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Old 06-22-11, 02:39 PM
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The holy grail for ADHD - BDNF and neurogenesis

I was reading scientific studies yesterday and came across one study that triggered my thought process on how everything that seems so unrelated or irrelevant but effective an reducing ADHD all ties together. Here is the study I was reading and it's probably too deep for many to grasp, but it's not about the specific outcome of the study, but one of the points made here:

Quote:
Stimulation of retinoic acid receptors (RARs) protects midbrain dopaminergic neurons, presumably via up-regulation of brain-derived neurotrophic factor (BDNF) expression. The present study was focused on unexplored signaling mechanisms linking RAR stimulation to BDNF expression. Rat midbrain slice cultures treated with an RAR agonist Am80 showed increased tissue levels of BDNF mRNA and protein as compared to cultures without treatment. Am80-induced increase in BDNF expression was observed in dopaminergic neurons, which was blocked by inhibition of extracellular signal-regulated kinase (ERK) activation. We also found that Am80 increased neuronal nitric oxide synthase expression in dopaminergic neurons even during ERK inhibition, and this increase was accompanied by 8-nitro-cyclic GMP formation. Notably, the effect of Am80 on BDNF expression was attenuated by inhibitors of nitric oxide synthase, soluble guanylyl cyclase and cyclic GMP-dependent protein kinase (PKG). Am80-induced ERK phosphorylation in dopaminergic neurons was also attenuated by inhibition of soluble guanylyl cyclase and PKG. Moreover, 8-Br-cyclic GMP induced ERK phosphorylation and BDNF expression in dopaminergic neurons. These results suggest that, by recruiting cyclic GMP and PKG, neuronal nitric oxide synthase-derived nitric oxide plays a novel and essential role in RAR signaling leading to ERK-dependent BDNF up-regulation in midbrain dopaminergic neurons.
To understand this you have to know what BDNF is and neurogenesis:

Quote:
BDNF acts on certain neurons of the central nervous system and the peripheral nervous system, helping to support the survival of existing neurons, and encourage the growth and differentiation of new neurons and synapses. In the brain, it is active in the hippocampus, cortex, and basal forebrain—areas vital to learning, memory, and higher thinking. BDNF itself is important for long-term memory.
Quote:
Although the vast majority of neurons in the mammalian brain are formed prenatally, parts of the adult brain retain the ability to grow new neurons from neural stem cells in a process known as neurogenesis. Neurotrophins are chemicals that help to stimulate and control neurogenesis, BDNF being one of the most active.
Recently BDNF has been implicated for many disorders like depression and OCD. With depression, BDNF production is slowed down and eventually halted corresponding with severity. SSRIs are effective but don't work immediately, because although seritonin is affected and adjusted, it takes one week for them to start producing BDNF mRNA and protein. Also, different paths to increase BDNF expression without affecting seritonin directly also alleviates depression.

BDNF is the neurotrophin responsible for helping create new dopaminergic neurons and protecting the existing ones from apoptosis (cell death). So up-regulation of BDNF expression alleviates ADHD symptoms. There are specific things that generate BDNF activity, and all of the activities, supplements, meds, and training known to help ADHD affect this.

Omega 3s normalize and regulate BDNF http://www.ncbi.nlm.nih.gov/pubmed/18620024
Exercise up-regulates BDNF circulation and concentration http://ep.physoc.org/content/94/10/1062.full.pdf
Amphetamines increase BDNF expression http://www.ncbi.nlm.nih.gov/pubmed/21570990
Meditation reduces stress and increases BDNF expression http://www.ncbi.nlm.nih.gov/pubmed/17905931
Short term sleep deprivation reduces BDNF http://www.sciencedirect.com/science...06899300027086
BDNF shows regenerative effect in Parkinson's http://www.ncbi.nlm.nih.gov/pubmed/21236244
Enriched Environment increases BDNF activity http://www.ncbi.nlm.nih.gov/pubmed/21236277
BDNF used for short term and long term memory and inhibitory learning http://www.ncbi.nlm.nih.gov/pubmed/12201640
There's also studies linking BDNF to food intake, such as toxins and heavy metals and lard lowering BDNF, as well as soy protein increasing expression.
I've read before about working memory training and learning how to play musical instruments increase BDNF.
I couldn't find anything on EEG biofeedback's effect though.

If you look up information on methylphenidate and amphetamine and BDNF the results are not encouraging, both showing reducing BDNF over time, coupled with short and long term memory loss. This connection makes sense due to the link between Alzheimer's and BDNF, and elevated BDNF levels being able to prevent cell death in methamphetamine use.

When looking up BDNF info on ADHD specifically the area is not very studied yet, but you will find studies on BDNF gene polymorphisms which are different but connected, showing certain polymorphism types are more at risk for ADHD, and one study that says BDNF plasma is elevated in ADHD people (this is the same as Alzheimer's), although it does not get into count of BDNF protein, mRNA, expression and circulation, all of which are lower in Alzheimer's (these are the things to look for - anything increasing these show improvement in symptoms).

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Old 06-23-11, 08:57 AM
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Re: The holy grail for ADHD - BDNF and neurogenesis

Quote:
Originally Posted by jlspartz View Post
I was reading scientific studies yesterday and came across one study that triggered my thought process on how everything that seems so unrelated or irrelevant but effective an reducing ADHD all ties together. Here is the study I was reading and it's probably too deep for many to grasp, but it's not about the specific outcome of the study, but one of the points made here:



To understand this you have to know what BDNF is and neurogenesis:




Recently BDNF has been implicated for many disorders like depression and OCD. With depression, BDNF production is slowed down and eventually halted corresponding with severity. SSRIs are effective but don't work immediately, because although seritonin is affected and adjusted, it takes one week for them to start producing BDNF mRNA and protein. Also, different paths to increase BDNF expression without affecting seritonin directly also alleviates depression.

BDNF is the neurotrophin responsible for helping create new dopaminergic neurons and protecting the existing ones from apoptosis (cell death). So up-regulation of BDNF expression alleviates ADHD symptoms. There are specific things that generate BDNF activity, and all of the activities, supplements, meds, and training known to help ADHD affect this.

Omega 3s normalize and regulate BDNF http://www.ncbi.nlm.nih.gov/pubmed/18620024
Exercise up-regulates BDNF circulation and concentration http://ep.physoc.org/content/94/10/1062.full.pdf
Amphetamines increase BDNF expression http://www.ncbi.nlm.nih.gov/pubmed/21570990
Meditation reduces stress and increases BDNF expression http://www.ncbi.nlm.nih.gov/pubmed/17905931
Short term sleep deprivation reduces BDNF http://www.sciencedirect.com/science...06899300027086
BDNF shows regenerative effect in Parkinson's http://www.ncbi.nlm.nih.gov/pubmed/21236244
Enriched Environment increases BDNF activity http://www.ncbi.nlm.nih.gov/pubmed/21236277
BDNF used for short term and long term memory and inhibitory learning http://www.ncbi.nlm.nih.gov/pubmed/12201640
There's also studies linking BDNF to food intake, such as toxins and heavy metals and lard lowering BDNF, as well as soy protein increasing expression.
I've read before about working memory training and learning how to play musical instruments increase BDNF.
I couldn't find anything on EEG biofeedback's effect though.

If you look up information on methylphenidate and amphetamine and BDNF the results are not encouraging, both showing reducing BDNF over time, coupled with short and long term memory loss. This connection makes sense due to the link between Alzheimer's and BDNF, and elevated BDNF levels being able to prevent cell death in methamphetamine use.

When looking up BDNF info on ADHD specifically the area is not very studied yet, but you will find studies on BDNF gene polymorphisms which are different but connected, showing certain polymorphism types are more at risk for ADHD, and one study that says BDNF plasma is elevated in ADHD people (this is the same as Alzheimer's), although it does not get into count of BDNF protein, mRNA, expression and circulation, all of which are lower in Alzheimer's (these are the things to look for - anything increasing these show improvement in symptoms).

Just look at John Ratey on this subject:


and
http://www.johnratey.com/newsite/Articles.html

While considering this, it pays to recall that the frontal lobe is an outgrowth of the motor cortex, and that increasingly, cognition is being understood in terms of its motor correlates. Hence the term so familiar to musicians "motor memory".

It is arguable that as well as increasing BDNF, the movement and coordination tasks required in fast, complex movements also directly boost neuroplasticity.

A very interesting area, and I am keen to watch the new developments as they arise.

For my money there is already more than enough evidence for me to be convinced to alter my behaviour on the basis of what is already known. Ratey gives adequate instruction on how to do this in the You Tube talk.

It pays to remember in this context that Ratey is one of the original doctors to take an interest in Adult ADHD- largely because he has it.

Now I don't know about methylphenidate having long term effects on BDNF- and I do not think there is much to support that yet- but my approach to managing my ADHD has always been to throw every practicable intervention in to the task of enhancing my attention. It has worked well, as my last prescription for medication ran out about 1 year and 1 week ago and I only continue to improve my attention skills- so long term effects are really only of academic interest to me.

My take on long term untreated ADHD is that it is socially isolating and depressing- and does not create the conditions required to support long term brain health.
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Old 06-23-11, 11:15 AM
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Re: The holy grail for ADHD - BDNF and neurogenesis

jlspartz, I couldn't get more than an abstract on the first one, since I don't have full (paid) access to PubMed. Didn't go to the other links since I'm SOOO far behind on my entire life - how have these been tested so far? The one you mentioned is ex vivo, anything in actual live tests?
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Old 06-23-11, 11:36 AM
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Re: The holy grail for ADHD - BDNF and neurogenesis

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Originally Posted by Barliman View Post
My take on long term untreated ADHD is that it is socially isolating and depressing- and does not create the conditions required to support long term brain health.
I'm going to watch this video, but I love this last line of yours, Barliman. Thank you for writing it. I had similar thoughts to these words a couple of months ago.

I took methylphenidate last year and while I didn't spend any more time with people while on the medication, I felt more social. I felt honest about myself. I had confidence. I didn't feel like I was hiding or defensive all the time. Then I stopped taking medication for the first four months of this year. I found myself falling back into into patterns of feeling guilty about my difficulties, trying to hide my mistakes, avoiding others and isolating myself. I probably spent just as much time with people, because I'm less productive and run around more without medication, but the social time was different. I should probably detail the specific behaviors so I can avoid them, but I know I was falling back into building walls around my inner life, falling into psychological defensive mechanisms.

When I tried to explain those thoughts (similar to your words) to my physician as I was making a decision to take medications for another period in my life, I think he was slightly worried that I just wanted to take them socially.

As for the thread topic, I'm looking forward to learning more about this BDNF stuff.
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Old 06-23-11, 02:58 PM
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Re: The holy grail for ADHD - BDNF and neurogenesis

Quote:
Originally Posted by Amtram View Post
jlspartz, I couldn't get more than an abstract on the first one, since I don't have full (paid) access to PubMed. Didn't go to the other links since I'm SOOO far behind on my entire life - how have these been tested so far? The one you mentioned is ex vivo, anything in actual live tests?
If you're talking about Omega 3s and BDNF there are many studies on that. Here is one full length although the whole study doesn't center around that. Look at the first discussion point near the bottom 'Effects on hippocampal BDNF levels. The findings are near in a graph in the middle of the document - I think in the 30%-40% range for BDNF mRNA and 20%-30% range for BDNF piptides (that's measuring the decrease in BDNF that corresponds to a decrease in DHA). http://www.ncbi.nlm.nih.gov/pmc/arti...tool=pmcentrez

Here's another but you'd just be able to get the abstract about DHA increasing BDNF in the frontal lobe in bipolar disorder. http://www.ncbi.nlm.nih.gov/pubmed/16983391

Most tests for counts of these types are done by slicing the brain afterwards. There are some less accurate and less invasive tests done for humans.
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Old 06-23-11, 03:27 PM
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Re: The holy grail for ADHD - BDNF and neurogenesis

Quote:
Originally Posted by Barliman View Post
Just look at John Ratey on this subject:


and
http://www.johnratey.com/newsite/Articles.html

While considering this, it pays to recall that the frontal lobe is an outgrowth of the motor cortex, and that increasingly, cognition is being understood in terms of its motor correlates. Hence the term so familiar to musicians "motor memory".

It is arguable that as well as increasing BDNF, the movement and coordination tasks required in fast, complex movements also directly boost neuroplasticity.

A very interesting area, and I am keen to watch the new developments as they arise.

For my money there is already more than enough evidence for me to be convinced to alter my behaviour on the basis of what is already known. Ratey gives adequate instruction on how to do this in the You Tube talk.

It pays to remember in this context that Ratey is one of the original doctors to take an interest in Adult ADHD- largely because he has it.

Now I don't know about methylphenidate having long term effects on BDNF- and I do not think there is much to support that yet- but my approach to managing my ADHD has always been to throw every practicable intervention in to the task of enhancing my attention. It has worked well, as my last prescription for medication ran out about 1 year and 1 week ago and I only continue to improve my attention skills- so long term effects are really only of academic interest to me.

My take on long term untreated ADHD is that it is socially isolating and depressing- and does not create the conditions required to support long term brain health.
Thanks for the video. His point about learning while exercising was brought out in a book called Brain Rules as well.

Methylphenidate on BDNF - these show increases and decreases in areas
http://www.ncbi.nlm.nih.gov/pubmed/20561592
http://www.ncbi.nlm.nih.gov/pubmed/20691787
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Old 06-23-11, 04:00 PM
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Re: The holy grail for ADHD - BDNF and neurogenesis

I also found something that might be of a lot of help through looking up ways to up-regulate BDNF - Green Tea.

Green Tea http://www.ncbi.nlm.nih.gov/pubmed/19409206
It not only upregulates the expression of BDNF which means protection of dopamine, but I found out it has two MAO-B inhibitors, which inhibits dopamine from being metabolized, and is a COMT inhibitor, which also protects from metabolizing dopamine - mainly in the prefrontal cortex. It also has caffeine and antioxidants that protect against memory loss from sleep deprivation.

Also blueberries increase BDNF. http://www.ncbi.nlm.nih.gov/pubmed/18457678
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Old 06-23-11, 04:13 PM
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Re: The holy grail for ADHD - BDNF and neurogenesis

More evidence http://www.ncbi.nlm.nih.gov/pubmed/16954211
This is proof - a direct connection to ADHD.
Signaling of ERK is what controlled hyperactivity. That is the pathway to signal BDNF (ERK-CREB-BDNF). The other 3 pathways signaled when taking methylphenidate or amphetamine had no effect.
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Old 06-23-11, 04:38 PM
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Re: The holy grail for ADHD - BDNF and neurogenesis

Quote:
Originally Posted by jlspartz View Post
I've read before about working memory training and learning how to play musical instruments increase BDNF.
I've read this too, and after trying to teach my 11-yr-old cousin how to play "Twinkle Twinkle Little Star" on the piano, I can believe it. I never appreciated how many things I'm doing at once when I'm playing music -- but your short and long-term memory have to be engaged, your auditory cortex has to be engaged, your motor cortex has to be engaged, and if you're reading the music, your visual cortex has to be engaged. It's *a lot*. And it makes me wonder how much worse my ADHD would be if I hadn't studied music.
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Old 06-24-11, 09:56 AM
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Re: The holy grail for ADHD - BDNF and neurogenesis

Quote:
Originally Posted by jlspartz View Post
I also found something that might be of a lot of help through looking up ways to up-regulate BDNF - Green Tea.

Green Tea http://www.ncbi.nlm.nih.gov/pubmed/19409206
It not only upregulates the expression of BDNF which means protection of dopamine, but I found out it has two MAO-B inhibitors, which inhibits dopamine from being metabolized, and is a COMT inhibitor, which also protects from metabolizing dopamine - mainly in the prefrontal cortex. It also has caffeine and antioxidants that protect against memory loss from sleep deprivation.

Also blueberries increase BDNF. http://www.ncbi.nlm.nih.gov/pubmed/18457678

The green tea link looks promising. Something i was not aware of, though I have encountered an ancient discussion between 2 zen monks discussing the mind altering effects of that third cup of green tea. I have never worked up the courage to go there

I need no persuasion to eat blueberries.
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Old 06-24-11, 12:05 PM
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Re: The holy grail for ADHD - BDNF and neurogenesis

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Originally Posted by Barliman View Post
The green tea link looks promising. Something i was not aware of, though I have encountered an ancient discussion between 2 zen monks discussing the mind altering effects of that third cup of green tea. I have never worked up the courage to go there

I need no persuasion to eat blueberries.
There are some other actions of green tea that I left out that also help.

Because it's a MAO-B inhibitor it also inhibits PEA from being metabolized. PEA is a natural norepinephrine and dopamine releasing agent. All these abilities to boost and protect dopamine also make it dangerous if taking too much green tea when taking it with ADHD meds since it would multiply the effect (so you'd probably want to lower your dose if you are taking anything)

Also, along the lines of sleep, it protects the brain from oxygen deprivation due to apnea and other sleep disorders that lower oxygen levels http://www.sciencedaily.com/releases...0515072944.htm and would most likely help with restless leg syndrome and period leg movement disorder, since higher dopamine levels are needed to cure these (they prescribe a D2 agonists for them). Sleep deprivation decreases D2 and D3 binding, which are the main receptors implicated in ADHD. http://www.ncbi.nlm.nih.gov/pubmed/18716203

On a sidenote it's also known to degranulate mast cells and prevent certain types of cancer due to the catechins in green tea. http://www.ncbi.nlm.nih.gov/pubmed/21538846
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Old 06-24-11, 05:36 PM
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Re: The holy grail for ADHD - BDNF and neurogenesis

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What I found interesting about this one was that it used a dietary change to induce changes in the brain. A lot of times, claims are made that one thing or another that you eat will inevitably lead to a particular chemical change in the brain without taking any other potential factors into account. However, this study was measuring differences between a normal diet and a deficient one. It didn't make any hypotheses about increasing the linoleic acid resulting in improvements in DHA levels in the brain.

The other thing I found interesting was the differences in the brains of the rats that were tested postpartum and the others - what this looked like to me was something that might lead to a better understanding of some essential differences between postpartum depression and other kinds.

I'm sure that many of the other bits and pieces that I understood, combined with the others that I didn't (so sad about not pursuing this at a more educable age!) provided a lot more questions than answers. In some of the findings, the changes in the virgin rats with the deficient diet, or the postpartum rats with the deficient diet, or the same with the control diet, didn't produce a number of the results that match what has been associated with depression in humans, and the paper concluded from that that this is only a piece of the whole picture. However, being able to see how dietary change combined with reproductive state create a measurable change in the number of specific receptors and volume of serotonin in various parts of the brains of these rats definitely shows some potential for understanding depression in humans.
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Old 06-24-11, 05:41 PM
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Re: The holy grail for ADHD - BDNF and neurogenesis

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Originally Posted by jlspartz View Post
Thanks for the video. His point about learning while exercising was brought out in a book called Brain Rules as well.

Methylphenidate on BDNF - these show increases and decreases in areas
http://www.ncbi.nlm.nih.gov/pubmed/20561592
http://www.ncbi.nlm.nih.gov/pubmed/20691787
Clearly, we don't have anything that helps one part or function of the brain without doing something else where we might not want it to, eh?
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Old 06-24-11, 05:47 PM
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Re: The holy grail for ADHD - BDNF and neurogenesis

Now, as to the green tea and blueberries, there's been lots of research showing all kinds of potential benefits, including the links above - but how much would humans have to take in to reach the same concentrations given to the rats? I love green tea and blueberries, but there's only so much of that I can take on a regular basis!
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Old 06-25-11, 06:05 AM
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Re: The holy grail for ADHD - BDNF and neurogenesis

Quote:
Originally Posted by Amtram View Post
What I found interesting about this one was that it used a dietary change to induce changes in the brain. A lot of times, claims are made that one thing or another that you eat will inevitably lead to a particular chemical change in the brain without taking any other potential factors into account. However, this study was measuring differences between a normal diet and a deficient one. It didn't make any hypotheses about increasing the linoleic acid resulting in improvements in DHA levels in the brain.

The other thing I found interesting was the differences in the brains of the rats that were tested postpartum and the others - what this looked like to me was something that might lead to a better understanding of some essential differences between postpartum depression and other kinds.

I'm sure that many of the other bits and pieces that I understood, combined with the others that I didn't (so sad about not pursuing this at a more educable age!) provided a lot more questions than answers. In some of the findings, the changes in the virgin rats with the deficient diet, or the postpartum rats with the deficient diet, or the same with the control diet, didn't produce a number of the results that match what has been associated with depression in humans, and the paper concluded from that that this is only a piece of the whole picture. However, being able to see how dietary change combined with reproductive state create a measurable change in the number of specific receptors and volume of serotonin in various parts of the brains of these rats definitely shows some potential for understanding depression in humans.
The interesting point is that many Western diets may predispose to all kinds of deficiency.
I have heard some interesting points made by some speakers re Taurine (amino acid) deficiency being almost universal in depression for instance.
I have not had time to evaluate this more fully- but it has got my attention.
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