Ep. 167: Phantom Limb Pain - The Vanished Passenger

00:00:00: Welcome to EANcast, your weekly source for education, research and updates from the European Academy of

00:00:17: Neurology.

00:00:35: were focusing on one of the most intriguing and elusive conditions in neuropathic pain, phantom limb pain, or PLP.

00:00:43: Phantom limb pain refers to painful sensation perceived in a limb that is no longer physically present.

00:00:50: It affects up to eighty percent of amputees, and while it's commonly described as burning, stabbing, or electric shock-like, its phenomenology is far more complex.

00:01:03: In addition to ongoing pain, patients often report a variety of sensations, such as telescoping, where the phantom limb seems to shrink toward the stump.

00:01:15: Referred sensations where touching the stump evokes feelings in the phantom limb and evoked paroxysmal pain triggered by movement or stimuli.

00:01:26: Clinically, PLP must be distinguished from residual limb pain.

00:01:31: which originates from the amputation site itself and often improves with healing.

00:01:36: Despite decades of research, the pathophysiology of phantom limb pain remains only partially understood.

00:01:44: It involves a dynamic interplay between peripheral factors like ectopic discharges and central changes, including cortical reorganization.

00:01:55: To help us unpack this complex topic, I am honored to be joined today by Professor Marshall DeVore, the Alpert Professor of Pain, research at the Hebrew University of Jerusalem.

00:02:07: He is author of over three hundred publications and has contributed considerably to the understanding of the physiological basis of neuropathic pain, and more recently, to mechanisms involved in loss of consciousness and pain-free surgery.

00:02:23: Welcome Marshall and thank you for joining us today.

00:02:27: Pleasure to be with you Simona.

00:02:29: I'd like before we begin though to point out to the audience that I'm a basic scientist.

00:02:35: I do research on animals and computers and in vitro some.

00:02:41: I'm not a physician and I don't see patients so keep that in mind during this discussion.

00:02:47: Perfect.

00:02:49: Phantom limb pain is a heterogeneous condition.

00:02:53: Besides ongoing pain, patients describe telescoping, referred sensations, and paroxysmal or revoked pain.

00:03:00: As a start, would you walk us through this phenomenology?

00:03:05: Well, yes.

00:03:07: Pain is certainly the main issue for the patients.

00:03:11: Although, as you mentioned, there is also non-painful phantom and the pain can come and go and some people just have a phantom.

00:03:22: The truth is that many of us, I mean people who are not amputees, have experienced a phantom.

00:03:28: So if you've ever had dental treatment where the dentist blocks a nerve before drilling your tooth, you probably noticed at the time and maybe for half an hour or an hour afterwards that your jaw feels a little bit puffy as if it's swollen.

00:03:47: That's a phantom.

00:03:49: Pinching that area, you don't feel a thing.

00:03:52: but you do feel an ongoing sensation of that puffiness.

00:03:57: So that's a phantom.

00:03:58: It's a non-painful phantom.

00:04:00: In addition to the sensations, pain, non-pain, and pain has many different aspects, of course, there are changes in the size and shape of the perceived limb.

00:04:13: For example, very common over time, and this usually takes weeks and months, the arm which starts off the phantom arm, which starts off at natural length, will sort of contract and telescope, as they call it, into the shoulder so that we can now have sort of a hand just moving out from the shoulder.

00:04:35: There's also circumstances of reference.

00:04:39: The clear reference is when one taps on the nerve end within the stump, This normally causes a sensation both locally and the stump, but also felt in the phantom itself.

00:04:52: That's a tenelle sign, which most neurologists would of course be very familiar with.

00:04:57: But in addition to that, there are references of a different sort.

00:05:02: For example, an upper limb amputee, if you touch the face, the cheek, he may feel here, she may feel a tingling or a sensation within the phantom limb itself.

00:05:14: So these these odd phenomena also have to be explained in addition to the pain itself although pain of course is the patient's primary problem and that's what we have to understand and hopefully from understanding the mechanism Try to come up with with better treatments.

00:05:30: the treatments that we have right now are generally unsatisfactory.

00:05:36: Let's move to the underlying mechanism of the phantom in pain.

00:05:41: Many studies point to maladaptive plasticity and cortical reorganization, particularly in the primary somatosensory cortex as a central feature.

00:05:51: How does this process interact with peripheral mechanisms like ectopic discharge?

00:05:58: Probably the central question in all neuropathic pain conditions is, are we talking about a pain signal driven from the peripheral nerves, from the periphery?

00:06:10: Or are we talking about something that's generated within the central nervous system itself?

00:06:16: In fact, the International Association for the Study of Pain, ISP, has defined a new word, a new fourth type of pain.

00:06:24: So we all know but not a set of pain, that's when somebody steps on your toe.

00:06:28: And inflammatory pain when there's some sort of inflammation, inflammatory mediators.

00:06:33: present neuropathic pain when there's injuries, frank injuries to the nervous system such as in phantom limb pain and something that's called nausea plastic.

00:06:44: Nausea plastic pain is pain that is believed to be to originate in with some sort of a central nervous system amplification of fibromyalgia being probably the the main example.

00:06:59: and in all of these the question comes up are we talking about the periphery or the central nervous system.

00:07:05: Now, the periphery is something we'll be talking about a fair amount, but in the central nervous system, there are two aspects that really need to be taken into consideration.

00:07:14: The first one, and I think the one that's probably most relevant, well, perhaps not most relevant, the one that's equally relevant, is are there impulses, neural impulses generated in the central nervous system which drive the sensation of pain?

00:07:31: And the second aspect of the central nervous system is that our conscious perception of anything, certainly of somatosensation and pain, is a function of a conscious brain.

00:07:43: So in addition to perhaps generating a pain signal, the brain is always there modulating pain signals, whether they come from the periphery or whether they originate in the central nervous system.

00:07:55: And when I say modulate, I'm referring to things.

00:07:59: Well, like the placebo, if you tell a patient that this drug is going to help, it generally does, even if the drug has no pharmacological effect at all.

00:08:11: Over recent years, the notion of this kind of subjectivity has expanded to concepts of the context in which the patient is.

00:08:26: So what the patient believes, what the patient expects.

00:08:29: So if the patient is expecting something to happen because an authority tells him, or just because the authority is wearing a white medical coat, this in itself can be equivalent to a fairly high dose of morphine in terms of how it can modulate pain.

00:08:50: So there's a lot of context involved in what will help the pain and what is amplifying perhaps the pain that has to do with these sorts of what's called psychosocial effects.

00:09:06: And then with phantom limb pain, there's something special that doesn't really happen when somebody steps on your toe or if you've had an injury to a leg.

00:09:17: And that's with phantom limb pain, we have something spiritual, almost mystical.

00:09:24: One of my favorite quotes on the subject of Phantom Limb Paine is from Admiral Lord Nelson of the Battle of Trafalgar fame.

00:09:34: So he was not for Limb Amputee, and he's quoted as saying the following.

00:09:39: He says, Phantom's sensation is the best possible proof of the existence of the eternal soul.

00:09:46: If an arm can survive physical destruction, why not the whole person?

00:09:52: And in fact, that's a good question.

00:09:54: How is it that with the arm gone, we still feel the arm?

00:09:58: Would we still feel ourselves as being awake and conscious and having sensations, even if there was no body left?

00:10:07: And the answer, of course, is no.

00:10:09: And the reason that it's no is that the sensation of the arm does not reside in the arm.

00:10:16: the sensation of the arm resides in the brain.

00:10:20: So if the arm is gone, the sensation of the arm can certainly remain and in fact does.

00:10:25: If the brain were gone, certainly my guess, and I apologize to true believers, that the we inside would also be gone.

00:10:35: So the question of periphery or central nervous system.

00:10:42: Let's consider first the periphery, which is certainly the oldest idea, and from my point of view, the most likely one still.

00:10:52: So a limb, let's talk about an arm.

00:10:55: An arm is amputated.

00:10:57: The major nerves of the arm are cut.

00:11:01: Neuromas form at the nerve end.

00:11:05: But the nerve itself, the nerve stump, the cut nerve stump remains.

00:11:10: except for some dying back of some axons, the cell bodies that maintain the peripheral nerve that reside in the dorsal ganglia, the ganglia there that fit between the vertebrae and the lower back or the upper back for the arm, the cell bodies there in the dorsal ganglia remain intact as do most of their axons which conduct into the central nervous system.

00:11:35: And it's for that reason that if you tap on the nerve end, on the neuroma nerve end, you will evoke electrical impulses which run up the nerve, past the ganglion, along the dorsal roots into the central nervous system, and then the individual says, yes, I feel a usually shock-like or painful sensation.

00:11:55: That's the tenelle sign.

00:11:57: But the individual, of course, also is feeling this pain somewhere in his body.

00:12:02: Where in his body does he feel it?

00:12:04: He fills it in the parts of the cortex which represented Where these nerve fibers where these nerve impulses went to normally and that is the arm.

00:12:16: so the the nerve fibers within the arm they are still mapped to the part of the brain which gives the conscious sensation of of arm.

00:12:26: and That it really is the obvious reason.

00:12:28: explanation of why there is a phantom pain, because their impulse is coming off the neuroma, spontaneous and evoked, which run up and activate the arm representation.

00:12:39: Now, is that the end of the story?

00:12:41: Well, probably not.

00:12:42: And the reason is that when one blocks the nerve above the neuroma or removes the neuroma, in some cases that actually, it always stops the tinella sign, of course, until a new neuroma forms.

00:12:53: But it does not always stop the sensation of phantom limb pain.

00:12:59: So from that observation that it does not always, sometimes it does, that the fact that it does not always block defense and limb sensation is an indication that there must be some generator, some driver of the pain that is central to where the block was done, say, in mid-arm.

00:13:19: And most people have tended to jump all the way into the brain, not only the brain, but the higher levels of the brain, the cortex, to say, well, that is where the signal must be coming from.

00:13:29: The same is offered, the same explanation is offered for a lot of other pain conditions, such as post-heropatic neuralgia or radicular low back pain, where the presumption is that if you block where you think the nerve has been damaged and pain remains, then it must be coming from the brain.

00:13:48: But this puts aside or ignores a very important observation that was discovered in animals more than fifty years ago, and I contributed to some of the earlier work on this, that after a peripheral nerve injury, many cell bodies in the spinal ganglion, in the paravirtibular ganglia, the dorsal ganglia, many of those cells start firing spontaneously, and they would also be driving a signal from where these cells end up in the periphery, which would be in the arm.

00:14:21: So, abnormal activity, In the wrong location, the normal location is the skin or other peripheral tissues.

00:14:31: The abnormal ectopic location in this case is the dorsal ganglion.

00:14:35: That is an alternative generator of impulses which will cause pain to be felt in the periphery, in the arm.

00:14:42: And I think that the neurological community has more or less ignored this observation even though it's been repeated with... certainly dozens, perhaps even hundreds of observations, not only in animals, but also in humans with chronic pain.

00:15:01: So it may be that the reason that nerve blocks do not stop phantom pain in all cases is that in the cases that it does not, the abnormal activity is generated in the ganglion.

00:15:14: And therefore, it's not the neuroma that should be the target for silencing, but but the dorsal ganglion should be a topic for silencing.

00:15:23: That's what I had to say, and there will be more I guess, about peripheral drivers.

00:15:29: But how about central drivers?

00:15:33: So quite a long time ago, and actually I was the first to make this observation with Professor Pat Wall, one of the real pioneers in pain research, we looked at the central maps of the leg and of the arm in animals.

00:15:49: So the map, there's a map in the spinal cord, and that map is projected onto the brainstem, and that's projected onto the thalamus, and that's projected onto the cortex.

00:16:00: We looked at the spinal cord map of the leg.

00:16:04: And the question was, what happens when you cut the nerve, as would happen with an amputation?

00:16:10: The animals didn't actually undergo amputation, but simply a transaction of the sciatic nerve.

00:16:18: And what we observed was that at first, for the first couple of days, the map in the spinal cord of the leg was missing, that none of the cells there could be driven by stimulation on the leg.

00:16:32: But if we waited just a little bit of time, a week or two or something like that, we're talking about rats and cats, if we just waited a certain amount of time, then the area that was now missing, the area that used to represent the leg, the foot, now responds to light stimulation and pain provoking stimulation on the upper thigh.

00:16:54: So we have really a shift in the map.

00:16:55: The map has now expanded from the thigh into the now empty leg area.

00:17:02: This remapping was unexpected but obviously present and our first publication on the subject was in in nineteen seventy eight.

00:17:13: In the nineteen eighties this was repeated by a number of investigators.

00:17:18: I guess we should give credit to Mike Mersnick and Pawns and another wall.

00:17:26: So this remapping, map reorganization, was worked out in monkeys.

00:17:32: And eventually it was worked when functional magnetic resonance imaging, functional MRI, began to be a practical tool.

00:17:43: It was repeated in humans with her to floor being the senior author on the first paper on this subject on remapping in amputees published in Nature in nineteen in nineteen ninety five.

00:17:59: So we're talking about a discovery in animals dating back fifty years than in humans dating back something like thirty years.

00:18:09: Now one of the things that hurt the floor and co-authors pointed out was that the more remapping she saw in the cortex, in the primary somatosensory cortex S-one, the more remapping she saw, the more pain there was in the amputees.

00:18:28: That is, the amputees that had more phantom limb pain had more remapping of their somatosensory cortex.

00:18:36: So there's a correlation here, some link between the amount of pain and the amount of remapping.

00:18:44: Now, Flora and co-authors concluded, or at least hypothesized, that it's the remapping that is causing the pain.

00:18:55: That is that something going on in the central nervous system is the actual driver of the pain.

00:19:01: and if we could prevent the remapping, that would remove the pain.

00:19:06: And so the ideas how to deal with this were ideas that she and others had about how one might be able to affect the mapping in the S-one cortex.

00:19:19: So she and others, her to floor and others, invented the idea of the mirror box, which now is probably the standard treatment for phantom limb pain.

00:19:31: The idea is that if you look sort of sideways at a mirror and you've got one good arm and one arm that's missing, you'll see in the mirror a reflection of the good arm on the other side, on the missing side.

00:19:45: And then you can imagine for yourself squeezing your phantom hand as you squeeze your intact hand.

00:19:53: And in fact, watching your intact hand move gives you a feeling that you have more control.

00:20:00: of your phantom hand.

00:20:03: And it's this idea of taking over, of having control of one's sensation.

00:20:08: I think that was basically the underlying idea in why the mirror box treatment might be effective.

00:20:17: It certainly gives the individual, the amputee, who's suffering from hand and pain, a context, a belief, an expectation.

00:20:27: that here's an expert who's got a method and the method will almost always help in very much the same way as the placebo helps.

00:20:37: But again, it's not a placebo, it's a context.

00:20:41: So we have this question.

00:20:43: Are we dealing with a primary driver in the neuroma and or the dorsal ganglia in the peripheral nerve?

00:20:51: Or are we talking about a primary driver in the S-one cortex?

00:20:58: Fascinating.

00:21:00: In this context, we know from experience that not all patients with abnormal sensations such as tingling or itching in a phantom limb will develop pain.

00:21:10: Your view, what differentiates patients who develop painful phantom sensations from those who only experience non-painful ones?

00:21:19: Well, there certainly is variability, and I think in any... sensory phenomenon, almost any medical phenomenon, there's very likely to be individual differences.

00:21:29: Certainly the pathology itself is the neuroma of a sort or is it lying in tissue which could be causing the generation of a lot of impulses.

00:21:40: It also may have to do with the patient himself or herself.

00:21:44: We know now that there are genetic factors, heritable factors that can Determined to an extent at least whether you're likely or less more likely or less likely to develop a neuropathic pain.

00:21:57: and of course there is there's learning in the family.

00:22:01: is severe pain Expected or is it not expected in a particular injury?

00:22:08: we always think about the stoic Vikings of of Norway and Sweden who will not complain no matter how much it hurts compared to the the sensitive more sensitive Southern Europeans.

00:22:23: Simona, can I say Italians who might make more fuss for a given baseline sensation?

00:22:33: So yes, there certainly are differences.

00:22:36: But beyond the differences, there are methods of approaching the question of which is the primary driver.

00:22:46: So I mentioned that the primary driver of phantom limb pain for many neurologists and others treating these patients, is that since nerve block doesn't consistently block the phantom limb pain, then the driver couldn't be in the periphery, then it must be in the central nervous system.

00:23:04: And since Florida all have this correlation that the more pain, the more central remapping, then the driver is very likely to be in the central nervous system.

00:23:15: And my guess is that if you take a pole among people who see patients with imbutations, you'd probably find that the large majority believe that this is fundamentally a central phenomenon.

00:23:28: But there are a number of buts here.

00:23:32: So first, the first demonstration of the correlation between the intensity of the pain and the degree of remapping.

00:23:41: That was done with fairly primitive methods in a time when the methodology of non-invasive imaging was just beginning.

00:23:50: And since then there have been tremendous advances in the technology.

00:23:55: I'd like to mention Tamar Makin at UCL in London as being one of the leaders of this using the more modern equipment.

00:24:04: As time has gone by since nineteen ninety-five when this idea was first published.

00:24:09: The size of the remapping has become smaller and smaller and smaller as the technology for measuring has become more and more accurate.

00:24:17: And just a couple of months ago, a paper came out from Macon's lab claiming that there is no remapping at all, looking at individuals who are mapped, individuals who are mapped.

00:24:34: pre-amputation, and then the same individual was mapped after amputation over some years.

00:24:41: So the basic observation that it's central is under question.

00:24:46: And then of course, the other issue, one can guess when there's a correlation that the amount of pain is the cause of the more mapping.

00:24:56: And that's not what was assumed.

00:24:58: The assumption was the more mapping, the more remapping, the more pain.

00:25:04: It could be, and in fact, this is certainly my position, that individuals that had pain, phantom limb pain, driven from the periphery, those are the ones that had remapping using the old-fashioned methods of measuring it.

00:25:20: So the cause and effect is now reversed.

00:25:22: I'm saying that it's very likely that the peripheral drive, the ectopic firing, that is what's causing the mapping, and it's not the mapping causing the firing.

00:25:31: So how would we know that?

00:25:33: We said that there are two main drivers in the periphery.

00:25:37: There's the neuroma and the tunnel sign.

00:25:40: So a fair fraction, probably thirty percent or so of amputees will feel relief when the nerve is blocked.

00:25:47: Of course, the relief will only be for the duration of the block.

00:25:51: If we're using a standard local anesthetic like lidocaine, the pain should go away for an hour or two or three and there's some systemic effect of lidocaine which might make it go a little bit longer.

00:26:01: But there's no reason to expect that blocking the nerve for an hour or two is going to make pain go, fentanyl and pain go away.

00:26:08: It's not a cure.

00:26:09: And it's even been tried to put in catheters and block nerves over a period of time.

00:26:15: And that also works fine as long as the catheter is present and the lidocaine is being put on the nerve.

00:26:22: But as soon as that stops, the pain comes back and it's expected to.

00:26:27: But much more problematic than that is the dorsal ganglion.

00:26:31: The dorsal ganglion as a potential driver, in addition to or instead of the neuroma, that's been largely ignored.

00:26:40: Now, I had the opportunity, after doing experiments on rats, putting lidocaine.

00:26:49: And one can put very dilute lidocaine.

00:26:51: It doesn't have to be a nerve blocking concentration.

00:26:54: non-blocking concentrations of lidocaine put onto the dorsal ganglion, stopped the ectopic firing, and stopped the pain in our animal models.

00:27:07: And with that under our belt, I had the tremendous opportunity to work with Apostle Vaso in Tirana, Albania, and Chaim Adahan here in Israel, with patients.

00:27:23: amputees with phantom limbs, phantom limb pain, all of them with phantom limb pain, thirty-one cases altogether, and the doctors, Arahan and Vaso, injected lidocaine, local anesthetics, around the dorsal ganglia of the appropriate part of the phantom.

00:27:46: And in all thirty-one cases, all of them, the pain went away.

00:27:51: for the duration of the block, that is, for a couple of hours.

00:27:55: With lots of placebo controls such as telling the patient, I'm about to inject a powerful local anesthetic that I expect will reduce your pain and then injecting saline.

00:28:08: And in none of those cases that the individual say, yes, the pain has gone away, the pain is severe, pain is serious, pain is still present.

00:28:15: And then without mentioning anything, the doctor has injected the lidocaine.

00:28:21: And then they would say after two or three minutes, hey, my phantom pain is gone.

00:28:24: I've had it for years.

00:28:25: Now it's gone.

00:28:27: Of course, it will come back.

00:28:29: In the Albania hospital, a couple of patients were to be in the hospital for some time.

00:28:38: And Dr.

00:28:39: Vassel put an indwelling catheter, a port.

00:28:42: onto the dorsal ganglia of these patients so that every couple of hours the nurses could inject a little bit of lidocaine on the surface of the ganglion.

00:28:51: And in these cases, again, all of them, the pain was gone for the period of the block.

00:29:00: If you go to the dentist and he drills your teeth, that's going to hurt.

00:29:04: If you're a Norwegian Viking, it may hurt less than if you're an Italian, but it's still going to hurt.

00:29:10: But if you block the nerve with something that really works, that really stops the pain driver, that's going to work in everybody.

00:29:16: It's not going to work in twenty percent of the people or thirty percent of the people or halfway.

00:29:22: So if you actually do know the driver, and I propose on the basis of these experiments in animals and in humans, that the principal driver of pain in amputees is the associated dorsal ganglion with a contribution, presumably, of the neuroma.

00:29:44: The vasodial paper was published in Pain, which remains the number one pain journal today.

00:29:50: in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, in, So when it comes to what is the mechanism, my position is very clear.

00:30:07: It's got very little to do with the S-one cortex.

00:30:10: In fact, if you directly stimulate and activate the S-one cortex, you'll get tingling sensations, but you will not get pain.

00:30:17: But if you stimulate the nerve or the dorsal ganglion hard enough to activate nausiceptors, then of course you will.

00:30:25: So my take is that this is the target, and that's where... Neurologists should be applying blocking drugs, but keeping in mind that it has to be continuous.

00:30:40: It has to be over a period of time.

00:30:44: Okay.

00:30:44: My last question is, what in your view are the most pressing and answered questions in the field of phantom in pain, and where should future research focus to meaningfully improve outcomes for these patients?

00:31:00: Yes, so as I said, the main question is the periphery or the central nervous system.

00:31:06: And in this case, phantom limb pain, I think it's quite clear that the principal driver is the periphery with all the various modifications that happen in a conscious brain.

00:31:17: I think for what it's worth, the same is true of ridiculous low back pain and of post-tropetic neuralgia and perhaps several others.

00:31:27: So if what I'm saying is correct, with respect to phantom limb pain, and we could do exactly the same experiment with respect to these other major neuropathic pain conditions.

00:31:39: Then the target you got.

00:31:41: The target is the dorsal ganglion.

00:31:43: And again, one can use dilute concentrations of a local anesthetic that don't block nerve conduction, but only block the ectopic generation, the abnormal generation of nerve impulses.

00:31:57: So how does one do that?

00:31:59: Well, today we have ports and pumps.

00:32:03: Pumps have been commercially available for a very long time, used intrathecally to provide opiates normally for cancer patients.

00:32:11: But in principle, these same pumps could be used with a catheter that reaches the foramen, the surface of the dorsal ganglion.

00:32:22: And one could just... You could fill the pump in principle with concentrated lidocaine, but pump very, very slowly so that enough would get in to provide the dilute lidocaine.

00:32:34: that's all that's necessary to stop ectopic firing.

00:32:37: And it may be that one filling of the pump would be enough to last for, I never calculated, perhaps a month or even more than that.

00:32:46: But beyond the pumps, which are technologically quite old fashioned, a lot of money has gone into developing better electrical stimulators, which add impulses rather than subtracting them, which is what the Vatican would do.

00:32:58: The pumps themselves are technologically weak and could be improved in the same way that simulators have been.

00:33:05: And then one can go in principle, at least, into biological pumps, bio pumps.

00:33:11: in which a small shim of say some skin tissue or some tissue of the individual patient is infected with an AAV or with another method of causing this piece of tissue to release, to synthesize and release a peptide which would act like a lidocaine which would suppress abnormal firing.

00:33:34: And then these little shims of tissue could in principle be injected into the foramen.

00:33:40: release over time the blocker molecule and perhaps give an individual a cure of phantom limb pain for the rest of his life.

00:33:50: And the same probably goes to for for post-herprick neuralgia and ridiculous low back pain.

00:33:57: So if someone would like to do good for mankind and perhaps benefit from some of the rewards him or herself, I recommend looking into this subject.

00:34:10: My deepest thanks to Professor Marshall DeVore for sharing his time and expertise with us today.

00:34:16: For our listeners, thank you for joining us and feel free to contact us if you want to know more about this interesting topic.

00:34:23: Thank you, Marshall.

00:34:25: Goodbye and until next time.

00:34:27: It's been a pleasure.

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