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An hypothesis about why some people's healing from antidepressants seems to proceed very slowly: BDNF and SSRI-induced "critical periods"
by Sheila Joshi, Ph.D., December 2015
Note: The theory put forth below does not apply equally to everyone. It applies more to the people who have experienced extensive periods of inexplicable stuckness in their healing.
The nervous system is ultra-complex, and I realize there are many things going on with us -- receptor downregulation, neurotransmitter levels, dysautonomia, HPA axis off, high adrenal chemicals, glutamate, mitochondria, epigenetics, etc. Not to mention the enteric brain, endocrine system, immune system, connective tissue, circulation, etc.
In reading the Doidge book (The Brain That Changes Itself), I have been made to think more about the role of neurogenesis, synaptogenesis, gliogenesis, etc.
And I read something in the Doidge book that made me wonder if it might be a clue to why some of us seem so stalled at getting better sometimes. See what you think.
The human brain is born largely undifferentiated. There are "critical periods" in infancy and childhood when the individual must receive environmental stimulation in order for the brain to develop. Put another way, these "critical periods" are times when the brain learns and changes more quickly than usual.
One of the mechanisms associated with a critical period -- a time when the brain can learn and change quickly -- is the release of BDNF or Brain-derived neurotrophic factor.
Michael Merzenich is an professor emeritus from University of California San Francisco who has done a lot of very creative research and is radically optimistic about neuroplasticity.
He hypothesizes that autism is caused by an interaction of genes and environment that causes a "massive, premature release of BDNF" during the critical periods of infancy and childhood. "Instead of important connections being reinforced, *all* connections are." This leads to the nervous system being too easy to stimulate and too easy to stimulate pervasively. So, the individual experiences being hypersensitive sensorily and emotionally. This also "explains the high rates of epilepsy in autism: because of BDNF release, the brain maps are poorly differentiated, and because so many connections in the brain have been indiscriminately reinforced, once a few neurons start firing, the whole brain can be set off." (Doidge, p. 81)
This caught my attention. I have been thinking for a long time that I now share a lot in common with an autistic person in terms of being hypersensitive and easily over-stimulated.
What does this have to do with us?
SSRI's artificially increase the production of BDNF. If we've taken an SSRI for years, this over-production of BDNF may have gone on for years (see some references below).
We also know that SSRI's increase neurogenesis, synaptognesis, and gliogenesis (probably due, in part to BDNF, but probably involving other mechanisms as well).
It seems possible that when we stop taking an SSRI, part of the problem we are left with is maladaptive neurogenesis -- certain parts of the brain have been over-enhanced and over-linked in such a way as to cause over-active H-P-A, excessive anxiety, difficulty with executive functions, and distorted memory. This seems to be excellent for reactivating long-ago traumas ( - sarcasm), but poor for anything else.
In fact, a lot of medications and industrial chemicals may be causing maladaptive neurogenesis, synaptogenesis, and gliogenesis.
We know that SSRIs and atypical antipsychotics cause neurogenesis. (We also know that psilocybin and cannabis cause neurogenesis, although they may do so in a more adaptive way.) Do pesticides, preservatives, flame retardants cause maladative neurogenesis?
What are the environmental factors that Merzenich hypothesizes contribute to causing excessive, premature release of BDNF in autistic kids? He has focused on noise pollution from machines as the environmental risk factor that is turning on too much BDNF. My guess would be that there are several important environmental risk factors, but chemical exposure might be the most important.
OK, fine, but when we stop taking the meds, shouldn't that now create the conditions for us to prune any excessive connectivity? Shouldn't all the good things we do -- exercise, Omega-3, meditation, turmeric, learning anything new -- now re-model the brain? Because the brain is always plastic, right? And these things we do are all pro-BDNF.
Here's the surprising thing.
During a developmental critical period, "BDNF turns on the nucleus basalis, the part of our brain that allows us to focus our attention -- *and keeps it on, throughout the entire critical period*. Once turned on, the nucleus basalis helps us not only pay attention but remember what we are experiencing. It allows map differentiation and change to take place effortlessly....'It is like a teacher in the brain saying, "Now *this* is really important -- this you have to know for the exam of life."' Merzenich calls the nucleus basalis and the attention system the 'modulatory control system of plasticity' -- the neurochemical system that, when turned on, puts the brain in an extremely plastic state." (Doidge, p. 80)
"When BDNF is released in sufficient quantities, it turns off the nucleus basalis and ends that magical epoch of effortless learning." In other words, if a lot of BDNF is released, there are mechanisms that eventually say 'that's enough', and the system closes down what it thinks has been a critical period. At this point, the system becomes less plastic in an effort to protect the achievements of the preceding critical period and make the system stable. It becomes harder to change.
This may explain why autistic kids typically have a very hard time learning anything, and require tons of repetition to acquire a new habit. In fact, a new study showed that neurotypical people and autism spectrum disorder (ASD) people show the same initial brain activation when they start learning a new task. But, neurotypical people's brains show less brain activity as they learn, become familiar with the task, and become more efficient, whereas ASD people's brains do not decrease activity with familiarity, and, in fact, show increasing activity in some areas. It could be said that things don't become second nature for them; they have to continue to labor.
In this sense, ASD people seem to have lower neuroplasticity. Per Merzenich, this is related to them having hyperconnectivity -- too much neurogenesis, synaptogenesis, gliogenesis.
So, when we stop taking the drugs -- which may have been artificially elevating BDNF for years -- does the production of BDNF not only decrease, but become blocked in some way? Is there a higher threshold or an obstacle to turning it back on? In addition to possible neurotransmitter downregulation, do we have BDNF "downregulation"?
This could explain why some of us don't get better for a long time.
It could explain why exposure therapy and other cognitive and behavioral repetition-based techniques have limited effectiveness in ADwd.
It could explain why huge efforts at meditation and relaxation exercises have limited effectiveness in ADwd.
I have noticed that my body doesn't seem to learn. I exercise but my muscles don't get stronger. My left leg hasn't gotten much stronger, despite exercising for years. Small muscle strains take years to repair. I eat legumes every day (which is supposed to be ideal for my blood type) but I don't ever get better at digesting them which is what's supposed to happen. My body can't seem to learn to stop having an excessive histamine response to everything despite years of normalizing experience. And, God knows, I have not been able to make much of a dent in my neuro-anxiety through my own efforts. I have just had to wait for it to very slowly lessen. I know there could be other mechanisms behind each of these items, but it's worth considering that there might be an overall mechanism behind the overall pattern of just not learning despite repeated practice.
Is this why TBI responds much better to mega-dose Omega-3 than does our particular toxin-induced neuro damage -- did the toxin artificially elevate BDNF in such a way that the system thinks it should now suppress BDNF? All things being equal, do we have less neuroplasticity than someone with a mild TBI or stroke?
Could this also explain why various other forms of dysautonomia don't get better, when, all things being equal, good health regimens should cause neuroplasticity?
Does this also go towards explaining why PTSD is so hard to change? Does trauma of sufficient severity cause so much neurogenesis / synaptogenesis / gliogenesis that it masquerades as a critical period, and therefore change is discouraged afterwards?
High cortisol lowers BDNF. Lack of sleep lowers BDNF. Low thyroid lowers BDNF. We have all of these. But, still, given the huge amounts of time that pass, and the significant pro-BDNF measures that many of us take, it seems possible that the problem is that BDNF is being blocked, perhaps by the brain's built-in mechanism to protect itself from change after a period of much change.
What can we do?
It's as though we are being protected from change. Inviolable. The system is thinking it should prevent change / learning.
I don't think we yet know what causes a normal developmental critical period to close. Some of the factors that correlate with it closing have been identified, but what triggers them? Another thing that would be useful to know that I don't think we know yet is what triggers the massive, normal, developmental pruning back of neural connections in adolescence. I'm assuming that the timing of critical periods and adolescent pruning have a genetic component. We know SSRIs have epigenetic effects, so they may have artificially triggered something that is usually genetically programmed -- a critical period, and then the cessation of a critical period.
The thing is, if this theory is right, we're not looking for yet another way to promote BDNF. We're looking for something bigger than that -- how to open a critical period. This is something that no one knows how to do, and, which, frankly, has a lot of obvious potential for abuse, in terms of manipulating human beings. We're looking for a meta-remedy -- something that makes it possible to take advantage of all the many good remedies that are out there already -- things that should work, but don't seem to work as well as they should. The usual suspects that increase BDNF don't work that well. It may be that something is needed that is more of a master switch for critical periods.
One possibility might be gamma waves. There's some indication that increased synchronous gamma firing might be associated with critical periods and with good brain development or learning. Gamma is also associated with better cognitive functioning, memory, consciousness, coordination among neurological operations, focus, calm, compassion, Flow. Interestingly, gamma is low in autism. Tibetan Buddhist monks who were very long-term meditators showed a great deal of gamma.
How might the incidence of gamma waves be increased? Transcranial magnetic stimulation, which I don't feel that comfortable with, but bears watching. Neurofeedback. Brainwave entrainment -- binaural or isochronic.
It's crucial to note that prolonged stuckness, and apparent deficiency of neuroplasticity, does not seem to happen to most people who withdraw from SSRIs, or even to most people who have painful recoveries of a few years' duration. This tells us it is not an inevitable result of taking SSRIs. And, if this theory of excessive BDNF shutting down plasticity is right, it actually should happen to more people. So, why doesn't it?
It's also important to note that even those of us who do seem to go through an extended stuck phase in our healing do slowly, slowly progress.
Some references --
accelerated BDNF leads to earlier start *and stop* of critical period --
SSRI's artificially increase the production of BDNF --
SSRIs are even being considered as a therapy to re-open critical periods (ha!) --
SSRIs cause neurogenesis in the hippocampus -- Doidge, p. 241
Full text of Doidge book free online --
Difficult to learn with autism --
Inverse relationship between cortisol and BDNF --
Positive correlation between cortisol and BDNF in normal people in diurnal rhythm (Goldilocks zone) --
SSRI's increase BDNF by triggering an inflammatory response, which then triggers BDNF to repair the injury --
Low thyroid lowers BDNF --
Lack of sleep lowers BDNF --
DHA modulates microglia in a good way --
Antipsychotics may cause neurogenesis --
What closes a critical period? --
http://synapse.princeton.edu/~sam/knudsen_critical_periods_jcn_2004.pdf pp. 1417 - 1422
Decreased neuroplasticity may play a role in IBS --
Decreased neuroplasticity and PTSD / anxiety --
SSRIs and epigentic effects --
gamma waves --
gamma waves and critical periods --
gamma waves and autism --
epigenetics and plasticity --
“Show me a sane man and I will cure him for you.”
- C.G. Jung
"Going to a psychiatrist has become one of the most dangerous things a person can do."
- Dr. Peter Breggin
"Twenty-five years before Prozac, 1 in 10,000 of us per year was admitted for severe depressive disorder – melancholia. Today at any one point in time 1 in 10 of us are supposedly depressed and between 1 in 2 and 1 in 5 of us will be depressed over a lifetime. Around 1 in 10 pregnant women are on an antidepressant."
- Dr. David Healy
"Rather than fix chemical imbalances in the brain, the drugs create them.”
- Robert Whitaker, Anatomy of an Epidemic
"Ritalin and amphetamine have almost identical adverse effects on the brain, mind and behavior, including the
production of drug-induced behavioral disorders, psychosis, mania, drug abuse, and addiction....Ritalin can cause permanent
neurological tics including Tourette's syndrome......Withdrawal from Ritalin can cause emotional suffering, including depression, exhaustion, and suicide.
This can make children seem psychiatrically disturbed and lead mistakenly to increased doses of medication."
- Dr. Peter Breggin, Talking Back to Ritalin.
“And what science had revealed was this: Prior to treatment, patients diagnosed with schizophrenia, depression, and other psychiatric disorders do not suffer from any known "chemical imbalance". However, once a person is put on a psychiatric medication, which, in one manner or another, throws a wrench into the usual mechanics of a neuronal pathway, his or her brain begins to function, as Hyman observed, abnormally.”
- Robert Whitaker, Anatomy of an Epidemic