Therapeutic lesions for addiction related neuroplasticity/hyperdopaminergic states

[Cotcha Yankinov]

I was wondering if anybody knew of any attempts to lesion (or some other surgical intervention) possible hyper-active dopaminergic brain areas in an attempt to reverse addiction related neuroplasticity/behavior.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3037848/ - Study shows that long abstinent MDMA users have increased dopamine. I was wondering if these increases in dopamine might be concentrated in an area(s) so that a well placed lesion might disrupt some of the activity and "turn the volume down".

 

[PINKoPANaTHER]

Without doing serious research on this specific topic I'd think you'd be playing with fire trying to lesion areas involved with addiction which typically are part of the survival mechanisms in your brain (risk/reward) and/or higher reasoning. The side effects of such a procedure could end you, as you know you. Maybe an implantable dopamine sink would be better (a nanomaterial that reacts specifically and with little affinity to dopamine, converating to a benign byproduct) just enough to lower dopamine levels at a local level while leaving other systems intact. I'd be interested in seeing the results of a lab model of this procedure though...

 

[PINKoPANaTHER]

Oh, and that study doesn't really have any robust conclusions by which to form hypotheses from, and it only looked at nigrostriatal neurons limiting any generalizations.

 

[palmanita]

Is it then even sure that increased dopamine has to be bad?

Does more dopaminergic activity mean more compulsive activity, more reward-seeking behaviour, and/or getting stronger pleasure when achieved something, or is it even unknown what this actually means?

If things were so simple, we could give the ADHD people some strong rolls and they'd be better (with more dopamine... know it doesn't work like this) ...

Maybe it's more relevant how these dopaminergic pathways are encoded, when they are drug-related, they are bad, the same for e.g. doing sports, would be good, or? Any possibility to use the already-there active dopamine reward circuits and re-wire them to something healthier?

 

[Cotcha Yankinov]

A dopamine sink is a good idea. But I guess this all assumes that excess dopamine is the issue. Maybe glutamate is really involved as well...

My idea for the future would be somehow identify individual "addiction" related synapses (maybe seeing which synapses light up with a drug cue) and then lesion those specifically somehow.

I wonder if maybe in the future will we modify projections to turn the volume up or down. Personally I have audio hallucinations and wonder if there might be some abnormal connection between my audio cortex and another area, resulting in too much activity. I would be very curious if with the right imaging an abnormally strong projection could be found and then with some surgical intervention we might reduce the dopamine and hopefully diminish the hallucinations.

 

[serotonin2A]

Experimental surgeries were conducted in the 1980s to treat cocaine addiction by making nucleus accumbens lesions. It didn't work. There aren't synapses whose sole purpose is to mediate "addiction". Addictive drugs work through the same circuitry that the brain uses to control movement and predict natural rewards. This type of treatment is akin to the use of a prefrontal lobotomy to treat schizophrenia.

 

[MeDieViL]

Is it then even sure that increased dopamine has to be bad?

Does more dopaminergic activity mean more compulsive activity, more reward-seeking behaviour, and/or getting stronger pleasure when achieved something, or is it even unknown what this actually means?

If things were so simple, we could give the ADHD people some strong rolls and they'd be better (with more dopamine... know it doesn't work like this) ...

Maybe it's more relevant how these dopaminergic pathways are encoded, when they are drug-related, they are bad, the same for e.g. doing sports, would be good, or? Any possibility to use the already-there active dopamine reward circuits and re-wire them to something healthier?

it depends on the da subtype, addiction shifts balance to D2 and D3, more implicated in impulsive, manic and addictive behavor, baclofen is one of the agents that kinda shifts balance in activation of brain areas related to decission making.

Id rather go for the opposite and turn the volume up, take something like baclofen to behave myself and then turn into party mode haha

in all serieusness, for example, more academic ppl are alot more serieus less outgoing then less intelligent popular people, this in a way related to da and acetylcholine inhibitjng eachother.

Why would you want to cut the brain open, id just pop a pill, save the dollars to give ya wife a boobjob

 

[serotonin2A]

What makes you think these changes have anything to do with addiction? The changes were observed in the putamen, which is primarily involved in movement.

 

[MeDieViL]

What changes you talk about? i ment what happeneds during drug addiction, particularry stim addiction, focus sifts from d1/4 to d2/3 in the past stims made me motivated and productive, now they make me want to party, wve seen those changes in rodents

 

[Cotcha Yankinov]

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3037848/table/tbl4/ - is this table saying that the only increase in dopamine was observed in the putamen? It seems they also did some office test type stuff and couldn't find anything significant except "Ex-ecstasy user group; ¹⁸F-dopa uptake in the putamen correlated negatively with the total number of false alarms on the Go/No-Go task (r=−0.815, p=0.001) and correlated positively with reaction time to hits (r=0.761, p=0.003)." Does this mean ex-ecstasy users have less impulse control? I think that's been observed before in some fMRI study...

Also, is the putamen the part of the brain where movement starts to become mediated by acetylcholine? Or do you think otherwise that increased dopamine/activity of the movement regions might result in more acetylcholine transmission in the periphery? There are many reports of fasciculations after MDMA and I am paranoid about excess acetylcholine in the periphery for other reasons.

Addictive drugs work through the same circuitry that the brain uses to control movement and predict natural rewards

Do you think there will be spill-over from what is going on in a movement center like the putamen to other regions that the putamen receives/projects to?

Also regarding the putamen from wiki (It seems it might play a role in reinforcement learning, which I assume is vaguely similar to addiction?) Along with various types of movement, the putamen also affects reinforcement learning and implicit learning.^[12]
Reinforcement learning is interacting with the environment and catering actions to maximize the outcome. Implicit learning is a passive process where people are exposed to information and acquire knowledge through exposure. Although the exact mechanisms are not known, it is clear that dopamine and tonically active neurons play a key role here. Tonically active neurons are cholinergic interneurons that fire during the entire duration of the stimulus and fire at about 0.5-3 impulses per second. Phasic neurons are the opposite and only fire an action potential when movement occurs.^[13]

 

[serotonin2A]

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3037848/table/tbl4/ - is this table saying that the only increase in dopamine was observed in the putamen?

Yes, it was only observed in the putamen. And although it is significantly different, it is a very small change. Just because something is significant doesn't mean it has any implications.

It seems they also did some office test type stuff and couldn't find anything significant except "Ex-ecstasy user group; ¹⁸F-dopa uptake in the putamen correlated negatively with the total number of false alarms on the Go/No-Go task (r=−0.815, p=0.001) and correlated positively with reaction time to hits (r=0.761, p=0.003)." Does this mean ex-ecstasy users have less impulse control? I think that's been observed before in some fMRI study...

It sounds like they have worse impulse control. But there is no reason to think that is linked to the dopaminergic effects in the putamen. Correlation does not equal causation.

Also, is the putamen the part of the brain where movement starts to become mediated by acetylcholine? Or do you think otherwise that increased dopamine/activity of the movement regions might result in more acetylcholine transmission in the periphery?

That happens at the neuromuscular junction

and I am paranoid about excess acetylcholine in the periphery for other reasons.

If you are worried about MDMA induced damage then I would recommend not reading studies on pubmed. You are just going to freak yourself out. And you won't find any answers because the answers don't exist.

Do you think there will be spill-over from what is going on in a movement center like the putamen to other regions that the putamen receives/projects to?

I wouldn't call it a "movement center". It is part of the circuit that generate habitual stimulus-response pairings. It is part of a network; you can't view it on its own isolated from the circuitry.

Also regarding the putamen from wiki (It seems it might play a role in reinforcement learning, which I assume is vaguely similar to addiction?)

It plays a role in the ability of reinforcement to cause some action to become habitual. For example, how smokers light up without realizing what they are doing.

 

[MeDieViL]

It sounds like they have worse impulse control. But there is no reason to think that is linked to the dopaminergic effects in the putamen. Correlation does not equal causation

Does this refer to poly drug users or people that only used XTC?

If you are worried about MDMA induced damage then I would recommend not reading studies on pubmed. You are just going to freak yourself out. And you won't find any answers because the answers don't exist.

Whys that? that study showing small minor structural changes has been contradicted.

There are many reports of fasciculations after MDMA and I am paranoid about excess acetylcholine in the periphery for other reasons.

your paranoia probably has bad more effects on your behavor then your mdma use.

 

[Cotcha Yankinov]

I agree, I wouldn't be surprised if worse impulse control is what led to the MDMA use in the first place, and you might be able to reconcile that even if you didn't find the same impulse control abnormality in non-MDMA polydrug users because maybe people with poor impulse control tend to favor MDMA over other drugs.

"If you are worried about MDMA induced damage then I would recommend not reading studies on pubmed. You are just going to freak yourself out." - I definitely agree that being a hypochondriac is not healthy and could perpetuate whatever temporary negative effects MDMA has and believe it or not I have strived to avoid this sort of thing.

"And you won't find any answers because the answers don't exist." - I respectfully but strongly disagree with this (Unless you were referring to specifically MDMA affecting acetylcholine, but even then I think I found some interesting things regarding MDMA, acetylcholine and pain). If you were referring to MDMA's negative effect's in general, I would actually compare this to saying "We don't understand how (insert mysterious phenomenon here) works, so it must be God, so don't bother trying to find out". Can you understand how I make that comparison? It is extremely well established anecdotally that even with tested MDMA people can have horrible issues, and it seems disproportionate/different to traditional psychedelics. One psychologist told someone who was having long term issues after MDMA something to the effect of "All drugs only stay in your system for 3 weeks so whatever effects you're experiencing now are entirely psychological" which of course is exactly what psychologist would say, but anyways I really disagree with that sentiment. I think there is a biological basis to some MDMA user's issues and one day it will be elucidated.

Regarding the putamen and how a change in dopamine there (I understand it might be a statistically negligible change but lets theorycraft for a moment) might affect physiology - If the putamen "plays a role in the ability of reinforcement to cause some action to become habitual" then it sounds to me like it could be a structure that engrains a behavior that is somewhat persistent. The name of the game here is essentially how does taking a drug that only stays in your system for a short period of time alter one's self, so don't you agree that (assuming the change in dopamine is not completely negligible) the putamen is possibly distantly important in adverse effects after MDMA?

In my particular case, I was addicted to playing guitar on ecstasy, I would play for 10 hours straight, I did this many many many times. Is it not possible that I could have music stuck in my head and even in my dreams so severely because the part of my brain that is partially responsible for habituation is abnormally connected with audio? (The parts of my brain timing my hand movements with the music MUST be related to audio areas). My old guitar teacher and many others I've talked to have talked about how during many performances its all about turning off your mind and just letting your muscle memory (One might say habituated movement) do it's thing. I even understand that, compared to movement of other body parts, an abnormal amount of the brain is used for hand movements.I realize we might have a deficit of knowledge regarding the neuroscience of music and audio, but I'm curious if you have any ideas on what's going on with people's ability to play music in their heads voluntarily. I can play hundreds of songs front to back, every little detail, voluntarily in my head, and I started doing this a lot when my hands stopped working and I couldn't play, but now for 5 years music is playing involuntarily. In fact, no matter how hard I try, I can't get it to stop (though I won't stop trying meditation). You might even say its habitual.

I know I seem like I'm grasping, but it seems to me that addicting drugs and the things I did on them could be contributing to my persistent issues.

 

[MeDieViL]

It is extremely well established anecdotally that even with tested MDMA people can have horrible issues, and it seems disproportionate/different to traditional psychedelics. One psychologist told someone who was having long term issues after MDMA something to the effect of "All drugs only stay in your system for 3 weeks so whatever effects you're experiencing now are entirely psychological"

There is no evidence that singly mdma use causes long term issues, those that suffered from issues after mdma use all seem to have triggered an underlying disorder, such as predromal shizophrenia looking at their symptions, i triggered predromal but never fully developped it with my testosterone cycle, after that, when i took mdma i developped some sort of forum anxiety, i felt to anxious to log into fora, after that i took mdma again and it got worse, but that was after testosterone triggered something in me whic i didnt know what it was at the time, and my response to drugs dramatically changed, also after that my brain was much more sensitive to damage caused by other substances

It seens that consistently mdma triggers the following long term issues:

- social withdrawal
- depression
- anhedonia
- ocd
- cognitive adhd like difficouldtys
- Diffcicouldtys with logical thinking

Over the longer run more positive symptions like delusions

Allmoest never it seems to induce just a single issue, but a combination of differened negative symption which is a sign that it triggered an underlying disorder, mdma can be quite stressfull for the brain so for those that have shizophrenia riskgene it could be a potential trigger.

 

[MeDieViL]

In my particular case, I was addicted to playing guitar on ecstasy, I would play for 10 hours straight, I did this many many many times. Is it not possible that I could have music stuck in my head and even in my dreams so severely because the part of my brain that is partially responsible for habituation is abnormally connected with audio? (The parts of my brain timing my hand movements with the music MUST be related to audio areas). My old guitar teacher and many others I've talked to have talked about how during many performances its all about turning off your mind and just letting your muscle memory (One might say habituated movement) do it's thing. I even understand that, compared to movement of other body parts, an abnormal amount of the brain is used for hand movements.I realize we might have a deficit of knowledge regarding the neuroscience of music and audio, but I'm curious if you have any ideas on what's going on with people's ability to play music in their heads voluntarily. I can play hundreds of songs front to back, every little detail, voluntarily in my head, and I started doing this a lot when my hands stopped working and I couldn't play, but now for 5 years music isIn my particular case, I was addicted to playing guitar on ecstasy, I would play for 10 hours straight, I did this many many many times. Is it not possible that I could have music stuck in my head and even in my dreams so severely because the part of my brain that is partially responsible for habituation is abnormally connected with audio? (The parts of my brain timing my hand movements with the music MUST be related to audio areas). My old guitar teacher and many others I've talked to have talked about how during many performances its all about turning off your mind and just letting your muscle memory (One might say habituated movement) do it's thing. I even understand that, compared to movement of other body parts, an abnormal amount of the brain is used for hand movements.I realize we might have a deficit of knowledge regarding the neuroscience of music and audio, but I'm curious if you have any ideas on what's going on with people's ability to play music in their heads voluntarily. I can play hundreds of songs front to back, every little detail, voluntarily in my head, and I started doing this a lot when my hands stopped working and I couldn't play, but now for 5 years music is playing involuntarily. In fact, no matter how hard I try, I can't get it to stop (though I won't stop trying meditation). You might even say its habitual. playing involuntarily. In fact, no matter how hard I try, I can't get it to stop (though I won't stop trying meditation). You might even say its habitual.

Im not sure i understand correcylu, do you mean you constantly hear music playing in your head and you cant make it stop? lkinda like how i constantly keep on moving my foot around in a anoyinf way? maybe a weird comparison,

 

[serotonin2A]

"And you won't find any answers because the answers don't exist[/I]." - I respectfully but strongly disagree with this (Unless you were referring to specifically MDMA affecting acetylcholine, but even then I think I found some interesting things regarding MDMA, acetylcholine and pain). If you were referring to MDMA's negative effect's in general, I would actually compare this to saying "We don't understand how (insert mysterious phenomenon here) works, so it must be God, so don't bother trying to find out". Can you understand how I make that comparison?

Hi CJ, you missed the point I was making in that sentence -- I was still talking about PubMed. The sentence was meant to read "And you won't find any answers [on Pubmed] because the answers don't exist [on Pubmed]." Of course, there is undoubtedly an explaination for what you are experiencing, but trying to find that explaination in the literature is probably an exercise in futility. I just don't think anyone really knows enough about what MDMA does to the human brain.

EDIT: Is it true that you have musical hallucinations? I am aware of one treatment developed by RK Siegel. He had a patient who had chronic auditory hallucinations due to excessive DMT use. I think the symptoms resolved when he instructed the patient to put an ear plug in one ear. I'll have to look up why it worked. But there should be some kind of therapy available to help your brain tune out the hallucinations.

That isn't something related to the putamen. It is a cortical gating problem, or possibly a cortical mapping problem (ie, sort of like phantom limb pain). Have you looked into treatments for tinitus? Maybe an anticonvulant like valproic acid?

 

[MeDieViL]

, but trying to find that explaination in the literature is probably an exercise in futility.

This is where i come, i dont have any sort of a degree and only a criminal record, but this is where my talent lies, figuring stuff like this out, amongst other things, i hope to bring my knowledge into a team to start a future business or anything like that, as organisation wise im a fucking disaster.

Either way its related to both shizophrenia and epilepsy which are in many cases connected, heres a quick article but ill further study the neurobiology anout it and have a further chat with you.
https://www.google.co.uk/search?q=a...firefox-b&gfe_rd=cr&ei=3EhJV-vBI_HR8geO_6CgCA

 

[Cotcha Yankinov]

I'm very sorry for misinterpreting that... I definitely understand what you're saying and will make sure not to obsess too much.

I absolutely have musical hallucinations, and am curious about the physiology... It was to the point that in the middle of the night I used to get up and check to make sure I didn't leave the stereo on, before I got used to it. I also have music in my dreams. I used to be an AVID musician but have tried to quit music because of these issues, but interestingly the hallucinations get better if I listen to music and get worse if I abstain, you might even say its music withdrawal, as stupid as that sounds..

Do you think people with musical hallucinations (as opposed to just a song stuck in the head, which I have both, more frequently just a song stuck in the head) might show "top down activation of sensory cortices" as if they were actually hearing a song? And then a song stuck in the head, as well as voluntarily playing a song in the head, might show up more as a working memory sort of thing (even though it's coming from long term memory I guess?)?

I would really appreciate it if you take a gander at my thread regarding mirror neurons and audio hallucinations, there appear to be mirror neurons that are specific to audio - I'm curious what you think of my theories and the data about internally generated stimuli activating mirror neurons http://www.bluelight.org/vb/threads...-top-down-activation?highlight=Mirror+neurons

My original theory (predicating off of serotonin axon injury) was that maybe an inhibitory projection to the audio cortex was injured resulting in increased excitability (increased cortical excitability was observed in a human fMRI study, though I'm not sure about the magnitude of the increase).

That's very interesting about RK Siegel... I have to admit I was using mushrooms while playing guitar around the time that I started having these issues and do remember specifically getting mild HPPD from mushrooms, and was combining mushrooms and ecstasy, so mushrooms certainly could have contributed as well. I did a lot of music listening on mushrooms... I have tinnitus as well (it was actually somewhat severe when I was younger, this could have been partially due to jaw issues however) but I have not looked into treatments for it yet. Depakote at 1000mg did help but I couldn't tell if it was because I was sleeping better or if the improvement in audio symptoms were separate from sleep debt.

NMDA antagonists help as well, and others have told me it helps them shut off their "voice in the head", my voice in the head is also extremely over active, and honestly many times is more a musical vocals type voice though it may not be speaking words. I get vocal notes stuck in my head, I wouldn't call them true hallucinations because they can be turned off with meditative type techniques though it is difficult.

Essentially I feel like the vocals (usually a powerful distorted note like in rock/metal) are coming from the same "area" or localization as the voice in my head that is heard when I read something, like has been occurring since as far back as I can remember, (whereas the true song hallucinations can be somewhat more external), so it's kind of blurring the lines between my normal voice in the head and music stuck in my head. It's weird to think that for maybe 30 minutes to 60 minutes or more on bad days I'm going around with a vocal rock note blaring in my head lol. I used to enjoy mimicking the vocal styles of different rock vocalists in my head (and actually singing different styles) but you might say it's gotten a little old, and for the past year I've been hearing (and performing) these vocals in my dreams. If I ever get Parkinson's my bed partner is going to murder me.

 

[Cotcha Yankinov]

There was a study done showing that distorted vocals can activate the amygdala and "engage subcortical structures to critically appraise danger" http://www.ncbi.nlm.nih.gov/pubmed/26190070 - from an interview with one of the scientists "Roughness refers to fast sound changes in loudness. Normal speech for instance only has slow differences in loudness—between 4 and 5 Hz—which is not rough and basically corresponds to the syllabic rate. Screams, on the other hand, modulate very fast—between 30 and 150 Hz—which is rough.” - I wonder if this effect is preserved with internally generated distorted vocals/screams.

http://www.ncbi.nlm.nih.gov/pubmed/19228981 - "Single-unit studies have reported neurons in auditory cortex sensitive to specific combinations of frequencies (e.g., harmonics)" - I wonder what the implications of this are regarding pitched screams that were my personal favorite (If they can activate both the amygdala and such like the other study suggested and they activate these harmonic sensitive neurons, maybe an abnormal connection between the two is formed).

I also understand that trained musicians have larger corpus callosums, though I wouldn't expect this to be pathological, but maybe I'm wrong.

 

[MeDieViL]

What mental issues do you suffer from, thats pretty much the best starting point.