scalp block
- Leksell frame application; CT head; image fusion for co-ordinates
- Robot (Neuromate) used for implantation
- Burrhole; burrhole cover; dura open; guide tube placement
- Full awake now in Glasgow with scalp block
- Guide tube is 1.5-2cm short of the target
- Microelectrode placed; recording from -10mm
- Stimulation plan; clinical assessment if awake, EMG recordings if under GA
- Decision on placement vs further exploration
- Repeat for contralateral side
- Right side permanently closed, left side temporarily closed
- CT; image fusion; lead position check
- Return to theatre; frame off; GA
- Connection of extension leads
- Placement of implantable pulse generator (“battery”)
- Complications
- Haemorrhage
- Infection
- Lead misplacement
- Pneumocephalus
- Stimulation-related side-effects
- Cognitive decline (STN)
- Ataxia (thalamus)
- Emergencies
- Infection
- Hardware exposure
- Sudden loss of stimulation (usually IPG failure)
- Lead fracture
- Short circuits / open circuits
- Infection, exposure, and loss of therapy are the critical clinical issues
- Contact a member of the DBS team ASAP
- Seek as much info as possible – last op, last clinic letter with settings, implant type, patient data (battery status, etc)
- Sudden loss of therapy can be dangerous – loss of ability to eat / drink / mobilise, or dystonic crisis
- If concern over physical problem – CT head, x-rays of leads
- Risk
- EARLYSTIM data Total surgical adverse event: 17.7%
Impaired wound healing | 3.2% |
Intracerebral abscess or edema | 1.6% |
Dislocation of device | 3.2% |
Reoperation necessary | 1.6% |
Other | 8.1% |
Future developments
- Variation in stimulation
- Currently, most pacemakers deliver stimulation continuously at a fixed rate, in what is a rather simple but nevertheless effective therapy.
- Can cause unwanted side effects
- Targeted stimulation:
- However, constant stimulation can incur unwanted side effects by spreading to other fibre tracts or by disrupting normal brain signals embedded in pathological activity.
- Alteration of such ‘normal’ signals may affect emotion or cognition
- By targeting stimulation specifically to abnormal oscillations, it may be possible to apply stimulation intermittently and thus allow normal signals to re-emerge.
- Indeed there is evidence that symptom suppression may be better with such intermittent stimulation than with continuous stimulation
- Pacemaker + telemetric device: Only stimulate when there is pathological signals
- Other prospects include a pacemaker with telemetric capabilities, which could aid the identification of pathological markers in various disorders.
- Pacemaker + accelerometer: Only stimulate depending on patient recumbency
- Pacemakers that respond to posture could also reduce side effects, as in the case of spinal cord stimulation where lower levels of stimulation may be required in the supine position than in the upright position. Such pacemakers use directional accelerometers to determine movement and position.
- Directional electrode
- A good clinical response is sometimes limited by the proximity of the contacts to structures adjacent to the target.
- An electrode may be placed in the subthalamic nucleus, for example, but if it is too close to the capsule, stimulation will induce side effects within the therapeutic window.
- To overcome this problem, technology companies have produced alternative electrode configurations, such as splitting the ring contacts into two or three, or even arranging 32 contacts in an array resembling a fish-scale
- Experimentally, the latter has been shown to offer directionality in the primate, as well as in a clinical case series in which it was also possible to record local field potentials from multiple contacts for better localization. At present, structural MRI is usually used for targeting electrodes.
- DTI
- Although not yet fully evaluated, the use of diffusion tensor imaging may improve results by allowing specific parts of a nucleus that are connected to another region or possibly part of a network to be targeted, rather than just the nucleus itself.
- As demonstrated in tumour surgery, diffusion tensor imaging can be used to identify fibre tracts that, if stimulated, would induce side effects, so that these can be avoided.
- It is also possible to somatotopically identify the best electrode position within homogeneous structures such as the thalamus
- Molecular and cellular therapies
- Much translational research is being undertaken but few treatments have demonstrated comparable safety and efficacy to DBS.
- Clinical trials of neurotrophic factors, stem cells and fetal cell transplants have all been undertaken with limited success
- Unilateral DBS does however provide an elegant potential control surgery for contralateral biological therapy implantation
Has there been any studies that outcome or targets are better with neurophysiology
- To explore another tract or not depends on:
- Risk vs benefit
- Intrusiveness of side effects
- Mitigation by Steerable
- Multiple contact DBS
- Types of tract
- Easy
- Poor cells/short tract
- No effect on symptoms
- Side effect at low current
- Trickier
- Reasonable cells/tract length
- Some effect on symptoms
- Side effects at higher current
- Stimulation side effects
- Anterior – no effect on symptoms
- Posterior- paraesthesia
- Medial – dysarthria
- Lateral – Internal capsule
- Too deep – almost all of above
- Stimulation side effects
- Under GA
- Only look for internal capsule effects
- EMG needles face, arm & leg
- Too medial & posterior = Internal capsule
- Role of Neuroimaging in DBS
- Role
- Diagnosis & exclusion of pathologies
- Selection of patients
- Localization of target nucleus
- Detection of complications
- Evaluation of the final electrode contact position
- Dormont D et al, 2010. Neuroimaging and Deep Brain Stimulation. AJNR 31:15–23
- Mascalchi M et al, 2012. Movement Disorders: Role of Imaging in Diagnosis. JMRI 2012 Feb;35(2):239-56
- Technical & operational aspects
- Pre-operative planning
- High-resolution (HR) imaging GA (long sequences, movement)
- CT imaging pre-and post implantation in stereotactic frame (Leksell); correlation/fusion with HR imaging for anatomical correlation
- Position & complication
- Post DBS – MR safety
- Risk of electrode heating in MRI imaging in patients with DBS because of electric current induced by radio-frequency electromagnetic waves
- May be conditionally safe (switch off, low field strength, SAR, sequences)
- Targets include
- VIM Thalamus (essential tremor)
- STN & GPi (advanced IPD)
- GPi (dystonia)
- Increased direct pathway increases hyperkinesia
- Increased indirect pathway causes akinesia
- Direct pathway over-activation – hyperkinetic
- Indirect pathway over-activation – hypokinetic
- DBS aims to modulate pathways within the cortico-basal-ganglia-thalamo-cortical loop to modify movements
- Targeting - Tremor
- Ventral intermediate nucleus of thalamus
- Caudal zona incerta
- Posterior subthalamic area
- VIN of thalamus → using atlas
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