Chronic Fatigue Syndrome is in part, 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 decisions 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." Information from inside the brain (cognitions) may be similarly dysregulated, resulting in inappropriate self-evaluation, self-monitoring, and self-prediction. These cognitions may occur automatically and cause a patient to make erroneous interpretations of situations, e.g., for depression, "people don't like me, therefore, they will reject me."

There are many possible beliefs that a person can have at any one moment. The perception of the saliency of these beliefs by prefrontal cortical neural networks determines which of them will be gated into awareness. Inappropriate perception of saliency will allow improper gating of beliefs producing dysfunctional cognitions. These dysfunctional cognitions can produce dysphoric or inappropriate mood and/or behavioral states, i.e. psychiatric disorders, such as depression, anxiety, paranoia, panic attacks, mania, etc.

The cognitions may be changed by psychotherapy. The best studied therapy is cognitive, or cognitive-behavioral therapy (CBT). Similar therapies are interpersonal therapy (IPT) and eye movement desensitization and reprogramming (EMDR). Pharmacotherapy, when successful, can also change the way a person thinks, and thereby change his attitudes and emotional responses.

The basic problem is the misperception of the saliency of information by the prefrontal cortex, which regulates 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 interaction of genetic, developmental, and environmental factors. Rapid pharmacologic remediation of CFIDS symptoms can be achieved by multiple approaches to enhance norepinephrine remediation of locus ceruleus and the superior cervical ganglion, as well as dopamine secretion from the ventral tegmental area into the mesolimbic and mesocortical pathways. Levels of longer-acting neuropeptide co-transmitters would increase also, as well as those of ATP and adenosine.

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

Substance P (SP) lowers STN ratio. There is a "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 down-regulation of the 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 glia 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 postsynaptic neuron. NO diffuses in a paracrine manner into firing neurons in the locality, enhancing glutamate secretion. If insufficient glutamate of NO is secreted, neural networks will not be appropriately reorganized (strengthened) and encoding 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 neu-rosomatic 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. Anesthetics with a prolonged emergence (waking up) time also may cause relapses since emergence is associated with massive increases in hypothalamic NE secretion.

 Humans, like animals in whom these experiments have been done more rigorously, respond to medication almost idiosyncratically, since everyone's brain is different. Animal research has highlighted the genetic, or "strain" differences among species to explain the marked variability in medication response that I see in the waiting room every day. The same pill can make one patient alert and pain-free, have no effect in a second, and exacerbate all the symptoms of a third. All effective medications cause a reduction of global cerebral blood flow which appears to be a result of increased secretion of NE and DA by many different functional neuroanatomic routes, something like "all roads can lead to Rome." I have demonstrated these immediate results of treatment on cerebral blood flow in Betrayal by the Brain. These changes also represent an immediate reconfigura-tion of neural networks.

When a patient reports immediate, marked CFS/FMS symptomatic improvement there is also a dramatic change in his beliefs, such as "maybe people do like me," if he is depressed. In my practice, CBT has not worked nearly as well as medication, which I currently view as "cognitive therapy in a pill."

Case Report

A 48-year-old married male Caucasian psychiatrist had not been able to work for two years due to exhaustion, exertional intolerance, diffuse pain, nonrestorative sleep, hypersomnia, and markedly impaired short-term memory. He had tried may pharmacologic treatment modalities prior to seeing me, and had also been psychoanalyzed. He was quite depressed about his somatic symptoms, but also had an apparent unresolved grief reaction about the death of his mother 10 years previously. When he recollected this event, even in the office with me, he would begin to cry.

 He had an immediate complete remission of all somatic symptoms after 400 mg of gabapentin (Neurontin). I asked him again to recall the death of his mother. He did so, and experienced an appropriate sense of loss, but none of the behavioral manifestations of severe sadness exhibited an hour previously. He reported that his cognitions about her death were profoundly altered, "Everyone dies, even those you love."

*Dunn AJ (1993). Role of cytokines in infection-induced stress. Ann NY Mead Sci 697: 189-202. *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.

Dr. Goldstein has published numerous times, is the editor-in-chief of a new medical monograph by Haworth: "Medical neuroimmunoendocrine networks in health and illness, book reviewer for the Journal of Nervous and Mental Disease, " as well as our medical advisor. He continues to work with treat-ment-resistant patients and his philosophy is not based primarily on making money but "on optimizing the health of each individual who consults me and teaching other health professionals to do the same. " Do not expect him to attend the forthcoming AACFS conference! He has lectured in the past few months to various support groups. Dr. Goldstein may be reached at 701 N. Glassell St., Orange, CA 92867, Tel: (714) 516-2830, FAX (714) 516-2707