Memory and Pain

Much to the relief of many, this will not be one of the brainbusting reviews of deep biochemistry. It will, hopefully, make you more self aware about your pain.

Always we are in search of models in order to help the public understand that there is actually such a thing as central pain. The public’s take on central pain seems to jump from disbelief to revulsion, with no resting place in between where rational discussion can take place. You are either loco at one end (making it up) or you are loco at the other end (incurable and therefore dangerously deranged). Even some doctors fly to pieces if you consult them for any other problem, once they learn you have central pain. knowing nothing about it, they are prone to attribute anything you suffer to central pain, and therefore excuse themselves from actually treating you.

Central pain is the heuristic disease of heuristic diseases. Heuristic means doctors overdiagnose any given disease if they have seen a lot of it lately. The mention of “central pain” is so traumatic to some insecure clinicans that they forever attribute ANYTHING you experience to what else, CENTRAL PAIN! Your CP becomes your Salem witch–one can never be too suspicious that whatever malady you suffer is actually imaginary, nefarious, and deluded. This is not healthy for the doctor/patient relationship. It increases the chance that something treatable will be glossed over. Not a few SCI patients with CP have had their broken bones attributed to the all mysterious CP, leaving the office without the needed cast, because the only real sign was pain, and after all, how seriously do we take these things in a patient who has a pain state we do not actually believe in.

The use of models seems to be moderately effective in educating those around us in what central pain might be like. An example is fear, or phobias. Certain people, in fact most people, have certain things they are afraid of. It may be dying of cancer, or it may be fear of being the victim of a violent crime. It may be fear of the sound of a dentists’s drill or it may be fear of abandoment, spiders, or snakes.

It is these kinds of fears which are now being called “hippocampal fear”. Not so long ago, neuroscientists thought the hippocampus was pretty routine stuff. It was known, along with the amygdala, as “part of the emotional centers”. That was about all you needed to know, even to get out of medical school. Neurology residents were required to learn a little more, but not much.

Then came functional MRI. Suddenly, people were made aware that the hippocampus was one very complicated structure. Its memories were possibly responsible for depression (the number one medical problem outside pain). The little hippocampus has increased in stature and perceived complexity until now, even the neuroscientist dares not claim to know much about it. The hippocampus was a real “sleeper”.

We mention “hippocampal fear” because there are reasons to believe that central pain may be “hippocampal pain”, ie. pain which the brain cannot forget. This is probably not true of the evoked portion of central pain, which requires present stimulus. However, the spontaneous burning may be some sort of memory trapped in time, the crying out of an injured cord–a trauma of such terribleness that the brain can only express its shock and awe, ie pain, forever more.

At the heart of all discussions of lingering impact is what is known as “long term potentiation”. This is a big medical term for what most people would call “memory”. It means that the brain recognizes the input (stimulus) and reacts to it much more powerfully than if it were the first go round with that arena of life. If a parent or a bully at school is likely to hurt you, your hippocampus can become a quivering blob of nerve tissue.

To understand better, it is necessary to reflect on the fact that the majority of what the brain does is inhibition. This is counterintuitive and requires a little explanation. The brain assimilates a very large amount of information. Filing this material away in usable order is important but requires great complexity. We need to forget (inhibit) some things. If the hippocampus, a sort of indexing and addressing organ, is considered, it becomes apparent that where really traumatic and painful events are concerned, the body needs to retain the warning aspect, but build a protective barrier against consciousness of those very events.

Some events are too big to stuff into the drawer where they belong. Some think central pain has elements of this aspect of brain function. Long term potentiation must therefore be viewed as potentially dysfunctional. The synapses along those pathways have little or nothing in the way of inhbition to stop their firing. Nothing gets “filed away”.

These pain signals, if that is a valid comparision, are bullies and toxic waste that the brain cannot put in its place, because inhibitory cells pertaining to those synapses are lacking. Presently, this is just a theory, but there is a surprising amount of information to suggest this is actually a crude description of how the brain works. Zhuo has evidence the anterior cingulate gyrus is at least partially responsible for the inability to make pain go away. There is general agreement, but the degree to which it is true is a matter of debate. Pain is very much interlaced with memory.

Back in the days the cingulum was surgically extirpated, it was alleged to stop pain, but it also turned the patient into something not genuinely human, with a loss of simply too many functions. In its heyday, this was a gross surgery, done by “jamming an icepick medial to the eye and stirring in the area of the prefrontal cortex” (prefrontal lobotomy). Perhaps selective stereotactic surgery may still be found to cut off pain memory without destroying personality. Central pain patients have always been the most desparate of subjects, and cingulectomies were virtually all done on central pain patients. Today also, CP patients will give up anything they have to try to escape the pain. We need to close the pain Auschwitz with better and more research.

Childhood neglect, for example, causes stress hormones to enable the child to go on functioning. Children neglected during infancy generally have some degree of retardation. This “dumbing down” may be necessary to avoid focus on the pain. However, the stress hormones block cell reproduction and force those cells to begin manufacturing whatever is needed to withstand stress. During this period, there is a cell population to be generated which does not occur. Whether and how soon the brain plays catchup ballgame is a point of great disagreement. Most scientists now feel the hippocampus never catches up. The result is failure in the ability to inhibit, giving certain signal, such as pain, depression, or fear an inappropriately powerful ability to override inhibition.

Since much is known about fear, we will consider it a model. Fear disables reason. Fear is the enemy of rational thought. Fear aborts the brain’s normal coping mechanisms. Normal fear response can be excitable, but still logical and measured out to a degree appropriate to the situation. Excessive fear changes all that. If you have a deep fear of something, you will not be logical, you will lose reasoning power, and you will behave like someone in massive fear, ie. largely incapacitated.

Fear is not really a good thing, because it disables reasoning. We are speaking of excessive, immobilizing fear.

Long term potentiation refers to a tweaking of the central nervous system so that certain stimuli cause an overresponse. No more obvious type of long term potentiation (LTP) exists than the abilty of light touch to evoke severe burning dysesthesia in central pain. Another type of LTP refers to a heightened response if an area is repeatedly hurt. If you have a sunburn, or have been rubbed raw, the next rub is going to give a bigger response. Any stimulation in the area is going to be overblown.

Biochemists refer to such a state as hypersensitization and are very interested in the chemicals which are responsible for such a response. However, we promised to lighten up on the biochemistry in this article. Similarly, neuroanatomists are interested in how parts of the brain interact to make for allodynia and the like, but we are going to avoid being too technical there also.

However, we can see it coming. Shortly, there will be scientifically based discoveries on just how this works in pain. And so we want to start you thinking about long term potentiation. Soon enough, you will want to know more about it. Potentiation represents a change in the products the genes of the chromosomes are manufacturing. The ability to modify gene output is known as “plasticity”. Plasticity means malleable or modifiable. It means something which can mold into something else and then perhaps be set there.

Hence, potentiation is important because brain plasticity is very important. Genes are dynamic, not static. Things can change, provided the right growth factors and transcriptional factors come into play.

We have already praised the legendary pain researchers of Toronto as much as it was in our power to do so. They practically have a corner on the market, except that their brilliant researchers spread out to other institutions as they graduate. This is feeding a revolution in pain research. M. Zhuo in Mol Cells. 2007 Jun 30;23(3):259-71, has published an article entitled, “A synaptic model for pain: long-term potentiation in the anterior cingulate cortex.”

What Zhuo proposes is that the anterior cingulate cortex, (Long known to be a participant in pain), and you might want to Google anterior cingulate cortex pictures, helps maintain nerve injury pain through long term potentiation similar to the mechanism of hippocampal fear. Basically, when trauma occurs, cells which ought to be forming in the hippocampus do not grow. This leaves a thinness, hypocellularity, weak place, a neuroconnectivity gap, which creates a vulnerability to fear, depression, or perhaps pain.

This is how it works in the body. A cell can either reproduce or it can do what it was designed to do. We see it in preemies. They don’t reach the normal number of lung cells until age 21, if ever (and there is argument about it) because the type II pneumocyte, which makes lung surfactant, is forced to quit dividing and producing more type II pneumocytes if they are born early. These cells are forced to become functional and start making surfactant to keep the lung expanded, with the cost of a permanent loss of reproductive ability. This is something like what happens in the hypothalamus with severe trauma, fear, or pain (if Zhuo is correct).

The hormones of stress, such as cortisol, help the body endure stress, but at the cost of borrowing from Peter to pay Paul. The cells will defend themselves from the onslaught, but that particular area will be forever vulnerable, perhaps crippled. If one reads Elie Wiesel’s Twilight, you will learn of how victims of the Holocaust could never quite regain their personality. Now we see even their children suing the German government to pay for psychiatric therapy for fears in the CHILDREN. This is really long term potentiation–into the succeeding generation!

However, for the purposes of painonline, we confine ourselves to the chemical mechanisms by which neuroinflammation elicits a stress response, which leads to neuroinflammation of a permanent nature. This is what will need to be prevented or undone if treatments for central pain are to be discovered. Fortunately, learning is progressing at breakneck speed and would almost certainly have produced a cure if there were any money around for researchers to follow up on the many, many leads which have come from studying neuroinflammation.

It is just good to remember that evidence already exists that the anterior cingulate cortex, once altered, can continue to exert an effect which favors long term potentiation. The value in such a model is mainly to help your clinician understand that you are a real patient, that you have a real disease, and that mechanisms are not so mysterious after all.

Our advice, if you have a sickness that needs treatment, don’t mention your central pain. Your doctor will refuse to take you seriously forever more. For the CP, go to the pain clinic, but park it there. For everything else, don’t frighten the doctor to death by making him afraid he must thread out central pain before your other problem may be treated. You should mention it, but not force the issue. Doctors still become undone by neuropathic pain, because they know so little about it. The PhD’s are forging ahead however and if we can just squeeze out a little research money, they will cure us. May God bless them all, every one.

In the not too distant future, you will no longer be pain Pinocchios, but you will be real patients, with a real disease, all through the miracle of cellular biochemistry. Your doctor will no longer see you as a puppet of your delusions about how bad your pain is. Instead, the doctor will proudly and with self affirmation administer whatever is needed to STOP YOUR PAIN. Doctors love to have grateful patients, and there are none greater than those relieved from pain. When they can cure it, then they will believe you had it.

It is true that there are a number of doctors trained in the Osler tradition at Johns Hopkins that you should listen to your patients, but Osler has been dead a long time. If you don’t believe the methodology of listening is waning, try running central pain past some of your local docs. If they don’t give you a psychiatry referral, you can consider yourself lucky. And if you actually go to the psychiatrist, and he/she acknowledges that you have real pain, and proceeds to call in your family to talk about minimizing stress, etc. you can really call yourself lucky.

Until we have a cure, central pain will be voodoo, or even the will of God. Once the cure appears, all will be right and God will be in His heaven marvelling that humans paid pain so little notice for so long, and CP will be perfectly respectable and medical, not theological. It is hard to live with it at the present time, with no cure, and no acknowledgement. This generation of CP sufferers will most likely be the last. Someday a PhD candidate somewhere will analyze WHY medicine took us so lightly. CP will become historical rather than tragic and brutal. A cure is the certain validation of a disease.