Rage disorders – DSM-5, psychopharmacology, & rabies

I congratulate all those who put together the newest version of the Diagnostic & Statistical Manual of Mental Disorders, DSM-5.  It must be an overwhelming task.  I am particularly pleased to see a unified chapter on “Disruptive, Impulse-Control, and Conduct Disorders”.  It is a step forward in putting into one place a number of conditions in which rage is prominent.  And it is recognition that explosive disorders are fairly common. 

Then one notices a new disorder, “Disruptive Mood Dysregulation Disorder”, which is defined by frequent outbursts of rage.  Of course that goes into this new chapter, right?  Wrong!  This rage, disruptive, impulse-control, and conduct disorder, that is, lyssantic disorder is placed in with Depressive Disorders!  That’s really lame, and casts serious doubt on the DSM as a whole.

This brings to the fore that clinical psychiatric disorders are the sum of all the symptoms seen in people with behavioral disorders.  These disorders don’t fit into neat little boxes that can be defined at the didactic level.  Comorbidity is the rule for psychiatric disorders rather than the exception.  The DSM is important for giving therapists and researchers a common set of symptoms to describe what they are hearing.  And it is critical to aid in determine the symptoms most interfering with a person’s life and livelihood in order to prioritize therapy.  Therapies, be they pharmacological, cognitive-behavioral, or even psychodynamic or humanistic must focus on one aspect at a time, however much the therapist wishes to treat the ‘whole patient’.

Yet it is evident that psychiatric categories are grounded in theoretical constructs conceived by individual therapists and the schools of thought in which they were taught.  The whole point of the DSM in the first place was to find commonality in the behaviors/problems patients described and did not depend upon theoretical constructs.  This was a huge advance over the way psychiatry was carried out previous to 1950 when each therapist could uniquely define, without much regard to the thoughts of others, each patient they encountered.  However, the DSM still clumps various disorders (collections of symptoms) into categories that reflect psychoanalytic systems; systems that cannot be directly tied to testable biological events.

This must change!  One criticism of the newest DSM is the intrusion of pharmaceutical interests into its construction.  I cannot comment on this directly.  However, pharmacology must inform psychiatry!  Psychoactive drugs, to the extent that we can define their mechanism of action, act as a kind of experimental psychiatry, a way of testing schemas.  The effects of psychoactive drugs on human behavior and disorders must become a manual of its own, to be an adjunct to the DSM.  If SSRI’s, for example, reduce symptoms X, Y, & Z, then we know there is a neural circuit mediated (in some measure) by serotonergic synapses that can modulate those symptoms, those behaviors.  It may be that such an analysis of each drug’s effect on various patients will, in the short term, confuse psychiatric terms even more.  However, in the long run it will lead to strong underpinnings for categorizing disorders and lead to more selective therapies.

Beyond that, the study of the brain itself, when and how various behaviors and concepts are produced and modulated, is critical to our understanding of human beings.  I am obviously keen to explicate where rage is constructed and carried out.  But, we know that our nervous systems are built up of many layers carrying out different types of analyses on the world around us.  Rage will reveal itself in many ways in many people based on their genetics and the environment they grew up in, and the environment they operate in today.  Defensive rage is a synchronized group of behaviors designed to protect us from a threat that cannot be fully analyzed – no time to analyze it, perhaps it is just beyond comprehension (or just too immense to see how to defend against it), or presently unseen.  But even in its most basic form, it is triggered, and held at bay, by analyses of numerous parts of the nervous system.  Still, we can only understand its complexity if we know its source.  And while that source might be, for some, feelings of inferiority with regard to superhuman parental figures, it still has a specific place in the nervous system.  Together, and only together, these three analyses can write the story of human beings.

I have invented the term lyssant for someone who exhibits rage, be it normal or abnormal.  That term and its underlying neurobiology have been specifically enslaved by the rabies virus for its own purposes.  In having done so, rabies can light the way to understanding this important part of our behavior.  More important than some other aspects because it is a part of our non-conscious/subconscious nervous system that we cannot directly access by language or bring under control by learning or conditioning. 

The DSM should be seen as one aspect of the way we look at human beings.  Psychopharmacology and neurobiology form the other parts, and the intersection of all three will be the final understanding of what it means to become human.

Rabid about rabies – why me?

Rabid about rabies – why me?

As a neurobiologist, I’ve been interested and intrigued about rage, emotions, & rabies for many years.  But without a clear model to work on, there’s never been an experimental approach to use to study rage.  As I mentioned earlier, the most promising model, septal rage, disappears after a short time leaving us with nothing to interrogate.  In terms of treating rabies, there is a very good prophylactic and post-exposure (but pre-infection) vaccine that vastly reduces the chance of infection.  So, there isn’t a huge (in comparison to, say, Alzheimer’s disease) patient population demanding the time and resources of academic or pharmaceutical researchers.  So, I’ve worked on many other projects and neuropsychiatric disorders.

For me, that all came to a crashing halt in 2005 when a boy, Zachary Jones, died from rabies just a few miles from where I live!  He was bitten in his sleep by a rabid bat.  To him, it was just a dead bat on the floor and he may not even have noticed the bite; certainly nothing to tell his parents about.  When the symptoms of rabies infection appeared, it was too late to save him.  Even though the best treatment, the Milwaukee protocol, was used, there really is nothing we can do to treat rabies infection.  Zachary died. 

That made me mad!  How could we have let this happen with all the modern tools and treatments that medicine and neurobiology have to offer?  Of course, at the time I was engaged in more immediate projects and still had no idea of how to engage rabies.  But, I began to re-read and read more about the rabies virus.  I found that its unique properties do make it amenable to understanding.  There is a straight-forward series of studies that will identify the rabies receptor.  I tried to garner interest within Pharma, but no one was interested enough to listen.  Neuroscience research groups, often made up of younger investigators who have never read about how the Papez circuit was discovered, if they’ve even heard of the Papez circuit at all, said that rabies is an infectious disease, so I needed to talk with the infectious disease or immunology department.  And the infectious disease/immunology departments said, that rabies only kills about 50,000 people a year, while HIV, etc., kill many, many more, and we don’t have the resources to work on all the viral diseases.  As a lone pharmaceutical researcher, without academic ties, I don’t have much access to government grants either. 

New treatments for rabies infection are important, and treatments that would block the effects of the virus after infection are critical.  But, in addition, and in some ways more critical is to understand and find treatments for human lyssants, for outbursts of rage that disable so many victims and hurt so many others.  Rage attacks come through many neuropsychiatric disorders as I’ve noted in earlier blogs.  But, as we have no central, biological understanding of rage, they are shoved into a vast array of disorders where they are a secondary, comorbid condition without any hope of treatment.  And then there’s simply the fact that lyssantic behavior is a normal part of being human and control of it a vital part of becoming an adult member of social society.  As long as we don’t know where rage comes from, we will continue to depict it as supernatural vampires and werewolves; creatures, feelings, and behaviors apparently beyond our control.  As long as we use that excuse, we won’t really become the humans that we actually are.

For all these reasons, I am rabid about discovering the target, the receptor, by which the rabies virus releases our inner lyssant, and why I’m determined that we better understand ourselves, and better protect ourselves from the virus and from ourselves when necessary.  We have the tools and reagents to discover the rabies receptor.  The path forward is straight-forward, but it is not inexpensive.  Help me!

Lyssants need help – we need understanding

 Lyssants need help – we need understanding

Leila Fowler’s 12-year old brother needs help.  I can hope that his inner rage, his self-defense mechanisms, didn’t kill his sister, but I don’t give that hope much chance.  I believe it will turn out that some stressful events triggered him to do the unthinkable, likely unthinking as it happened.  Rage, lyssantic behavior, is in all of us, but for some and sometimes for any of us it escapes our social inhibitions and becomes reality. 

Werewolf, vampire, monster, lyssant; they all reflect a natural part of our behavior, but one that we still can’t even talk about straight.  I’ve given it a name, lyssant, and a probe, the rabies virus.  Now we need to put that into action, discover the receptor that the virus disrupts our own defensive behaviors to attack others.  The virus needs us to turn victims, to survive.  The behavior is self-defense in its most extreme form that doesn’t really recognize its victim; it just feels there is a threat and attacks wherever (whatever, whoever) that threat appears to be coming from.

Psychiatrists will parade out their useless terms; sociopath, psychopath, antisocial personality disorder, ADHD and autism with conduct disorder, intermittent explosive behavior.  All these prove is that we know there’s a problem, but we have no clear way of defining it.  Dr. Tom Insel, head of the National Institute of Mental Health (NIMH), recently brought this basic issue out into the light (where vampires are supposed to burn up) again saying that even the new version of the DSM, the Diagnostic and Statistical Manual of Mental Disorders, was irrelevant unless its definitions were grounded in neurobiology.  I couldn’t agree more.  Of course, the onus is then on neurobiology and the NIMH to identify those underlying biological mechanisms. 

So, once again I state that the effects of rabies, especially furious rabies, produces all the behaviors that have been ascribed to the daimona Lyssa, to werewolves, to vampires, and to all the other aspects and avatars of rage.  We’ve written about rabies for 4,000 years.  Isn’t it about time we actually discover what the virus understands so well about us, our nervous system, and our behavior?  It’s time to quit pretending rage is some supernatural invasion and recognize it is a natural part of what it means to becoming human.  And to recognize that some of us can’t always keep it under wraps and may need help in controlling it.                  Lyssants need help!

Transneuronal tracing – rabies virus excels!

Transneuronal tracing – rabies virus excels!

The National Institutes of Health has made it a major goal to define the connectome, that is, how all the parts of the central nervous system (CNS) are connected to, communicate with, each other.  This is critical information if we are to understand ourselves, our mental processes and how the CNS mediates the expression of those processes.  And, it is critical if we are to understand how those processes can go awry or, like rage, perilously surprise us.  The rabies virus can be a very important tool in defining the circuitry of the CNS because of its unique ability to infect, without damaging, almost all the regions.

A number of neuroanatomists, scientists working to understand how the parts of the CNS communicate with each other, have found the rabies virus to be a nearly perfect tool for identifying connections.  They have taken on the risks of working with the deadly virus because it is such a unique and powerful tool.  People working in these labs must be vaccinated against rabies, and the strength of their immunity against the virus rechecked frequently.  It is an enormous commitment to better our understanding of ourselves.  Below is an excerpt from a review by just one of these intrepid investigators.

“Powerful transneuronal tracing technologies exploit the ability of some neurotropic viruses to travel across neuronal pathways and to function as self-amplifying markers. …rabies virus is the ideal tool for studying motor innervation, since its peripheral uptake occurs exclusively at motor endplates. Rabies virus is the only viral tracer that is entirely specific, as it moves exclusively across chemical synapses by strictly unidirectional (retrograde) transneuronal transfer without altering neuronal metabolism, allowing for the stepwise, time-dependent, identification of neuronal networks across an unlimited number of synapses.” [Advances in viral transneuronal tracing. Ugolini G., J Neurosci Methods. 2010;194:2-20. PMID:20004688]

As I’ve written before, rabies is very unique in that it specifically infects neurons (nerve cells) of the CNS.  It does not infect sensory neurons or neurons of the peripheral autonomic nervous system, and, it does not infect any other cell that we know of.  It is, in a way, a perfect storm.  Moreover, infection of neurons by rabies does not lead to damage of those neurons.  It uses the neurons to replicate/to multiply and to move along, but without evidence of damage to them.  To do its job, to turn new victims, it must maintain the basic operation of the CNS, only redirecting it to become a lyssant, a rage machine.  The rabies virus does not burst out of the neurons as many viruses do from the cells they infect.  Amazingly, when newly synthesized viral particles do leave a neuron they have infected, they do so only at the neuron’s normal communication sites, called synapses. 

At these synapses, specifically chemical synapses, two neurons come very, very close to one another.  The two communicating neurons create specializations that allow the ‘first’ neuron to release chemicals, neurotransmitters, which will attach to receptor molecules on the ‘second’ neuron.  The second neuron will use the attachment/binding of those chemicals as a means to detect and transmit the signal on to additional neurons.  The synapses also use various means, such as trophic factors and adhesion molecules, to maintain the specializations and to keep them located directly across from one another so that communication is optimal.  Rabies uses these communication ports to move from neuron to neuron, disrupting the normal flow of information to direct its host to go out and turn additional victims – all so that the virus can survive. 

I believe, but am speculating, that the receptor that the rabies virus uses to initially infect skeletal motor neurons is exactly the same as the one that it will use to be taken up into, infect, each new neuron.  I can’t imagine that the extreme selectivity that limits the virus to only infecting the presynaptic endings of skeletal motor neurons will not be maintained at each synapse that the virus crosses.  Therefore, it is this receptor and the brain circuits it controls that are the key to us understanding lyssantic behavior, be it intermittent explosive behavior or a human werewolf.  And, once again we come back to wonder why this receptor has not been discovered.

playing 'possum, for the better

playing 'possum, for the better

The rabies virus is particularly insidious.  Many potentially lethal viruses appear to become less virulent, less rapidly lethal, as they spread through a population of victims.  Or perhaps it is more correct to say that variants that do not immediately kill victims become more prevalent.  Many deadly viruses require close, social contact for transmission from the infected host to another victim.  If the original host dies too quickly, before interacting closely with others, the virus dies with it.  No transmission and no survival of the viral species.  Rabies has not had to weaken itself at all because it forces its victims to actively seek out and actively infect additional hosts, actively turns new victims.  Therefore the former host can die relatively quickly and still complete its deadly mission.  The rabies virus uses the propensity of all mammals to bite to secure its own survival! 

But, biting comes in several varieties, with differing intents.  Biting can be aggressive and predatory used to kill a victim for food.  It can also rend foodstuffs in order to make them small enough to swallow.  And then there’s defensive biting used to damage and drive away foes and predators.  Finally there’s biting, nipping, that is at the height of emotional pleasure.  Our search involves the latter two forms.

The behaviors expressed as furious rabies make it clear that the rabies receptor is in a position within neuronal circuits to control rage and other emotional outburst behaviors.  The level of expression of this receptor in various people and various mammalian species may help explain their personalities.  And with tools to modulate its activity we can help those who find it nearly impossible to avoid the negative consequences of rage.  In this regard, I find it interesting that the opossum is known to be much less susceptible to rabies infection than other mammals.  Opossums do exhibit defensive rage, hissing and baring their teeth, but this is relatively short-lived, and when push comes to shove they quickly “play possum”.  That is, they play dead rather than attacking and biting their foe.  The opossum’s behavior is particularly amazing because the opossum is an omnivore, that is, it kills and eats other animals (although it tends to prefer carrion) as a routine part of its diet.  Clearly, aggressive, predatory behavior is not lacking in opossums, it’s only defensive rage that appears cut short. 

Is it possible that opossums express less of the receptor that rabies needs, that our brains need, to express rage behavior?   It will be very interesting to determine whether the rabies receptor protein is expressed at lower levels in opossums.  More speculation, but another testable hypothesis, at least once we identify the rabies receptor.

Rabies – infection, furious vs. paralytic forms, bats vs. wolves, motorneurons

Rabies – infection, furious vs. paralytic forms, bats vs. wolves, motorneurons

Rabies first infects a motorneuron, a neuron whose function is to tell skeletal muscles to contract to make our bodies move.  Inside the axon of the neuron it travels back (formally: in a retrograde manner) to the main cell body of the motorneuron that is situated inside the central nervous system (CNS) proper.  The cell body is where the protein- and the RNA-making machinery are located.  It is here that the virus finally begins to multiply and then spreads out to other neurons. 

Axons of motorneurons heading back into the CNS are clustered together in bundles.  These bundles are known as nerves.  Thus, once taken up by the presynaptic ending of a motor neuron, the virus travels inside nerves, that is, inside axons, to the CNS.  Because the viral particle is inside a neuron it is fully protected (unfortunately) from any antibodies the immune system might have made that could capture the viral particles.  This trip to the CNS takes some time, and that time will depend on the length of the axon/nerve that has been infected.  Infection that began in the toe will take longer to enter the CNS proper than a bite on the neck.  However, this length of time only accounts for a small part of the time between infection and symptoms, and does not at all account for the wide variability in time from exposure to symptoms.  That variability – up to a couple of years at least – is completely a function of the time it takes a viral particle to find and be internalized by the receptor that will take it into the CNS.  In the meantime, the virus is simply floating around in the body.  To emphasize again, if this were not true, Pasteur’s vaccine would be useless.

Yet, infection does occur more rapidly following some bites than others.  Moreover, some infections result in furious rabies while others produce paralytic rabies.  Both of these differences need to be explained. 

Bat bites, or possibly bat rabies, are more frequently associated with the paralytic form of rabies, while dog and wolf bites are more often associated with induction of furious rabies.  It is possible that this is due to differences in the virus itself, yet bat bites clearly can induce furious rabies in dogs and other animals.  It is certainly true that one can determine which animal a particular rabies viral particle came from.  However, this is a result of the virus using cellular components from the particular animal it has infected in order to make its outer shell, e.g., Hardy plank vs. aluminum siding.  It is not the result of any known difference in the viral RNA or the receptor recognition motif.  There are not different types of rabies virus that could possibly account for differences in the time to infection nor in inducing furious versus paralytic rabies.

A more plausible explanation might be because a bat’s bite is likely to introduce less virus-laden saliva into the victim than most dog or wolf bites.  It seems very reasonable that being exposed to more viral particles would shorten the time before one find its way into the central nervous system, that is, shortens the period between exposure and infection.  Perhaps the difference between furious and paralytic rabies is also largely a function of the amount of viral particles the victim is exposed to, leading to a greater number of axons, of neurons, infected.  But, infected at the same time?  That strains credulity. 

The site of initial exposure does appear to play a role, at least in the period of time between exposure and infection.  “Closer to the CNS” is often used to describe this observation.  As the time from initial infection to the onset of symptoms is not hugely different when traversing the axons from the toes or the neck, I propose that it is something else, something about the density and/or location of the rabies receptor that accounts for the difference.  A bat bite penetrates the skin, but probably does not often enter muscles directly, certainly not very deeply into them.  On the other hand, a wolf’s bite will almost certainly penetrate and gore muscle, breaking the various membranes that cover muscle tissue.  The dog’s bite has a much greater chance of directly exposing neuromuscular junctions to the virus.  This seems reasonable to explain why wolf bites might induce rabies infection more quickly, but still doesn't explain the two types of rabies, nor that wolf bites seem more likely to result in furious rabies.

It is possible that the rabies virus can enter the axons of both types of skeletal motorneurons, alpha and gamma, although I’m not aware of data on this point.  And, perhaps gamma-motorneurons have more, or stronger affinity, receptors for rabies than alpha-motorneurons.  Muscles of the neck, for example, have a high density of gamma-motorneurons and therefore infection via gamma-motorneurons could occur more rapidly.  Being closer to the CNS may simply mean a muscle being responsible for more types of controlled movements -- those required to let our eyes, ears, and nose have the best chance of picking up information about the world around us -- and therefore having more gamma-motorneurons.  Gamma-motorneuron endings are encased in an additional membrane, a joint capsule, which would also have to be penetrated in order to access the gamma-motorneuron terminals.  In this way, as well, a wolf’s bite, designed to rip and tear flesh, that is, muscle, would be more likely to rip open those joint capsules, exposing the nerve terminals to the virus.  Moreover, as the neuronal pathways from alpha- and gamma-motorneurons into the brain are different, at least for the first few steps, I further propose that infection of gamma-motorneurons primarily leads to furious rabies, while infection via alpha-motorneurons primarily induces paralytic rabies.  This is speculation, but testable.

Rabies – selectivity unequaled

Rabies – selectivity unequalied

Before continuing, it is important to note a number of implications regarding this extreme selectivity of the target for rabies infection.  First, it is the scarcity of the rabies receptor outside the CNS that accounts for the long, often extremely long, time period between exposure and infection.  The virus must chance across one of these rare receptors to gain access to the CNS. 

On the other hand, it is known that neurons within the CNS express the rabies receptor in very great numbers.  So, once the virus does infect the CNS it is rapidly transported to almost all areas of the spinal cord and brain.  Even here, however, infection of additional neurons only takes place at specialized connections between neurons.  These specialized junctions are known as synapses.  Just like the neuromuscular junction (synapse) where the rabies virus first enters the CNS, synapses are where neurons communicate with each other.  Binding to these communication sites, these receptors, the rabies virus can alter, most likely inhibits, certain avenues of communication in the brain.  Importantly, rabies does not exit from the host cell at any point except via synapses (the communications portals).  Nor does rabies induce the host neuron to burst – thus releasing a large number of viral particles, but killing the host – as many viruses do.  Rabies does not appear to structurally damage the CNS at all, only altering it functionally.  There are some reports of damage associated with injection of rabies virus.  Given the extensive use of rabies as a neuroanatomical tracer without reports of damage, I believe that reports of damage are the result of additional material contained in a preparation from an infected animal that has been injected along with the virus.

Some authors have suggested that the rabies virus infects some, particularly skeletal muscle cells, during the time between exposure and infection.  I have not seen a direct demonstration that this occurs, and certainly there is no evidence of replication in, or release of new viral particles from, these hypothetical cells. What has been observed is a high concentration of virus within skeletal muscle tissue; not necessarily within muscle cells themselves. Of course, the neuromuscular junctions are located in muscles and these contain the receptor by which rabies normally first infects the CNS.

 In reality, rabies virus is just pushed along around through the body until by chance it encounters the appropriate receptor, or, if the victim is extremely lucky, it may be excreted before producing infection.  It is certainly possible that the areas near the appropriate receptor may have special properties that make them reservoirs for the virus.  It may even be that the virus becomes attached to the receptor, but the conditions needed to internalize the receptor have not yet occurred.  In either scenario, this indicates the virus is sitting outside of all cells waiting for whatever stimulus induces its internalization into skeletal motorneurons.  If this were not the case Pasteur’s world-changing vaccine would be of little value.  The antibodies evoked by the vaccine are themselves too large to enter the CNS.  Their only chance of stopping rabies infection is to capture it, all of it, before any viral particles enter the CNS.  The vaccine does this very, very well, fully confirming that the virus remains outside of cells, most certainly outside of the nervous system, for a fairly long time.  We know this because the vaccine can be administered post-exposure (but pre-infection) and be completely effective.

In the laboratory, one can get rabies to infect a number of cells.  This does not imply any lack of specificity by the rabies virus.  Cells internalize (by a process called endocytosis) many external substances and membrane components (e.g. receptors) via large vesicles (sacs).  Given a high enough concentration of rabies virus in the solution cells are living in, it is highly likely virus will be accidently internalized.  There may also be receptors with very low affinity for the virus that, coupled with the high laboratory concentrations of virus, may allow internalization.  In the body however, the specific neuronal receptor is critical.  

A report of infection via inhalation of aerosolized virus has been made.  The conditions for this – millions of bats within a small cave – were certainly extreme.  This, possibly single, report does not imply a lack of specificity either; some neurons of our smell (olfactory) system, part of the CNS, are directly apposed to the external world.  In this case, infection most likely occurred via the unique neuronal rabies receptor that is well-known to be highly expressed within the CNS. 

Given that laboratory infection of cells is probably mainly non-physiological – does not represent natural infection – why don’t investigators use cultured neurons to study rabies infection in the laboratory?  Unfortunately, it is difficult to grow neurons in the laboratory.  While numerous reports and examples exist, these neurons were overwhelmingly gathered from embryonic tissue, long before the nervous system fully grew and developed.  Even when harvested from (early) post-birth tissue, the neurons are immature and do not express many of the receptors seen in adult neurons, at least not in their adult form, and also do not have many of the between-cell attachments standard in the native CNS.  Our understanding of how the rabies virus moves through the nervous system strongly suggests that specialized connections between neurons must be in place in order for it to infect most areas of the brain.  The study of rabies infection of neurons in vitro is difficult and simply has not been carried out very often.  And, it is actually the receptor, whose activity is changed by viral attachment and not the virus per se, that holds the promise for us understanding lyssants.  The virus is just there to survive and reproduce itself.  The virus is, in its characteristically horrifying way, goading us to find the receptor.