Parkinson drug

>> [slide 1] hello and welcome back toour third lecture and week 5 in nanohub-u's introductionto bioelectricity. [slide 2] in this lecture,we're going to go back to deep brain stimulation aswe did in parkinson's disease but we're going to be talking about a differentsort of circuit. so in a first lecture this week,we talked about parkinson's and applying electrodes to the basal ganglia circuitrydeep inside the cerebral

hemispheres and stimulatinga structure further down in the subthalamic nucleusto compensate for the death of neurons in thesubstantia nigra and the dopaminergic projections of those neurons tothe basal ganglia. in epilepsy, we talkedabout a different circuit, which really revolvesaround the hippocampus. but more so than that,we were even talking about stimulating the vagusnerve and the projections,

the atrium projections ofthe vagus nerve to the brain in the hopes of affecting thebalance of excitation inhibition up around the hippocampus. in this lecture,we're going to talk about an entirelydifferent circuit. the circuit that's associated with the reward pathwaysof the brain. and this will bring us backto the lecture in week two in which we talked aboutthe various different types

of neurotransmittersand their role in various different addictivebehaviors and illicit drugs. [slide 3] so let's begin by looking at theanatomy of the reward pathway. so the reward pathway inthe brain, otherwise known as the limbic loop, isassociated with a number of different corticalstructures. the anterior cingulate,the orbital frontal cortex, and the amygdala,all on the cortex of the brain haveprojections down into the brain

to the hippocampus,the orbitofrontal, anterior cingulate, andtemporal cortex, and from there to the ventral striatum. so the ventral striatumincludes a particular structure that we're going to come backto again and again today, which is the nucleus accumbens. the nucleus accumbens andthe ventral striatum project to the ventral pallidum,the substantia nigra, both parts of it, and fromthere -- or beg your pardon --

to the pars reticulata from thesubstantia nigra, and from there to the mediodorsal nucleus. and again, rememberfrom our first lecture, when we were talking aboutanatomical structures, that i said that the name ofthe structures that you'll learn in the brain will often giveyou a clue as to where they are. so for example, when we talkabout the mediodorsal nucleus, we can infer medial, meaningthat it's towards the center of the brain, and dorsal,

meaning it's towardsthe back of the brain. so it will be towardsthe center and back of the central nervous system. these projections are eachexcitatory or inhibitory. so the projections fromthe cortex are excitatory to the ventral striatum, the ventral striatum isinhibitory towards the ventral pallidum, and thesubstantia nigra, which is, in turn inhibitory, tothe mediodorsal nucleus,

which is then excitatoryto the cortex. and so you have a loop. and there's a particularbalance in this loop and that balance is keyto associating a reward with the expectationof the reward, and then with a pleasurablefeelings that arise from receiving areward that is expected. and both parts of thatare equally important and we'll come back to that.

it's not just receivinga reward. for example, eating. but it's receiving thatreward and coupling that reception withthe expectation. so it's not justfilling your stomach, but it's filling the stomachalong with the active eating which tells your body toexpect to become full. so those two things have tobe coupled in a healthy brain. and here again, we have acoronal slice of the brain

as we saw in parkinson'sdisease; and in the coronal slice, youcan see the caudate and putamen, which are part ofthe basal ganglia. they're also involvedin motor control and you see the nucleusaccumbens of the ventral striatum andit's role in the reward pathway with the projections thatdopaminergic projections from the substantia nigra, which two of the nucleusaccumbens are inhibitory.

[slide 4] so let's look atyour brain on drugs. most of us, when we werekids, got to see commercials of what happens toyour brain on drugs and it's not really a friedegg, if you're old enough to remember those commercials. it's a little bit more likewhat's shown on this slide. so you have neurons fromthe ventral tegumental area and neurons from thevta, which is right next to the substantianigra in the medulla.

neurons from the vta project toneurons in the nucleus accumbens and they project andrelease dopamine, neurotransmitter dopamine. these two sets of neurons bothreceive glutamatergic excitatory inputs from the cortexof the brain. and so you have excitatorydescending projections from the brain and youhave a dopamine release between the vta, theventral tegumental area -- ventral, meaningtowards the front,

tegumental meaningtowards the top area -- and the nucleus accumbensin the striatum. furthermore, in theventral tegumental area, you have interneuronswhich act by releasing gaba on the projectingneurons out of the vta. and gaba, if you recall, is the primary inhibitoryneurotransmitter of the brain. and then what we can seeis, in these yellow boxes, all of the different -- or manyof the different illegal drugs,

narcotics that affectthis very simple circuit and how they affectthe reward mechanism. and the reason thisis important is because affecting thereward mechanism can do one of two things. it can either give youan unearned reward, make you feel goodfor no reason, or it can take awayan earned reward, make you feel bad eventhough you should feel good.

that second category, thoseagents i'm sure they exist, but why would you take them. so we don't worry about those. we worry about thefirst category. the ones that makeyou feel good even when you haven't done anythingthat warrants feeling good. and opiates, for example -- we'll go throughsome of these -- opiates act in a numberof different areas.

opiates act on the ventraltegumental area interneurons that project inhibitoryprojections onto the projecting neurons. they also act on the dendritesof the nucleus accumbens. alcohol acts at thesynapse of the interneurons and the projecting neurons within the ventraltegumental area. nicotine, if you recall,there was a whole category of ion channels of receptors --

ion channels that wetalked about in week two, the nicotinic receptors. well, nicotine acts onthe nicotinic receptors in the dendrites of both thedopaminergic projecting neurons in the vta and thenucleus accumbens neurons that receive thedopamine from them. so it affects theglutamatergic inputs that descend from the cortex. cannabinoids work on thereceptors and the dendrites

of the nucleus accumbens. and then cocaine, which isone of the better examples of the mechanisms of addiction,acts, if you'll recall, as a dopamine reuptakeinhibitor. and dopamine reuptakeinhibitors are fantastic in the globus pallidusbecause they help with parkinson'sdisease as l-dopa does. but they're not fantasticeverywhere and they're not fantasticall the time

and they have thisundesirable effect of leading to an excess amount of dopamineexcitation at the synapse between the vta projectionsand the post synaptic neurons by increasing the durationfor which a given release of dopamine is presentin the synapse. [slide 5] and so what happenswhen we do that? what happens is thatyou get, simultaneously, when you repeatedly stimulate -- overstimulate by taking anillicit drug, what happens is

that you get a desensitizationto the stimulus. so you have bothan ongoing response and you have aphasic response. aphasic responseis a response given to a particular actual stimulusand that will be sharpened, and you have theongoing response, which is your baseline level, and that will belower dramatically. and so what happens is that whenyou take a drug, you increase --

let's say you take cocaine. you take cocaine, youincrease the duration during which dopamine is presentin the synaptic cleft between the vta neurons andthe nucleus accumbens neurons. and that leads to anexcess of excitation there. so your body is receivinga reward but you haven't doneanything to get a reward. so where is this rewardcircuit is very, very important to drive behavior and it acts topromote activities like eating,

for example, as pleasurablebecause of this reward circuit. sex is pleasurable becauseof this reward circuit. so those are specific activitieswhich are coupled to a reward. so there's an expectation of thereward and there's the activity which delivers the reward andthose are tightly can coupled. when you take anillegal narcotic, there is no expectation ofreward because you're not eating and you're not having sex. you're not doing a naturalbehavior with with we'd expect

to have a coupled reward. you're just consuminga chemical agent. and so your body receives areward without the expectation of the reward and that throwsthe entire reward circuit out of balance. and so what we need to dois try to come up with ways to restore the balancein that reward circuit. one way is by just stoppingwhatever chemical agents you're taking.

but there's a problem with that. first of all, there'sa withdrawal and a withdrawal comes aboutbecause the body compensates for the excess stimulation bydecreasing the ongoing amounts of dopamine and glutamate and sowhen you stop taking your drugs, your body takes some time torecalibrate and begin producing at the original levels. and so you have, to some extent,you have this delayed effect in which you have to waitfor your body to compensate

for the absence of that drug,and that's going to feel, subjectively, exactlythe opposite of how the original high feltand you have to get through that and that's what wecall withdrawal. but in a secondary sense, youhave this concern that you are, to some extent, rewiring theprojections in the brain. and so you have plasticityin the brain and you're changing the wiringof the brain in some cases, permanently, and so or overa much longer period of time

than the initial withdrawaland so even though you cease to take a drug overa period of time, you will go throughthat initial withdrawal, but it takes muchlonger than that and possibly an indefiniteamount of time to rewire the brain backto its original state, which is why drug addictswill always tell you that the first high isalways the best high. and that when they go clean,and then they go back,

there's a danger of overdosing because their brain is nolonger used to that acute dose because it's recalibrated. but even without the overdose,the high will not be the same as it was the first time. so they progressively becomeless and less sensitized and they never quite experiencepleasure as, say in the case of heroin addicts the same way that they did beforebeginning to consume heroin.

[slide 6] so there are long termplastic affects as well. in this particular lecture, iwant to talk about one example of that and that is the gabaagonist response of neurons in the nucleus accombensof alcoholic subjects. so we have alcoholic animals, just like we have alcoholicpeople, and those are animals that are predisposed tothe consumption of alcohol. and there's a particularstrain of rats called p-rats and those rats, if yougive them the opportunity

to consume alcohol, will do so. and in fact, if you takea pup and you put alcohol in their chamber and youput them in the same chamber as their mother, they willpreferentially select alcohol to their mother's milk. and they'll drink until theypass out and then as soon as they're able to walk again, they'll go back anddrink some more. so what can we do to changethat sort of behavior?

twelve steps is not got to helpwith an animal and so we begin to look at purely interventionalengineering approaches. one is to deliver a drug. and so you can deliver adrug that's a gaba agonist. so agonist increasestheir response to gaba. gaba is inhibitory so you'reincreasing the inhibition of the neurons in thenucleus accumbens and in that way you're counteringthe effect of the addition. and what happens is,in a particular animal,

if you have some baselinelevel of alcohol consumption, over a series ofinjections, you map the level of voluntary alcoholconsumption in the animal. and you can see that the level of voluntary alcohol consumptiongoes down dramatically. half as much alcohol as theydrank before while you're providing the injectionsof this drug. and then when you stopproviding the injections, it shoots right back upto what it was before.

in fact, higher thanit was before. and this corresponds withobservational behavior or observations ofbehavior in addicts. if you administer a placebo,shown here with a black dots, you get no change over thesame time period in the level of alcohol consumption. and the asteriskshere are to denote that we have a statisticallysignificant difference between the animals on placebo

and the animals receivingthe gaba agonist. what we want to do ismove away from drugs because drugs are verydifficult to inject focally and that requires a focalcannula to deliver the drug. it requires a drug pump, itrequires a reservoir of drug, all of which are verycomplicated to do on the brain and especially with our fearof infection of the brain. so to avoid infection of thebrain, we take drugs orally, which means that you're going

to have an ecaba agonistresponse everywhere in your body and that's not what you want. you want it in thenucleus accumbens. [slide 7] so we're back to deepbrain stimulation. and it turns out that indeep brain stimulation, if you apply an electricalcurrent of 1 mic grams to an alcoholic animal,the consumption of alcohol will decrease,but it will fluctuate and it won't quite give youthe results that you saw

in the gaba agonist animal. [slide 8] but if you increase the dose,increase the amount of current, then you get a muchmore dramatic reduction, almost to a third ofthe original level of alcohol consumptionin the animals. so this is an even betterresponse than we had and it's statisticallysignificant. an even better response thanwe had in the original animal and when we stop theelectrical stimulation,

the animal immediatelygoes back to drinking at pre-therapy levels. and all of this work that i'mdescribing here is the work of a colleague of ours atlsu, dr. jessica willdon, along with a colleague inindianapolis, dr. zac rod, [slide 9] and an md, ph.d. studenthere at purdue, kurt chang. kurt's work is what i'llbe talking about now. so what kurt wantedto do is having looked at this dbs stimulationand the fact

that you can reduce addictivebehavior without any kind of therapy beyond anelectrical stimulus directly into the reward circuitto alter the function of that circuit he thenwanted to say, well, okay, but when we stimulate,we stimulate with these square waves, right? because that's whateverybody does. but is that the bestway to stimulate? and so he started to ask if wecan make these square pulses

out of smaller little pulses,which he calls pulsons, and the square pulses wouldbe composed of the pulsons and that would achievetwo things. first of all, hopefully, it would achieve an improvedphysiological response, and second of all, it woulddo so with less current. so if you integrate thearea under the curve, you'll find that you haveless current being delivered for the pulsons than youdo for the square pulse.

so you have a smaller dose,which means that you're going to have less desensitizationof the brain. you're going to haveless electrodeposition of the electromaterial intothe brain when you stimulate, even though that's biphasic. you're never perfectly biphasic. and most importantly,perhaps, you're going to have less power consumptionof the medical device, which means that your batterylife is going to be much longer,

which means that your batterycan either be much smaller leading to a less invasivedevice or your battery, perhaps won't need to be replaced every fewyears as it does now. and that means surgery avoided. [slide 10] so this approachleads to a series of wave form parametersthat we can discuss. one is the amplitudeof the pulse. one is the width of a pulse, pw.

one is the amplitudeof a pulson in a burst. and then the width ofthe pulson in the burst, amx and pwx respectively. and then there's theinterpulse interval, the spacing between pulsons andthere's the number of pulsons in a particular pulse. there's the effectivepulse width, which is the correspondingwidth to the original pulse, and then there's theburst duty cycle.

so each of these can becalculated and we can look at a continuous pulse versusa continuous pulse chopped up into two pulsons, each ofthe 20% duty cycle or 5 pulsons with an 80% overallduty cycle or free form where you have little pulsonsand big pulsons and all sorts of combinations in between. [slide 12] and if you look at all ofthese potential wave forms, you can begin to recordthe response of a volume of tissue to that stimulation.

and so you can beginto say, all right, we know that 200 mic gramsof current works better than 100 mic grams ofcurrent, but why is that? and is it necessary to go from100 mic grams to 200 mic grams or can we achievethe same effect by playing with that wave form? and so we begin to lookat the a, b, and c fibers in a vagus nerve beingstimulated with pulsons and you can look at thepeak values and track those.

you can look at the width of allof the a fibers firing together. so if they all fired atexactly the same time, you would have avery small width. and if they all fireover a period of time, that's distributed, you wouldhave a larger width here and then you couldlook at spacings between a and b and c fibers. [slide 13] and then, having thatinformation, we can begin to calculate and plot thedifferential fiber response.

so you can look at a fibersat the top, or you can look at c fibers on the bottom,where on the left hand side, we're looking at measured afiber and c fiber response in micro volts withdifferent colors for different stimuluswave forms. so the stimulus wave formsare color coded at the bottom, and what you find is thatyou have the blue wave form, which is a continuous wave formhas some particular response. and then the otherones, which consist

of pulsons have differentresponses. and in fact, if you look at thegreen wave form, which consists of these two pulsonswith a 20% duty cycle, the green wave shows youthat for a given amount of electrical stimulationyou get a much higher level of activation than you wouldwith a continuous pulse. so we do, in fact,see better efficacy with less current ratherthan better efficacy with more current as we did inthe earlier dbs example we went

from 100 mic gramsto 200 mic grams. so this is a veryimportant finding. and it works for a fibers. it works for c fibers. and we can calculateit all as a percent of the maximum activations. so rather than absolute values, we can look at maximumactivation of the continuous pulse and sayokay, that's maximum activation

and then when we switch topulsons, we find out that in fact, it's notmaximum activation. we can get more thanthat using pulsons. so you can get moreat lower currents and you can get more over all. [slide 14] so if you're just looking atthe 50% maximum activation and looking acrossdifferent wave form types, you can map out what thevariation is and you'll find that some of these with theasterisks are statistically

significant and thoseshow, particularly, in the case of the 20% dutycycle, that you have again, much lower current needed to deliver the sameamount of activation. [slide ] q50 incidentally q is charge required for 50/50% maximum activationand the a is of a fibers. so you have q50a isthe charge required for 50% maximum activationof a fibers. q50c is the samething for c fibers.

so we can reduce this dosing and we can increasethe cell activity. that's the take homemessage, using pulsons rather than continuous time pulses,we can reduce the total amount of dosing that is required toachieve the therapeutic effect, and we can increase thecell activity of the fibers that we're interested in to preferentially selectsome fibers over other fibers to achieve that sametherapeutic effect.

so whether you're doingdeep brain stimulation in parkinson's diseasein the substantia nigra, in epilepsy in thehippocampus, in alcoholism in the nucleus accumbens,wherever it is that you're doing deepbrain stimulation, you can use this approach to getmore effect with a smaller dose over a longer period of time. and that's wherewe'll end for today. in the next lecture, we'regoing to move out of the brain

and into the peripheralnervous system and talk about prosthetic arm control. and i'll see you then.