©Jay W. Seastrunk II, M.D.

Kindling

In the 1960’s, while doing research at Tulane medical School, I became interested in the correlation between the electrical manifestation of brain activity and behavior. I was fortunate enough to be able to participate in deep electrode long term implant studies in non-psychotic individuals. This experience strongly imprinted in me the connection between brain activity and behavior. In reviewing the literature for Dr. R.G. Heath, my department chairman, I came across the “mirror focus” literature. In 1949, Pope et.al., described the ‘mirror focus” phenomenon, while working with Penfield on man and monkeys. In “mirror focus” development, an epileptic focus (a mirror focus) is found to develop in the hemisphere opposite to an original epileptic focus, even though there has never been an injury in that hemisphere. This developed focus takes ten to fifteen years to emerge in humans. In 1969, Goddard and two other researchers in the field of epilepsy published an article entitled, “A Permanent Change in Brain Function Resulting from Daily Electrical Stimulation.” They were curious as to why an incubation period often elapsed between a traumatic brain injury, and the occurrence of a first seizure, months to years after the injury. What they discovered was that repeated applications of either chemical or electrical irritants to the brains of animals eventually produce intense seizure discharges, even if each one of the irritating stimulations themselves is incapable of producing a seizure. They discovered that a stimulus to the brain, that ordinarily would produce no change in either the animal’s behavior or in the electrical activity of its brain, did produce significant changes in both behavior and electrical activity, if it were repeated and repeated. They called the repeated stimulus “a chronic irritant,” and the resulting effect “kindling.” In Vietnam veterans, psychosis took fifteen years to emerge following brain injury, illustrating that the limbic and/or more subtle behavioral manifestations of brain injury take a long time to emerge perhaps related to the “kindling” phenomena.

In 1992, Bell and her co-workers applied this reasoning to chemical sensitivity. They pointed out that the olfactory system of animals and humans permits access (via the nose) of environmental chemicals directly into the brain. These molecules pass into the entry point of the smell system, called the olfactory bulb. Numerous projections from this part of the brain are present in the upper regions of the nose and permit aromas, perfumes, aromatic hydrocarbons, and solvents to pass into the brain. Even more remarkable than the fact that these molecules pass directly into the brain, is the fact that they can progress neuron by neuron to the furthest reaches of the emotional portion of the brain, called the limbic system.

The limbic system, located primarily in the temporal lobe, serves not only as the location of our emotions, but even more interestingly, it is the location where we organize our information into understandable categories. This is because in animals, smell has great significance. An odor can mean the difference between food or poison, a friend or foe, so it is reasonable that odors and their significance would be closely linked in the animal brain.

The limbic system, located partially in the temporal lobe, serves, not only as the location of our emotional-system, but even more interestingly, as an information organizer, where we process information into understandable perceptions, whether they are olfactory, visual, tactile, or auditory. Memory with its emotional connections is stored here. However, it is tuned into many more inputs than just a single sensory perception. In fact, it seems to be tuned into all possible inputs, whether sensory, imaginative, verbal, or motor. This is why odors, movements, sights, sounds, ideas, or a combination of these, can rapidly trigger memories, emotions and behaviors.

When the limbic temporal lobe is injured, the individual cannot always recall memories at will, even though the memory is still in the brain. Individuals affected with chemical injuries, frequently report that they are having memory problems, yet, are surprised when psychological tests show no memory damage. This is because the system where the memories are stored, which is analogous to the bookshelves in a library which are intact; it is the memory organization and retrieval system or the card catalogue of the library that has been injured.

How does kindling and the mirror focus phenomenon fit into this? Researchers into epilepsy have long known that the olfactory and limbic systems are particularly susceptible to kindling. In fact, two limbic structures, the amygdala and the hippocampus are frequently used in animals to study epilepsy, because of the ease with which they can be kindled. This means that individuals whose brains have been injured can be kindled by either repeated low level stimulation of a chemical or electrical irritant, or by a peak exposure. Thus, an individual will continue to experience more and more effects from exposures too weak to affect a previously unaffected person, and possibly, become more and more sensitive to weaker and weaker exposures.

Time-Dependent Sensitization

A second mechanism, called time-dependent sensitization, is almost identical to kindling. According to Bell, et. al. (1992), time-dependent sensitization is very similar to kindling in that an external substance, e.g. a chemical, that has no effect at first on an animal’s brain will later produce a major reaction. This sounds almost like kindling, except for a few minor differences. By definition, kindling eventually leads to seizures, whereas time-dependent sensitization does not necessarily lead to seizures. Instead, it can lead to changes in the animal’s behavior, its sensations, cognitions, autonomic nervous system responses, vestibular (balance) responses, motion responses, and/or in its immune or hormonal function. Another difference is that time-dependent sensitization can occur after a single intense exposure, rather than a few small, repeated ones. After a passage of time, and without further exposure, a new exposure will suddenly produce the altered experience an/or behavior, or alter the immune function. Finally, time-dependent sensitization shows cross-sensitization, which means that after a given individual is sensitized, other substances, different from the one causing the initial exposure, will now, produce the altered experience, and/or behavior or function in a stereotyped way for each individual.

Kindling and time-dependent sensitization answer one of the most mysterious aspects of chemical and electrical sensitivity, i.e. who gets affected and why? Another phenomenon, known as cacosmia, must be introduced to understand this.

Risk Factors for Chemical Neurotoxicity

On November 13, 1993, over 400 affected workers, health care professionals, and interested labor and management representatives listened to Dr. Bell present her latest findings at a conference hosted by the Wahington Toxics Coalition in Seattle, WA. What she and her co-workers suggested is that there is an identifiable group of people more at risk for the development of chemical brain injury than other more resistant individuals.

To be able to identify these individuals, it is necessary to understand the term. The new term is cacosmia (ca-COS’-mi-a) which means “an altered sense of smell, accompanied by a tendency to feel ill, i.e. nausea, headache, and dizziness, from the odor of chemicals at low levels that have no effect on normals.” In other words, cacosmic individuals are the ones who first notice and are affected by the chemical odors in the environment. Six percent of college students report cacosmia when asked if they develop illness when exposed to pesticides, car exhaust, paint, perfumes, or new carpet. Among the individuals that were studied, women represented 79% of those identified as the most cacosmic. Among both women and men who were identified as strongly cacosmic, there was a much higher incidence of reported food allergies, self-reported memory loss, and somatic symptoms in general, when compared with noncacosmic subjects. For electro magnetically sensitive patients, a similar recruitment sometimes by subliminal, visual, or auditory inputs, or by electromagnetic waves themselves activate a kindled brain focus, causing it to fire, producing the characteristic, stereotyped, repetitive symptoms of that individual’s “reaction.”

A second risk factor appears to be stress. Ester Stemberg described how the central nervous system affects the immune system through endocrine, paracrine, and neuronal mechanisms. Bell, also points out, that one of the stress hormones in the brain, CRH, cannot only itself produce kindling, but when present in above normal amounts, makes it more likely that other external stimuli will induce kindling. Stress and sleep deprivation have long been known to increase epileptic seizures.

I feel that a third necessary factor is focal brain injury related to trauma, infection, or toxic insult. The location of this injury determines the scope of the repetitive, stereotyped symptoms, which becomes the “reaction” kindled by the external stimulus whether chemical, electrical, and/or stress and sleep deprived related.

Conclusions

• 1. It appears that perhaps some of the mystery of chemical sensitivity syndrome is beginning to disappear. Repeated small exposures to inhaled toxins, chemical or visual kindling, auditory, and/or electrical stimulation, or single overwhelming exposures, acting on focal injuries can bring about sensitization of the brain’s limbic system injury.
• 2. Because the brain’s limbic system modulates emotions and memory organization systems, emotional and memory symptoms will be common features of the disease. This area of the brain also controls balance, gastrointestinal motility, the autonomic nervous system, and auditory and visual integration of stimuli as well as memory..
• 3. Repeated exposures after the kindling or sensitization of the focus has occurred, will produce effects out of proportion to the intensity of the exposure..
• 4. Cacosmic people seem more at risk than non-cacosmic people, but this has not yet been proved by a prospective study..
• 5. Stress may play some role in who becomes affected, but how big a role is still uncertain. Stress definitely increases the occurrence of “reactions,” as does sleep deprivation due to its effect on focal brain irritability..
• 6. Because a fundamental brain mechanism is involved in the production of chemical sensitivity, continued exposure of individuals without protection or treatment is sure to increase the number of affected individuals and the severity of the symptoms in any particular individual..

Treatment

To be effective, treatment must interrupt these processes. Certainly, avoidance of the stimuli can stop the setting off of the focal firing, either directly or by stopping the kindling. Medications that stabilize the irritated cell decreasing its sensitivity to the kindling stimulus would be helpful. In this approach the amino acid anticonvulsant gabapentin has been very promising in our experience. Decreasing stress and improving sleep will also be beneficial. Removing any toxin that is still present in the brain should also decrease cell irritability. Desensitization’s of all types, allergic, and behavioral, seem to provide benefit.

References

• Bell, I., Miller, C., & Schwartz, G. An olfactory-limbic model of multiple chemical sensitivity syndrome, possible relationships to kindling and affective spectrum disorders. Biol. Psychiatry, 1992; 32; 218-242..
• Bell, I., Schwartz, C., Peterson, A., et.al. Possible time-dependent sensitization to Xenobiotics: Self-reported illness from chemical odors, foods, and opiate drugs in an older population. Archives of Environmental Health. 1993, 48: 315-327, 60p cit #4 p. 316..
• Goddard, G., McIntyre. D., Leech, C. A permanent change in brain function resulting from daily electrical stimulation. Exp. Neurology 1969; 25:295-330..
• Heath, R., Correlation of brain function with emotional behavior. Biol. Psychiatry, 1976; 11:463-480..
• McNamara, J., Bonhaus, D., Shin, C., et. al. The kindling model of epilepsy: a critical review. C. R. Clin. Neurobiol.-1985; 1:341-391..
• Monroe, R., Limbic Ictus and Atypical Psychoses. Jour of Nervous and Mental Disease, 1982; 170 #12: 711-716..
• Morrell, F., Experimental epilepsy in animals. Arch. Neurol. 1959; 1: 141-147..
• Morrell, F., Secondary epileptic lesions. Epilepsia, 1960; 1538-1560..
• Pope, A., Morris, AA., Jasper, H., et.al. Histochemical and action potential studies on epileptogenic areas of cerebral cortex in man and the monkey. Res. Publ. Assoc. Res. Nerv. Ment. Dis. 1946; 26:218-233..
• Schwartzkroin, P. A., Epilepsy: Models. Mechanisms and Concepts. Cambridge University Press. 1993; 27-47; 40p Cit #2 pg 221..
• Sternberg, E.M., The role of the hypothalamic-pituitary-adrenal axis in susceptibility to autoimmune/inflammatory disease. Immunomethods. Aug. 1994; 5(1): 73-78..
• Sutula, T., Experimental models of temporal lobe epilepsy: new insights from the study of kindling and synaptic reorganization. Epilepsia. 1990; 31 (suppl. 3): S45-S50..