Jay A. Goldstein, MD

Chronic Fatigue Syndrome is a disorder of the management of sensory input by the brain. Information from inside and outside the body is misperceived, resulting in inappropriate sensations. Touch can be painful, odors can cause illness, climbing a flight of stairs can be like climbing a mountain. If input is dysregulated, output will be also, because the brain will make regulatory decision based on improper "data processing." Actually, processing occurs properly, but "gating", the control of data input and output from processing centers, is dysfunctional. Thus, patients frequently complain, "my body doesn't work right."

The basic problem is the misperception of the saliency of sensory information by the prefrontal cortex, which regulates sensory gating as well as neurotransmitter secretion by neurons, which secrete the excitatory amino acid glutamate. There appears to be insufficient glutamate secretion resulting in decreased levels of several neurotransmitters, especially norepinephrine. The cause of prefrontal cortex dysfunction is an interaction of genetic, developmental, and environmental factors. Rapid pharmacologic remediation of CFS symptoms can be achieved by multiple approaches to enhance norepinephrine secretion from the locus ceruleus and the superior cervical ganglion.

Norepinephrine (NE) enhances the "signal-to-noise (STN) ratio" in the processing of sensory input by the brain. If there is a high STN ratio, important information will be extracted from a welter of sensory input. If STN ratio is low, much more sensory input will reach the cerebral cortex, some of it irrelevant. STN ratio is low in neurosomatic patients, accounting for misperception of sensory information, as well as distractibility in stimulus situations where cues are increased, environments as disparate as malls and short-term memory testing.

Substance P (SP) lowers STN ratio. There is an "Yin-Yang" relationship between NE and SP - when one is high, the other is low. NE metabolites are low in neurosomatic disorders and SP levels are quite elevated. Reasons for these abnormalities will be discussed.

There are four influences on the development of a neurosomatic illness in an individual.

1. Genetic susceptibility. This tendency can be strong, weak, or anywhere in between. If it is strong, the patient will develop a neurosomatic illness no matter what, often beginning in childhood. Otherwise, expression of the trait is influenced by other factors.
2. Developmental issues. If a child feels unsafe for a period of time from birth through puberty, he may become hypervigilant and interpret the saliency of sensory input differently than a child who feels secure. The neurochemical expression of this experience might be elevated levels of SP enabling him to attend to a wide range of stimuli, as well as transiently elevated cortisol with subsequent downregulation of HPA axis. Central NE levels would also be low, contributing to dysautonomia as well as abnormalities in sensory processing in the circuit between the dorsolateral prefrontal cortex, thalamus, and the hippocampus.
3. Viral encephalopathy. Individuals may be exposed to microbes that produce a persistent infection in neurons and gila without being lytic or initiating an immune response. Susceptibility to such infections would be largely genetically predetermined, but could also be influenced by situational perturbations of the immune response. Persistent CNS viral infections could alter production of transmitters and receptors as well as cellular mechanisms.
4. Increased susceptibility to environmental stressors due to a reduction in neural plasticity. The summation of causes 1-3 results in an impaired flexibility of the brain to alter the function of its neural networks to deal with changing internal or external circumstances. An example of this deficit may be encountered in the well-known problem that many neurosomatic patients have in making new memories. In order to encode a memory, a fragile neural network must be strengthened. This process may occur by augmenting secretion of glutamate from firing presynaptic neurons by secretion of a retrograde messenger, such as nitric oxide (NO) by the post synaptic neuron. NO diffuses in a paracrine manner into firing neurons in the locality, enhancing glutamate secretion. If insufficient glutamate or NO is secreted, neural networks will not be appropriately reorganized (strengthened) and incoding will be fragile. Neurosomatic patients have an impairment in neural plasticity. Deficiency in the neurobiology of encoding is one example of this pervasive disorder. Thus the individual who is predisposed to develop a neurosomatic disorder may have neural network function dysregulated by overtaxing his capacity for neural plasticity. This concept relates to that of "allostatic load" and explains why most neurosomatic patients develop their illness in a milieu of increased environmental stressors of various types. An example of this propensity may be seen in the predilection of neurosomatic patients to develop their illness after an acute infection, which produces an increase in hypothalamic activity and a decrease in NE (Dunn, 1993) (Watkins, Maier and Goehler, 1995), as do sustained attention, exercise, or orgasm, other activities which may produce or exacerbate symptomatology.

Watkins LR, Maier SF, Goehler LE (1995. Immune activation: the role of pro-inflammatory cytokines in inflammation, illness responses, and pathological pain states. Pain 63: 289-302.