BETRAYAL BY THE BRAIN: THE NEUROLOGICAL BASIS OF CHRONIC FATIGUE SYNDROME, FIBROMYALGIA SYNDROME AND RELATED NEURAL NETWORK DISORDERSBETRAYAL BY THE BRAIN: THE NEUROLOGICAL BASIS OF CHRONIC FATIGUE SYNDROME, FIBROMYALGIA SYNDROME, AND RELATEDNEURAL NETWORK DISORDERS

by Dr. Jay A Goldstein

(summarized by Dr. J. A Sherkey; full text available from The Haworth Medical Press 1-800-3 HAWORTH. Reprinted on the CFS Society of Victoria's web site with the kind permission from Dr Sherkey.)

The mechanism of symptom production in CFIDS/FMS may be conceptualized as impaired sensory information processing in a neural network, resulting in dysfunctional responses. CFIDS results from neurotransmitter/receptor dysfunction. There are four influences on the development of a neurosomatic illness in an individual. 1) Genetic susceptibility. This tendency can be strong or weak or anything 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 (trigger ) factors. HLA-DR4 is significantly increased. There is an increased family incidence of panic disorder (a primarily limbic mechanism). HLA-DR1 is increased asit is in narcolepsy. Both are increased in persons with a family history of panic disorder. Triggering stimuli (one or more) can be: a history of childhood abuse, viral infections, anesthetics, pronounced physical or emotional over exertion, childbirth, trauma. 2) Developmental issues. Neonatal stressors can alter central information processing in children for years afterwards, causing an increase in somatic symptoms, changes in adrenal responsiveness to stress, and abnormalities in hippocampal CRH receptors. ( Minimal stressors such as 15 minutes of maternal deprivation for a total of 41/2 hours in the first 3 postnatal weeks of rats can cause lifelong HPA axis dysfunction). If a child feels unsafe for a period of time from birth to 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 is elevated levels of substance P enabling him to attend to a wide range of stimuli, as well as transiently elevated cortisol with subsequent down regulation of the HPA axis. Indeed, victims of childhood sexual abuse have abnormal plasma cortisol levels and have attenuated plasma ACTH response to CRH compared to controls. Central noradrenaline(NE) levels are low, contributing to dysautonomia as well as abnormalities in sensory processing in the circuit between the dorsolateral prefrontal cortex ( which regulates sensory gating), and the thalamus and hippocampus. genetic predisposition +/- childhood stress +/- other triggers-->altered prefrontal cortex gating-->altered thalamic signal modulation-->abnormal hypothalamic response-->decreased CRH-->dysfunction of prefrontalcortical function, midbrain function, and superior cervical ganglion (sympathetic) function. Studies in psychiatric units of children & adolescents who have been physically, psychologically and sexually abused (compared to controls) by EEG and BEAM scans show neglected children to have abnormalities in the left temporal lobe region. Differences in coping styles are partly genetic. Exaggerated or insufficient HPA axis response to defend a homeopathic state in a stressful situation could result in behavioral and neuroimmunoendocrine disorders in adulthood.

The prefrontal cortex (PFC), which gates sensory input according to its saliency every millisecond, must learn what is salient over time and integrate those experiences and attitudes with a genetic developmental predisposition. Dorsolateral prefrontal cortical (DLPC) dysfunction, therefore, would also be responsible for negative expectations. Persons who always anticipate adversity should be depressed and/or anxious and have HPA activation. Stress hormones are further elevated by peceived lack of predictability of events and lack of personal control over them. The role of the amygdala in this process has been emphasized. Activation of the amygdala is known to lead to anticipation of fearful events. Abusive or insecure childhood probably -->hypervigilance-->differentneural network structure and therefore their brains learn to attach increased relevance to incoming stimuli i. e. increased noise to signal ratio, i. e. they cannot discard irrelevant input. These patients often develop somatic symptoms as adults. Since the limbic system is the primary mediator of the stress response, it is reasonable to assume long lasting functional changes can occur in this network. The prefrontal cortex via the neurotransmitter glutamate is responsible for gating, i. e. attaching relevance or saliency to incoming sensory information. Regulation of signal to noise ratio occurs in the thalamus. GABAergic fibres in the reticular nucleus of the thalamus do not filter out extraneous input properly, therefore the signal to the cerebral cortex of, say, a mild/moderate touch is misinterpreted as pain (as in FMS).

prolonged stress-->hypercortisolemia-->hippocampal neuronal damage & altered regulation of hippocampal corticosteroid receptors (an effect which can be ameliorated by nimodipine) Changes occur not only in transmitters and receptors but also in the second messenger cascade, transcription factors, peptides, proteins and growth factors. 3)Viral infections may produce persistent or ‘hit & run’ infections 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 neurotransmitters as well as cellular functions. A decrease in K+ evoked serotonin release from virally infected cortical synaptosomes has been demonstrated. (Serotonin exerts a modulatory function on the rate of firingin the PFC). Latent herpes viral infections are well known to exist in nerve ganglia and to appearat times of stress. The trigeminal nerve, which can modulate limbic activity through projections to the pontine reticular formation and the hypothalamus, is commonly involved in the production of herpes labialis, for example. Herpes simplex is the commonest virus to infect the limbic system, usually in the anterior temporal cortex.

Viruses may enter the limbic system via retrograde neuronal transport. Therefore a viral infection could alter neuronal function in a genetically vulnerable individual, who may already have some premorbid limbic-related disorders such as bruxism, irritable bowel syndrome, and allergic rhinitis, in such a way that the function of the neural network could be further dysregulated, so that sensory gating and processing abnormalities would produce more symptoms. More than one virus may be involved. Two viruses may interact with each other and enhance virulence (well known wih HHV-6 and HIV). Viral gene products and host gene products may interact as well. Viral gene products &/or cellular products may affect bystander cells. These products may be cytokines, glycoproteins such as gp120 in HIV infection, or other transmitter substances. These products may also cause systemic effects or immune activation. A viral infection may cause decreased secretion of a cellular product. Fairly non-specific immune activation may be caused by viral gene products combining with variable segments of the T-cell receptor and to the major histocompatability complex molecules.

Flu-like illnesses are known to deplete brain norepinephrine (NE). Cognitive dysfunction in CFS/FMS may be caused by a similar mechanism as the gp120 glycoprotein in AIDS causes dementia. A CMV-related recombinant virus has been isolated in 50% of CFS/FMS patients and has been recovered in brain biopsy from patients with ideopathic neurological diseases. ( African green monkey CMV was a contaminant of oral polio vaccines. ) 4)Environmental stressors. Influence of genetic, developmental and/or viral factors results in impaired flexibility of the brain to alter the function of its neural networks to deal with changing internal or external circumstances (i. e. a reductionin neural plasticity). Neural systems adapt to the changing demands of their environment by modulating both the intrinsic membrane properties of neurons and the strength of the synaptic connections between them. Synaptic density of neurons fluctuates depending on circulating levels of various neurotransmitters and hormones.

In CFS/FMS there is decreased neural plasticity, i. e. , decreased ability tore-regulate the brain’s response to stimuli. Therefore various stimuli (smells, increased concentration, exertion, shopping malls) make the patient sick. The individual who is predisposed to develop a neurosomatic disorder may have neural network function dysregulated by overtaxing his capacity for neural plasticity. This explains why most neurosomatic patients develop their illness in a milieu of increased environmental stressors of various types. Waxing and waning of symptoms may be related to variable production of compensatory factors, such as TRH, CRH, GABA or one of the subunits of the GABA receptor. SPECT scans of patients with neurosomatic disorders show anterior temporal, and dorsolateral prefrontal hypoperfusion, with the right hemisphere worse than the left. Regional blood flow (rCBF) is consistently found to decrease after exercise or after anyactivity that makes the patient worse (e. g. doing calculations). There are low levels of CRH in CFS/FMS. Besides regulating ACTH secretion, CRH is involved in the regulation of the sympthetic nervous system as well as of the prefrontal cortex. The pluripotential cytokine IL-1B regulates CRH secretion through IL-6 and prostaglandins E2 and F2a. Since IL-1B levels are normal in CFS/FMS, there may be antagonism to IL-1B effects. central IL-1B antagonism-->decreased CRH secretion-->peripheralimmune activation (since CRH is immunosuppressive by stimulation of cortisol as well as stimulation of sympathetic activity in the spleen and lymph nodes). When Exercise ergometry is done in CFIDS patients to compare IL-1 regulated functions pre and post exercise, there is not the expected increases in cortisol, IL-1, IL-6, growth hormone, catecholamines, B-endorphin, somatostatin and core body temperature after exercise.

Hyperventilation is more common in FMS patients as is a marked irregularity in tidal volume at maximal exercise (evidence of limbic dysfunction i. e. , automatic respiration regulation). Sensory inputs produced by touch and pain are transmitted to the thalamus by separate pathways, but travel to the cortex in a single projection. When pain occurs, touch neurotransmission from the thalamus is inhibited by GABAergic interneuronsin the thalamic reticular nuclei. Impairment of thalamic GABA secretion could result in touch sensation being perceived by the cortex as noxious, and could be one mechanism of central pain in neurosomatic disorders. (GABAminergic medications such as gabapentin and lamotrigine should be effective in reducing the central pain of fibromyalgia syndrome. Xanax and other benzodiazepines enhance the effect of GABA and could act in the thalamus to reduce the central pain of FMS. )Stimulation of part of the thalamus by electrodes in awake subjects causes them to re-experience pain they may have had many years ago. CFS/FMS patients often complain of reoccurrence of pain in old wounds/scars and complain when the fatigue gets worse of odd sensations in their bodies, skin etc.

The prefrontal cortex interprets the relevance of incoming information and determines the strength/magnitude of the impulses to the CNS processing centers. . If the glutamate neurons in the PFC don’t stimulate the neurons that make norepinephrine (NE), then brain NE production decreases. Neurons compete for NE and substance P (SP) for nerve growth factor(NGF). Therefore if there is decreased NE, then SP receptors get the NGF and (since SP increases noise relative to signal) the signal to noise ratio decreases (genetic factors and learned hypervigilance figures here), and increased relevance is erroneously given to the incoming sensory information. The PFC also regulates the hippocampus in new memory production. Because of the predominance of right DLPFC dysfunction in neurosomatic disorders, many situations may be erroneously interpreted as being those for which none of the pre-existing strategies in the subject’s cognitive repertoire readily applies---> producing anxiety and other inappropriate responses. Processing of information then occurs in the amygdalawhich then projects to the brainstem areas involved in autonomic and somatomotorhippocampal response control. The PFC further modulates amygdalar input and output which is also dysregulated in CFS/FMS. DLPFC dysfunction-->glutamate dysfunction-->limbic system dysfunction The limbic system controls appetite, pain, mood, sleep, and the autonomic nervous system (all of which are dysfunctional in CFS/FMS). NE-->increases signal to noise ratio (NE levels are decreased in CFS/FM)SP-->decreases signal to noise ratio (SP levels are substantially increased in CFS/FM & in other neurosomatic disorders). Increasing noradrenergic (NE) function of the locus cerulus has an anxiolytic efffect and could ameliorate some of the symptoms of neurosomatic disorders.

Stress-susceptible individuals may have decreased locus cerulus cell numbers, which can be regenerated to an extent by the antidepressant desipramine. PET scans show decreased metabolism of glucose in the frontal lobes ( dysfunctionalsignal gating). SPECT scans show decreased rCBF to the frontotemporal (especially right) lobes. This worsens after exercise or other stimuli that make the patient worse. Treatments that make the patient feel better also decrease (by about 7%) rCBF (probably via increased NE and neuropeptide Y production. Therefore the decrease in rCBF is an epiphenomenon and not relevant to how a patient feels. All the treatments that acutely improve CFS symptoms cause global hypoperfusion. SPECT scans in healthy women experiencing transient happiness demonstrate widespread reductions in rCBF especially in the temporoparietal and right frontal cortices, suggesting that reduction of rCBF is not deleterious. Transient sadness produces an increase in rCBF, especially in limbic and paralimbic areas.

Endothelin causes vasoconstriction and endothelin excess may contribute to neurosomatic symptoms. It increases cerebral metabolism while decreasing rCBF. (a very singular property!) The hypermetabolic activation is mediated by L-type Ca++channels and is inhibited by nimodipine. There are at least 3 different endothelins and two endothelin receptor types (complicated). Different endothelins can be vasoconstrictive or vasodilatory. Endothelin-1 acting at the ET-alpha receptor stimulates neuronal release of dopamine(DA). Low levels of dopamine are vasodilatory (can be blocked by nimodipine and hydergine). High doses are vasoconstrictive. Endothelin acting at the ET-beta receptor stimulates the release of glutamate acting at the NMDA receptors on striatal dopaminergic nerve terminals. This has stimulatory and neurotoxic actions. It also increases secretion of nitric oxide (NO). Endothelins are thought to be involved in long-term cellular regulation(memory) and may be important in several pathologies, many of them stress-related.

CFS Endothelin levels are elevated in CFS/FMS and may account for the regional hypoperfusion seen in baseline CFS/FMS brain SPECT and also after exercise and cognitive activation stress. In these situations endothelins might be elevated disproportionately to NE and could be responsible for neurosomatic dysfunction, especially since it induces the secretion of substance P, which widens receptive fields and increases the gain of neuronal assemblies i. e. , it decreases signal to noise ratio. Nitric oxide is the primary vasodilator in the brain. It regulates local blood flow and synaptic efficacy. Its presence may be necessary for the release of catecholamines and other neurotransmitters. NO synthetase is heavily concentrated in the hippocampus as well as the rostral ventrolateral medulla, another site for sensory gating. Nitroglycerine is converted to nitric oxide. Low doses sometimes improve CFS/FMS symptoms, especially pain. NO->guanosine monophosphate(GMP)-> glutamate secretion. (glutamate is the important neurotransmitter for proper gating of signals i. e. attaching proper weight to the incoming stimulus, in the prefrontal cortex. )NO potentiates signals, causing long-term potentiation, for example, in the hippocampus and in the neocortex, where long-term potentiation is important inthe making of new memories. Memory production occurs if post-synaptic neuronsincrease secretion of NO. NO diffuses in a retrograde manner into firing presynapticneurons which then secrete glutamate which strengthens the synaptic connection. If there is not enough glutamate, or not enough NO, the individual cannot strengthen that synapse to make a new memory.

Increasing synaptic strength in other types of neural assemblies may be an important aspect of CFS/FMS treatment. Serotonergic agents are often useful in CFS/FMS and may work by producing long-term enhancement of synaptic efficacy. Short-term memory is often poor in CFS. Long-term potentiation also occurs in the frontal cortex and impaired secretion of NO could detract from the precision of interneuronal communication there. NO is anxiolytic. NO releases dopamine which could relieve fatigue and produce behavioral stimulation as well as enhance cognition and attention. NO inhibits dopamine uptake and may inhibit glutamate uptake. NO also increases release of serotonin and NE. NO is also a Ca++ channel blocker. NO stimulates the secretion of VIP (vasoactive intestinal peptide) and VIP stimulates the production of NO. NO may be colocalized with VIP and is found in the trigeminalganglion. NO often significantly potentiates the effect and duration of opioid analgesics (e. g. inFMS patients). NO is involved in the maintenance of spontaneous sleep. A central NO deficiency may exist in CFS/FMS on the basis of NO synthetase inhibition. Inhibition of IL-1B causes decreases NO synthetase which decreases regional NO. Inhibition of IL-1B also could be responsible for decreased CNS serotonin, dopamine, certain prostaglandins, IL-6, and CRH. Many effects of NMDA receptor activation are mediated by NO via glutamate. The pain of fibromyalgia is a result of central sensory dysregulation (especially in the thalamus)Studies have shown patients with CSF/FMS have rbc membrane defects and therefore rbc shape alterations making them less deformable than normal. At proper concentration, NO can preserve or enhance rbc deformability. A possible mechanism of action for the medications useful in CFS/FMS would be the stimulation of NE release----->enhancement of CRH secretion ----->decrease in substance P levels. CRH might also be stimulated directly. CRH may cause cerebral vasoconstriction either directly or by causing release of NE

All sensory information (except smell)---->DLPC (monitors & judges the activities of the cognitive networks & selects preferred responses that are influenced considerably by limbic input) thalamus(the most sophisticated gating structure of the CNS)Smell---->piriform cortex of the limbic system ------>mediodorsal thalamic nucleus- - - ->cortexAs a result of dysfunctional sensory processing, responses are not appropriate to a given stimulus situation. i. e. a patient may feel burning pain or severe weakness for noapparent reason, perspire profusely when he is not hot, or gain 30 lbs in 6 weeks without changing eating habits. Dysfunction in the PFC may then cause abnormalities of limbic regulation. The DLPFC controls mood, organization, planning activities that require sequential tasks, motivation and drive, self-analysis, and neural regulation. It is also involved in memory encoding (the making of new memories. )Processing in the anterior cingulate circuit enables the intentional selection of environmental stimuli based on the internal relevance those stimuli have for the individual. Input about that internal relevance is provided by the activity of the orbito-frontal (or prefrontal) cortex. Therefore, one would expect to find anterior cingulate, PFC, and insular dysfunction in patients with IBS (irritable bowel syndrome), and , generalized somatosensory dysfunction, especially tactile (FMS). PFC hypoperfusionis found in every IBS patient studied with SPECT scan. PET scan, qualitative EEG, and evoked response mapping in CFS/FMS constantly show hypofunction of the DLPFC and often the hippocampus (often worse in FMS). (Depression imaged by PET & SPECT is similar but usually involves the left DLPFC, as does schizophrenia. )The anatomy of these connections is complex, and involves the striatum, globus pallidus/substantia nigra, and the thalamus, which then project back to the frontal cortex. SPECT scans in CFS patients consistently show worse perfusion of the right side thanthe left. The right caudate and both thalami may also be selectively hypoperfused.

The right hemisphere is critical for processing of novel situations and the left hemisphere is key to the processes mediated by well-routinized representations and strategies. The left frontal systems appear to be critical for the cognitive selection driven by the content of working memory and for context-dependent behavior. The right frontal systems are responsible for cognitive selection driven by the external environment and for context-independent behavior. The right frontal systems are important in task organization and in the assembly of novel cognitive strategies. The left hemisphere tends to process outputs from neurons with relatively small receptive fields. The right hemisphere tends to process outputs from neurons with relatively large overlapping receptive fields. Possible biochemical correlates to this specialization include the lateralization of NE pathways to the right hemisphere and dopamine to the left.

NE is critical to cognitive novelty and dopamine to cognitive routinization. Activation SPECT scans done in CFS patients while they are doing calculations inappropriately activate the right hemisphere, especially the right DLPFC, a region involved in dealing with a novel stimulus. This finding corroborates the hypothesis of cognitive novelty misinterpretation in CFS. Normally it is the left hemisphere that is activated when performing a well-learned task, and the left parietal lobe normally has increased rCBF when the subject is doing calculations. PET scans show activation of the DLPFC associated with decreased rCBF in the leftangular gyrus, a region thought to be part of a disturbed neural network involved with tasks that require "willed action". The left angular gyrus is also important in visual spatial orientation and attention.

Hypoperfusion of the inferior parietal cortex(also called the angular gyrus) and the medial temporal gyrus occurs in many psychiatric disorders. These two regions appear to be part of a distributed neural network which may malfunction in various multicausal ways to produce inappropriate sensations, behaviour, emotions, and physiologic regulation. Auditory evoked responses, (a method to record the path of a sound stimulus as it is transmitted through the CNS), suggest an abnormality in sensory processing in aDLPFC-hippocampal-superior temporal auditory cortex circuit in patients with CFS.

There is decreased amplitude of the N-100 wave, which appears to be a trait marker, since it does not change with treatment of CFS. The N-100 wave is thought to signify attention (i. e. low signal to noise ratio). Impairment of signal to noise ratio would decrease the ability to attend to a specific stimulus and might reduce N-100 wave amplitude. N-100 amplitude is decreased in dementia and is either decreased or increased indepression. A course of ECT restores the decreased N-100 wave to normal in depression but antidepressant treatment does not. Antidepressants may increase extracellular dopamine in the PFC. ECT increases production of neuropeptide Y(NPY) which is a vasoconstrictor and is associated with numerous regulatory functions, including anxiolysis. Decreased NPY is found in the frontal lobes of suicide victims. NPY is co-localized with NE in noradrenergic neurons. Alone it has little vasoconstrictor effect, but if vessels are primed with alpha-agonists (e. g. Modafinil - a centrally acting alpha-agonist, or, Midodrine, a peripheral alpha-agonist; both are available from Zurich) , it is a potent and long acting vasoconstrictor. NE and NPY stimulation may be the mechanism for producing global hypoperfusion and symptomatic improvement in patients by rapidly-acting agents in the neurosomatic treatment protocol. ECT results in restoration of the N-100 wave in auditory evoked responses, and in the treatment of depression also decreases global CBF except in the left DLPFC. ECT also increases CSF NPY levels.

All stressors that require more NE when the patient cannot produce enough make the patient worse. If an individual is on the fence of NE signal to noise control and gets a flu, there is a depletion of brain NE, and the patient can develop CFIDS if he/she is genetically programmed to have increased substance P, for example. Exercise should cause an increase in NE, in cortisol, GH, beta-endorphins, IL-1, IL-6, chatecolamines, temperature, regional cerebral blood flow ----- but doesn’t in CFS. Infection there is antagonismStress ------> Increased CNS IL-1B -----/-----> Increased CNS CRHExertion to this action in CFSTherefore there is decreased CRH secretion -----> increased peripheral immune activation since CRH is immunosuppressive.

We should be able to alter NE input to lymphocytes and may be able to treat autoimmune diseases such as lupus and allergies. The treatment should increase noradrenergic tone which is immunosuppressive. Decreased CRH levels lead to decreased NE secretion in various parts of the brain, e. g. the locus ceruleus ganglion and the prefrontal cortex. CRH regulates reproduction, growth, thyroid and immune functions ( all may be deficient in CFS) Infection/vaccines - can precipitate CFS/FMSStress - can make symptoms worse paying attention ----->deplete brain NE - causes immune activation exertion -dysautonomia (e. g. abnormal ejaculation tilt table test)etc. , etc. , Low signal to noise ratio---> decreased ability to make new memories --->low levels of exposure to perfumes or previously subclinical food intolerances now make the person ill (Olfactory information goes directly into the limbic system instead of being modulated by the thalamus first [thalamus is also mal-functioning]-->chemical sensitivities [which is also a decreased signal to noise phenomenon]

Low signal to noise ratio in the immune system (immune cells produce the same neurotransmitters/receptors as brain cells and therefore can be considered as an extension of the CNS) may be responsible for autoimmune diseases such as lupus and psoriasis. The PFC is unique in that it regulates its own neurotransmitter input from brainstem nuclei. It sends excitatory neurons which secrete glutamate to regulate the output of brainstem nuclei which produce NE and DA. In CFS there appears to be a deficit of glutamate, and also NE. dopamine, neuropeptide Y, oxytocin, and NO. Elevations of substance P found in the CSF of FMS patients may be due to sympathetic (i. e. , NE) denervation hypersensitivity. SP also inhibits CRH release from the hypothalamus and therefore may be involved in CFS CRH deficiency. ( Increasing CRH results in increased NE secretion. ) If the superior cervical ganglion (SCG), a sympathetic ganglion, in rats is removed, serum growth hormone, prolactin, TSH, and somatostatin increase, thus suggesting projections from the SCG to the medial basal hypothalamus. Mestinon, which does not cross the blood-brain barrier, still increases the secretion of growth hormone, as well as GHRH, perhaps by stimulating the SCG. NE fibres from the locus ceruleus (LC) suppress weak inputs and enhance strong inputs, increasing the efficacy of feature extraction from sensory input and deciding what is relevant from one set of information to another. LC hypofunction could therefore produce attention deficit disorder because an individual’s ability to decide what is salient when exposed to sensory input would be impaired. It would also explain the common complaint of CFS patients that it is difficult to drive on the freeway or to go to shopping malls, because they are impaired in their ability to filter out irrelevant stimuli. Blood vessels in the carotid territory are sympathetically innervated primarily by fibres from the SCG.

The neurochemical network involved in the production of neurosomatic symptoms thus appears to be: The amygdala receives information from all neocortical sites and integrates external events with internal signals. CSF CRH is elevated in depression, schizophrenia, and obsessive-compulsive disorder (OCD). In CFS CRH is decreased, likely because of increased inhibition from the hippocampus. Prefrontal cortex glutaminergic hyposecretion to the amygdala may decrease CRH levels. Viral infections could also decrease levels of neurotransmitter substances. All information processed in the limbic system is referred to the PFC. Short-term memories made in the hippocampus are strengthened by recurrent hippocampalneuronal firing during delta (slow-wave) sleep. REM sleep is also vital for consolidation of new memories. These are both dysfunctional in CFS/FMS. Mg++ ionsare required to be removed from the NMDA receptors in order to increase excitatory neurotransmission. Because of insufficient presynaptic glutamate secretion, the Mg++block may not be removed and therefore synaptic strength which would be enhanced by NO, would also be reduced. glutamate--->attaches to adjacent non-NMDA receptors---->increased influx of Ca++, Na+, and efflux of K+, causing Mg++ to leave the binding site--->increased synaptic strength via NO enhancement. DLPFC altered glutaminergic secretion----->perturbed encoding and problem solvingin the hippocampus and decreased attention mechanisms and stimulus recognition in the inferior parietal cortex and medial temporal lobe, as well as perturbed pain messages to the neocortex from the thalamus.

Basal ganglia neurons encode pain intensity but not location. This suggests that the basal ganglia could be involved with a diffuse central pain disorder such as fibromyalgia. Case history: A 45 year old physician with familial Parkinson’s disease, right side far worse than left, since age 38, refractory to treatment, developed FMS. A stereotactic left pallidotomy was performed which markedly decreased his right-sided dyskinesia and decreased his right-sided fibromyalgia by 75%, but had no effect on his left-sided pain. (The substantia nigra determines pain intensity but not location, and is analgesic. The globus pallidus inhibits the substantia nigra. )On SPECT scans, the degree of caudate hypoperfusion is directly related to patients’ report of pain. Hypoperfusion of the right caudate is common in patients with neuro-somatic disorders. Caudate injury------>depression, mania, disinhibition, apathy, OCD, and defects in planning, sequencing, attention, and free recall. Lesions of the globus pallidus------>OCD, Tourette’s syndrome, apathy, irritability, mania, and amnesia. Defects in mood regulation are prominent symptoms in patients with neurosomatic disorders. Most peripheral neurons pass through relay nuclei in the thalamus where inhibitory GABA neurons modulate their input to the cortex.

The reticular nucleus of the thalamus, via GABA inhibition, controls the transition from awake to sleep. Therefore, impaired reticular nucleus function would impair sleep onset and sleep maintenance. The cortex and the reticular nucleus also play a major role in the genesis of delta (deep slow-wave) sleep. If brainstem cholinergic input and PFC glutaminergic neurons are not sufficiently deactivated by GABA during sleep, delta wave production would not occur properly and there would be frequent awakenings(as we see in CFS/FMS). Overstimulation or under-inhibition of cholinergic pontine neurons would result in vivid dreams or nightmares during REM sleep. Slow-wave delta sleep is restorative and replenishes neuronal glycogen stores that are progressively depleted during waking. Transient local decreases in cerebral glucose leads to decreased cellular energy which leads to increased adenosine production from AMP producing EEG manifestations of increased sleep need. The magnitude of adenosine release in NREM sleep determines the intensity of EEG slow-wave sleep. Adenosine is an inhibitory neurotransmitter which increases K+ conduction and promotes sleep onset and potentiation of NREM sleep. Wakefulness depletes brain glycogen and increases adenosine release as a result. Adenosine release during sleep may facilitate sleep maintenance.

Disorders of sleep maintenance could be caused by defects in adenosine metabolism. S-adenosylmethionine, a precursor of adenosine, has been shown to be an effective treatment for FMS in three double blind studies. Alternatively, increased substance P may overcome the adenosine effect and causethe release of excitatory neuromodulators to be sustained leading to night sweats, bruxism, nocturnal panic attacks, and nightmares. Dysfunction of the subthalamic nucleus--->dysregulation of mitochondrial oxidative mechanism--->decreased ATP production. ATP production elsewhere in the brain, andeven in other organs could be affected by a similar type of neural dysregulation. There are two network which produce cortical activation. The reticular formation in the brainstem 1) projects into the ventromedial, midline intraluminar thalamic nuclei; 2) also projects a pathway to the posterior hypothalamus, subthalamus and basal nucleus and from there diffusely to the cortexand hippocampus.

Damage or dysfunction of this pathway can cause insomnia. Transmitter substances involved in wakefulness include the neurotransmitters NE, DA, acetylcholine, histamine and glutamate, and the neuropeptides CRH, VIP, and SP. The neuropeptides are often co-localized with the neurotransmitters. Deficiency of one or more of these agents could result in somnolescence. NE, DA, glutamate, and CRH are reduced in neurosomatic disorders. Serotonin acts primarily as a neuromodulator, altering post-synaptic neural responses to other neurotransmitters. Transmitters regulating slow -wave sleep include serotonin (onset only), GABA, adenosine, opioids, alpha-MSH, somatostatin, prostaglandin D2, uridine, insulin, cholecystokinin and bombesin. Certain dipeptides from gut microflora can produce sleep directly as well as stimulating the synthesis and release of sleep-inducing cytokines such as IL-1. Neuroendocrine responses can also occur during slow-wave sleep, notably the release of GH. If slow-wave sleep is interrupted by alpha-wave intrusion, as in CFS/FMS, or if slow-wave sleep is otherwise deficient because of functional deficiencies in the caudate nucleus and elsewhere, GH secretion could be reduced.

No one brain structure is uniquely involved with the control of a single sleep or waking state. Different densities of sleep or wake-active cells occur in each region. Slow-wave sleep can be distinguished from wakefulness and REM sleep by high amplitude and synchronous EEG rhythms. Synchronization occurs when one or more neural networks, usually responding to the same neurotransmitter, fire together in a rhythmic manner. Desynchronization of the EEG replaces large, fairly regular recurring waves with fast rhythms of low amplitude. This state is associated with internal activation. Activation implies vigilance and readiness of neural networks to receive information and produce a rapid response. Blockade of thalamic inhibitory effects by GABA at the level of the reticular nucleus produces such activation. Inhibitory neurons in all the thalamic nuclei block some local information transmission to provide better receptive field specificity and response selectivity (signal to noise ratio). The reticular nucleus is also involved in selective attention by focusing a particularly active thalamic input, to the cortex like an internal attentional searchlight. Dysregulation of the reticular nucleus and its cortical connections could account for many of the somatic symptoms experienced by neurosomatic patients such as, pain, dysesthesias, feeling hot and cold, sleep disorders, and could explain how these symptoms could "move around" in an apparently non-neuroanatomic manner. The trigeminal nerve synapses in the reticular formation and in the thalamus. Both structures modulate how the brain interprets sensory information.

Other dysfunctioning thalamic areas are likely the cause of the fatigue in CFS/FMS. Personality structure is mediated by complex relationships with the thalamus and its connections to the brainstem, hypothalamus, orbitofrontal and dorsolateral prefrontalcortices. Thalamic reticular nuclei-prefrontal cortex dysregulation results in inappropriateperceptions and neural regulation. Thalamic microstimulation in humans produce visceral pain like that which have previously been experienced by the patients (a phenomenon that relates to FM patients experiencing pain in the sites of old injuries when relapsing, or to the persistence of pain in these sites). Control of energy metabolism is in the limbic system, primarily in the ventromedialnucleus of the hypothalamus (VMH) which also regulates various stress hormones , especially glucocorticoids. The hypothalamus VMH is also intimately concerned with skeletal muscle and cardiac muscle glucose metabolism. The VMH is thought to be the major hypothalamic component of the sympathetic nervous system.

VMH sympathetic nerve control of mitochondrial function in muscles is likely responsible for the lowered anaerobic threshold and increased lactate levels following exercise in CFS patients. Isometric exercise muscle contractions in CSF patients were found to increase substance P in the thalamus and other midbrain structures. High levels of SP have repeatedly been found in CFS patients and maybe responsible for inappropriate post-exertional fatigue. SP is secreted in excess and secretion persists for longer than normal after muscle contraction ceases in CSF/FMS. Exercise should increase levels of IL-1B, CRH, and NE. If this does not occur appropriately and if elevated baseline concentrations of substance P are augmented, post-exercise exacerbation of sensory input dysfunction and neuroendocrine dysregulation may occur. Exercise neuroendocrine findings in Chronic Fatigue Syndrome Normal CFS Cortisol õ --Growth Hormone õ -- or ß Somatostatin õ --Beta Endorphin õ --IL-1 õ variable IL-1ra õ ß IL-6 õ --Catecholamines õ --Temperature õ -- or ßRegional Cerebral Blood Flow õ ßRats who have VMH lesions show acutely depressed NK cell function and decreasedgrowth hormone levels, cited as the hallmark of CFS in the early days of its investigation(GH enhances NK activity).

NK cell dysfunction in CFS is of neuroimmunoendocrine etiology and not due to a primary immune dysfunction. Post-exercise elevations of cortisol, catecholamines, GH, B-endorphin, and core body temperature are blunted in CFS/FMS. This is likely due to blockade of IL-1B stimulation of CRH. CRH plays a vital role in VMH function. Exercise-induced temperature elevation is not the result of heat generated by increased activity, but is neurohormonally mediated. Similar mechanisms may be involved in the temperature intolerance commonly experienced in CFS/FMS patients and in the often low basal body temperatures seen. Dysautonomia in neurosomatic disorders is manifested by low blood pressure, orthostatic hypotention (you don’t need a tilt table test to show this!), Raynaud’s phenomenon, rapid heart rate, thermoregulatory dysfunction and livedo reticularis. CRH increases prefrontal NE production. Since CRH is decreased, production of muchof the brain’s NE is decreased. Barrington’s nucleus is rich in CRH neurons and a deficiency there could be responsible for sone of the symptoms of interstitial cystitis, another neurosomatic disorder in which elevated levels of urinary SP is found. Interstitial cystitis may be caused by CRH-noradrenergic denervation hypersensitivity in the bladder mucosa and submucosa. In summary, PFC function could be rapidly changed by many triggering agents in the predisposed individual; viral infections which alter neuronal function, immunization which deplete biogenic amines, organophosphate or hydrocarbon exposure, head injury, trauma childbirth, electromagnetic fields, sleep deprivation, emergence from general anesthesia, physical or emotional stress. Prefrontal cortex glutamate hyposecretion appears to be related to most neurosomatic disorders. The action of glutamate is potentiated by serotonin and VIP.

If neuropeptide Y secretion is dysregulated, circadian rhythm disturbances may be one of the symptoms. The PFC could maintain chronic pain states. When functional brain imaging is used to study cognitive and language tasks, the cerebellum becomes activated. The neodentate of the cerebellum targets the brainstem, thalamus, and cerebral cortex frontal lobes, especially the DLPFC and Brocka’s language area. These areas are involved in the process of word finding, a task with which neurosomatic patients often have difficulty. There are two-way communications between the cortex and the cerebellum, as there are between the cortex and the thalamus, to improve the co-ordination for performance of cognitiveand language tasks. The neodentate acts as a "computer" in controlling the traffic of PFC symbolic representations of information, ideas or concepts, and is involved in carrying out such operations as counting, timing, sequencing, predicting and anticipatory planning, error-detecting and correction, shifting of attention, pattern generation, adaptation, and learning. Many of these abilities are impaired in neurosomatic disorders. Therefore the corticopontine cerebellar system contributes to cognitive function and other aspects of neurosomatic disorders. Serotonin has been implicated in controlling feeding behaviour, thermoregulation, sexual behaviour, sleep and pain modulation. Serotonin has multiple subtypes, pre-and post-synaptic receptors, and interaction with other neurotransmitters such asglutamate, GABA, and NO, and many neuropeptides and hormones. Serotonin, probably acting at the 5-HT1A presynaptic autoreceptor, inhibits the glutamate-induced secretion of NE in the locus ceruleus, suggesting that the NE denervation hypersensitivity could be treated by a 5-HT1A antagonist (such as pindolol). Antidepressants’ mechanism of action is likely postsynaptic since NE reuptake inhibitors do not differ from SRI’s in clinical efficacy and tryptophan (a serotonin precursor) depletion in drug-free depressed patients does not acutely worsen their depression.

Serotonin exerts a modulatory function on the rate of firing in the PFC. There is a directsynaptic contact between serotonergic fibres to the vast majority of sympatheticpreganglionic neurons that send axons either to the SCG or to the adrenal medulla. Thus, serotonin may be sympathoexcitatory. A complex postsynaptic dysfunction of serotonin utilization is likely in depression. The sensorimotor thalamic nuclei receive about 90% of their innervation from brainstem acetylcholine fibres. The associational and diffusely projecting thalamic nuclei, which are more involved inneurosomatic disorders, receive NE-producing brainstem projections. Noradrenergic projection are denser in the right hemisphere than in the left. The opposite is true for dopamine and acetylcholine. Thus, problems with signal to noise extraction might be more common in right hemispheric disorders, as some neurosomatic disorders may be. It is proposed that:- a decrease in NE function increases distractability (seen in CFS). - impairment of mesolimbic dopamine output increases responselatency (seen in depression). - dysfunction of the cholinergic basal forebrain reduces discrimination accuracy (possibly a factor in CFS/FMS). - dysfunction of forebrain serotonergic cells increases impulsivity. (CFS/FMS patients are rarely impulsive, suggesting that serotonin deficiency is not important in their pathophysiology). Many neurosomatic patients state their symptoms are worsened by the ingestion of sugar. Yet, increasing blood sugar should enhance memory by increasing acetyl-Co-A, a substrate for acetylcholine. Both acetylcholine and insulin produce cortical activation.

Insulin receptors are very dense in limbic structures. Insulin induces the release of dopamine and NE from the hypothalamus. It is possible that these mechanisms could be dysregulated in neurosomatic patients. A large number of illnesses can be classified as neurosomatic, meaning disorders of central information processing, or dysregulations of widely distributed neural networks with problems of regulation of receptors, and neurotransmitters and other neural messengers. i. e. neurosomatic illnesses are neurological illnesses. The genes involved may be those that influence the capacity for neural plasticity, i. e. receptor-signal pathways that can modulate the adaptive capabilities of neurons, and hence neuronal networks. Treating neurosomatic disorders seems to be a matter of pushing the right neurochemical button.

People who have been ill for years can feel normal in a few minutes after taking the right medication. Patients whose symptoms do not wax and wane may have structural lesions and/or genetic dysfunctions that are not amenable to rapid remediation. These patients tend to respond poorly to the medications on the neurosomatic treatment protocol but may improve with antidepressants. The most effective medications are nimodipine, gabapentin, oxytocin, baclofen and intravenous lidocaine. A central noradrenergic deficit appears likely, perhaps accompanied by a neuropeptide Y and an oxytocin deficiency. Some of the medications do not cross the blood-brain barrier yet are still very effective. It is poorly appreciated by many clinicians how profoundly the brain can be modulated by molecules acting at the level of peripheral nerves, or autonomic ganglia. Acupuncture also has this mode of action. Most neurosomatic patients can bemarkedly improved in a short time with medications that have a good risk-benefit ratio.

Proof of Disability for Insurance: 1)SPECT scan - has to be done on a ‘brain dedicated SPECTscanner’2) Neuropsychologist’s assessment - preferably by someone familiar with CFS/FMS- tests for signal to noise ratio problems; problems with encoding new memories; encoding problems made worse by intention loading3)Occupational Therapist’s assessment - preferably by someone familiar with CFS/FMS - assess functional capacity physically (especially repetative tasks, work capacity and ADL); cognitive & aptitude tests Ref: Functional Capacity Evaluations of Persons With Chronic Fatigue Immune Dysfunction Syndrome Diane M. Barrows The American Journal of Occupational Therapy, April 1995, Volume 49, Number 4, pages 327 -3374)Possibly a Bicycle Ergometry Test - measures oxygen utilization against work done

Examples of neurosomatic illnesses other than chronic fatigue syndrome/fibromyalgiar: -allergic manifestations, asthma, food intolerances, chemical sensitivities, environmental illness, Gulf War syndrome; -psoriasis, urticaria, autoimmune illnesses such as lupus, mixed connective tissue disorder, - irritable bowel syndrome, chronic viral illnesses, chronic mononucleosis. - atypical neurological symptoms, paresthesiae, dysthesiae, pseudoseizures, near- syncope or syncope, headaches, sleep disturbances, nocturnal myoclonus, paroxysmal leg movements during sleep, sleep apnea; - endometriosis, dysfunctional uterine bleeding, PMS, post-partum mood disorders, dysmenorrhea; - chronic low back pain, carpal tunnel syndrome, phantom limb pain; - tinnitus, - attention deficit disorder +/- hyperactivity, - virtually all psychiatric conditions except schizophrenia, situational depression and anxiety, personality disorders, mental retardation; irritable bladder, interstitial cystitis, decreased libido, and many more.