Evidence for locus coeruleus-norepinephrine system abnormality in military PTSD revealed by neuromelanin-sensitive MRI

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Clifford Cassidy discusses the complex neurobiology of posttraumatic stress disorder (PTSD) calls for the characterization of specific disruptions in brain functions that require targeted treatment.

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Institution: University of Ottawa

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Clifford Cassidy discusses the complex neurobiology of posttraumatic stress disorder (PTSD) calls for the characterization of specific disruptions in brain functions that require targeted treatment.

Image courtesy of interviewee. May 2, 2024

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This video video discusses a study aimed at finding better treatments for PTSD, particularly military PTSD, which is challenging to treat. While psychotherapy is effective, it requires significant time and resources, and medications often do not work effectively for all patients. The study focuses on understanding neurotransmitter systems that may be dysregulated in individuals with PTSD, specifically examining the locus coeruleus and its relationship to the norepinephrine system.

The researcher highlights that PTSD is a heterogeneous condition, with varying symptoms among individuals. The study utilizes neuroimaging methods, particularly neuro melanin-sensitive MRI, to investigate brain activity in critical regions related to norepinephrine and dopamine. The findings indicate that veterans with PTSD exhibited higher neuro melanin signals in the locus coeruleus compared to healthy controls, suggesting increased activity in this area is linked to hyper-arousal symptoms.

Overall, the research underscores the importance of the norepinephrine system in PTSD and advocates for further exploration of individualized treatments based on identifiable chemical imbalances. It also notes the clinical application potential of the neuro melanin MRI method, which has received FDA clearance for use in diagnosing PTSD. This video video approach could lead to more effective, personalized treatment strategies for those affected by PTSD.

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There's different angles to it.

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I mean, I think the most important reason

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to do a study like this, ultimately is to, you know,

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kind try to find better treatments for PTSD.

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So, you know, PTSD is difficult to treat, especially,

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military PTSD.

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Um, and the best treatments, are psychotherapy, which,

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you know, work well, but they take time

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and they don't work for everybody

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and they're, you know, costly.

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There's a lot of resources to, to make them happen.

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And medications for PTSD are, you know, some, some work

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for some people, but they don't work as well as they might.

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And, and there's not a lot

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of dedicated medications for PTSD.

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Often they're u re, you know,

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using antidepressants basically.

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Um, drugs like that.

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So ultimately, you know, most

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of the psychiatric medications we use are acting on

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neurotransmitter receptors in the brain.

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So maybe, you know, by understanding better

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what neurotransmitter systems are,

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are dysregulated in PTSD, we could be in a better position

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to medicate it with drugs.

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A lot of these, you know, neurotransmitter, systems

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that are targeted by psychiatric drugs are called neuro

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neuromodulators, so they kind of amp up

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or dampen down brain activity.

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Um, so they can kind of, you know, affect people's level

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of arousal or mood or, or things like that.

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So, yeah, so that's an easy way

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to use a drug to manipulate the brain.

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That kind of leads into where I was going.

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Another, important point about all this is, you know,

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one reason a condition like PTSD is hard to treat is

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because, most people have a bit of a different picture.

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Um, so it's a pretty heterogeneous condition,

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and there's a different set of symptoms.

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Um, you don't need all the symptoms

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to have to have the disorder.

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Um, and different people have more prominent

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deficits in different areas.

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So, so, yeah,

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you couldn't maybe have one drug

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that would be like a magic bullet

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that would hit all the different targets for,

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for PTSD, for instance.

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Um, but you could think about certain types of symptoms

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that are common in PTSD that are easier to link to,

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you know, brain functions that you could treat.

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Like the, the system that we were talking about,

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or the symptom that we're concerned with in the study is,

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is hyper arousal, which is a pretty easy,

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symptom to relate to.

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I think most people have had some kind

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of low level experience of, of hyper arousal.

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Um, so you can think of it as,

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elevated vigilance like watchfulness or fearful, long

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after a threat has passed.

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So people have trouble relaxing

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and calming down, even if, you know,

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they're in a safe environment, cut into people's quality

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of life and make it not, yeah, that's a lot

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of negative consequences.

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So that's, you know, where I come at it as a researcher,

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you know, it's hard sometimes to,

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to think about the big picture,

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and usually you start out with the methods

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that you have strength in

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and finding relevant applications for them.

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So a lot of my recent work has been about developing a

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certain neuroimaging method and making it better,

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and at the same time finding new applications for it

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where it could be most useful.

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So that's definitely, you know, a big part of

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what this study was about is, is working on these methods.

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So there's, neuroimaging method that has been around

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for a while, but, you know, we've done a lot of work to,

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to improve it and to show how it can be used in different,

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different types of applications.

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So this method is called neuro melanin sensitive, MRI,

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so it's a very specific method

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because it only can look at two brain regions,

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so it doesn't even scan the full brain,

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but those two brain regions are extremely important

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for many, neuropsychiatric conditions.

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So there's the locus aurelius, which is the, you know,

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subject of this study,

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and that's kind of like the heart of the norepinephrine

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or the noradrenergic, same thing,

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neurotransmitter system.

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And then there's also the substantial nigra,

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which is the heart of the dopamine,

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neurotransmitter system.

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And a lot of the work we've done has also been

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in the substantial nigra.

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But, so, so these two brain regions are,

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are important for so many brain functions

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and so many different, psychiatric conditions

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and also neurological conditions.

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So even though we only looking at two very specific regions,

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they are important for almost all

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of psychiatry one way or another.

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Um, so for, for this study,

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we're looking at the locus aurelius

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and, in general, these,

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this imaging method is able, so

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the subtlety to it is, it's, it's sensitive to this,

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this brain chemical called neuro melanin,

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which is only found in those two regions of the brain,

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the locus aurelius and the sub substain nigra.

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And the idea is you're born without any neuro melanin,

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and it gradually accumulates over the lifespan

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and just builds up inside the neuron cell bodies in those

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two brain regions.

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And, it's actually visible to the human eye.

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So that's why those regions, have the names.

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They do that substantial nigra is black

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because it has this black pigment neuro melanin in it.

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And the locus aurelius is bluish aurelius

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because of the same pigment.

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Um, so the idea is that it's a marker

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of if the cells are there or not.

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If that pigment's there, it means the cell is there.

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The only way to get rid of that pigment is if the cell dies.

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It just builds up gradually

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and it can't be destroyed unless the cell dies.

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So the, this method, this imaging method started out

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as a marker of neurodegeneration of those structures.

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So it was used a lot in Parkinson's disease to see the death

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of the dopamine neurons

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and in Alzheimer's disease to see the death

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of the locus s neuros.

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And we did work in Alzheimer's also.

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So that's where this, you know, the, the

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basic, work started for neuro melanin sensitive MRI,

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but then bringing it from research

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and neurodegeneration to research

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and psychiatry where it, these cells aren't dying,

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or even healthy people.

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That's kind of the leap that our group

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and our collaborators have made a big push on.

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So, so we're saying

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that even when the cells aren't dying, the amount

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of neuro mein and neuro mein, MRI signal

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is telling you something about how active these cells are.

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So, you know, there's this idea of an imbalance, a

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chemical imbalance in psychiatry

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that psychiatrists will tell their patients they have a

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chemical imbalance and you know, it's an oversimplification,

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but a method like this can, can tap into that.

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We can see if there's excess signal in this locus aerius,

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it's perhaps due

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to this chemical imbalance in the norepinephrine system.

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It may not be just PTSD,

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but if you know more directly to this hyper arousal idea,

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so veterans with hyper arousal, it,

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that hyper arousal could be due to excess activity

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of this locus, aurelius norepinephrine system.

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So, so yeah, that's, that,

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that excess activity would mean this neurotransmitters being

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released too much, it's cycling around

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and every time it cycles it's released

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and then it's taken back up into the cell.

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It can lead to more of this norm neuro mein formation.

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And over the span of months

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and years that we could maybe detect that with,

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with this MRI sequence it there,

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we had basically two, two main findings.

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So we had a group of military veterans with PTSD

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who had served in Afghanistan in the Canadian armed forces.

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Um, so we had I think, 34 of them.

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And we also had a group of healthy controls

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who didn't have any psychiatric history.

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We had 32 of them,

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and everybody was, was scanned in the MRI

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to get this neuro melanin sensitive,

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MRI signal in the locus aurelius.

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And we found that as a whole, the people

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with PTSD had higher signal

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in the locus aurelius than the controls.

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So it was suggesting that, you know,

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that this system in general is more active in PTSD.

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Now, it wasn't active, it wasn't higher in every single

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person with PTSD compared to the controls.

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So, you know, that also is consistent with the idea

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that maybe this isn't a problem for every person with ptsd

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SD, but if you take them

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as a group on average, they're higher.

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Um, and so, you know, we thought that what type of person

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with PTSD would be most likely

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to have elevated neuro melanin signal in the locus Aurelius,

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we thought it would be those people

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that have these hyper arousal symptoms.

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So we looked within that group of people with PTSD,

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and we found that the people

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that had a higher locus really signal were indeed the ones

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who had more hyper arousal symptoms.

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The convenient thing in our case is that if you, you know,

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look up on Wikipedia, the norepinephrine system

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or sometimes called the noradrenergic system in, in Britain,

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the first thing it'll tell you about the functions of

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that system, it'll will be, it regulates level of arousal.

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So when you're sleeping, the system is totally quiet,

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and if you are, if someone's chasing you with a knife,

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then it's gonna be going in overdrive.

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So most of the time we're somewhere in

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between on those levels of, of arousal.

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Um, so, so you know, there's a,

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there's a strong theoretical reason why this system would be

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relevant for this behavior and then in how that leads

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to an MRI as something we could measure with MRI.

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Um, the idea is if these neurons are firing more often, then

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this neuro melanin pigment is,

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is depositing more readily into the,

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the cell bodies in the locus Aurelius

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and the more neuro melanin present, you know, at some point,

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if there's enough of a difference, it'll,

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the MRI is sensitive enough to see it

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and we can tell that, you know,

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that person has an elevated signal.

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Yeah. So I think, you know, there's two branches

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of conclusions, one that's more relevant to the methods.

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Um, but I'll start with the, the broader conclusions

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that are relevant for people with PTSD.

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Um, and,

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and that is highlighting the relevance

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of the norepinephrine system to PTSD symptoms.

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And there's certainly plenty of research

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that's been done on that in the past.

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Um, you know,

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using different methods like even animal models of of PTSD,

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but also human studies.

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So, you know, there is quite a bit of research,

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but at the same time, if you read a review about PTSD,

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it may not even be mentioned.

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Like there's a lot of theories

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and a lot of other I models of PTSD, TSD out there as well.

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So I think, you know, it's, it's lobbying

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for more attention on the role of the norepinephrine system,

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especially in these particular, behaviors in P ts D

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and in turn that matters

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because chemicals can, can give a very direct link

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to drug treatments, right?

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So studying brain chemicals is different than

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studying, you know, brain activity.

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It may be harder to know

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how you would change brain activity,

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but if you see that there's a chemical imbalance,

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you can give a drug that can rank,

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remedy that imbalance.

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And indeed there is a drug that's been used in PTSD,

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with mixed results called prazocin,

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which blocks the norepinephrine system activity.

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Um, and I think, you know, there could be more work on

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that drug or maybe similar types of drugs.

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And maybe part of the reason it's had this mixed evidence,

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some studies showing that razin works, especially

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for nightmares in PTSD.

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Um, there's a whole other story about nightmares in the

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norepinephrine system, but, some studies show

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that it didn't work, and it could be that if you were

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to prescreen people

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and see who actually has an imbalance in the norepinephrine

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system using a method like this imaging scan,

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you might be more likely to get a good response to the drug.

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So it's kind of moving towards this idea of individualized

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medicine, by, you know, finding a biomarker

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that could predict who would be likely

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to respond to a treatment.

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You know, that would be something with collaborators in,

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you know, due to clinical clinical studies,

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we could follow up on that.

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But I would say, just as an aside that this method

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that we're talking about, the neuro melanin, MRI,

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we've had a bit of a, an experience about how, you know,

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we just talk about bringing ideas from science

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to the clinic, but in our case, we actually did partner

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with an industry, partner.

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And now the, the neuro melanin, MRI has been FDA cleared

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to be used, clinically.

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So, you know, to be used for the indication of PTSD,

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that would be, you know, more steps down the road.

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But at least in principle, the method can be used now.

Quick Answers

Advancing Treatments for PTSD Challenges

00:00:00 - There's different angles to it. I mean, I think the most important reason to do a study like this, ultimately is to, you know, kind try to find better treatments for PTSD. So, you know, PTSD is difficult to treat, especially, military PTSD. and the best treatments, are psychotherapy, which, you know, work well, but they take time and they don't work for everybody and they're, you know, costly. There's a lot of resources to, to make them happen. And medications for PTSD are, you know, some, some work
00:00:36 - And, and there's not a lot of dedicated medications for PTSD. Often they're u re, you know, using antidepressants basically. drugs like that. So ultimately, you know, most of the psychiatric medications we use are acting on neurotransmitter receptors in the brain. So maybe, you know, by understanding better what neurotransmitter systems are, are dysregulated in PTSD, we could be in a better position
00:01:06 - A lot of these, you know, neurotransmitter, systems that are targeted by psychiatric drugs are called neuro neuromodulators, so they kind of amp up or dampen down brain activity. so they can kind of, you know, affect people's level of arousal or mood or, or things like that. So, yeah, so that's an easy way to use a drug to manipulate the brain. That kind of leads into where I was going.
00:01:39 - one reason a condition like PTSD is hard to treat is because, most people have a bit of a different picture. so it's a pretty heterogeneous condition, and there's a different set of symptoms. you don't need all the symptoms to have to have the disorder. and different people have more prominent deficits in different areas. So, so, yeah, you couldn't maybe have one drug that would be like a magic bullet
00:02:08 - for PTSD, for instance. but you could think about certain types of symptoms that are common in PTSD that are easier to link to, you know, brain functions that you could treat. Like the, the system that we were talking about, or the symptom that we're concerned with in the study is, is hyper arousal, which is a pretty easy, symptom to relate to. I think most people have had some kind of low level experience of, of hyper arousal. so you can think of it as,
00:02:43 - after a threat has passed. So people have trouble relaxing and calming down, even if, you know, they're in a safe environment, cut into people's quality of life and make it not, yeah, that's a lot of negative consequences. So that's, you know, where I come at it as a researcher, you know, it's hard sometimes to, to think about the big picture, and usually you start out with the methods

Advancements in Neuro Melanin Sensitive MRI

00:03:12 - and finding relevant applications for them. So a lot of my recent work has been about developing a certain neuroimaging method and making it better, and at the same time finding new applications for it where it could be most useful. So that's definitely, you know, a big part of what this study was about is, is working on these methods. So there's, neuroimaging method that has been around for a while, but, you know, we've done a lot of work to, to improve it and to show how it can be used in different,
00:03:46 - So this method is called neuro melanin sensitive, MRI, so it's a very specific method because it only can look at two brain regions, so it doesn't even scan the full brain, but those two brain regions are extremely important for many, neuropsychiatric conditions. So there's the locus aurelius, which is the, you know, subject of this study, and that's kind of like the heart of the norepinephrine or the noradrenergic, same thing,
00:04:17 - And then there's also the substantial nigra, which is the heart of the dopamine, neurotransmitter system. And a lot of the work we've done has also been in the substantial nigra. But, so, so these two brain regions are, are important for so many brain functions and so many different, psychiatric conditions and also neurological conditions. So even though we only looking at two very specific regions, they are important for almost all of psychiatry one way or another.
00:04:52 - we're looking at the locus aurelius and, in general, these, this imaging method is able, so the subtlety to it is, it's, it's sensitive to this, this brain chemical called neuro melanin, which is only found in those two regions of the brain, the locus aurelius and the sub substain nigra. And the idea is you're born without any neuro melanin,
00:05:24 - and just builds up inside the neuron cell bodies in those two brain regions. And, it's actually visible to the human eye. So that's why those regions, have the names. They do that substantial nigra is black because it has this black pigment neuro melanin in it. And the locus aurelius is bluish aurelius because of the same pigment. so the idea is that it's a marker of if the cells are there or not.
00:05:54 - The only way to get rid of that pigment is if the cell dies. It just builds up gradually and it can't be destroyed unless the cell dies. So the, this method, this imaging method started out as a marker of neurodegeneration of those structures. So it was used a lot in Parkinson's disease to see the death of the dopamine neurons and in Alzheimer's disease to see the death of the locus s neuros. And we did work in Alzheimer's also. So that's where this, you know, the, the

Neuroimaging Insights into PTSD and Norepinephrine

00:06:28 - but then bringing it from research and neurodegeneration to research and psychiatry where it, these cells aren't dying, or even healthy people. That's kind of the leap that our group and our collaborators have made a big push on. So, so we're saying that even when the cells aren't dying, the amount of neuro mein and neuro mein, MRI signal
00:06:57 - So, you know, there's this idea of an imbalance, a chemical imbalance in psychiatry that psychiatrists will tell their patients they have a chemical imbalance and you know, it's an oversimplification, but a method like this can, can tap into that. We can see if there's excess signal in this locus aerius, it's perhaps due to this chemical imbalance in the norepinephrine system. It may not be just PTSD, but if you know more directly to this hyper arousal idea,
00:07:28 - that hyper arousal could be due to excess activity of this locus, aurelius norepinephrine system. So, so yeah, that's, that, that excess activity would mean this neurotransmitters being released too much, it's cycling around and every time it cycles it's released and then it's taken back up into the cell. It can lead to more of this norm neuro mein formation. And over the span of months and years that we could maybe detect that with, with this MRI sequence it there,
00:07:59 - So we had a group of military veterans with PTSD who had served in Afghanistan in the Canadian armed forces. so we had I think, 34 of them. And we also had a group of healthy controls who didn't have any psychiatric history. We had 32 of them, and everybody was, was scanned in the MRI to get this neuro melanin sensitive,
00:08:30 - And we found that as a whole, the people with PTSD had higher signal in the locus aurelius than the controls. So it was suggesting that, you know, that this system in general is more active in PTSD. Now, it wasn't active, it wasn't higher in every single person with PTSD compared to the controls. So, you know, that also is consistent with the idea that maybe this isn't a problem for every person with ptsd SD, but if you take them as a group on average, they're higher.
00:09:03 - with PTSD would be most likely to have elevated neuro melanin signal in the locus Aurelius, we thought it would be those people that have these hyper arousal symptoms. So we looked within that group of people with PTSD, and we found that the people that had a higher locus really signal were indeed the ones who had more hyper arousal symptoms. The convenient thing in our case is that if you, you know, look up on Wikipedia, the norepinephrine system or sometimes called the noradrenergic system in, in Britain,

Understanding Arousal in PTSD Treatment

00:09:34 - that system, it'll will be, it regulates level of arousal. So when you're sleeping, the system is totally quiet, and if you are, if someone's chasing you with a knife, then it's gonna be going in overdrive. So most of the time we're somewhere in between on those levels of, of arousal. so, so you know, there's a, there's a strong theoretical reason why this system would be relevant for this behavior and then in how that leads
00:10:04 - the idea is if these neurons are firing more often, then this neuro melanin pigment is, is depositing more readily into the, the cell bodies in the locus Aurelius and the more neuro melanin present, you know, at some point, if there's enough of a difference, it'll, the MRI is sensitive enough to see it and we can tell that, you know, that person has an elevated signal. Yeah. So I think, you know, there's two branches of conclusions, one that's more relevant to the methods.
00:10:36 - that are relevant for people with PTSD. and, and that is highlighting the relevance of the norepinephrine system to PTSD symptoms. And there's certainly plenty of research that's been done on that in the past. you know, using different methods like even animal models of of PTSD, but also human studies. So, you know, there is quite a bit of research, but at the same time, if you read a review about PTSD,
00:11:05 - Like there's a lot of theories and a lot of other I models of PTSD, TSD out there as well. So I think, you know, it's, it's lobbying for more attention on the role of the norepinephrine system, especially in these particular, behaviors in P ts D and in turn that matters because chemicals can, can give a very direct link to drug treatments, right? So studying brain chemicals is different than studying, you know, brain activity. It may be harder to know
00:11:36 - but if you see that there's a chemical imbalance, you can give a drug that can rank, remedy that imbalance. And indeed there is a drug that's been used in PTSD, with mixed results called prazocin, which blocks the norepinephrine system activity. and I think, you know, there could be more work on that drug or maybe similar types of drugs. And maybe part of the reason it's had this mixed evidence, some studies showing that razin works, especially
00:12:07 - there's a whole other story about nightmares in the norepinephrine system, but, some studies show that it didn't work, and it could be that if you were to prescreen people and see who actually has an imbalance in the norepinephrine system using a method like this imaging scan, you might be more likely to get a good response to the drug. So it's kind of moving towards this idea of individualized medicine, by, you know, finding a biomarker that could predict who would be likely

Neuro Melanin MRI Receives FDA Clearance

00:12:37 - You know, that would be something with collaborators in, you know, due to clinical clinical studies, we could follow up on that. But I would say, just as an aside that this method that we're talking about, the neuro melanin, MRI, we've had a bit of a, an experience about how, you know, we just talk about bringing ideas from science to the clinic, but in our case, we actually did partner with an industry, partner. And now the, the neuro melanin, MRI has been FDA cleared to be used, clinically.
00:13:13 - that would be, you know, more steps down the road. But at least in principle, the method can be used now.

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