Regular excercise also can increase the level of BDNF in brain and increase hippocampal neurogenesis which can improve cognitive impairments.

A great deal of studies have been done on BDNF, but when perusing pharmacological studies, it indicates that even with increased BDNF, cognitive impairments and deficits do not necessarily fully improve, which leads to the possible role of IGF-1 and the possible hypothesis that both are necessary for full cognitive recovery. I have not found any research as yet which indicates whether this is the case. I agree with both of you, plasticity is definitely impacted as mentioned above. Thank you so much as this information is invaluable and I would appreciate your thoughts on the role of IGF-1 in this.

What I know is that IGF-1 plays an essential role in neural stem cell proliferation in subventricular zone but I am not sure about the cells in hippocampus.

As I understand it, lack of BDNF also contributes to a decrease in dendritic spines in hippocampal nuerons which decreases long term potentiation which is associated with cognitive impairment.

Hi Hassan, from the research I have seen, IGF-1 does also play a role in the hippocampus, but my knowledge is lacking here, hence the need to establish on a more definitive level what the role is. In TBI, the administration of exogenuous GH incresaes the proliferation and differentiation of stem cells in the hippocampus, alters genetic expression and cognitive recovery is seen - no clinical trials available as yet. This is why I am considering that both BDNF and IGF-1 need to be present to effect proper recovery. Thank you for also sharing your thoughts on this, the sub ventricular zone is also a critical area.

Hi Darren, that is definitely right and BDNF decrease is most certainly linked as you mentioned. If you have any more information on it and any links between BDNF and IGF-1 I would be most grateful to gain more information.

Here's a pretty good review of this this topic. It's about 5 years old...

http://www-ncbi-nlm-nih-gov.ezproxy.hsc.usf.edu/pubmed/19470236

Hi Cheryl,

Stress in general term can decrease BDNF level which is related to Glucocorticoids released during this events. Cortisol by binding to GRE ( Glucocorticoid response element ) which resides in promoter of BDNF repress expression of this growth factor or even may be others. Question is whether by increase the level of growth factors solely , could we counter clock back what happened? studies on MDD revealed that although antidepressants by increase the level of BDNF exert their effects but it is not necessary that for antidepressant effects , the level of BDNF should be high. our study also revealed that chronic consumption of Alpha linolenic acid regularly increase the level of serum BDNF. We should consider the brain as a network system. disequilibrium in this system effects whole system. thus to bring this system back to work, correction in each single affected region in orchestrate with other part should be consider. My experience showed that in different kind of injury to brain system, potential healing power turning it to developmental state in order to replace the injury site, which may happened by increase in growth factor levels, switching the GABA system to excitatory system and so on. so subsequent of these changes are gene modification and secretion of un-wanted proteins that make repairs being harder than even. I suggest that you also add some thing more to two interested growth factors and look for their combinational effects.

good luck

The subject toward searching of effective impact at cognitive and motor disorders, neurodegenerative diseases is not new, but every day is becoming more important. I think this is due to the fact that pathomorphologies , biologists, geneticists, biochemists and immunologists have come at some stop-bloc. Today it is fashionable to reduce all health problems to metabolic and immunologic disorders with certain genetic background's. However, we may neglected principle of sustainability assessment of scientific theory only due to positive clinical outcome of treatment of a nosologies. In my practice I have always adhered to the principle : " If I have gotten a positive clinical outcome during treatment , then I'm on the right track in understanding the pathogenesis of this disease ." This principle is usefull not just to help me in solution of many incurable states of various diseases, but in finding the ways of understanding the secrets of diseases. This allowed me to begin treating patients with apallic syndrome ( chronic vegetative state) since 1997 and learn to withdraw deep decompensated state in such patients to the level of self-service or even to return them to the level of social and occupational rehabilitation (http://angio-veritas.com/technologies/nejroreabilitatsiya-psyhonevrolohichnyh-hvoryh/apalichnyj-syndrom/?lang=en). This analysis gave me the understanding of the logic process, which may be happend in the living organism, when neuropsychiatric diseases were appeared like congenital and acquired origin. My experience with patients with neurodegenerative diseases showed that it is necessary to develop a new approach to the pathogenesis of the diseases. When we working with patients not in acute, but in the chronic stage , we actually have working with the result of the process that had disrupted in the nervous system and led to loss of the CNS function. Therefore, the process of recovery of the brain we must started from a completely different side. We believed that hemodynamic factors of venous stasis and brain ishemic's disorders led to the nerve tissue failure and they are the dominant reason in the tissue metabolism disorders and disorders of the nervous - humoral regulation.

Dear Ulyana, I agree with you completely and also find your comments on neurodegenerative disease of great interest. In the absence of converging evidence from clinical trials, but through the examination of case studies, and one that I have been recently involved with, we applied melatonin in conjunction with exogenuous GH once baseline blood tests (such as IGF-I levels) and neuropsychological status had been established. This was in a case of chronic persistent post concussion syndrome whereby normal neurorehabiitation had not demonstrated improvement in cognitive functioning. The patient has since the application of treatment shown strong progress and recovery in cognitive and motor impairments. Having done a great deal of research across clinical psychological disorders and TBI, a pattern began to emerge and hence the extrapolation that perhaps it requires both BDNF and IGF-1 to boost recovery over and above normal endogenous production. However, I could not find research that looked at both factors together. I think the hemodynamic factors you mention are very interesting indeed and provide a new perspective. Having insight into different perspectives is critical in gaining a better understanding of very complex problems. Thank you for this input, it is fascinating!

Dear Mahmoudreza, what you say is perfectly right and your opinion is greatly valued. It goes without saying that the brain is complex system with multi level processes, functions, connectivities etc, and any threat to homeostasis will have a ripple effect elsewhere in other systems and processes.Pharmacological drugs in some cases do increase BDNF and in other cases symptomology is improved without an apparent direct effect on BDNF (due to perhaps factors such as increased serotonin exerting effects on BDNF and increasing the levels). Even though GABA is the main inhibitory transmitter, it most certainly has other functions and most definitely has an excitatory function as well.

I am naturally excluding other factors which impact on plasticity etc, such as exercise, intelligence level, environmental factors, temperament, endophenotypes in general, genetic vulnerabilties and the like.

Looking at different disorders and diseases I have (as mentioned previously) picked up a pattern which I am trying to gain more knowledge on.

For instance, I have been looking at various neurotransmitters in relation to Treatment-resistant Depression and their relationships with cognitive impairments. Your input would be most welcomed. Bear with me on the following explanation, it is fairly simplistic, but will perhaps indicate where I am heading with regards to cognitive impairments and neurotrophins in the hippocampus. The hippocampus is essentially the gateway for memory and learning. In TRD the most severly affected systems are explicit memory processes and attentional networks. Without these functioning the ability for instance to couple emotions and new events in the amygdala for instance, is dramatically reduced and forms one of the vulnerability factors to relapse. GABA can be modulated by BDNF, and GABA has an inhibitory effect on GH (IGF-1 in hippocampal regions). Glutamate which is known to play a role in memory and learning, with memory being impacted by the co transport with dopamine and it also kickstarts NMDA receptors in hippocampal regions thereby increasing BDNF. Dopamine also plays a role in memory, specifically working memory and responds well to seratonin levels. Serotonin is also important to learning and memory and plays an important role in working memory too. BDNF and the srotonergic system have a cyclical relationship, with each affecting the other. Naturally chemical transmissons in general such as dopamine, serotonin, noradrenalin, glutamate, glucorticoids, and so forth have complex relationships. What I noticed across the research I was looking at, was that BDNF levels increase, cognitive impairments improve. In other studies if IGF-1 levels are poor, but increased to normal cognitive impairments improve. So, the question perhaps should be does GABA inhibit IGF-1 to the point whereby even though BDNF is increased, IGF-1 has not increased which could result in poorer cognitive recovery?

If anyone has any comments, or ideas on there, they would be most welcome.

Thank you so much Darren for the study, it is greatly appreciated!

Dear Cheryl,

I am wondering whether you have any evidence showing that increase in BDNF level in impaired-cognitive model can not do any thing until IGF-1 increase. so,in that case you can say increase in BDNF level is not sufficient for cognitive impairment until IGF-1 also increase.

Dear Mahmoudreza, that is what I am trying to establish. I cannot find anyone who is working on this, or any studies pertaining to this and it is the question that I am asking, so any information I can get from experts such as yourself would be most welcome.

Dear Cheryl, one of popular model of impaired cognition is " maternal deprived" which separate new born mice from the cage that mother hold. In that case it has been shown that BDNF level was decreased and there is some epigenetic changes on Methylation in some gene happened. So you can first check the level of both growth factors and then supply the model with BDNF while using blockage of IGF-1. it may revealed the role of IGF-1 in this situation. Hope this idea can help.

This seems to be a very good idea Mahmoudreza and definitely worth trying. Thank you for this idea!

does alendronate affect BDNF, igf-1, (apologise pl), also what does kyphoplasty cement contains? can BDNF be added, sorry again

i know bone morphogenic protein, BMP WHICH CAN BE USED, IT SHOULD HAVE READ BMP instead of BNF, THX

Hi Chandramouli Balasubramanian,

What do you mean? BMP is the same as BDNF?

I have two small concepts to add to this discussion.

First, your hypothesis mirrors one voiced in several papers that depression, for one, is primarily a disease of impaired neurogenesis (see http://www.ncbi.nlm.nih.gov/pubmed/15271580 if you haven't read it already). Not only have anatomical analyses suggested the presence of hippocampal atrophy in depressive patients (cf. http://www.pnas.org/content/98/22/12320.long, incidentally, like the first linked paper, also written by Professor Robert Sapolsky, a big proponent of this hypothesis), but the time scales at which classical antidepressants like SSRIs and increasingly promising ketamine-like glutamatergic agents manage to ameliorate depressive symptoms (a few weeks and hours, respectively) also seem to mirror those at which their biochemical pathways might theoretically start affecting neural plasticity (a large and ambiguous term that I will not attempt to unpack in detail right now).

Second, it is important to remember that IGF-I and BDNF translation and release are linked to a complex system of varied and distinct types of synaptic plasticity: the enlargement of existing dendritic spines, dendritogenesis, synaptogenesis, neural proliferation, sometimes the generation of lasting neurons. And in light of findings that stimulation of dentate granule cell neural proliferation does not necessarily correlate with a net increase of cells in the hippocampus in the absence of other factors like concomitant environmental enrichment (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2858601/), it is probably important to be careful about keeping clean distinctions among these concepts: BDNF might not necessarily equal neural proliferation, which might not necessarily equal the development and establishment of persistent new neurons, which might not necessarily equal measurable symptoms reductions of the illness in question.

A fantastic response Kelley, just the type of information I was looking for. I am aware of the studies on BDNF in relation to Depression, as well those linked to Pharmacological agents, but in my searches could not find any in relation to IGF-I, (except in regards to Brain Injury) so thank you so much for the reference, I am on the same page as the Professor with regards to this and will see if I can contact him for more information as well. I do think that there is a great deal that is linked to timing within the generation of certain effects within the hippocampus etc, as well as complex interelationships between other physiological factors, so I am in wholehearted agreement with your comments. If you know of any other research I would love to know about it as I have had great difficulty ocating any with regards to IGF-I...I can find a great deal in relation to BDNF, but not much with regards to the first. Thank you so much, this has been of great value!

As we look for recovery from the support to neuroplasticity from neurotrophic factors either intrinsic or supplied and from stem cell support we need to consider what science tells us about the other needed elements for motor and cognitive recovery. Current methods of inactivity an a non enriched environment( Bernhart- inactivity and alone , insufficient intensity and duration, focus on compensation rather than impairment, timing of initiation as it relates to true neuro and angio genesis, as well as the concepts of functional connectivity. Researchers such as Krakauer, Corbett have done excellent work in introduction to the scientific merits of how recovery occurs and what promotes or suppresses. In the United States current system does not support what science is beginning to indicate needs to be done, for this to change much education is indicated on multiple levels from medicine, therapy, hospital administration, third party payers. As a researcher one can not know if the stem cells , or added neurotrophic factors are supporting recovery when experience dependent plasticity ( spontaneous recovery also needs experience to rewire- Hebbin, Krakauer, and multiple others) is not promoted within the environment. As Researchers and Clinicians have started to communicate and work together more readily we should be able to get a better picture of what works and what does not

This is wonderful, thank you Hendrika! I agree with not knowing what has contributed to recovery based on complex variables, and isolating them is extremely difficult! I worked on case whereby we conducted baseline tests to measure for instance IGF-I levels, neuropsychological status, mental health and complete blood tests, scans etc in a brain injury whereby recovery did not occur, even though cognitive rehabilitation and physical rehabilitation had been carried out for nearly two years, consistently. It was initailly diagnosed as post concussion syndrome, however, chronic metabolic dysfunction had occurred, genetic expression was altered etc. What I found of interest is that due to the impact of incorrect signals to the heart, affecting heart function, exercise had to be limited after two years, until the patient's heart had been cleared as being undamaged. At the time exercise was stopped and all rehabilitation (which had occurred consistently and regularly) ceased. After this, the utilisation of off label exogenous GH and melatonin brought about improvements in cognitive functioning initially (over 6 month period), then after 9 months, signals to the heart began to return to normal. Tests recently conducted indicated improvements in both cognitive and physiological functioning. The difficulty was establishing the extent (quantifiable results) of the improvements, and what other variables may have further contributed to improvement. During the two year period before this treatment was tried, physical rehabilitation would have impacted on BDNF expression, when rehabilitation had occurred, The new treatment - exogenous GH was applied (after cognitive rehabiitaion and physical rehabilitation had been done and finally given up on, after two years), the possible variables that may have impacted on cognitive and physiological improvements could have been IGF-I, or IGF-I in combination with BDNF. Naturally other factors could have been involved, but we were unable to measure any others. I would love your opinion and expertise on this.

Thank you so much for the article I am delighted to receive it and will enjoy reading through it!

It sounds like excellent effort was made on the rehabilitation front. Current thought that impairment recovery occurs between month 1 and 3 and that following is compensation. So many factors hypothetically could effect your outcomes such as: when did therapy start? As Neurotrophic factors peak and decline within the first few weeks, a 2-3 week delay in afferent information comming into the sensory motor cortex of a hemiplegic arm and subsequent reorganization not occurring, could account for diminished recovery as the patient being medically managed in an ICU for example. Other variables to consider than timing of initiation of therapy are type of therapy. Enriched environment with opportunity and assist to explore may be different from traditional interventions. Motor learning concepts of cross limb interference which looks at degradability of the cortical spinal tract activity which is upgraded after a motor learning task activity and then the subsequent down grade of the activity from a learning activity with the cross limb vs. a resting phase and how this interferes with consolidation of learning,when looked at by rTMS. A therapist could unknowingly have the patient do some learning activity with the contralateral limb during the rest period of the hemiplegic limb and not be aware they might actually be interfering with reorganization, if we follow the premise of this line of research. The biggest issue right now is that therapy protocols and interventions are not sufficiently established in applications in the rehabilitation field and probably even in academic settings, as findings from fMRI and TMS research and their implications to current thought , are just beginning to get to therapy providers and end users.

I agree with what you say, that "therapy protocols and interventions......end users" this is definitely the current status and I believe that there are many more discoveries to be made, which will change our thinking in the future and remaining open to these is going to be critical to the recovery of patients. I have never done any work around crossed limbs, but it sounds fascinating, thank you for this very interesting information Hendrika!

In this particular case, treatment such as physical rehabilitation started within 24 hours of arrival in acute high care (Here in my country, it is a small ward with a centre area and each bed visible to staff. This is the most intensive form of care, where patients are in critical condition and assigned two trauma sisters per bed per shift, whose sole job is to care for one patient only). However the patient had not been correctly diagnosed and the sequellae of the brain and neck injury only began to show approximately 2-4 weeks afterwards, with serious consequences, which landed them in Acute high care.

Hi Hassan Azari,

Just noticed this. BMP stands for bone morphogenic protein :

http://en.wikipedia.org/wiki/Bone_morphogenetic_protein