From Mouse to Man

Youtube helps identify a new tool in the evaluation of brain injury

Phil Newton — Fri, 28 Aug 2009 08:28:52 +0000

How Youtube^TM helped researchers identify a new tool for rapid evaluation of head injury.

Boxing, bomb blasts, bar brawls, bike accidents and the Baltimore Ravens.......what do all these things have in common? They're all a cause of Traumatic Brain Injury, or TBI. To many people, that's a "bang on the head", the consequence of which might just be seeing stars.......or something much worse.

In any case of suspected TBI, rapid assessment of the severity of the injury is vital to ensuring a good recovery. Medical staff use a variety of indicators to determine whether a patient has suffered a TBI. Many of these, including amnesia and disorientation are subjective (require a response from the victim) and are not always reflective of the severity of the injury. More objective measures such as convulsions and vomiting do not occur very frequently and may be confounded by other factors such as the presence of alcohol.

Thus there is a need for a bigger panel diagnostic indicators for use in assessing head injury, especially for discerning between mild and moderate TBI where the victim may not show signs of gross damage but may or may not have sustained a serious internal injury.

With this need in mind, Ario Hosseini and Jonathan Lifshitz at the Spinal Cord and Brain Injury Center at the University of Kentucky set out to evaluate cases of TBI for evidence of diagnostic indicators. They used an ingenious approach in keeping with the modern age. Rather than heading out on a Saturday night dressed in white coats looking for bar-room brawls, Hosseini and Lifshitz simply logged into Youtube^TM where there exists a vast database of knockouts and heavy hits, mostly from boxing, mixed martial arts and the NFL.

Existing diagnostic markers of TBI include "tonic posturing preceding convulsion", meaning that the victim exhibits a distinct body pose prior to entering a convulsion. This body pose is very similar to the "en garde" position adopted at the beginning of a fencing bout.

The response is clearly visible in this YouTube ^TM video of NFL Baltimore Ravens player Willis McGahee getting knocked down by Ryan Clark of the Pittsburg Steelers. Note how the prone player has his right arm raised in the "en garde" position.

What Hosseini and Lifshitz observed was that this so-called "fencing response" is very frequent when an individual is knocked out. They scanned over 2000 Youtube videos and observed ~ three dozen in which the victim did not get back up. The fencing response occurred in two thirds of these "knockout" videos. Importantly most of these knockouts did not result in a convulsion, which I mentioned earlier is a fairly rare event. These observations suggested that, following a head injury, the fencing response and convulsions were separate phenomena with the fencing response being very common. Perhaps the fencing response was a useful marker of moderate head injury?

Back in the lab, Hosseini and Lifshitz probed into the fencing response. They found that it was most commonly associated with a blow to a part of the brain called the brainstem, which is located at the base of the brain on top of the spinal cord. Specifically, Hosseini and Lifshitz found that the fencing response was associated with damage to a part of the brainstem called the lateral vestibular nucleus. The force of the blow ruptures blood vessels, the contents of which appear to activate the lateral vestibular nucleus, producing the characteristic extension and stiffening of the forearm that defines the fencing response.

By conducting a series of detailed laboratory studies, Hosseini and Lifshitz determined that the fencing response only occurs in response to moderate TBI, it did not occur in response to a mild TBI that still might otherwise produce concussion and/or knockout.

The authors conclude that the fencing response is a useful marker of moderate brain injury, suggesting it should be added to the panel of assessments made immediately following a head injury.

This author concludes that research is changing. The availability of huge public databases such as youtube means that a mass of data is now available to everyone. Careful detailed analysis of these data can be a great "hypothesis-generator" for more controlled laboratory studies.

TBI is, unfortunately, a growth area, especially in the military. Improvments in body armor mean that soldiers are now much more likely to survive a blast that would previously have killed them through damage to internal organs. Instead, they are left with intact internal organs but the consequences of a severe blast injury to the head (read about it here).

In fact, TBI is emerging as the signature injury of the ongoing Iraqi and Afghan conflicts due to the prevalence of roadside blasts. Nearly six out of 10 casualties entering the military hospital at the Walter Reed Medical Center in Washington DC have been diagnosed with some degree of traumatic brain injury.

TBI is also a prominent issue in professional sports, especially those such as boxing and NFL where a hefty blow to the head is not uncommon. In sporting cases, the need is often to determine whether the victim is safe to return to the field of play or needs more detailed medical attention.

The fencing response is a useful tool in evaluating these head injuries and ensuring that the victim receives the appropriate level of care.

ABC News (WTVQ Lexington, Kentucky) report on the fencing response.

Wikipedia entry on the fencing response.

The full Hosseini and Lifshitz paper in the September 2009 edition of "Medicine & Science in Sports & Medicine", official journal of the American College of Sports Medicine (subscription or payment required)

What is dopamine?

Phil Newton — Mon, 27 Apr 2009 01:47:42 +0000

What is dopamine? What does it do and how does it do it? These questions have caused controversy in neuroscience for decades. A new study from the UK may have some of the answers.

The word dopamine means very different things to different people, from drug addiction to Parkinsons disease to a Hollywood movie dopamine is part of mainstream culture as well as an enduringly fascinating research topic in neuroscience. It has been part of over 110,000 research papers in the last 60 years but is still a source of controversy among neuroscientists. Attempting to sum up the function of dopamine in a brief blog post is not going to be easy. I am going to leave many research scientists dissatisfied and some downright angry!

Lets start with the basics. Dopamine is a neurotransmitter, one of those chemicals that is responsible for transmitting signals in between the nerve cells (neurons) of the brain. Very few neurons actually make dopamine. Some, in a part of the brain called the substantia nigra, are the cells that die during Parkinsons disease. The functions of others, located in a part of the brain called the ventral tegmental area (VTA), are less well defined and are the major source of the aforementioned controversy (and the focus of this post). When dopamine neurons become activated, they release dopamine.

One of the best described roles for VTA dopamine neurons is in learning about rewards. VTA dopamine neurons become activated when something good happens unexpectedly, such as the sudden availability of food. Most abused drugs cause the release of dopamine and this is thought to contribute to their addictive properties.

But what about bad things? Do they activate dopamine neurons? It's perhaps even more important to learn when something bad is going to happen than something good; with predators or disease you often don't get a second chance. Is dopamine involved in learning about bad things? Herein lies some of the controversy surrounding dopamine. Not all the neurons in the VTA make dopamine. Many studies had suggested that the sudden presentation of aversive or noxious stimuli such as pain caused the activation of some neurons in the ventral tegmental area, but were these dopamine neurons?

In 2004 Mark Ungless and colleagues at the University of Oxford (UK) published a paper in the journal Science indicating that dopamine neurons were universally inhibited by aversive events. They used a painstakingly detailed approach to identify those neurons which were activated or inhibited by aversive stimuli and then biochemically analysed those neurons to determine if they truly were dopamine neurons. They did find that some neurons became activated by aversive stimuli, but these neurons did not make dopamine.

The findings were very clear but were controversial. They did not sit well with other studies on the role of dopamine, including some which showed that treatment with drugs which block the action of dopamine could block learning about aversive events. Also, chemical measurements indicated that dopamine was released by animals undergoing a stressful experience. If dopamine neurons are not activated when learning about aversive events, how is this dopamine being released? and why would blocking the effects of dopamine prevent learning about aversive events?

Ungless and co, now at the UK Medical Science Research Council, Imperial College, London, hypothesized that the devil may be in the detail; maybe the VTA isn't a single, uniform part of the brain but is composed of functionally different subregions. Before conducting their latest study, published in the Proceedings of the National Academy of Sciences (USA) they went back and looked again at the literature about dopamine neurons in the ventral tegmental area. They observed an experimental quirk; most studies of VTA dopamine neurons, those showing that dopamine neurons aren't activated by aversive stimuli, were measuring responses from a same small part of the VTA, called the dorsal VTA. What if neurons in a different part of the VTA became activated by aversive stimuli and released dopamine?

To test this, they gave rats an electric shock (not an electrocution, just a moderate electric shock, much the same as a dog would receive from a shock raining collar). During this electric shock, they recorded the activity of neurons from the dorsal VTA and a slightly different part of the VTA called the ventral VTA. They found, like others had previously, that neurons in the dorsal VTA were either inhibited by an aversive stimulus or did not respond at all. In contrast, those neurons in the ventral VTA became activated by the footshock. In fact, they became very activated, exhibiting a type of response known as "burst firing" that would be expected to produce a profound dopamine release.

So, that would appear to be that, problem solved! But there was another twist. As I wrote earlier, one of dopamine's best known roles is in learning about rewards. Relief from an aversive event can be considered as a reward. The pattern of learning exhibited by animals and humans is similar when comparing a "real" reward (e.g, food) or relief from an aversive stimulus (e.g; when an electric shock is turned off). What Ungless and co. observed was that those neurons in the dorsal VTA, those which were unresponsive or were inhibited by the electric shock, those neurons became transiently activated when the shock was turned off. This would be consistent with their role in reward learning while also partially explaining why dopamine blockers impair learning about aversive events.

So, the story of dopamine has evolved a little but further while becoming a little but more complicated; not all parts of the ventral tegmental area are the same!

To clarify; alcoholics and liver transplants

Phil Newton — Wed, 18 Feb 2009 19:11:38 +0000

I have received a number of comments on my original post and I want to make sure I'm absolutely clear. My intention was to use the issue of liver transplantation to highlight how some people view alcoholics as being at fault for their alcoholism.

There are multiple issues surrounding organ donation. One of these is that the clinical team performing the transplant has to determine whether the person receiving the organ is fit and healthy enough to receive it. Having a current diagnosis of alcoholism will obviously impact that assessment. In the oft-cited hypothetical situation where a surgeon has to choose between giving a liver to an alcoholic vs a non-alcoholic patient, that surgeon may well conclude that, due to a likelihood of further alcohol abuse, the alcoholic will not benefit as much from the liver as the non-alcoholic. This clinical assessment is not the issue for me, it makes perfect sense.

My concern is the notion, highlighted in the quotes in my original post and in the subsequent published comment, that alcoholics do not deserve a liver transplant because them being an alcoholic is somehow their fault. Non-alcoholics chose whether or not to drink, alcoholics do not, they have completely lost control over this "choice". It may once have been a choice, but by very definition of them being alcoholic, it no longer is.

Do alcoholics deserve liver transplants?

Phil Newton — Sun, 15 Feb 2009 22:29:45 +0000

This story is making the rounds again. It reveals a lot about how society thinks of alcoholics.

Here is an example from the latest incarnation of the story from the UK. Eunice Booker, whose 26-year-old daughter died in a car crash in 2006, is quoted by the UK's Observer newspaper as saying: "I find it offensive that one in four of the livers donated go to alcoholics. If there are two people side by side wanting a liver, and both have the right tissue match, and one is an alcoholic and one isn't, there's no contest - you take the one who's not an alcoholic, they are more entitled."

This "entitlement" issue is at the heart of the controversy. One of the previous occasions this story came up was when the soccer legend George Best was given a liver transplant in 2002 after battling with alcoholism for all his adult life. After receiving his liver transplant, he was seen out drinking more than once. He had been warned repeatedly that drinking would kill him, even after his transplant. He died three years later. Here is a quote about Best's transplant from a reader of the Daily Mail, a British tabloid newspaper.

"George Best's liver transplant was morally indefensible. A viable liver was wasted on him. There are not enough livers available for transplant to people with non-alcoholic related diseases, people who are ill through no fault of their own".

Here we have "fault" as well as entitlement. Somehow alcoholics are at fault for becoming alcoholics. Almost everyone drinks or smokes at some point in their lives, but the majority of people do not develop problems and this seems to make it harder for them to understand those that do. This issue is exacerbated by the heavy drinking culture of the UK (George Best once said "I spent a lot of money on booze, women and fast cars. The rest I just squandered").

Alcoholics, like all addicts, are usually diagnosed once their drug use has become a problem. It has become a problem because they are suffering from the defining symptom of addiction; loss of control. In fact the very definition of an addiction is "continued drug use in spite of adverse consequences". George Best is a classic example. Here is a man who has been told, like so many alcoholics, that his drinking has ruined his liver function to the point where he needs major surgery. If he carries on drinking, he will die. So what does he do? He goes drinking. I'd say death was an adverse consequence. Is there any more direct example of the loss of control that defines an addiction?

The public understanding of addiction lags behind that of other mental disorders. Telling an alcoholic to "stop drinking" is like telling a victim of depression to "cheer up" or an anxiety sufferer to "calm down". In the past few decades, great progress has been made in recognizing diseases like depression, anxiety and posttraumatic stress disorder for what they are; medical conditions deserving of sympathy and treatment. We still have a long way to go with addiction.

The anatomy of posttraumatic stress disorder

Phil Newton — Fri, 30 Jan 2009 04:07:39 +0000

What parts of the brain are involved in posttraumatic stress disorder? A recent study of Vietnam veterans used a novel and clever strategy to produce some unexpected results.

Recent developments in brain imaging have allowed scientists to study the brains of patients afflicted with a variety of disorders. Identifying the parts of the brain that are involved in those disorders is key to understanding how the disorders arise and are maintained.

Brain imaging studies of posttraumatic stress disorder (PTSD) have identified a few key brain regions whose function appears to be altered in PTSD, most notably the amygdala, the ventromedial prefrontal cortex (vmPFC) and the hippocampus.

The amygdala is an almond-shaped region ("amygdala" is greek for almond) that is key to the normal expression of emotions, especially fear. Brain imaging studies see high activity in the amygdala when subjects experience anxiety, stress or phobias.

The vmPFC can be thought of as a "higher" or "more sophisticated" part of the brain, involved in less well defined activities such as "emotional processing" and "decision making".

The hippocampus is a large region that is, very simply, involved in memory, especially spatial memory (such as for, and of, places)

A very generalised model of what happens during normal responses to anxiety is this; a person enounters some environmental cue that signals danger, for example, they see a tiger. This information is sent to the amygdala, which gets fired up and starts sending out "fight or flight" responses to other parts of the brain. However, the vmPFC, being involved in "higher thinking", has a quiet word with the amygdala, saying "look, the tiger is in a cage, you know what a cage is, tigers can't escape from cages, it's OK, calm down". Another part of the brain, the hippocampus, helps out, providing information about the context of the event (we're at a zoo, we know what zoo's look like, we've seen them before). In summary, the vmPFC inhibits the amygdala to keep fearful responses in check.

Brain imaging studies of PTSD sufferers generally show two things; reduced activity in the vmPFC and increased activity in the amygdala. A long-held interpretation of these studies is that, in PTSD, the vmPFC is asleep at the wheel, allowing the amygdala to go unchecked and thus produce many of the intense anxiety symptoms that are a key feature of PTSD.

What these studies don't tell us tho', is how this imbalance comes about; does having reduced vmPFC function lead to PTSD, or does having PTSD shut down the vmPFC? To address these issues would require shutting down or damaging the vmPFC and looking for the development of PTSD, obviously not an experiment that can or should be performed with people. However, Michael Koenigs, Jordan Grafman and colleagues at the NIH came up with a very elegant way of answering these questions.

Grafman is one of the scientists behind the Vietnam Head Injury Study (VHIS). This study is a 30 year analysis of Vietnam veterans that measures a whole host of outcomes. Among the myriad of unfortunate effects of combat on soliders, two things occur frequently; brain injury and, especially in Vietnam, PTSD. The VHIS analyzed 245 Vietnam combat veterans, of whom 193 had some permanent brain damage. The remaining 52 had experienced combat but not suffered lasting brain damage. As part of the VHIS, the location and extent of brain damage was determined in each subject using brain imaging. Koenigs and colleagues then asked a simple question of each veteran; have you ever experienced PTSD? Around 45% had. They then grouped patients into PTSD+ and PTSD- groups based upon their responses and re-analyzed the results from the brain scans to see if damage to particular parts of the brain correlated with the occurrence of PTSD.

What they found was startling; patients who had damage to the vmPFC and amygdala were much LESS likely to have developed PTSD. For the amygdala, this makes sense, but for the vmPFC, this was the complete opposite of what would be predicted from previous studies. Also noteworthy; hippocampal damage was not associated with an increase or decrease in PTSD symptoms.

To be sure of this conclusion, Koenigs and co flipped their analysis; they classified their patients into those who had damage of the vmPFC or amygdala and then looked to see if there was an increased incidence of PTSD. There was. In fact, of those with amygdala damage, none had ever experienced PTSD symptoms. The reduction in PTSD presented as an overall reduction in the intensity of all symptoms rather than a complete absence of PTSD or a reduction in a subset of symptoms. It's important to make clear that the injury that caused the brain damage is not necessarily the traumatic event that caused the patients to develop PTSD; the brain damage here is just being used as an anatomical indicator of what parts of the brain are important for developing PTSD

The most obvious interpretation is that persons with damage to these areas are protected from the development of PTSD, which could be interpreted as good. However, this protection comes at a significant cost. Damage to these areas is associated with other cognitive problems, most notably in emotional processing and decision making.

From a scientific perspective, these findings require a reassessment of how we think PTSD develops, most notably, how do the findings with the Koenig study fit with studies showing that PTSD sufferers have reduced activity in their vmPFC?

As always, the devil may be in the detail. Perhaps the conversation between vmPFC and amygdala is not all one way; perhaps the amygdala talks back. Or perhaps the vmPFC opens multiple lines of communication with the amygdala and not all are inactive during PTSD. Maybe even having most of those lines shut down allows others to be heard more clearly. Evidence from animal studies points to these answers. Other brain regions are almost certainly involved and these may influence the activity of the vmPFC or amygdala. Or the amygdala and vmPFC may be required for the storage and processing of traumatic memories, or the reactivation of those memories in response to reminders in the environment. Again, basic science studies indicates that this may be the case, but only now do these studies make sense in terms of the clinical picture.

Whatever the final answer, these studies show the importance of addressing human psychiatric disorders with a basic science approach. Brain imaging studies can only show a snapshot of the current situation; experimental manipulations are obviously very difficult to do; one cannot just shut down a patients vmPFC and then see if they develop PTSD. In this paper, Koenig and Grafman's clever use of the Vietnam Head Injury Study allowed them to ask a question that would otherwise have been difficult to answer, and has provided vital new information for the development of treatments to combat PTSD.

The full version of the paper appeared in Nature Neuroscience in February 2008.

Image credit; Molecular Psychiatry 2008 Mar;13(3):313-24

Potential Treatments for Alcoholism and Drug Addiction

Phil Newton — Mon, 12 Jan 2009 07:48:13 +0000

A lot of work, in both the public and private sectors, is being put into the development of medications to treat alcohol and drug addiction. Here I will give you an overview of ongoing research and highlight some of the most exciting developments.

I recently disagreed with fellow blogger Stanton Peele about the nature of addiction as a treatable disease. I pointed out that there are a couple of medications available to addicts, but had to concede that these don't work for everyone. In summary, I wrote, "these addiction treatments are not perfect, but they do help some patients and form the basis of further research aimed at developing more effective treatments". I thought I would bring you an overview of that research to highlight some of the progress that is being made. In future posts I'll come back to some of these experimental treatments and go over them in detail.

A search of www.clinicaltrials.gov using the keywords "alcoholism" and "treatment" reveals 312 clinical trials. Of these, 137 are currently recruiting participants. A large number of medications are being tested in these trials. To highlight this number and demonstrate their diversity; here's a list of the drugs, with the trade name given in brackets; gabapentin (Neurontin), topiramate (Topamax), varenicline (Chantix), quetiapine (Seroquel), prazosin, zonisamide (Zonegran), mecamylamine (Inversine), LY2196044, modafinil (Provigil), sertaline (Zoloft and others), fluoxetine (Prozac and others), aripiprazole (Abilify), ondansetron (Zofran), nalmefene (Revex), olanzapine (Zyprexa) and others), n-acetylcysteine, org25935, vitamin B1, levetiracetam (keppra), baclofen (Lioresal and Kemstro), Lamotrigine (Lamictal), flumazenil, vanlafaxine (Effexor and others), vigabatrin, clozapine (Clozaril), d-cycloserine, lisdexamfetamine (Vyvanse), SYN115 and amlodipine (Norvasc and others). Thats a lot.

There are also new trials with the established medications; naltrexone (Revia), acamprosate (Campral), methadone, buprenorphine (Subutex) and disulfiram (Antabuse). I should also mention that there are a number of behavioral therapies being tested in clinical trials, including variations on existing therapies and more novel approaches, including yoga. I am a basic scientist tho', so I'll leave discussion of the behavioral therapies to those experts.

Alcoholism and drug addiction are complex, heterogeneous diseases with many different symptoms that affect people in different ways. This heterogeneity is reflected in the nature of the trials being conducted; some are for straight-up heavy drug use, some are specifically designed to treat the alcoholism or drug abuse of patients who have co-occuring disorders such as depression, anxiety, schizophrenia and posttraumatic stress disorder. Other trials are to treat patients who are addicted multiple substances, most commonly to alcohol and another substance such as nicotine or cocaine. There are also trials which are testing combinations of these different test medications together and also combining medications with behavioral therapies.

From this overview we can see some common themes, despite the large number and wide variety of treatments being tested. First, as you can tell by the number of familiar names, a lot of these medications are already approved by the US Food and Drug administration for the treatment of other diseases. This is a plus because it means a lot of the hard/expensive work has already been done for these compounds and positive results obtained in these clinical trials could be rapidly applied.

Secondly, along similar lines, many of these medications are being tested because a patients drug and alcohol problems may be inextricably linked to another disorder against which that medication has shown efficacy. An example of this is the SSRI anti-depressants, which have not shown much promise in the treatment of alcoholism alone, despite extensive testing. However, where that alcoholism occurs with depression, treatment of the depression can have a significant impact on the alcoholism symptoms. The same can be true of anxiety and schizophrenia.

A third common theme is that many of these trials have arisen as a result of positive results obtained in basic science research. As we begin to understand more about the neuroscience of addiction, new treatments suggest themselves. These can be tested in the laboratory and positive results form the basis of proposing clinical trials in people. There are still more questions than answers though.

As a neuroscientist, perhaps the most interesting feature is the abundance of epilepsy medications that are being tested as potential treatments for addiction. From the list above we have Zonisamide (Zonegran), levetiracetam (Keppra), gabapentin (Neurontin), topiramate (Topamax) and lamotrigine (Lamictal). Positive results have also been obtained studies with older drugs like carbamazepine and valropate. Unlike the aforementioned depression/anxiety/schizophrenia drugs which appear to work by treating a disorder that is co-occuring with the addiction, these epilepsy medications appear to work directly on the addiction itself, providing a window into the neuroscience behind addictive disorders. As I said above, scientists gazing through this window currently see more questions than answers; why are epilepsy medications effective? Most of these anticonvulsant treatments seem to work best for alcoholism, where they reduce craving as well as being effective in treating the alcohol withdrawal syndrome. Epilepsy sufferers know that anything more than a few drinks can be dangerous; during their hangover, the risk of seizures is greatly increased as the brain goes through a mild version of withdrawal. In detoxifying alcoholics, this process is more extreme; many need to have their withdrawal managed ina hospital setting as they will suffer full blown seizures (even if they do not also have epilepsy). The fact that epilepsy medications are effective against alcoholism has some scientists speculating that the intense neural activity seen during epilepsy and alcohol withdrawal may also drive the relentless craving that is such a debilitating symptom of drug and alcohol addiction. This neural activity may be "calmed" by treatment with epilepsy medications. The ability of these anticonvulsant drugs to act as mood stabilizers and anxiety medications may also be beneficial in the treatment of addiction.

Hopefully we'll hear a lot more about these drugs in the future. I'll highlight some more of them as new results come out and go into some depth about the neuroscientific basis for their actions. Until then; fingers crossed.

Addiction IS a treatable disease

Phil Newton — Thu, 08 Jan 2009 21:35:27 +0000

(Update, Jan 15 2009. This post was written in response to one from Stanton Peele entitled "Lies that addiction experts tell us part 3......". The title of Stanton Peeles post has subsequently been changed to "Addiction myth #3.......". I tell you this to explain the numerous references to "lies" and "lying" that appear here).

Unfortunately the biggest and most damaging lie from Stanton Peele's post is the one he announces in his title. The idea that addiction is not "treatable" is, at best, simply untrue and at worst will mislead sufferers of addiction into thinking that modern medicine can do nothing for them. For people to believe this lie would be a tragedy.

Naltrexone (Revia^TM) and acamprosate (Campral ^TM) are both medications that are prescribed to addicts to will help reduce their symptoms, most notably craving. Both are indicated for the treatment of alcoholism.

Any actual "addiction expert" will freely admit that neither drug works especially well and that their effects are moderate, but they do work. A recent, very large study, called the "Combining Medications and Behavioral Interventions for Alcoholism" (or COMBINE) study attempted to fully address whether naltrexone works in the treatment of alcoholism. They found that it did. So in fact, does behavioral therapy. The findings were published, by Anton and colleagues, in the Journal of the American Medical Association (JAMA).

The moderate overall effect of medications like naltrexone may be explained by them working for some people and not others, so that the averaged effect appears small. This variation in individual responses to naltrexone has long been thought to have a genetic explanation and follow-up analysis of subjects in the COMBINE study revealed this to be true.

Naltrexone works by blocking the mu-opioid receptor. The gene for the mu-opioid receptor, like almost all genes, is slightly different from one individual to another (as I discussed recently for social anxiety disorder).

Anton and colleagues performed a genetic analysis on their subjects and found that patients carrying one particular variant of the mu-opioid receptor gene, a variant called Asn40Asp, were significantly more responsive to naltrexone, raising the possibility that sufferers of alcoholism could undergo a simple genetic test to determine if they might benefit from naltrexone treatment.

As I stated earlier; these addiction treatments are not perfect, but they do help some patients and form the basis of further research aimed at developing more effective treatments. Anything which is proven, in clinical trials, to help addicts overcome their disease has to be a good thing. To claim that scientists who think that "addiction is a treatable disease" are somehow lying is a to willfully seek to deny patients of an opportunity to get better.

Bad Science

Phil Newton — Wed, 31 Dec 2008 14:25:51 +0000

Bad science is everywhere, from late night informercials to the worlds biggest drug companies. Fortunately, Dr Ben Goldacre has written a very entertaining book to help us identify the telltale signs.

I haven't posted for a while; I've been back in my native Britain for Christmas. My sister, knowing that I'm a miserable cynic and derive pleasure from the company of other cynics, gave me the book "Bad Science" for Christmas. I was very impressed with Bad Science, so much so that I am compelled to share my thoughts with you.

Bad Science is written by Dr Ben Goldacre, who has maintained a column by the same name in The Guardian (UK) newspaper for many years. I am aware of the column and have read it occasionally, although not for a few years. I remember it as a gentle analysis of news stories that misrepresented or manipulated science. The general message was "I think you'll find it's a bit more complicated than that".

Now, I find, Dr Goldacre is a much angrier man. The tipping point was apparently the controversy over the MMR (measles, mumps and rubella) vaccine, where bad research, a scientist with an agenda (Andrew Wakefield), poor political leadership (Tony Blair) and a hysterical media combined to produce a scare wherein the MMR vaccine was "linked" to autism. The link is nonsense (and the "evidence" is thoroughly reviewed in the finale to Bad Science), but hysteria still won't go away and vaccination rates have fallen.

The book, new this year, shows us that bad science is everywhere. Using numerous examples, we are shown how bad science is generated, it's effects amplified by the media and other non-scientists. We are shown the effects of bad science; it has, unfortunately, killed a lot of people. We are taught how to spot bad science, how to tease out the truth from the hyperbole and where to go for good science. The placebo effect is explained and quantified. Links are given for detailed information and articles on the bad science website; www.badscience.net

There is bad science everywhere, but certain purveyors come in for detailed criticism; homeopaths and "nutritionists" (in inverted comma's because, we learn, anyone can call themselves a "nutritionist" without training or expertise. Many people do). Homeopathy is carefully explained and systematically debunked.

Two individuals are also singled out; "Dr" Gillian McKeith and Professor Patrick Holford. McKeith describes herself as an "internationally acclaimed Holistic Nutritionist". She who has a large national TV audience in the UK where she peddles remedies for pretty much everything that ails the British public. However she no longer describes herself as a "Dr", after being exposed as a fraud by a badscience.net contributor. Professor Patrick Holford perpetuates fraud with a similar breadth and reach, so much so that there is an website dedicated to exposing it.

Many of you will never have heard of these people. I hadn't. This is perhaps the single notable weakness of the book; it's written for a British audience. These two charlatans are well known to the British public but less well known outside the country, although their stories are very entertaining and the lessons learned can be applied the world over. People like Holford and McKeith are ten-a-penny here in the US. A day spent with cable TV would give Goldacre enough for material for 10 follow up books. Or a nervous breakdown.

An oft repeated message is that the science one reads in the popular press is grossly distorted for the purpose of increasing readership. I knew this and I suspect you did as well, but the examples given are still breathtaking and depressing in equal measure. Perhaps most notable is the number of times science stories are covered by persons with no scientific training whatsoever (but maybe with a very respectable journalism degree). The bigger the story, the less likely a specialist science writer is to cover it. For those less familiar with science reporting, reading "Bad Science" will provide an education in what to look for in science stories that will set alarm bells ringing. For example, how many times have you heard scare stories where there has been a "50% increase in A Bad Disease following exposure to Something Previously Thought of as Harmless". Pulling back the hysteria and examining the facts often reveals that the 50% increase is from a small number to a slightly larger but still very small number. Such as 2 people to 3. Out of thousands. Be aware of percentages and look for real numbers! More importantly, look for proper statistical analysis. This too, is explained in simple, helpful terms.

It's not all bad, good science is out there in readily digestible forms and Goldacre directs us toward it. Special praise is given for the Cochrane Collaboration, a non profit that "produces and disseminates systematic reviews of healthcare interventions and promotes the search for evidence in the form of clinical trials and other studies of interventions". The Cochrane Collaboration has tackled many large and controversial issues, such as whether Vitamin C is effective in the prevention of colds (it isn't) or the treatment of colds (maybe). I was unaware of the existence of the Cochrane Collaboration before I read "Bad Science", but shall be using them extensively as a resource in the future.

Social Anxiety Disorder and The Placebo Effect

Phil Newton — Thu, 04 Dec 2008 04:57:59 +0000

The Placebo Effect, where patients derive benefit from a "dummy" pill, has been described many times over the years. New research shows that there is a genetic basis for the placebo effect in sufferers of social anxiety disorder.

The Placebo Effect is a well described phenomenon wherein patients given only a "dummy" pill, or placebo, nevertheless experience an improvement in their symptoms. Placebo effects have been described for a wide variety of diseases with some experts estimating that up to 90% of medical disorders benefit from a placebo effect. In some controversial cases, such as selective serotonin reuptake inhibitor (SSRI) anti-depressants, placebo effects are thought to account for a major proportion of the positive effects of a drug.

A recent paper by Mats Fredikson and colleagues at Uppsala University, published in the Journal of Neuroscience, describes how a person's genes may determine whether or not they experience a placebo effect. The study was conducted using sufferers of social anxiety disorder. One of the major symptoms of social anxiety disorder is a fear of negative evaluation by others. A classic example is that sufferers show a strong fear of public speaking.

In the Frederikson study, social anxiety disorder sufferers were asked to engage in a stressful public speaking event. They were then "treated" for 8 weeks (with placebo) and then again asked to speak in public. 40% of the placebo-treated patients showed an improvement in their symptoms over the 8 week period. Symptoms were rated by psychiatrists.

A key area of the nervous system involved in the generation and control of fear is the amygdala, a small, almond shaped part of the brain. When anyone gets scared or stressed, their amygdala becomes activated. Multiple human imaging studies have revealed that, when sufferers of social anxiety disorder become stressed, their amygdala shows a greater activation than that of non-sufferers. However, when social anxiety disorder patients are successfully treated, such as with cognitive behavioral therapy or citalopram, their amygdala function is restored to normal. In the Frederikson study, placebo-treated patients who experienced a reduction in their social anxiety disorder symptoms also showed a reduction in their amygdala activation.

Among the most common therapies for social anxiety disorders are SSRI's, which work in part by increasing the abundance of serotonin in certain parts of the brain (including the amygdala). The Uppsala team analyzed two genes that control the natural synthesis and reuptake of serotonin. Like all genes, subtle variants exist in some people. The most fascinating finding was that the patients who responded best to placebo carried different variants of these serotonin-related genes compared to those that did not respond to placebo. The icing on the cake was that one variant, in a gene called tryptophan-hydroxylase-2 (TPH2) could predict whether a person would respond to placebo. That is to say, if a sufferer of social anxiety disorder were to be tested and found to carry this variant of TPH2, then they would probably benefit from placebo treatment.

This study provides further stunning evidence of the power of genetic analysis, as well as providing some molecular and genetic explanations for the placebo effect. It may also provide some new clues into understanding the controversies surrounding SSRI treatment, which is often claimed to be no better than placebo. The powerful placebo effect in some people may make it harder to see a significant difference between placebo and SSRI-treated groups, even though the SSRI drugs may be having beneficial effects in patients who do not carry the "placebo genes".

Full study; Furmark et al, A Link between Serotonin-Related Gene Polymorphisms, Amygdala Activity, and Placebo-Induced Relief from Social Anxiety. The Journal of Neuroscience, December 3, 2008, 28(49):13066-13074.

Posttraumatic Stress Disorder and Cannabis. A Potted History

Phil Newton — Tue, 25 Nov 2008 00:09:13 +0000

"....because I can't forget no matter how hard I try.........."
Corporal Cloy Richards, PTSD sufferer.

Cannabis has often been proposed to treat posttraumatic stress disorder (PTSD) and rates of marijuana use are significantly higher in PTSD sufferers. However like all medical marijuana issues it's controversial and complicated. I will try and explain some of the science behind the issue.

The basic rationale is this; a defining feature of PTSD is that sufferers cannot "forget" a traumatic event such as combat or rape. It is well established that cannabis use impairs certain types of memory and may help sufferers "forget". Additionally cannabis often reduces anxiety and promotes sleep, both of which are beneficial for PTSD where elevated general anxiety and sleep disturbances are very common.

Cannabis acts upon receptors in the brain called, appropriately enough, cannabinoid receptors. The first and best described of these is called CB1, or cannabinoid receptor-1. CB1 is found throughout the brain. These receptors don't exist to get people high! What this means is that there are substances produced naturally by the brain, called endocannabinoids, that act at cannabinoid receptors.

The best described endocannabinoids are called anandamide and 2-arachidonyl glycerol (2-AG). These endocannabinoids are flighty molecules, they are rapidly synthesized only when required and don't stick around for long, being swiftly broken down by an enzyme by the name of "fatty acid aminohydrolase", less tongue-twistingly known as FAAH. Endocannabinoids are involved in many biological processes including appetite regulation, pain, anxiety, mood, nausea and blood pressure. All of which are also affected by marijuana.

One of the most interesting things these endocannabinoids appear to do, according to research in rats and mice, is stimulate the ability to forget about bad things. The basic research paradigm used is called "fear conditioning" and works on the same principle as Pavlov's dogs; rodents are played a sound, usually a beep, just before a very slight electric shock. This shock, much like a threat in the wild, causes the animals to freeze in their tracks. Although the shock is mild and brief, the animals obviously don't like it and learn very quickly that the beep means a shock is coming. After a short time, just the beep (without the shock) causes the animals to freeze and, crucially, causes the production of endocannabinoids in the brain. The relevance of this model to the human condition is obvious. PTSD symptoms are often triggered by exposure to something in the environment that reminds the sufferer of trauma.

After a while, rodents, like most people, will learn that the beep no longer means that a shock is coming and will no longer freeze when the beep is played. If animals are treated with a drug that blocks CB1 receptors then they show a profound inability to forget. The same result is found in mice genetically engineered to not have CB1, playing the beep causes them to freeze long after normal animals have learned to forget. Again, the relevance to PTSD is obvious; only some people who experience an extreme trauma will develop PTSD. Could genetic differences in their endocannabinoid system help explain why this is?

Perhaps most interestingly, animals given an extra booster of endocannabinoids find it easier to forget. Drugs which inhibit the breakdown of endocannabinoids by blocking FAAH have the same effect, suggesting that medications which stimulate the endocannabinoid system may be beneficial in the treatment of PTSD.

Exposure therapy is a commonly used treatment for PTSD; patients are repeatedly re-exposed to those triggers which precipitate their symptoms, much like the rodents and the beep. This tactic is completely at odds with the intuitive response of PTSD sufferers, who will actively avoid these triggers. As I mentioned above, basic research findings indicate that exposure to these triggers causes the brain to produce it's own cannabinoids, which then help the brain to forget. Perhaps the brains of PTSD sufferers have impaired cannabinoid synthesis, or maybe they break it down more quickly. Thus maybe cannabis treatment would be the most effective when given during exposure therapy?

That's the basic science. Sounds simple right? In fact it should be a no-brainer that cannabis use will be beneficial for PTSD sufferers?

Well, as so often occurs in science, it's not that simple. A major problem is that the cannabinoid system is found in almost all part of the brain and as such is involved in many different biological processes. A sobering example of this is the weight loss drug Acomplia ^TM from Sanofi-Aventis. The rationale behind this drug is reasonable enough; smoking pot gives people "the munchies", suggesting endocannabinoids promote eating. Blocking the CB1 receptor (with Acomplia^TM) should therefore reduce food intake. Sure enough, it does. But it also makes people depressed and has other psychiatric side effects. These side effects are so severe that Acomplia^TM has been withdrawn.

Cannabis also has a lot of potential side effects, many of them undesirable; apathy, psychosis, respiratory problems associated with smoking, prenatal toxicity, addiction (although this is controversial). One of the most troubling side effects of cannabis is that high doses can, in some people, trigger bouts of extreme anxiety. Not something any PTSD sufferer would want.

Another problem is that THC, the major active ingredient of cannabis, is not the same as the endocannabinoids found normally in the brain (otherwise we'd all be high all the time). It's not entirely clear that THC has the same "memory-erasing" effects as the brains natural endocannabinoids. In fact some researchers even think that treatment with pure THC may have the opposite effects, delaying an animal's ability to forget.

Nevertheless, a holy grail of "medical marijuana" programs for cancer and pain is the design of drugs which have the beneficial effects of marijuana without these undesirable side effects. Drug design programs based upon this reasoning may themselves eventually have a very beneficial side effect; drugs which can help PTSD patients forget.