Neuromodulation Flashcards
define neuromodulation:
- alteration of nn activity through targeted delivery of stimulus, such as electrical stimulation or chemical agents to specific neurological sites in body
neuromodulation: altered nn activity = altered
- altered communication btw pre/post synaptic neuron
neuromodulation: 2 Qs to ask
- chemical synapse inhibitory/excitatory?
- are we trying to increase/decrease activity at synapse?
neuromodulation: some applications eg.
- essential tremor
- parkinson’s disease
- epilepsy
- depression
- OCD
- tourette syndrome
- obesity
- angina
- hypertension
neuromodulation: where can we apply this in nervous sys?
- anywhere
- entire NS operates on converting electrical energy -> chemical signals = all aspects can be neuromodulated
neuromodulation: list (5) ways of modulating
- electrical
- physical
- pharmacological
- genetic
- optogenetic
ANS regulation of HR: where para preganglionic neurons (2)
- nucleus ambiguous
- dorsal motor nucleus of vagus
ANS regulation of HR: where sym preganglionic neurons (1)
- intermediolateral cell column
ANS regulation of HR: which postganglionic nn for para
- vagus nn
ANS regulation of HR: which postganglionic nn for sym
- inf cardiac nn
ANS regulation of HR: symp features (5) HR, NT, receptor, pre/postganglionic neurons
- increase HR
- NAd
- ß adrenoreceptors (atenolol -> bradycardia)
- postgang: stellate ganglia
- pregang: arise from SC
ANS regulation of HR: para features (5) HR, NT, receptor, pre/postganglionic neurons
- decreases HR
- Ach
- mACh receptors (atropine -> tachycardia)
- postgang: ‘fat pads’ on heart
- pregang: arise from brainstem
ANS regulation of BP: MAP =
TPR x CO
ANS regulation of BP: major regulator of BP? para/sym NS
sym NS
prazosin -> lower BP
ANS regulation of BP: to change CO
- inn heart
ANS regulation of BP: to change TPR
- inn vasculature
ANS regulation of BP: topographical arrangement- upper SC
- blood v in head + neck
ANS regulation of BP: topographical arrangement- lower SC
- blood v in lower limbs
ANS regulation of BP: major resistance vessels? and inn by which NS
- arterioles
- sym NS (å adrenoreceptors)
ANS regulation of BP: baroreceptor reflex features (3)
- reacts to sudden/ongoing changes in BP (keep BP 120/80)
- increase BP= increase activity of reflex (vice versa)
- alters BP: simultaneously changing vagal outflow to heart + sym outflow to heart and vasculature
why modulate activity of ANS? 3 answers
- to understand what function particular nn has
- understand pathological changes occur in disease
- to correct pathological changes that have occurred
why modulate activity of ANS? 1) how to test function of nn
- using donor heart stimulate vagus - HR slows - remove fluid sample
- using recipient heart: add fluid to heart = HR also slows
why modulate activity of ANS? 2) elevated HR in CVS related disease may be due to (3)
- increased sym tone
- reduced para tone
- BOTH increased sym and reduced para tone
why modulate activity of ANS? 2) pharmacologcially block input to heart, measure change in HR BUT con?
- doesn’t tell u why diff, only acknowledges diff exists
why modulate activity of ANS? 2) nn stimulation controls for? and can determine
- controls for diff in activity of nn
- determines if diff at level of heart (eg. receptor)
why modulate activity of ANS? 2) assumption of NT
- quantal release of NT the same
why modulate activity of ANS? 2) use optogenetics, if no diff to nn stimulation exists?
- diff must be due to diff in nn activity (brain not prod enough/ generating too much nn activity)
why modulate activity of ANS? 3) correct pathological changes characterised by (3)
- reduced vagal tone
- increased sym nn activity
- reduced baroreflex function
why modulate activity of ANS? autonomic dysfunctions/pathological changes eg.
- hypertension
- heart disease
- arrhythmias
how to restore ANS activity using neuromodulation? correct reduced vagal tone?
- vagal stimulation
how to restore ANS activity using neuromodulation? reduce cardiac sym overactivity?
- stellate ganglionectomy
how to restore ANS activity using neuromodulation? correct reduced vagal tone/sym overactivity? also baroreceptor reflex dysfunction
- baroreceptor activation
how to restore ANS activity using neuromodulation? sym overactivity
- renal denervation
vagus nn: mixed fibre nn types (3)
- afferent fibres
- somatic motor
- visceral motor
vagus nn: aff fibres
convey info:
- sensory receptors in upper airways, ear
- visceral receptors in aortic bodies, aortic arch, thoracic, ab aorta
vagus nn: somatic motor fibres
- inn mm in upper airways
vagus nn: visceral motor fibres
- inn CV, resp and GIT sys
vagus nn: current treatments only target para/sym NS?
- sym NS
vagus nn: increasing para activity (eg. exercise, direct vagal stimulation) prevents
- arrhythmias and sudden cardiac death
vagus nn: experiment- stimulation of vagus
- increased contralateral vagal input to heart
- reduced contralateral sym input to heart
vagus nn: experiment- stimulation also helps (3)
- prevents ventricular fibrillation following myocardial infarction
- decreases mortality
- improves L ventricular function in myocardial induced heart failure model
vagus nn: experiment- cardiofit sys
- senses HR and stimulates vagus nn exactly 70ms after each atrial contraction
- make sure HR doesn’t fall too low (55 bpm)
phase II feasibility study: study 1 demonstrated?
- safety and efficacy
phase II feasibility study: study 2 showed reduction in
- reduced severity of heart failure, increased quality of life
INOVATE-HF trial: primary efficacy endpoint
- death or first event triggering worsening of heart failure
INOVATE-HF trial: summary vagal nn stimulation
- reduces symptoms of heart failure, improves quality of life BUT not effective in reducing rate of death from any cause/ heart failure events
vagus stimulation: possible mechanisms (7)
- decrease HR
- increase HRV
- improve baroreflex
- reduce arrhythmias
- activation of cholinergic anti-inflammatory pathway
- cellular changes (NO and cytokines)
- inhibit RAS
vagus stimulation: increase in both aff/eff activity may underlie positive effects observed BUT
these changes not sufficient to reduce mortality
- more studies needed
targeting sym input to heart: reducing postgang sym input to heart improves? and results
- improve autonomic control of HR
- very challenging
- anaesthetic block of sym ganglia attempted= variable success
targeting sym input to heart: cell bodies/axons gives rise to sym nn inn AV node? location?
- cell bodies
- R stellate ganglia
targeting sym input to heart: optogenetic stimulation of R stellate ganglion (RSGS) increases/decreases HR
- increases HR
targeting sym input to heart: how can optogenetics be used to modulate NS
- excite/ inhibit neurons
- those that silence cell bodies of nn which give rise to cardiac sym eff -> hypothetically prevent ventricular arrythmias
targeting sym input to heart: L stellate ganglion gives rise to inn? and if overactive?
- inn L ventricle
- overactive = ventricular arrhythmias
targeting sym input to heart: what is used to ‘measure’ para and sym control of HR?
- HR variability
targeting sym input to heart: LF =
sym control
targeting sym input to heart: HF =
para control
targeting sym input to heart: LF/HF =
sympathovagal balance (questionable though)
targeting sym input to heart: optogenetic inhibition of stellate can?
- reduce sym tone
- ‘correct’ sympathovagal balance
targeting sym input to heart: optogenetics use stimulates nn more ? than electrical stimulation and can translational capacity now
- more physiological
- need more knowledge of neural circuitry in HR control, utilising techniques in translational capacity
baroreceptor: what mimics activation of baro reflex?
- electric stimulation of aortic depressor nn
baroreceptor: normal reflex = (2)
- freq dependent decrease of sym nn activity (RSNA)
- HR
baroreceptor: normal reflex collectively =
decrease BP (MAP)
baroreceptor: use modulation of baroreflex to examine how well brain is prod reflex changes in? and eg.
- in BP in disease (kidney disease, LPK)
baroreceptor: stimulation of aortic depressor nn understand how changes in CNS cont to ? function in disease
- abnormal baroreflex function
baroreceptor: eg. obesity increased/decreased leptin levels causing reduced baroreflex function
increased leptin
baroreceptor: microinjection of leptin into? will reduce?
- into nucleus solitary tract (baroreceptor aff terminate in CNS) reduce RSNA, HR and BP
baroreceptor: define resistant hypertension
- BP >140/90
- despite 3+ antihypertensive meds (incl. diuretic)
baroreceptor: resistant hypertension- likelihood of CV event than treatment responsive hypertension
3x
baroreceptor: what causes/common in people w hypertension
- chronic unloading of baroreceptors
- baroreflex dysfunction
baroreceptor: goal for hypertension? baroreceptor stimulation
- decrease sym nn activity, TPR = decrease BP
baroreceptor: activation therapy- experiment control and result
- 6 male normotensive dogs
- electrodes bilaterally around carotid sinus ‘continuous’ baroreflex activation
- reduced BP, HR, plasma NAd
- consistent w activation of baroreflex
baroreceptor: activation therapy- experiment induced hypertension and result
- fed high fat diet for 6 weeks -> hypertension
- baroreceptors activated chronically during week 5 of diet
- reduced BP, HR, plasma NAd which reversed when stopping stimulation
baroreceptor: activation therapy- CVRx rheos sys?
- pulse generator (like pacemaker)
- 2 leads wrap around carotid bulbs like hand
baroreceptor: device based therapy in hypertension trial? and results
- human patients w resistant hypertension
- reduced SBP 2 yrs
baroreceptor: activation therapy (BAT)- rheos pivotal trial experiment
- BAT for first 6 months
- BAT delay initiation for 6 months
baroreceptor: activation therapy (BAT)- rheos pivotal trial result
- failed short term efficacy and safety
- 35mmHg reduction of SBP at 12mths
renal nn: types of fibres (2)
- both sym eff and
- sensory aff fibres
renal nn: increase renal sym activity
increased:
- renal vascular resistance
- renin release
- sodium
- water retention
renal nn: excitatory reflexes (aff sensory nn/sym eff?) and increase/decrease sym outflow to other vascular beds
- aff sensory nn
- increase outflow
renal nn: nn cont to?
resting BP
renal nn: renal sym nn activity (RSNA) higher BP = higher/lower sym nn activity?
- higher activity
renal nn: increase nn activity = increased/decreased contractility
- increased
renal nn: stimulation renal aff nn -> increase/decrease BP through activation of CNS regions of BP
- increase BP
renal denervation: surgical sympathectomy increases/decreases BP in malignant hypertension?
- reduces BP
renal denervation: hypertension- renal sym nn activity chronically elevated/depressed
- elevated
renal denervation: process and correlation of BP reduction =
- surgically/chemically destroying renal nn slows dev hypertension
- magnitude of BP reduced correlates to kidney NAd content
renal denervation: HTN1 test and results?
- BP reduced 1mth sustained 12mths post procedure
- some renal NAd reduced in patients
renal denervation: HTN2 test and results?
~40% patients in office systolic BP <140mmHg 6mths post
renal denervation: HTN3 test and results?
- failed to show clinically sig effect
- 1/3 non responders
renal denervation: why went wrong? (3)
- inexperienced interventional cardiologists
- procedural efficacy
- rush to get to clinic?
neuromodulation: ethical considerations- safety and feasibility (3)
- procedural complications (risk?)
- long term consequences
- patient pop
neuromodulation: ethical considerations- efficacy (2)
- does procedure really work (eg. renal denervation)
- placebo controls? (ethical consideration too)
neuromodulation: ethical considerations- consent (1)
- are patients truly able to consent to procedure
neuromodulation: ethical considerations- conflict of interest (1)
- will treating physician benefit? eg. financial gain?
