Chronic Fatigue Syndrome and its many related disorders are in part, a disorder of the management of sensory input and selection of cognitions by the brain. Information from inside and outside the body is misperceived, resulting in appropriate 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 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 attended to, and thus given more "synaptic weight." Information with sufficient synaptic weight will enter the "gate" into various neural networks. Inappropriate perception of saliency will allow improper gating of beliefs producing dysfunctional cognitions. These dysfunctional cognitions can produce dysphoric and 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 neurotransmitter secretion by neurons which secrete the excitatory amino acid glutamate. There appears to be dysregulation of prefrontal cortex glutamate secretion as well as "tuning" of the N-methyl-d-aspartate (NMDA) receptor for glutamate by various other neurotransmitters, especially gamma-aminobutyric acid. If the NMDA receptor is activated by weak stimuli, too much input will be recognized as being novel, and thus possibly threatening. This malfunction causes decreased levels of several neurotransmitters, especially norepinephrine and dopamine.

The cause of prefrontal cortex dysfunction is an interaction of genetic predisposition, intrauterine development, and environmental factors. Rapid pharmacologic remediaton of CFS symptoms can be achieved by multiple approaches to enhance norepinephrine secretion from the locus ceruleus and the superior cervical ganglion, as well as dopamine secretion to the ventral tegmental area and into the mesolimbic and mesocortical pathways. Levels of longer-acting neuropeptide co-transmittters would increase also, as well as those of ATP and adenosine.

Norepinephrine (PE) 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 is low, much more input will reach the cerebral cortex, some of it irrelevant. STN ratio is low in neurosomatic patients (too many stimuli are perceived as salient, novel, and attended to, usually out of awareness). This error accounts 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 (Pallanti S et al. 1999).

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. 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, as found in fibromyalgia, enabling him to attend to a wide range of stimuli, as well as transiently elevated cortisol with subsequent downregulation of the HPA axis. Central EN levels would also be low, contributing to the dysautonomia present in almost all neurosomatic patients. Hypervigilance also causes remodeling of sensory and cognitive processing in the circuit between the dorsolateral prefontal cortex, thalamus, hippocampus, cingulate gyrus and amygdala. The intrauterine environment of the fetus may be significantly altered by maternal illness, experiences, or drugs, which may influence the behavioral state of the newborn for an indefinite period.

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 influence(d) by situational perturbations of the immune response. Persistent CNS viral infections could alter production of transmitters and function of receptors as well as intracellular 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 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 neurosomatic patients to become chronically symptomatic 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 which these experiments have been done more rigorously, respond to medications 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. The same medication can make one patient alert and pain-free, have no effect in a second, and exacerbate all the symptoms of a third. All rapidly effective medications cause an acute reduction in global cerebral blood flow which appears to be a result of increased secretion of NE and DA by many different functional neuroanatomic routs. I have demonstrated these immediate results of treatment on cerebral blood flow in Betrayal by the Brain (1996. New York, Haworth Medical Press) and Tuning the Brain (2000. New York, Haworth Medical Press). These changes also represent an immediate reconfiguration of neural networks.

A forty-eight-year-old married male Caucasian psychiatrist had not been able to work for two years due to exhaustion, exertional intolerance, diffuse pain, non-restorative sleep, hypersomnia, and markedly impaired short-term memory. He had tried many 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 ten years previously. When he recollected this event, 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 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."

REFERENCES.

Dunn AJ (1993). Role of cytokines in infection-induced stress Ann NY Acad 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.

Pallanti S, Quercioli L, Pazzagli A, Rossi A, Dell´Osso L, Pini S, Cassano GB (1999). Awareness of illness and subjective experience of cognitive complaints in patients with bipolar I and bipolar II disorder. Am J Psychiatry 156: 1094-1096.