Lecture 20: Deep Brain Stimulation and Other Emerging Treatments for Parkinson's Flashcards
define: deep brain stimulation
* give the frequency, length of time per impulse, and current
High frequency electrical current passed
through a focused region of the brain to inhibit the abnormal activity occurring in the brain
- turn off regions in the brain related with pain or abnormal movements (Parkinson’s, dystonia, tremours)
- 185 Hz, 120 us, 60mA
What is the proposed mechanism for DBS?
debated but likely a combination of the following:
* Neuronal inhibition - direct inhibition of neurons
* Inhibitory circuits activation
* Hyperpolarizing neurons (directly or indirectly through interneurons)
Describe the basal ganglia motor circuit
Basal ganglia circuitry is under control of the cerebral cortex
cerebral cortex –> putamen/striatum –> globus pallidus external –> subthalamic nucleus –> globus pallidus internal and SNr (substantia nigra pars reticula) –> ventral lateral and ventral anterior nucleus of thalamus –> frontal cortex–> spinal cord and brainstem
substantia nigra pars compacta
With Parkinson’s disease, dopaminergic neurons in the substantia nigra pars compacta die, resulting in the striatum/putamen more strongly inhibiting globus pallidus externus
globus pallidus externus is inhibited from inhibiting the subthalamic nuclei. Subthalamic nuclei increases its stimulation of GPi and SNr. GPi and SNr (substantia nigra pars reticula) increase their inhibition on the ventral lateral and ventral anterior thalamus. This decreases the excitation of the frontal cortex, making movement initiation difficult
DBS targets the subthalamic nuclei, decreasing its stimulation of Gpi and SNR, and thus decreasing GPi and SNr’s inhibition of the ventral latera and ventral anterior thalamus
What are 3 surgical procedures proposed for parkinsonism
deep brain stimulation: introduce electrode to target the subthalamic nucleus to reduce how much it excites globus pallidus internus
pallidotomy: the surgeon destroys a tiny part of the globus pallidus by creating a scar. This reduces the brain activity in that area. 1 time procedure that is risky
neural transplantation: replace lost dopaminergic neurons lost from parkinsons by transplanting tissue with dopaminergic neurons. generally not successful. recognized as foreign tissue by the body, encapsulated in fibrous tissue eventually
How is DBS implanted? Is patient awake or asleep?
Pre-surgery
MRI images in multiple planes (coronal, sagittal, axial) of the brain are taken first to localize target subthalamic nuclei. taken in multiple planes
pictures are sent to a navigation computer which helps guide the advancements of electrodes during surgery
during surgery:
patient is strapped down in stereotaxic frame to prevent head movements.
patient is sedated as they drill the hole in the brain and then brought out of sedation during implantation so surgeon can assess patient response to stimulation.
Stage 1: bilateral electrode implantation into subthalamic nucleus (approx. 10cm deep from top of head)
Stage 2: implant pulse generator (control unit) in chest. wires run percutaneously, behind ear up to electrodes.
Stage 3: stimulation parameters adjusted (titrated) - to reduce symptoms and avoid side effects
choose 2 out of 4 electrodes to stimulate at a high intensity to get the effect you want
what drug is normally given for parkinsons?
Levadopa: replaces missing dopamine
taken orally, daily
How do surgeons know they reached the subthalamic nucleus during implanatation?
MRI pictures and navigation computer helps with positioning +
record electrical activity from the electrodes during implantation.
Electrical signals are displayed on a screen and also tranduced into sound.
white matter creates a 0.1 mV signal and a hush-like sound
electrodes in the anterior thalamus create large spikes and sound like popping.
electrodes entering the zona incerta create a 0.1mV signal and a hushlike sound. white matter so cannot detect any action potentials
electrodes in the subthalamic nucleus show distinct higher density of action potentials
Describe the decay in dopaminergic neurons overtime, causes, and what it can lead to
~ 4000 dopamine neurons in the brain. you have the most at birth, declines as you age
declines with age, virus, trauma, toxin, genetics.
parkinsonian symptoms occur when you decay to 20% amount of at birth. most people don’t reach this amount of decay before they die but it can occur in an isolated incident (virus, trauma, toxin) or due to genetic disease causing acceleration of loss
Describe how dopamine levels change over the day in parkinson patients. describe how levadopa modulates the dopamine levels and what happens as parkinsons progresses. how does DBS control this?
Y axis: dopamine levels in the brain
* bradykinesia (slow movements - too little dopamine)
* dyskinesia (uncontrolled fast movements – too much dopamine)
an early parkinson’s patient may have a normal amount of dopamine in the morning but it can decline in the day, reaching bradykinesia
Thus, you give them Levodopa orally. over an hour, dopamine levels will rise to the normal range and persist until drug wears off
as parkinsons progresses, you
must give them a larger amount of Levodopa, but then you can overshoot into dyskinesia and drop back down into bradykinesia. this patient will have on and off fluctations. periods in normal range but also dyskinesia, and bradykinesia
DBS:
raise level of dopamine with deep brain stimulation of subthalamic nucleus.
inhibits STN which may be good enough to not reach bradykinesia
or can be used in tandem with levodopa to decrease amount of levodopa given
How should patients be counselled about deep brain stimulation?
Pre-operatively, if you experience bradykinesia for half the day, normal function for a quarter of the day, and dyskinesia for another quarter of the day, you can expect DBS will result in 2/3 of the day normal function, with 1/3 being a mix of some periods of bradykinesia and dyskinesia
You may still need to take levodopa but for many patients medication is often reduced to 0-50%
What are the indications for deep brain stimulation?
- Parkinson’s Disease
- Dystonia
- Tremor
- (rare)
- Depression
- Obsessive Compulsive Disorder
- Tourette’s
- Cluster Headache
- Epilepsy
Watch this video: NSDA Research Update: Deep Brain Stimulation for Spasmodic Dysphonia with Dr. Honey (2019)
https://www.youtube.com/watch?v=MwvBWClOptk
a disorder in which the muscles that generate a person’s voice go into periods of spasm. This results in breaks or interruptions in the voice, often every few sentences, which can make a person difficult to understand. The person’s voice may also sound strained or they may be nearly unable to speak.
Prospective study continuing
DBS helped with 2 patients
Describe adaptive closed loop DBS system study
* what were the issues?
Self-adjusting brain pacemaker may help reduce Parkinson’s disease symptoms
DBS treatment changed brain activity so much, that the signal that was expected to control the aDBS system was no longer detectable.
The initial setup of the device
requires considerable input from highly trained clinicians. Researchers envision a future where most of the work would be managed by the device itself, greatly reducing the need for repeat visits to the clinic for fine tuning.
Focused Ultrasound Therapy for Parkinson’s disease
* benefits proposed
* how it works
Non-invasive
Decreases the cost of care for patients with Parkinson’s disease
one time procedure
Focuses ultrasonic energy beams precisely and accurately on deep brain targets without damaging surrounding tissue. The FUS target is the globus pallidus or subthalamic nucleus.
FDA has approved use of focused ultrasound for treatment of tremor-dominated Parkinson’s disease and dyskinesia. FUS is only being assessed to treat one side of the brain (out of caution).
note: if done on one side, will affect control on the other. This is because the motor pathways in the brain are largely contralateral, meaning that the right hemisphere of the brain controls movement on the left side of the body, and vice versa.
What did the editorial describe for Focal Ultrasound Therapy?
* benefits
* adverse effects for FUS
* adverse effects for electrode implantation with DBS
reduction in the severity of motor signs of 40-60% (on opposite side of body) and a reduction in medication use of up to 50%. HOWEVER, these patients had 5x more adverse events as controls including dysarthria (difficulty speaking) , weakness, gait unsteadiness
- implantation had 1-5% risk of major adverse effects (stroke, infection, hemorrhage)
- less severe complications related to implantation: dystonia, dysarthria, gait impairment
