We treated a number of patients with hippocampal missfunctions, such as lost of recent memory. Treatments were based on exogenously given growth hormone. Results are, generally, very good. In rats we observed that GH increases the number of proliferating neural cells precursors from the Dentate Gyrus of the Hippocampus. So, I think that the answer to your question is yes, it depends on the age of the patient though.

By the way, GH also increases survival of newly formed neurons in hippocampus. In addition you can use melatonin, at high doses (i.e: 20-100 mg/day). It works very well and it lacks any secondary effect.

There is a complex and yed not understood relationship between structure and function in psychiatric illness or psychiatric comorbidity (sensu strict), like in your patient. A lot of literature has been published on isolated aspects of volume loss in different neurological and psychiatric conditions, especially in the field of epilepsy. However, to find an association, is just the first step; causal inference needs also the proof that reverting the situation (e.g. volume loss in the hippocampus) can ameliorate the condition (e.g. depressive symptoms). Jesus Devesa correctly pointed out the homon based treatments. Other strategies my encompass stimulation of neurogenesis with humoral factors, small molecules or neurostimulation. Yet, none of these studies was controlled and had a clinical endpoint. in sum, yes, depending on the age of the patient volume loss in the hippocampus may be reverted to some extent, but there is no evidence, that this will improve the clinical condition in your patient.

Dear Jesus, I have heard of the use of pharmacological treatments, such as T3, Lithium etc, that have been used in MDD and TRD,and atypical depression has been shown to improve in patients who have presented with GH Deficiency, but none of the studies specifically mention GH in these types of Depression in relation to Ischemia. I find the idea of the use of GH mentioned by you, extremely interesting. From what I have been able to establish GH has been shown as you mention to improve cognitive impairments, amongst for instance beneficial effects on the cardiovascular system. In preoperative environments it has been shown to prevent ischemia, reperfusion - induced diaphragmatic dysfunction. I know that studies have shown that the benefits relating to GH treatment dissipate on the stopping of treatment, and wonder if the GH deficiency cannot be reversed on permanent level - your expert opinion would be most valued! From what I can establish, it has not been indicated as a treatment for Depression in patients with Ischemia, and I would be delighted if you have any further information in this regard. Thank you for such an excellent response.

Dear Eugen,I agree with you completely. Trials are often small and literature is "fragmented" across different types of disorders etc, that is without even taking into account factors such as severity of disorder, sub-type, age, gender, concomitant complications, type of clinical trial being conducted, size of sample etc. The other concern is if a reversal is attained, can it be sustained? Naturally the link between symptomologies, cognitive processing and neuroanatomical factors need to show some significant convergent, correlational evidence, which I also am unable to establish at this stage. I have not found many longitudinal studies which point to the long term outcomes, though side effects are generally hailed as minimal with most of the hormone treatment, the permanency of sustaining normative volume is not detailed sufficiently should a patient stop treatment. If you have any information in this regard I would be most grateful if you could let me know.

Dear Jesus, you mentioned the age of the patient which naturally makes sense to me, but a concern I have is that in cases of Ischemic depression, the patients generally tend to be >60 yrs, would GH be of value (bearing in mind other factors, such as medical and psychological profile) in these cases? Thank you so much, I look forward to your response!

Dear Cheryl, thank you for your kind words and your questions.

GH world is an amazing world that just now is beginning to be revealed. Apart of its well known physiological effects, GH is a powerful hormone for inducing stem cells proliferation, differentiation, migration and survival in a number of human tissues, including the nervous system (central and peripheral). But, together with these effects the hormone leads to increased catecholamines metabolic turnover. This is due to the fact that if we administer exogenous GH it leads to increased hypothalamic somatostatin release, because pituitary GH secretion is tonically inhibited by somatostatin. In turn, increased somatostatin release leads to increased dopamine and noradrenaline synthesis and release, because noradrenaline is the main inhibitor of somatostatin. This is a matter of continuos feed-back that we can break by administering exogenous GH.

In our data there are no clear significant differences between GH-deficient patients and patients without a well established GH deficiency. In fact, as we published in Brain Injury, exogenous GH may cooperate with the endogenous hormone.

However we did not use GH for depression, but it makes sense to think that it could work well. We usually treat patients with very important TBI, stroke, cerebral palsy and spinal cord injuries. We combine GH administration, short-term doses and changing doses, with melatonin. Melatonin can work very well for depression, but a doses higher than those used for jet-lag (ie 20-100 mg/day). Melatonin is neuroptrotective, but is has a number of very important positive effects (antitumoral, immunoestimulant, main blocker of free radicals, it acts at the mitochondrial level too...). Melatonin is being used for breast cancer treatments, and as protector during chemo and/or radiotherapies.

With regard to patients older than 60 yr, melatonin has to be very useful, but GH too. In the case of trying GH you should discard: hypothyroidism, diabetes and typical cancers (breast, prostate, colonic cancer....) because the hormone might favor the proliferation of any of them, it doesn't produce them though.

Typical GH doses for elder people should start at 0.1-0.2 mg/day and then increased until 0.5 mg/day. A good regime of administration is: 0.5 - 0.2 - 0.5 - 0.2- 0.5 mg/day, 5 days per week. High GH doses facilitate proliferation while low GH doses facilitate differentiation; we found it and soon it will be published.

I hope that these words may be useful for you; in any case don't hesitate about asking me about GH, it is my favourite hormone since many years ago.

This is excellent information Jesus - and it is very exciting. I would love to know more when you publish your findings. Also, I was not aware of the impact melatonin could have. In the case where someone comes in with ischemia, could treatment within the first 24 hours provide a neuroprotective factor if one used both, or a combination thereof? It would be extremely interesting to know if this attenuates the severity of Depression experienced.

Well, this is a very interesting topic and it will take a lot of time to deciphrate the big number of relationships between GH and other factors acting after a brain injury. But, I will try to let you know what we found and how we found it.

First of all, there is a Spanish law allowing us the use of GH (and other hormones and drugs) off-label, but the same law impedes to publish results obtained unless they proceed from an authorised clinical trial. Because my Foundation tries to help in the recovery of people with brain injury and not to carry out clinical trials with them (they join us from any part of Spain and many foreign countries, including USA and Australia) I can't develop clinical trials with these patients that come to us for being cured if it is possible. This is the reason by which we only publish studies carried out in lab rats or in cultured cells, but not in human patients excepting those in which a clear GH-deficiency exists and GH can be used without any legal restriction. We treated about 800 patients, TBI, stroke, cerebral palsy, etc..., with very good results in general and full recovery in many of them.

After this long prologue I can explain to you why you are right in your idea that giving GH soon after a brain injury a successful result can be expected. I did it, for the first time, 11 years ago, with my oldest son, aged 22 at that time, after a terrific car accident. He had fronto-temporal contusions and hemorrages, blood in the III Vc, diffuse axonal injury and brain-stem injury. 8 months later he was able for finishing his university studies (Molecular Biology) and later he reached the maximal qualification in his International Doctoral Thesis. No sequelae exist. After it I proposed myself to create the Foundation for helping others without hopeness.

Coming back to your question. Three years ago a baby was born after a cardiac arrest of 30 minutes; he was bleeding in utero because of a vasa previa. MRI showed diffuse encephalomalacia and big cavities in the occipital lobes. Prognosis was: deafness, blindness, lack of speech and spastic tetraparesia (if he was able to be alive). His father asked me if I could do anything....., we commenced with GH and rehabilitation and 1 year later MRI was absolutely normal; that is the brain had been fully recovered and looked as a normal brain (radiologists couldn't believe it). This child is now 3 years old; he speaks, he plays, he walks, and he is learning english...., absolutely normal. Another amazing case: a child aged 3, 40 minutes under the water in his parents swimming pool, 50 minutes in cardiac arrest. I received a phone call from the ICU of the hospital (miles away from my town) and I explained to pediatrics how to act. 16 months later this child is also normal, without significant sequelae.

That is, if you administer GH as soon as possible after an injury or isquemia, you can be sure that for at least 6 hours neurons will be protected from death, then continued GH administration will allow the production of new neurons and the replacement (if possible) of lost neurons or the appearance of brain plasticity. We have many data in human patients about it, but for understanding better what is happening we carried out an experiment in rats. They were severly injured by frontal ablation and then they were given GH or placebo for 5 days; rehabilitation started them. Rats given GH were able to move their hands and fingers as normal rats, reaching the food without problems, but rats given placebo were not. Immunohistochemistry studies showed that in the perilessional area a big number of nestin-expressing cells existed (nestin is a marker of proliferating neural stem cells); however, the severity of the injury impeded that the lession cavity could be filled with new neurons. Then how to explain the recovery after GH? we studied the contralateral (intact) hemisphere and we found a number of nestin-positive neurons (therefore, newly formed neurons) in GH-treated rats but not in rats given placebo. That is, GH plus rehabilitation led to: 1) neurogenesis and 2) brain plasticity. I can send these papers to you if you give me your email or postal adress.

Moreover, in previous papers we published that rats treated with kainate (a strong toxic) and GH showed an increased proliferation of neural precursors in the Dentate Gyrus and an increased survival of these cells. Recently we deciphrated the biochemical pathways by which GH is acting at the central level. Neural stem cells produce GH and its receptor; GH receptor is present in big amounts in migrating newly formed neurons and GH has chemoattractant properties. Therefore, most likely, after a brain injury GH "is called" for reparation and if we administer exogenous hormone (it is able to pass the brain-blood barrier) it will reinforce the reparative properties of endogenous GH.

I am sorry for this long writting, and I hope that it will be useful for you.

Thank ypu for your interest.

Dear Jesus, This is extremely interesting indeed, and I find what you have written to be of great import. It would be a great achievement if you were able to carry out clinical trials, as this would be of incredible value. I would be delighted if you could send me the papers!! My email address is [email protected].

Dear Merilyn,

thank you very much for the interesting articles. The increase in grey matter volume is striking, but we have to be cautious with our conclusions: Do you really think this is due to neurogenesis? We know, that there are cyclic changes in grey matter volumes, which can be influenced by many external factors (I remember an article in Science a few years ago on Hippocampal volume loss after transatlantic flights). I woouls suggest that we talk about activity or treatment induced grey matter increase instead of neurogenesis.

Eugen

Dear Jesus, many thanks for your answer to Cheryl. Very interesting indeed. I would also be interested if you could send me the pdf of your papers regarding these extremely interesting work. Best regards

Eugen

Dear Merilyn, the articles are of interest and I have had a look at them. The NIMH have highlighted studies that show that Therapies alter activity, by increasing activity in the prefrontal lobe, particularly the left hemisphere, which in turn reduces activity in the HPA regions...thus reducing cortisol levels and thereby attenuating loss of volume. However, in the case for instance of TRD, only 75% of patients treated pharmacologically, with Therapy and with other forms of treatment such as deep brain stimulation appear to recover from sub types of Depression. This is one of the reasons why I ask the question with regards to hippocampal volume and its possible role in mental disorders. Your information is extremely relevant in helping integrate findings across various treatment types and the outcomes in various disorders and contribute to bringing us closer to the answers that we seek. Thank you for your contribution, it is good to see that diverse perspectives are available and they assist in the evolution of scientific answers to difficult questions.

Dear Eugen, attached is one of these papers. I don't have others you requested but if you give me your email address I will send them to you this afternoon. In the case that you want your email to be unknown here is mine: [email protected] or [email protected]

Dear Cheryl, from studies in animal models we know that adult neurogenesis and major depression are correlated with each other. One of the factors which might play a crucial role in this correlation is BDNF, but also VEGF and Glucocorticoids invluence both to a strong extend. Going back to your question it has been shown that Antidepressants can increase hippocampal volume and also enhance adult neurogenesis. The first publication on the importance of new neurons for antidepressant treatment was by Santarelli (Science, 2003, PMID 12907793), but there a many others out there. The only problem here is the question how well do the animal models fit human depression, but the evidence for a positive effect of antidepressant treatment on HC size is definitely out there!

Thank you Imke, I quite agree with you, a fantastic answer! The issue as you so rightly state is the evidence in human related trials. BDNF etc is definitely crucial, but the big question (based on morpohological evidence), is the role that a more than 19% reduction in hippocampal volume plays, and the reversal thereof. Though I can find clinical trials on pharmacological treatments, etc, there is not much available on the aspect that I am considering, which makes it difficult to determine the extent of the correlation between Depression and this type of volume reduction (There are so many variables to consider when attempting to understand the relationship). The birth of new neurons are critical for the coupling of physiology with events (specificaly in the amygdala), such that new memories (which form schemas) will allow the forming of new content within cognitive processes, which can alleviate depression. The Cognitive Mode (Beck) or CAS (Wells and Matthews) amongst other things indicate that cognitive processes are locked in, which prevents the orienting of attention to new events that have a physiological basis. Sorry this is a very shortened version/explanation. In some cases patients do not recover from Depression and in suicide cases, morphological evidence has shown this 19% reduction, and in imaging studies similar findings have been found. This has motivated the question, as to the role this may have in Ischemic patients with Depression. If you have further information, I would be delighted to hear more from you.

Dear Imke, dear Cheryl,

I agree with you and you are right, that stimulating neurogenesis is a potential mechanism for treating depression (or depressive symptoms!). however, it is not clear, whether MR detectable volume changes is related to cell loss or neurogenesis. We have to be cautious here. There is also some evidence, that ECT stimulates neurogenesis, which itself may be hormonally mediated, but is this the mechanism, which is related to clinical improvement?

some recent papers of interest to you may be:

1: Minelli A, Zanardini R, Abate M, Bortolomasi M, Gennarelli M,

Bocchio-Chiavetto L. Vascular Endothelial Growth Factor (VEGF) serum

concentration during electroconvulsive therapy (ECT) in treatment resistant

depressed patients. Prog Neuropsychopharmacol Biol Psychiatry. 2011 Jul

1;35(5):1322-5. doi: 10.1016/j.pnpbp.2011.04.013. Epub 2011 May 3. PubMed PMID:

21570438.

2: Nakamura K, Ito M, Liu Y, Seki T, Suzuki T, Arai H. Effects of single and

repeated electroconvulsive stimulation on hippocampal cell proliferation and

spontaneous behaviors in the rat. Brain Res. 2013 Jan 23;1491:88-97. doi:

10.1016/j.brainres.2012.10.052. Epub 2012 Nov 2. PubMed PMID: 23123207.

3: Bolwig TG. How does electroconvulsive therapy work? Theories on its mechanism.

Can J Psychiatry. 2011 Jan;56(1):13-8. Review. PubMed PMID: 21324238.

Best regards

Eugen

Thanks so much Eugen, these articles look interesting and I will definitely be going through them. Your input is greatly valued!

Eugen, I also agree with you with regards to imaging studies in relation to cell loss and neurogenesis. This is often not clear and in many cases the population samples are too small to render significant results, or the time periods too short to ascertain consistent volume loss,or increase, vs neurogenesis in conjunction with treatments which are administered at the time. It would be wonderful if a database of imaging studies could be built, but with the differentiations in methodologies, treatments etc I have not been able to compile a convergence of evidence with enough similarities to pinpoint crucial findings and the devil is often in the very subtle details. I was unaware of the effect of imaging on neurogenesis and find this very interesting as this could confound certain types of results. Thank you for the information, it is super!

Beautiful topic. I am physiologist specialized in Endocrinology, therefore many of these concepts are far away from my mind. However, both BDNF and VEGF are strongly induced by GH. GH and its receptor are found in neural stem cells and newly formed neurons show a big amount of GH-R, perhaps a key for allowing them to migrate.

With regard to antidepressants, it is well known that they stimulate neural precursors proliferation but they don't allow these proliferated cells to significantly differentiate into neurons. This can achieved by adding glucorticoids. they inhibit proliferation but allow differentiation. We are using such a kind of combination in a programmed manner in human patients (stroke, TBI) with very good results.

That is excellent information Jesus, perhaps you have provided an answer which may solve the mystery for me with regards to BDNF and the actions of some pharmacological treatments, the fact that they don't allow for differentiation of cells may help in explaining why some treatments are not effective in 25% of TRD cases. Naturally there will be other factors, but perhaps this needs to be looked into very seriously in relation (I do not know if anyone is or has been) to utilising GH to increase BDNF in patients with Depression. What do you think of this? I am now very excited about the potential that GH may have in mental disorders. I had a look at the MRI scans and was overwhelmed by the results. They were nothing short of miraculous and I have let a number of people know as I have never seen a result like that. I hope they also find it fascinating.

Thank you again Cheryl. GH is a very important hormone, but not the unique solution. In fact we had several bad results when using it, but also a big number of very incredible and unexpected results allowing babies with cerebral palsy to be normal children or young people with important brain injuries to come back to a normal life of students or workers, also hemiplegic patients... GH is able to induce the expression of a number of neurotrophic factors: IGF-I, BDNF, EPO, VEGF, EGF (and strong induction of EGF-R) and also induces the release of neurotrophic interleukines. Acutely leads to significant neutrophilia. GH plays a key role during brain development. Unfortunately it is the hormone of youthness, but perhaps this is the reason by which it plays so big number of important positive actions. Still there is a lot to be studied about this hormone and its variants. Years ago we published that depending on the tissue the hormone is metabolized to different shorter peptides; most likely each of them plays an independent and specific role but it remains to be studied.

Thank you Jesus, based on the information you have given me and the studies, I will be doing some research into GH as a partial contributor to the attenuation of Depression in Ischemic patients. Thank you for contributing such valuable knowledge and experience, it has been greatly appreciated!

Jesus, I am now attempting to form a more focused question and would love your input (as this is not my field of expertise). If GH administered exogenously "increases hypothalamic somatostatin release, because pituitary GH secretion is tonically inhibited by somatostatin. In turn, increased somatostatin release leads to increased dopamine and noradrenaline synthesis and release" (Jesus - see your prior answer), would the increased presence of of noradrenaline (co-transporter of dopamine) thereby increase the presence of dopamine servicing the prefrontal lobes, which has been found through various pharamacological trials on SSRNI's to be an important factor in the treatment of Depression, specifically as this may increase activities in the left prefrontal lobe? It may be possible to establish a specific correlation between GH and the alleviation of some depressive symptomologies. Naturally GH affects other brain regions etc, but I am just trying to establish possible hypothetical correlations one by one. Thank you so much for your time.

Of course, your idea seems to be correct, we never tested it in experimental models though. But it is true, and we see it in clinics, that a lot of patients experience a kind of GH-dependence in terms of that they ask for the hormone when we stop a treatment.

I tried GH in myself 15 years ago, despite of I am not GH-deficient. I used it for 3 months and during this time I felt myself as if I were in my twenties. I noticed it more when I stopped the administration, the sky became to be black instead of brilliant blue as it was under GH.

Kind regards

Jesús

By the way, I forgot to tell it to you in my previous answer. A SPECT analysis was made in one of our patients under GH treatment and captation (that is activity) in frontal lobes was highly increased in comparison to a previous SPECT before GH treatment began.

Thank you Jesus, that is very useful information!

Hippocampal volume is a complex subject. Of itself, it says nothing about why volume is reduced, what layers are involved, and whether glia or neurones are primarily responsible. Function rather than volume per se is perhaps more relevant. There may also be considerable functional redundancy in the hippocampus. Of note too is whether the finding is unilateral or bilateral. Of all the brain locations we know of, the hippocampus is the most likely area for regeneration to occur. How much regeneration that is required to restore some level of normalcy is an important question. The degree of volume loss may not be so important if function can be restored, which relates to connectivity amongst other things. The latter is a slow process. If volume alone were to be restored, there is no guarantee that function will be restored too. Finally, scarring and other pathology may hinder proper anatomical restoration.

Thank you John, your expert input is much appreciated. I agree with what you say, and one of the factors I am trying to establish is whether the restoration of the hippocampus will have an effect on certain aspects of symptomology, or cognitive impiarment, and if so, how much of an effect it has. The question is based on findings from morphological studies, and I have quoted aspects for you:

Reductions in the volume of the hippocampus are reported in subjects with a

history of depression (Bremner et al 2000; Krishnan et al

1991; Shah et al 1998; Sheline et al 1996; 1999). Interestingly,

the loss of hippocampal volume is correlated with

the total lifetime duration of depression but not with the

age of the patients (Sheline et al 1999). It has been

proposed that repeated stress during recurrent depressive

episodes may inflict cumulative hippocampal injury as

reflected in the loss of structural volume (Duman 1999).

The volume reduction in the hippocampus in depression

may be a result of a loss in the number of neurons due to

a neurotoxic effect of glucocorticoids (McEwen 1997;Sapolsky et al 1990, 1991)."

"In a recent study, significant reductions in MR messenger

RNA (mRNA) in the hippocampus and GR mRNA in the

PFC were detected in suicide victims with a history of

mood disorders (Lopez et al 1998; 42). Thus, stressinduced

alterations in glucocorticoids and subsequent

decreases in MR or GR populations in the hippocampus

and PFC may be a mechanism whereby stress triggers or

exacerbates depression."

These are two excerpts from a morphological study"

G, Rajkowska. 2000. DYSFUNCTION IN NEURAL CIRCUITS INVOLVED IN THE

PATHOPHYSIOLOGY OF MOOD DISORDERS. Postmortem Studies in Mood Disorders Indicate Altered Numbers of Neurons and Glial Cells. Biological Psychiatry. 767 (48) pp:766–777

Dear John I responded, but for some reason the response has gone missing. I quite agree with you, and though functionality can be retained one of the issues is that in Suicide cases of Depressed people this specific factor has been found (amongst others). I am now trying to establish if one was to reverse this occurrance, if this would have an impact of certain functionalities and symptomologies. I have included excerpts below from the morphological study concerned, there are other studies, but this was the key one.

"Reductions in the volume of the hippocampus are reported in subjects with a

history of depression (Bremner et al 2000; Krishnan et al

1991; Shah et al 1998; Sheline et al 1996; 1999). Interestingly,

the loss of hippocampal volume is correlated with

the total lifetime duration of depression but not with the

age of the patients (Sheline et al 1999). It has been

proposed that repeated stress during recurrent depressive

episodes may inflict cumulative hippocampal injury as

reflected in the loss of structural volume (Duman 1999).

The volume reduction in the hippocampus in depression

may be a result of a loss in the number of neurons due to

a neurotoxic effect of glucocorticoids (McEwen 1997;

Sapolsky et al 1990, 1991)................."Thus, stressinduced

alterations in glucocorticoids and subsequent

decreases in MR or GR populations in the hippocampus

and PFC may be a mechanism whereby stress triggers or

exacerbates depression.

Chronic stress or the repeated administration of glucocorticoids

to animals results in the degeneration of

specific types of hippocampal neurons (Sapolsky et al

1990, 1991; Watanabe et al 1992). Stress- or glucocorticoid-

related cellular changes observed in the primate and

rodent hippocampus include dendritic atrophy, shrinkage

of the neuronal cell body, and nuclear pyknosis (Sapolsky

et al 1990; Watanabe et al 1992). Stressful experience also

suppresses the normal production of granule cells in the

hippocampal dentate gyrus during postnatal development

and in adulthood (Gould and Tanapat 1999). Such postnatal

reductions in the production of new cells are likely to

alter the structure and function of the adult hippocampal

formation and related structures. Thus, it has been proposed

that changes in the hippocampus, secondary to

stress, may be central to the development of depression in

genetically vulnerable individuals (Duman 1999)."

Grazyna Rajkowska. 2000.DYSFUNCTION IN NEURAL CIRCUITS INVOLVED IN THE PATHOPHYSIOLOGY OF MOOD DISORDERS. Postmortem Studies in Mood Disorders Indicate Altered Numbers of Neurons and Glial Cells. Biological Psychiatry. 48:766–777.

Cheryl, these are intriguing questions and thoughts to ponder. Might you, or someone following this line, have insight into whether a positive correlation has been made between hippocampal volume and mood? Do inherently happy people have increased hippocampal volume compared to those with sever chronic depression?

Dear John, thank you for asking and it is an interesting question indeed. None of the research I have come across examines 'normal' mood states in relation to Hippocampal volume, but there are a number of clues that may provoke some interesting thoughts.

Yes, there would be a differentiation in hippocampal volume loss between a 'normal' person and one with severe chronic depression as studies have found that the duration of the depression suffered is closely linked to hippocampal volume loss. If you wish I can send you studies relating to this.

On another note, when I consider Bipolar Depression and the Manic phase of the disorder, which I would define as an extreme form of happiness I noticed that the findings indicated in general that there is no increase in hippocampal volume. I humbly stand to be corrected by any of my colleagues. I will send you some interesting articles I have on hippocampal volume loss in relation to BD that might help. In the meantime, please see excerpts of some studies and articles below that might assist on this particular train of thought:

I have not put the references in proper APA format for this post, but the information is there.

What the studies indicate to me is that there is no increase in hippocampal volume in a happy mood state, if one considers that there is none in a manic phase of BD. What might occur (amongst many other things!) is reduced number of serotonin receptors which cause hippocampal volume loss, or damage to the hippocampus may result in fewer serotonin receptors.

Note - BD = Bipolar Disorder

"For both the amygdala and hippocampal regions, we found an overall significant volume reduction in the BD compared with the control group (P

Dear Cheryl, thank you for sharing your thoughts. Might you have more info on the imaging studies? How was hippocampal volume measured?

With respect to the BP work, whereas changes in the same individual would provide key internal controls, significant changes on such a timescale may be improbable. Many structural changes in the adult brain have been thought to be irreversible until recently, and may occur slowly over a period of months or years. Thus the lack of a quantifiable difference between manic and depressed state may be unsurprising. Another consideration is that although a manic phase of BP may appear as extreme happiness, dysfunctional circuitry is likely to be an underlying factor common to the bidirectional extremes of the disorder.

Thank you John, your explanation on BD makes a great deal of sense! It would be wonderful to know more about the dysfunctionl circuitary in BD, as it is not a disorder that I have had time to focus on specifically. I will have a look for the imaging studies ( I have to go into my archives) and I will send them to you via the message system in the next two days. Keep well!