Friday, September 26, 2008

The Mysteries of Vision








One of the most misleading analogies in neuroscience is "eye is like a camera". It is nothing of the sort. The anatomy of the eye makes that plainly obvious. For example, look at the graphic above. The top most part is the Retinal Pigment Epithelium. It plays a vital role in re processing vitamin A, absorbing excessive light, providing nutrients for the photoreceptors, and eliminating waste from the retina. Some studies suggest that the failure of the RPE to process and remove waste products is a cardinal feature in Age Related Macular Degeneration. The photo-sensitive portion of the photoreceptors is directly underneath the RPE.

Here's the rub: light does not travel from the top but from the bottom of this graphic. For light to stimulate the photooreceptors it must travel through the ganglion cell layer right up to the tip of the photoreceptors near the RPE. Quite amazing that we see it at all and it explains why some bods refer to the retinal structure as being "back the front". Now find me a camera that works like that ... .

Over and above that consideration the brain also goes to tremendous lengths to process visual information. It has been estimated that up to 30% of all CNS tissue can be involved in visual processing. The signals from the retina first must travel to the lateral geniculate nucleus(LGN) a set of small nuclei in the thalamus, from there the journey continues to the back of the brain to the VI or striate cortex, which appears to involve rudimentary visual processing, and then must travel forwards again to the temporal lobe(for object identification) and the parietal cortex(for position in space determination). This is the simple explanation!

What is becoming intriguing in our the research into vision is the research indicating that when we see the world the image we have in our minds is the result of this visual processing that is combined with our visual memory storage. That is, to a certain extent at least, the world we see is contingent on what we have been seeing our whole lives. With this little introduction in mind, have a look at these interesting visual hallucinations.

Go to this link and then download the relevant files. Have fun!

The Dark Side of Statins(cholesterol lowering drugs)

Cholesterol-lowering drugs and the effect on muscle repair and regeneration

Statin drugs are life savers and a principal component in allowing many people with high cholesterol to avoid heart attacks and strokes. Many statins exhibit anti-inflammatory properties and there have been trials for statins in dementia treatment. The results have not been that promising.

Many patients have reported problems with statin drugs and the research is now starting to bear this out. While statin drugs are life savers as with nearly all drugs there can be untoward effects. If you are taking statins and experience any of the symptoms mentioned in this article speak to your doctor. Take the article with you so they know you are not just dreaming up the symptoms.

If you are taking a statin drug it is strongly advisable to also take a co-q10 supplement with the statins because statin drugs typically inhibit HMG-CoA, a rate limiting enzyme for co-q10 production in the body. It is very important to maintain co-q10 levels because it is a strong antioxidant that plays a pivotal role in the electron transport chain, the "powerhouse" in our cells.

Caloric Restriction is a NoGo for Humans

Differences between People and Animals on Caloric Restriction

Most people interested in health related issues have heard of caloric restriction, the only known laboratory method for extending life. In this study they recruited members of the CR Society who had been practicing caloric restriction for 7 or more years. The results are disappointing and back claims by other scientists that human beings may not benefit from caloric restriction. My personal view is that caloric restriction is too severe and cannot be applied in our busy and work oriented society. Additionally other studies have indicated that constant caloric restriction can cause the following problems

  • reduces immunity(some studies indicate it can lead to death of helper B cells, thereby restricting our adaptive immune capacity),
  • loss of fertility for both males and females,
  • cognitive issues, in fact a recent study claimed that chronic CR can actually cause brain damage.

In this study the researchers did find a way to alter the key physiological marker for the beneficial effects of CR: reducing IGF1 expression. IGF is Insulin Growth Factor. Under stimulation from human growth hormone, IGF is released by the liver and travels throughout the body. The researchers asked one set of the participants to lower their protein intake and within 3 weeks this caused a dramatic reduction in IGF levels. Again however I must stress: that reducing protein intake induced a favourable IGF response, one has to be consider that such a radical reduction in protein intake may have serious long term implications that easily outweigh the benefits of reduced IGF levels.

A point of clarification. Many people think that the more growth hormone the healthier they are. This is misleading and false. Reducing growth hormone levels in age is consistently associated with less pathology and a longer life.

References:

Fontana L, Klein S, Holloszy JO. Long-term low-protein, low-calorie diet and endurance exercise modulate metabolic factors associated with cancer risk. American Journal of Clinical Nutrition, vol. 84; pp. 1456-1462, Dec. 2006



Fontana et al. Long-term effects of calorie or protein restriction on serum IGF-1 and IGFBP-3 concentration in humans. Aging Cell, 2008; 7 (5): 681 DOI:

Thursday, September 25, 2008

The Horror, The Horror!

Political Conservatives Fear Chaos; Liberals Fear Emptiness

Mistah Kurtz died long ago so get over it. (With apologies to the wonderful Joseph Conrad)

Keep in mind that with these studies the results are statistical so don't go around thinking that because someone has liberal or conservative political beliefs ipso facto that particular person experiences what the study results suggest.

According to this study conservatives fear of social chaos and absence of order while liberals fear emptiness. The potential for social chaos and absence of order is always a problem for societies so these things need to be guarded against. As for feelings of emptiness just get over it. The universe is a cold heartless place and the sooner you realise that and go on living the better off you will be. Stuff the rubbish touted by Deepak Chopra, Gary Zukav, and even Anthony Robbins for that matter. These people are fools who delude others into thinking that life truly is meaningful. It isn't. This has long been known but few are willing to embrace it wholeheartedly. When people do truly accept the meaninglessness of existence they realise it was a stupid thing to worry about. Alas I fear that humanity will continue to generate all manner of Imaginary Friends to keep The Horror away. As that wonderful French writer Albert Camus noted, "Seeking the truth is not seeking what is desirable." More importantly, remember his words:

But it is bad to stop, hard to be satisfied with a single way of seeing, to go without contradiction, perhaps the most subtle of all spiritual forces. The preceding merely defines a way of thinking. But the point is to live.


The Myth of Sisyphus.

So if you are a conservative and fear emptiness the problem is that you fear nothingness. When you think about it, that's kinda stupid. At least conservatives aren't that silly.

Parkinson's Disease and Pesticides

There are now many reports concerning the relationship between some pesticides and Parkinson's Disease. The disturbing aspect of this recent study(abstract below) is that they found high levels of two commmon pesticides in the nigra region of Parkinson's patients. This region of the brain is typically referred to as the substantia nigra. It is a rather small round nuclei that contains a great many dopamine producing neurons. These neurons play a critical role in modulating motor function, hence the classic gait of Parkinson's patients and the slow loss of control over motor function. It is important to note though that loss of movement control is not the only problem in Parkinson's patients, cognitive and emotional problems also arise. There is also evidence of neural destruction beyond the nigra region and this can extend into the temporal lobes. As always, when we look at the actual results of neuroscience studies we find that the living brain is not as neat and tidy as our lovely diagrams of it.

Parkinson's Disease is one the strangest neuropathologies. We have very little idea concerning the etiology of Parkinson's Disease but the linkage with some pesticides is very strong. Rotenone, a "natural" pesticide favoured by organic farmers, is great at killing neurons in this region. Epidemiological studies have established very strong linkages with occupational exposure to some pesticides and the incidence of Parkinson's Disease. If you enjoy playing golf make damn sure that in the very least you wash your hands after each game, preferably have a shower. Make sure you don't wear your golf shoes in the house, the residues could spill onto the floor surface where your kiddies love to play. Golf courses are toxin sinks, so much so that a few studies have found a direct correlation with living near a golf course and in the incidence of cancer in children and pets. If you are an active gardener who uses pesticides be very careful. Follow the safety instructions and be very careful about spillages. You have been warned.





Neuroreport. 2008 Aug 27;19(13):1317-20.
Synergistic microglial reactive oxygen species generation induced by pesticides lindane and dieldrin.
Mao H, Liu B

Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, Florida, USA.
Elevated environmental exposure to pesticides is a known risk factor to the development of sporadic Parkinson's disease resulting from the degeneration of nigral dopamine neurons. Among the suspected agents are the highly persistent and bioaccumulative organochlorinated pesticides (OCPs). We report here that lindane and dieldrin, two widely present OCPs that are found enriched in the nigra of postmortem Parkinson's disease brains synergistically induced the production of reactive oxygen species (ROS) in microglia. Inhibitor studies indicated that the lindane and dieldrin-induced ROS generation was mediated by NADPH oxidase. As microglial ROS is a key contributor to the degeneration of the oxidative damage-vulnerable dopamine neurons, our findings shed significant light on the role of OCPs in the development of Parkinson's disease.

Saturday, September 20, 2008

Dying to See the Light

It was Dr. Fenwick who first proposed this study into near death experiences. Many argue that near death experiences are proof of an after life but I remain cynical of the same. One possible reason why some can still have perceptions when the heart has stopped is that the brain has a unique supply of glucose and oxygen. Brain cells(neurons) can only use sugar as a fuel source. Remarkably, there is a type of buffer built into this energy source. Astrocytes, glia that are in direct contact with the blood vessels, absorb glucose from the blood, process it, then release pyruvate into the intra-cellular spaces. Neurons will take up the pyruvate as their energy source. A couple of years ago there was also a study indicating that the CNS may have a "reserve oxygen supply". So there remains the possibility that the brain can continue functioning, albeit for a very short time, after the heart has stopped.

This research should settle the matter once and for all.

For information on Dr. Peter Fenwick's research, just google the name.

Cannabinoids and Multiple Sclerosis

Previous studies have indicated that cannabinoids can act as potent neuroprotectants in a variety of contexts. Hampson et al found that the two major cannabinoids in cannabis sativa, THC and cannabidiol, demonstrated antioxidant capacity greater than vitamins C and E and comparable to the most powerful laboratory antioxidant available to them. This finding may explain why, independent of cannabinoid receptor CB1 or CB2 activation, these cannabinoids demonstrate neuroprotective and anti-inflammatory properties.

This recent study highlights how CB2 receptor activation demonstrates powerful neuroprotective capacity in the animal model(EAE) of Multiple Sclerosis. (Click here for the news release.) In this study the administration of a CB2 agonist reduced neuron cell death by 50%, a remarkable result but one that is consistent with many other studies. They focused on activation of the CB2 receptor. This receptor plays an important regulatory role in the immune response and is also found in the broad equivalent of immune cells in the CNS: microglia.

The great promise of CB2 agonists is that these are non-psychoactive, thereby allowing a potent therapeutic effect without the patient having to deal with the psychoactive effects of THC, which activates the CB1 receptor. Some may retort that this is not a good thing and there may even be some merit in that because CB1 activation has been found to induce neurogenesis and also demonstrates some neuroprotective properties. However in relation to MS, because CB1 tends to inhibit neuronal activation(retrograde inhibitory transmitter), excessive activation of this receptor may make their symptoms worse. There have now been a number of studies where Multiple Sclerosis patients have been allowed to smoke cannabis. The results have been equivocal but there has been enough evidence that some governments have allowed the smoking of cannabis for those suffering MS. There are now so many studies pointing to the therapeutic of cannabinoids that even a study group in conservative Australia has called for the introduction of medicinal cannabis. Unfortunately there is also strong evidence that smoking marijuana can damage the lungs though there is no evidence of it increasing the risk of lung cancer.

A very important word of warning: women who are pregnant or planning to become pregnant must not smoke marijuana. While the evidence is slight it is sufficient to raise very serious concerns about smoking marijuana during pregnancy.

An important finding in this study is that CB2 agonists inhibited the recruitment of immune cells into the CNS. It may even be the case that this is a critical pre-condition for MS attacks to occur. Further research is required to clarify this issue.

With many studies now demonstrating considerable therapeutic potential for cannabinoids it is time for governments and the medical community to adopt a scientific attitude towards the use of cannabinoids in the treatment of a variety of inflammation related conditions. By way of example, consider this study of THC and cannabidiol in relation to Alzheimers. The results indicated that these cannabinoids not only inhibited production of ACHe, an enzyme targeted by many Alzheimers related drugs, but also played an important role in inhibiting the production of amyloid protein, considered by many to be very important in preventing Alzheimers Disease. In fact this study found that both THC and cannabidiol demonstrated greater efficacy than all the current Alzheimer drug interventions they tested.

Apart from their neuroprotective qualities, various studies have indicated that cannabinoid based therapies may be useful in the following pathologies:

Preventing the complications of diabetes
Allergies
Autoimmune conditions
Cancer treatment, particularly brain tumours.
Neuropathic pain.
Atherosclerosis

Thursday, September 18, 2008

Conquering Depression

Over at SkepticLawyer Legal Eagle has commented on the prevalence of depression in the legal profession. As noted in her post there are many obvious reasons for those in the legal profession experiencing such high rates of depression. Her post prompted me to go over some old data I had read long ago.

Understanding the physiology of depression very much remains a work in progress. In this post I provide a cursory introduction to the these problems.

There are many types of depression.

Dysthymia: a mild form of depression that is very common
Major Depression: less common but much more disabling, major depression is now being perceived as a risk factor for the following conditions:

  • heart disease
  • dementia in latter life
  • cancer
  • Gut problems like Irritable Bowel Syndrome
  • mild cognitive impairment

Bipolar Disorder: a condition where the individual swings from manic states to intense depression
Cyclothymia: a milder form of bipolar disorder that is frequently misdiagnosed as depression.
SAD: Seasonal Affective Disorder: strangely enough while SAD is usually associated with depression onset with winter, it can also occur with the onset of summer; though the latter is much rarer.
Post partum Depression: a condition experienced by mothers shortly after giving birth.
psychotic depression: depression so severe the individual becomes psychotic
Atypical Depression: where the individual is not necessarily melancholic but demonstrates lack of motivation and anhedonia(lack of pleasure in activities that formerly provided pleasure). People with atypical depression often over eat, tend to be tired all the time, and are often overly sensitive about rejection from others.

Note: The definitions of depression types can vary over time and from place to place.

As the foregoing demonstrates "depression" is a highly variable condition that can manifest itself in a wide variety of ways. It is hardly surprising that trying to understand the physiology of depression remains a work in progress. One obvious problem is that how depression is diagnosed can vary widely from country to country and from clinician to clinician. At the clinical level the issues are very difficult to address. One patient may actually be in a state of major depression but their self reports might be more indicative of dysthymia. More commonly, patients reporting symptoms of depression are cyclothymes. So have mercy on the clinicians, they face a daunting task.

Fortunately recent research may have stumbled upon a "final common pathway" that proffers the potential for better clinical interventions in the years to come. If you have taken anti-depressants you may have experienced what a great many people experience: it can take quite some experimenting to find the anti-depressant that works for you. This can be very frustrating but with ongoing research there is increasing hope for better treatments.

The recent breakthrough I am referring too is the claim that the final common pathway for the successful treatment of depression may well be the re-invigoration of both neurogenesis(new neurons being produced) and gliogenesis. The latter term refers to the "support" cells of the brain, glia. Neurons are amongst the busiest cells in the body and have a specialised network of supporting cells to both nourish and protect them. This is especially crucial for neurons because while new neurons can be produced these can only be produced in relatively small numbers.

It has long been recognised that depression is strongly associated with changes in the endocrine and immunological axes. In 1960's it was hoped that glucocorticoid resistance would prove to be a reliable biological marker of major depression. No such luck, at best 40% of individuals with major depression will exhibit glucocorticoid resistance. Sadly though this was an important clue that was overlooked. Most turned their attention to the amines and for many years the predominant focus was on serotonin and norepinephrine. Fortunately though some researchers maintained a different focus.

Horrobin and Bennett wrote a fascinating paper in 1999 that highlighted some intriguing relationships between psychiatric disorders and immune regulation. When I first read this paper I told my collaborator that "their theory is for s*&t". I have come to rue that arrogant criticism. Their paper was prescient in that it paved the way for a biologically based understanding of how fatty acids, in particular the omega 3 - omega 6 balance in our diets, can have significant implications for our cerebral health and propensity towards depression. It is now well established that omega 3 supplements or boosting fish intake can serve as a valuable adjunct treatment in depression.

Other researchers kept up the good work. In particular, this striking study from Capuron & Dantzer, made no apologies for demanding a new approach towards understanding depression. Recent genetic research indicating that polymorphisms for inflammation related genes are very strong indicators for the propensity towards depression have vindicated this approach.

This post is already too long so I'll cut to the chase.

  • Glucocorticoids, induced by psychological stress and other stressors, inhibit growth factors.
  • A key growth factor that regulates neurogenesis is Brain Derived Neurotrophic Factor(BDNF). This is particularly important in the hippocampus.
  • Ongoing stress initiates inflammatory mediators which in turn induce the expression of nitric oxide.
  • While nitric oxide is an important component of neural activity excess nitric oxide inhibits BDNF production.
  • Because the hippocampus can modulate the stress response, ongoing loss of neurogenesis in the hippocampus can cause a vicious positive feedback loop; thereby increasing the stress response and the expression of inflammatory mediators.
  • If, as is common today, there is an excess of omega 6 fatty acid relative to omega 3 intake, this will exacerbate the inflammatory response.
  • Most antidepressant drugs are agonists(increasing the levels of) serotonin and norepinephrine. Activation of some serotonin receptors increases BDNF production and increased norepinephrine appears to lower the expression of inflammatory mediators in the brain.
  • Increasing BDNF re-commences neurogenesis and helps pave the way for recovery.
What are the Important Lessons Here?

  • Manage Stress! An uncontrolled stress response is the most common cause of depression. In our fast paced world all of us are exposed to real and potential stressors. This is one reason why meditation has been found to be useful in helping those with depression. Also, learn the relaxation response.
  • Kill the ANTs: Automatic Negative Thoughts. We all have these little creatures in our skulls and they can be very irritating. Cognitive Behavioral Therapy can be very useful in exterminating the little blighters. Initially though try and develop the habit of suppressing these thoughts. That can take time but the benefits will last you a lifetime. It may even save your life.
  • Maintain good sleep habits. One of the first warning signs of looming depression is insomnia. This can constitute a vicious cycle because loss of sleep increases the expression of inflammatory mediators. In fact loss of sleep and chronic circadian disruption can often by the final insult that casts us into a deep depression.
  • Boost your intake of fish and consider taking fish oil supplements. Additionally, have a careful look at your diet and if necessary improve it.
  • Where possible enjoy the sunshine for short periods each day. Sunshine is essential for vitamin D production and there is now a strong body of evidence indicating that maintaining a strong vitamin D status is not only important for the bones but also confers protection against many cancers, excessive systemic inflammation, and reducing the risk of dementias. Sunshine also gives a slight boost to serotonin production hence its association with being happy and the converse, "gloomy days". Early morning sunlight exposure is also important in maintaining circadian stability which aids sleep and promotes general well being.
  • Be realistic. Some evidence indicates that those who consistently experience depression expect too much of themselves. You are only here once so enjoy it. Being happy is much more important than being productive or being special. Look at how many celebrities end up in rehab or with serious drug problems. Remember this: Work has its place and its place is not to replace living.
  • Don't surround yourself with negative people. Most people are kind and generous of spirit so why bother with those who want to put you down or always criticize you?
  • Remember this: Life is not a problem to be solved but a reality to experienced. (Van der Leuww)
  • If at first you don't succeed so bloody what!? Have a rest and remember: If you reach for the stars at least you won't end up with a handful of mud. (Og Mandino, University of Success) Success is great, happiness is greater.
  • Remember: All sunshine makes a desert(Arab proverb). We all go through trying times and many of us will experience depression. Tackle depression before it tackles you.
  • Antidepressant drugs are one of the great breakthroughs in medicine. Don't be afraid to use these to help you recover but try not to become reliant upon these drugs. When you feel yourself becoming depressed don't dig yourself so deep that you can't see the sun.
  • Remember: Man is most nearly himself when he achieves the seriousness of a child at play. (Heraclitus) Granted it is not always possible to like a child at play but aiming for that is much better than taking life so seriously that we completely lose our playful nature.

Homocysteine, Alzheimers, and Cerebrovascular Disease

Elevated homocysteine is generally regarded as an indicator that all is not well with our health. The vitamins B6, B12, and folate are crucial regulators of homocysteine levels. Anyone interested in maintaining optimal health must ensure that they have adequate intake of these nutrients. It is important to remember that some individuals experience very poor absorption of B12 and injections of B12 may be required. Symptoms of B12 deficiency are pernicious anaemia and fatigue. In particular, elderly people have may B12 absorption problems. A study reported in the eMJA found that many older Australians have B12 deficiency. Vegetarians can also experience B group deficiencies which goes some way to explaining why vegetarians, in spite of a low fat diet, are susceptible to cardiovascular disease.

Those experiencing chronic fatigue syndrome may benefit from injections of B12. Anyone with cardiovascular disease or a history of anaemia needs to carefully monitor their intake of B6, B12, and folate. It is a good idea to periodically have your homocysteine levels checked. If elevated, a B group supplement is advisable but it is far preferable that a good diet rich in these nutrients is followed all the time.

If you are experiencing ongoing fatigue that cannot be explained then consider the possibility that you are experiencing a deficiency in these nutrients. Because such a deficiency is so damaging to our health it is advisable to start taking a B group supplement immediately but much more importantly you should simultaneously change your diet to make sure you are receiving an adequate supply of these nutrients.

This recent study highlights why it is important to immediately address any suspected deficiency in these nutrients. The importance of immediate intervention is further highlighted in this mice study published in the PNAS. A vitamin B deficient diet for as little as ten weeks induced elevated homocysteine, neurodegeneration, and loss of capillaries.




Sources of B6:

Beef liver(warning: be careful of consuming too much beef liver because of the very high vitamin A levels)
wheatgerm
Bananas
Chicken Breast
Tuna
chickpeas
kidney beans
dairy products

Sources of B12:

chicken breast
Tuna, canned in water
Corn kernels
mango
Eggs
Dairy products
red meat, poultry, and fish

Sources of folate:

Asparagus, Bran flakes, Broccoli, Spinach
Oranges, peas, wheatgerm
Bee liver
Collard greens
spinach, raw
oranges
peanuts, dry roasted
wholewheat bread
broccoli



Note: pregnant women need to be particularly careful to maintain good folate levels.

Wednesday, September 17, 2008

Plastics And Poison

Numerous studies are now finding that worrying implications regarding bisphenol A, a chemical found in many plastics. Previously animal studies had raised concerns, this study from JAMA highlights the risk to humans. We need to do something about all the chemicals that we are now exposed too. All of us are exposed to these chemicals and research is increasingly pointing towards dangerous implications of this exposure.

The news item can be read here.

ScienceDaily (Sep. 16, 2008) — Higher levels of urinary Bisphenol A (BPA), a chemical compound commonly used in plastic packaging for food and beverages, is associated with cardiovascular disease, type 2 diabetes and liver-enzyme abnormalities, according to a study in the September 17 issue of JAMA. This study is being released early to coincide with a Food and Drug Administration (FDA) hearing on BPA.
...

The research article can be read here.

Association of Urinary Bisphenol A Concentration With Medical Disorders and Laboratory Abnormalities in Adults