Showing posts with label Stress. Show all posts
Showing posts with label Stress. Show all posts

Sunday 5 May 2013

Stress, Neuroinflammation and Magnolia before bed

In earlier posts we learned about two kinds of stress:-
  • Oxidative stress is a biological stress that is measurable (GSH redox) and has been shown to be present in most autistic people.
  • Psychological stress is a feeling we experience in difficult situations and is measurable by sampling the level of the hormone cortisol in saliva.
It would appear that both types of stress are interrelated.
We have already established that oxidative stress in autism can be successfully be treated with NAC.  NAC acts both as an anti-oxidant in its own right and as a precursor chemical to form GSH, the body’s own antioxidant.  NAC is cheap and widely available.
The scientific literature regarding autism includes many references to inflammation of the brain, or neuroinflammation. It turns out that this inflammation is also measurable.  When samples of cerebrospinal fluid (CSF) are taken, elevated levels of chemicals called cytokines are found.  Certain cytokines are markers for neuroinflammation, such as TGF-ß1 and MCP-1.
In studies at Johns Hopkins, a leading teaching hospital in the US, they have tested all their autistic research subjects for neuroinflammation and they all tested positive.  It also appears that this is the result of on-going damage to the brain, not residual damage from the pre-natal or early post natal period.  Such damage was exhibited in autistic subjects of all ages.  These researchers were also able to locate the part of the brain most affected by neuroinflammation.
“Our study showed the cerebellum exhibited the most prominent neuroglial responses. The marked neuroglial activity in the cerebellum is consistent with previous observations that the cerebellum is a major focus of pathological abnormalities in microscopic and neuroimaging studies of patients with autism. Based on our observations, selective processes of neuronal degeneration and neuroglial activation appear to occur predominantly in the Purkinje cell layer (PCL) and granular cell layer (GCL) areas of the cerebellum in autistic subjects. These findings are consistent with an active and on-going postnatal process of neurodegeneration and neuroinflammation.”
There are numerous other researchers who concur with these findings; the problem is that they do not take the logical next step of finding how to reduce this inflammation.  Indeed John’s Hopkins go as far as to tell us
“At present, THERE IS NO indication for using anti-inflammatory medications in patients with autism. Immunomodulatory or anti-inflammatory medications such as steroids (e.g. prednisone or methylprednisolone), immunosupressants (e.g. Azathioprine, methotrexate, cyclophosphamide) or modulators of immune reactions (e.g. intravenous immunoglobulins, IVIG) WOULD NOT HAVE a significant effect on neuroglial activation because these drugs work mostly on adaptive immunity by reducing the production of immunoglobulins, decreasing the production of T cells and limiting the infiltration of inflammatory cells into areas of tissue injury. Our study demonstrated NO EVIDENCE at all for these types of immune reactions. There are on-going experimental studies to examine the effect of drugs that limit the activation of microglia and astrocytes, but their use in humans must await further evidence of their efficacy and safety” 
Here the researchers were experimenting with various chemical including NAC as an antioxidant.
“Activation of microglia has been implicated in the pathogenesis of a variety of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Creutzfeld-Jacob disease, HIV-associated dementia (HAD), stroke, and multiple sclerosis (MS) . It has been found that activated microglia accumulate at sites of injury or plaques in neurodegenerative CNS. Although activated microglia scavenge dead cells from the CNS and secrete different neurotropic factors for neuronal survival, it is believed that severe activation causes inflammatory responses leading to neuronal death and brain injury. During activation, microglia secretes various neurotoxic molecules and express different proteins and surface markers.
Although microglia populate only 2 to 3% of total brain cells in a healthy human being, the number increases up to 12 to 15% during different neurodegenerative diseases. Microglial activation is always associated with neuronal inflammation and ultimately neuronal apoptosis. Although microglial activation may not be always bad as it has an important repairing function as well, once microglia become activated in neurodegenerating microenvironment, it always goes beyond control and eventually detrimental effects override beneficial effects. Therefore, microglial activation is a hallmark of different neurodegenerative diseases and understanding underlying mechanisms for microglial activation is an important area of study. “ 
Another piece of research that looked at activated microglia in a neurological condition (this time Alzheimer’s disease) also used NAC as an antioxidant and anti-inflammatory agent.

Now, to better understand the terminology and the science, a little bit of biology would be useful.  If you wish to skip this part, you can go forward a few pages to the part where I look at practical steps that seem likely to reduce neuroinflammation.
 Here are the key words we need to understand:- 
  • Neurons
  • Neurotransmitters
  • Glial cells
  • Microglia
  • Astrocytes or astroglia
  • Cytokenes

Thanks to Wikipedia I have presented a summary.
 1.  Neurons
A neuron is a cell that processes and transmits information through electrical and chemical signals. A chemical signal occurs via a synapse a specialized connection with other cells. Neurons connect to each other to form neural networks. Neurons are the core components of the CNS (Central Nervous System), which includes the brain and spinal cord. A number of specialized types of neurons exist: sensory neurons respond to touch, sound, light and numerous other stimuli affecting cells of the sensory organs that then send signals to the spinal cord and brain. Motor neurons receive signals from the brain and spinal cord, cause muscle contractions, and affect glansa. Interneurons connect neurons to other neurons within the same region of the brain or spinal cord.


2.  Neurotransmitters - interaction between neurons
A neuron affects other neurons by releasing a neurotransmitter that binds to chemical receptors. The effect upon the postsynaptic neuron is determined not by the presynaptic neuron or by the neurotransmitter, but by the type of receptor that is activated. A neurotransmitter can be thought of as a key, and a receptor as a lock: the same type of key can here be used to open many different types of locks. Receptors can be classified broadly as excitatory (causing an increase in firing rate), inhibitory (causing a decrease in firing rate), or modulatory (causing long-lasting effects not directly related to firing rate).
The two most common neurotransmitters in the brain, and GABA, have actions that are largely consistent. Glutamate acts on several different types of receptors, and have effects that are excitatory at ionotropic receptors and a modulatory effect at metabotropic receptors. Similarly GABA acts on several different types of receptors, but all of them have effects (in adult animals, at least) that are inhibitory. Because of this consistency, it is common for neuroscientists to simplify the terminology by referring to cells that release glutamate as "excitatory neurons," and cells that release GABA as "inhibitory neurons." Since over 90% of the neurons in the brain release either glutamate or GABA, these labels encompass the great majority of neurons.

GABA is very important in autism and we will return to it in greater depth when we will look at the three types of GABA receptors.

3.   Glial cells
Glial cells are non-neuronal cells that maintain homeostasis and provide support and protection for neurons in the brain, and for neurons in other parts of the nervous system such as in the autonomic nervous system.
Four main functions of glial cells have been identified:
  1. To surround neurons and hold them in place,
  2. To supply nutrients and oxygen to neurons,
  3. To insulate one neuron from another,
  4. To destroy pathogens and remove dead neurons.
Glial cells do modulate neurotransmission, although the mechanisms are not yet well understood.

Some glial cells function primarily as the physical support for neurons. Others regulate the internal environment of the brain, especially the fluid surrounding neurons and their synapses, and nutrify neurons. During early embryogenesis glial cells direct the migration of neurons and produce molecules that modify the growth of axons and dendrites. Recent research indicates that glial cells of the hippocampus and cerebellum participate in synaptic transmission, regulate the clearance of neurotransmitters from the synaptic cleft, and release gliotransmitters such as ATP, which modulate synaptic function.
Glial cells were not believed to have chemical synapses or to release transmitters. They were considered to be the passive bystanders of neural transmission. However, recent studies have shown this to be untrue. For example, astrocytes are crucial in clearance of neurotransmitters from within the synaptic cleft, which provides distinction between arrivals of action potentials and prevents toxic build-up of certain neurotransmitters such as glutamate (excitotoxicity). It is also thought that glia play a role in many neurological diseases, including Alzheimer’s disease. Furthermore, at least in vitro, astrocytes can release gliotransmitter glutamate in response to certain stimulation.
Glia have a role in the regulation of repair of neurons after injury. In the CNA (Central Nervous System), glia suppress repair. Glial cells known as astrocytes enlarge and proliferate to form a scar and produce inhibitory molecules that inhibit regrowth of a damaged or severed axon. In the PNS (Peripheral Nervous System), glial cells known as Schwann cells promote repair. After axonal injury, Schwann cells regress to an earlier developmental state to encourage regrowth of the axon. This difference between PNS and PNS raises hopes for the regeneration of nervous tissue in the CNS. For example a spinal cord may be able to be repaired following injury or severance.

4.  Microglia
Microglia are a type of glial cell that are the resident macrophages of the brain and spinal cord, and thus act as the first and main form of active immune defense in the CNS. Macrophages are highly specialized in removal of dying or dead cells and cellular debris. This role is important in chronic inflammation, as the early stages of inflammation are dominated by neutrophil granulocytes, which are ingested by macrophages if they come of age.
Microglia constitute 20% of the total glial cell population within the brain.] Microglia (and astrocytes) are distributed in large non-overlapping regions throughout the brain and spinal cord.  Microglia are constantly scavenging the CNS for plaques, damaged neurons and infectious agents. The brain and spinal cord are considered "immune privileged" organs in that they are separated from the rest of the body by a series of endothelial cells known as the blood brain barrier (BBB), which prevents most infections from reaching the vulnerable nervous tissue. In the case where infectious agents are directly introduced to the brain or cross the blood–brain barrier, microglial cells must react quickly to decrease inflammation and destroy the infectious agents before they damage the sensitive neural tissue. Due to the unavailability of antibodies from the rest of the body (few antibodies are small enough to cross the blood brain barrier), microglia must be able to recognize foreign bodies, swallow them, and act as antigen presenting cells activating T-cells. Since this process must be done quickly to prevent potentially fatal damage, microglia are extremely sensitive to even small pathological changes in the CNS. They achieve this sensitivity in part by having unique potassium channels that respond to even small changes in extracellular potassium.
5.  Astrocytes or astroglia,
Astrocytes or astroglia are characteristic star-shaped glial cells in the brain and spinal cord. They are the most abundant cell of the human brain. They perform many functions, including biochemical support of endothelial cells that form the blood-brain barrier, provision of nutrients to the nervous tissue, maintenance of extracellular ion balance, and a role in the repair and scarring process of the brain and spinal cord following traumatic injuries.
Research since the mid-1990s has shown that astrocytes propagate intercellular Ca2+- waves over long distances in response to stimulation, and, similar to neurons, release transmitters (called gliotransmitters) in a Ca2+-dependent manner. Data suggest that astrocytes also signal to neurons through Ca2+-dependent release of glutamate. Such discoveries have made astrocytes an important area of research within the field of neuroscience..
Previously in medical science, the neuronal network was considered the only important one, and astrocytes were looked upon as gap fillers. More recently, the function of astrocytes has been reconsidered, and are now thought to play a number of active roles in the brain, including the secretion or absorption of neural transmitters and maintenance of the blood–brain barrier.  Following on this idea the concept of a "tripartite synapse" has been proposed, referring to the tight relationship occurring at synapses among a presynaptic element, a postsynaptic element and a glial element.
  • Structural: They are involved in the physical structuring of the brain. Astrocytes get their name because they are "star-shaped". They are the most abundant glial cells in the brain that are closely associated with neuronal synapses. They regulate the transmission of electrical impulses within the brain.
  • Glycogen fuel reserve buffer: Astrocytes contain glycogen and are capable of glycogenesis. The astrocytes next to neurons in the frontal cortex and hippocampus store and release glycogen. Thus, Astrocytes can fuel neurons with glucose during periods of high rate of glucose consumption and glucose shortage. Recent research suggests there may be a connection between this activity and exercise.
  • Metabolic support: They provide neurons with nutrients such as lactate.
  •  Blood-brain barrier: The astrocyte end-feet encircling endothelial cells were thought to aid in the maintenance of the blood–brain barrier, but recent research indicates that they do not play a substantial role; instead, it is the tight junctions and basal lamina of the cerebral endothelial cells that play the most substantial role in maintaining the barrier. However, it has recently been shown that astrocyte activity is linked to blood flow in the brain, and that this is what is actually being measured in fMRI.
  • Transmitter uptake and release: Astrocytes express plasma membrane transporters such as glutamate transporters for several neurotransmitters, including glutamate, ATP, and GABA. More recently, astrocytes were shown to release glutamate or ATP in a vesicular, Ca2+-dependent manner.
  •  Regulation of ion concentration in the extracellular space Astrocytes express potassium channels at a high density. When neurons are active, they release potassium, increasing the local extracellular concentration. Because astrocytes are highly permeable to potassium, they rapidly clear the excess accumulation in the extracellular space. If this function is interfered with, the extracellular concentration of potassium will rise, leading to neuronal depolarization by the Goldman equation. Abnormal accumulation of extracellular potassium is well known to result in epileptic neuronal activity.
  • Vasomodulation: Astrocytes may serve as intermediaries in neuronal regulation of blood flow.
  • Nervous system repair: Upon injury to nerve cells within the central nervous system, astrocytes fill up the space to form a glial scar, repairing the area and replacing the CNS cells that cannot regenerate.
  • Long-term potentiation: Scientists continue to argue back and forth as to whether or not astrocytes integrate learning and memory in the hippocampus. It is known that glial cells are included in neuronal synapses, but many of the LTP studies are performed on slices, so scientists disagree on whether or not astrocytes have a direct role of modulating synaptic plasticity.
6.  Cytokines
Cytokines are small signaling molecules used for cell signaling.  The term cytokine encompasses a large and diverse family of regulators produced throughout the body by cells of diverse embryological origin.
The term cytokine has been used to refer to the immunomodulating agents, such as interleukins and interferons. Biochemists disagree as to which molecules should be termed cytokines and which hormones. As we learn more about each, anatomic and structural distinctions between the two are fading. Classic protein hormones circulate in nanomolar (10-9M) concentrations that usually vary by less than one order of magnitude. In contrast, some cytokines (such as IL-6) circulate in picomolar (10-12M) concentrations that can increase up to 1,000-fold during trauma or infection. The widespread distribution of cellular sources for cytokines may be a feature that differentiates them from hormones. Virtually all nucleated cells, but especially endo/epithelial cells and resident macrophages (many near the interface with the external environment) are potent producers of IL-1, IL-6, and TNF-a. In contrast, classic hormones, such as insulin, are secreted from discrete glands (e.g., the pancreas).  As of 2008, the current terminology refers to cytokines as immunomodulating agents. However, more research is needed in this area of defining cytokines and hormones.
Part of the difficulty with distinguishing cytokines from hormones is that some of the immunomodulating effects of cytokines are systemic rather than local. Further, as molecules, cytokines are not limited to their immunomodulatory role. For instance, cytokines are also involved in several developmental processes during embyrogenesis.

Several inflammatory cytokines are induced by oxidant stress. The fact that cytokines themselves trigger the release of other cytokines and also lead to increased oxidant stress makes them important in chronic inflammation, as well as other immunoresponses, such as fever and acute phase proteins of the liver (IL-1,6,12, INF-a).
Practical Steps to reduce neuroinflammation
Neuroscience is both complex and an evolving science; much remains unknown and so often there cannot be definite answers; rather judgements based on the balance of probabilities.
What is clear is that in autism we have oxidative stress and inflammation.  There also appears to be a vicious circle where the inflammation messenger itself makes that inflammation worse.  In some cases, it is the oxidative stress that triggers the inflammation; in other cases the inflammation may have other causes.
A more complex explanation relates to where the signal to the microglia came from in the first place.  Mast cells from the immune system are proposed to be the source of this signal.
For the time being let us focus on the simpler solution; that the anti-oxidant should also be the anti-inflammatory agent.  Surprise, surprise, our friend NAC is being used in numerous studies as the anti-inflammatory agent.
This is good news for Monty; it may be that NAC is not just reducing his state of oxidative stress, but gradually his neuroinflammation as well.  It certainly does seem to be doing him good.  As indicated in the research, the effect of NAC seems to be highly dose dependent.
But not to have all our eggs in one basket, it would be nice to have another anti-neuroinflammatory agent.  It seems there is one at hand, but we have to look to the East to find it.
The bark of the magnolia tree has been used in Korean, Chinese and Japanese medicine for more than a thousand years.  It seems that one compound in particular within magnolia, obovatol, has powerful properties to reduce neuroinflammation.
In another paper
and another
This is all experimental but it is clear that in theory at least, obovatol looks very interesting.
For a wider view of the medical properties of the magnolia family, there is an excellent paper from Korea that reviews the possible mechanisms. Therapeutic applications of compounds in the Magnolia family
 The proposed benefits are in the treatment of:- 
  • cancer
  • neuronal disease
  • inflammatory disease
  • cardiovascular disease 
The four active compounds are: 
  1. magnolol
  2. honokiol
  3. 4-O-methylhonokiol
  4. obovatol 
Also, anxiolytic-like effects of obovatol appeared to be mediated by the GABA benzodiazepine receptor Cl− channel opening and obovatol potentiated pentobarbital-induced sleeping time through GABA receptors/Cl− channel activation.

This data suggest that components of Magnolia could be used for treating anxiety, and its effect may be linked to GABA receptor/Cl− channel activation. 
Anti-inflammatory mechanisms of Magnolia have been reported to be associated with the suppression of NO production, the expression of iNOS, IL-1β, TNF-α and COX, the generation of prostaglandins, thromboxanes and leukotrienes, and the activation of MAPKs, AP-1 and NF-κB.
Magnolia Bark Extract
Magnolia bark extract is extensively produced in China and sold inexpensively by the supplement industry.  The individual compounds could be separated, as in the Korean research, but the extract that is sold is just a mixture of what happened to be in that batch of bark.  If you read the reviews, it seems that many people experience a reduction in cortisol allowing them to sleep better; reduced anxiety is widely reported.  It even seems to stop some people snoring, which I am certainly all in favour of.
So while it is far from the scientific basis on which you could use NAC, it would seem that Magnolia bark extract will unlikely do harm and just might do some good as an anti-neuroinflammatory agent.  In about 20 years, the research will show whether you were wasting your money, or whether you were a pioneering early-adopter.
I think I will do some primary research on this one and be a pioneer.


Wednesday 17 April 2013

Cortisol, AVP, Oxytocin - Part II Stress Reactivity Model

I think today's post is going to be one of my better efforts.  We are continuing with the theme of Cortisol, depression and stress; but we are going to add two further chemicals, both "social neuropeptides".

The reason than today's post is worth reading is that it will bridge neurobiology and neuropsychology.   For me at least, psychology is light reading whereas biology needs more thought and understanding.  A social neuropeptide is a nice term not invented by me; it seems to come from Dr Stein from the University of Cape Town.

Rather than understand everything about human hormones, we are just trying to understand stress and coping mechanisms, so that we can reduce or  just better manage autistic behaviours. 


Cortisol is a hormone that is very easy to measure; saliva samples will do just fine.  Cortisol levels, or changes in cortisol levels, tell us about how the body is coping with emotion stress.  We are not talking about oxidative stress, but clearly there is direct linkage between the two.

We know that cortisol is a hormonal body clock (it maintains diurnal rhythms), cortisol levels should peak 30 minutes after waking, decline rapidly in the morning and then reach its lowest level in the evening.  This is well illustrated in the figure below, from an excellent study by Vahdettin Bayazit from Turkey.  He was studying the effect of exercise and stress on cortisol levels.


Children with ASD are known to have atypical response to stress and some have dysregulation of diurnal rhythms and abnormally high evening cortisol levels.  Among children with ASD there are significant individual differences, so the level of dysregulation is variable.  Note that many children with ASD have sleeping disorders; not surprising really if their body clock is malfunctioning.

In Bayazit's study he comments:-
"The more unexpected finding was that the evening values (of cortisol) for the children with autism tended to be consistently elevated in comparison with the neurotypical group."
I do not find this result surprising; in fact I would expect it.
He goes on to tell us that it is known that older children with depression have altered hormone levels, including hypersecretion of cortisol in the evening.
Now back to a stressful event.  In Turkey, a group of high functioning children with ASD were given a public speaking task; their heart rates and saliva cortisol were measured, before, after and during this "stressful event".
All we need to note is that the stress tended to cause a spike in cortisol level.

Stress Reactivity Model

Now we combine biology with psychology.  I took an existing model from an excellent book called "The neuropsychology of Autism".  Chapter 22 has a paper by Suma Jacob et al; she provided the biology and I just added the psychology (the opposite of what you might have expected)

This model shows how the equilibrium in managing stress is hopefully maintained.

The two little interlopers on the chart above, oxytocin and AVP are social neuropeptides.  Oxytocin is seen as beneficial; it reduces stress levels and gives a feeling of wellbeing.  AVP (Arginine Vasopressin) works in conjunction with CRH (Cortisol Releasing Hormone) to control the release of cortisol.  AVP seems to work in a "bad" way, in that it exaggerates/magnifies natural changes in cortisol.  So if you have a lot of AVP, a small spike in cortisol would become a big spike in cortisol.

Both AVP and cortisol have numerous other functions in the body. For example AVP is also known as the antidiuretic hormone (ADH) and a version of it is used in therapy in extreme cases of bedwetting by children. Whoever designed the human body was either short of chemicals, or likes to play practical jokes.

We already learned in Part I, that you can reduce your own level of cortisol just by singing.  It is reassuring to know that you do not always need drugs.  There are in fact other ways that you can maintain your own homeostatis and reduce cortisol.

A clever clinical psychologist from the University of Zurich, called Markus Heinrichs,  has provided us with an excellent study that compares the effect of social support vs oxytocin as regulators of stress.  What he did was to create two groups of people, in one group each subject brought along their best friend; the other group all came alone.  Then each subject was put through this stressful process:-

"During the introduction to the TSST (Trier Social Stress Test) they were then told that they would be required to give a 5-min mock job interview to an unknown panel (consisting of one man and one woman) on personal suitability for a job and to enumerate their strengths and qualifications in an unstructured manner, followed by 5 min of mental arithmetic performed out loud. To increase task engagement, the job description was matched to each participant, taking into consideration his own individual goals and aspirations. The panel of evaluators were presented as experts in the evaluation of nonverbal behavior."

The subjects were typical males in their early 20s.  Half the subjects had social support of a friend being present, and then each group had either a placebo or had a dose of oxytocin.  Here are the results:-

The base case is the "No social support + placebo".  This shows the highest increase in cortisol (i.e. stress).  The calmest group had "social support + oxytocin".  Of great interest is that the "social support + placebo" ended up less stressed than the "no social support + oxytocin".

This experiment showed the clear positive effect of both social support and oxytocin.

So in the stress reactivity model (the blue one up top) I decided to add social support and singing.  Clearly there are plenty of other social/psychological strategies that would likely have a similar cortisol reducing effect. 

Another dose of cortisol will come shortly in Part III.


Sunday 14 April 2013

Cortisol, AVP, Oxytocin - Part I Depression & Stress

Today starts a mini-series inspired by a reader’s comment about depression.  Angie, from Australia, pointed out that while the kids with ASD might not be depressed, many of the parents certainly are.  Not only will we address Angie’s point, but we will extend it a little and show how this can also help in our quest for the grail.

Many people have stressful lives, but some have discovered a special way to overcome this.  I was reading an English newspaper recently and there was an article about a celebrity cook, Nigella Lawson, who is very popular on the BBC.  While Jamie Oliver appears not to overindulge on his own cooking, it appears that Nigella does. Nigella was giving her tips to losing those excess pounds or kilograms.  The interesting part was not the treadmill in the spare room, but her comment about singing extremely loudly while using it.  
Here comes the science part.  Cortisol is an important hormone; and as we learnt previously when studying TRH, while a hormone may have a well-documented primary function, there may also have numerous additional effects.  The most important roles of cortisol are the activation of three metabolic pathways:-

1.    Generating glucose

2.    Anti-stress

3.    Anti-inflammation

The function that Nigella has stumbled upon is number two.  While we all need cortisol, too much is not good for you.
Cortisol is released in response to stress and while short term increases serve a valuable purpose, prolonged cortisol secretion, perhaps caused by chronic stress, can cause damaging physiological changes.
It would be nice if there was a way to reduce excess, stress-induced, cortisol and then you would feel calm, refreshed and ready to fight on.  While exercise is also very good for you, it is actually the singing that really makes Nigella feel good.

It is scientifically established that singing substantially reduces your level of cortisol, which in turn makes you feel much better.  Here is a link to simple study done in Angie’s home country and with the help of the Macquarie University Choir.
I could now tell you all about music therapy and its application in psychiatry.  If you are interested, do look into it; it is used to treat everything from autism to alcoholism.

In essence music is good for you; but it seems that making your own music is far more beneficial than just listening to other people.

Tip for parents
Follow Nigella’s example (and mine) and sing.
I will check to see if Angie does.

Back to ASD
Have you noticed that an autistic child is at their most stressed first thing in the morning?  I certainly have; this was particularly marked when Monty’s behaviour regressed.  My approach was and remains to have Monty through this possible trouble zone quickly; so once he is up, he should have breakfast, brush teeth and get dressed promptly. It proved an effective strategy.
I did wonder what the reason for this phenomenon was.  Originally, I thought it was just the fact that he had not eaten for a long time and so his blood sugar level had dropped.  This applies with all kids; if they have not eaten, they will get cranky.

Now I have an alternative explanation, and probably a better one. It is likely to do with the natural variation in cortisol levels in the blood that apparently peaks at about 8am and falls to a low for the day at bed time.  Wait to read more in Part II.

Autism, Depression and Suicidal Tendencies
It may not make cheerful reading, but one factor these three groups all have in common is dysregulation of the HPA, which is the Hypothalamic-Pituitary-Adrenal Axis.  There is also the well documented phenomenon of enhanced cortisol response to stress in children in autism. This will be continued in a science-heavy Part II and quite possibly will result in another hypothesis regarding a practical intervention.

Just to let you know, that my very long recent post about the TRH hypothesis has now gone for review to a clever and interested neuroscientist in the US.  I have a feeling that it will shortly be joined by my CRH (corticotropin releasing hormone) hypothesis; but maybe it should be called Angie’s CRH hypothesis?