Betrayal by the Brain(full text available from Amazon.com and Amazon.co.uk.)

 

I am a family physician who developed CFS in October 1993. Naturally since then I have become very interested in this illness and have been doing extensive reading on the topic.

 

The first book I found that made sense of this disorder was Dr. Jay Goldstein’s 1993 book, CHRONIC FATIGUE SYNDROMES: THE LIMBIC HYPOTHESIS. In this book Dr. Goldstein offers a neurological explanation for the myriad of bizarre symptoms one sees in Chronic Fatigue Syndrome and suggests treatments that often work. I began to use his treatment protocol on myself, without success, and on my CFS patients, often with dramatic success.

 

In March 1996 I spent a week in his clinic in Anaheim Hills, California seeing patients with him and trying several more of the medications myself. Again I saw dramatic successes in patients, but so far nothing has worked for me.

 

Dr. Goldstein has now published a new book entitled, BETRAYAL BY THE BRAIN: THE NEUROLOGICAL BASIS OF CHRONIC FATIGUE SYNDROME, FIBROMYALGIA SYNDROME AND RELATED NEURAL NETWORK DISORDERS. In my opinion this book is even better than his 1993 book and I will attempt to give you a very brief synopsis.

 

After ruling out the many illnesses that can cause fatigue, many physicians will tell their CFS patients that their symptoms are " psychosomatic". Well, there is overwhelming evidence that CFS/FMS symptoms are "neurosomatic", and not psychosomatic; that is to say that CFS/FMS is a NEUROLOGICAL ILLNESS. It is a neurotransmitter/receptor dysfunction problem. The symptoms occur because sensory information is not properly managed by the brain.

 

The basic problem starts with the prefrontal cortex of the brain. The PFC receives sensory information from the environment, both the external and the internal environment. It does not interpret the information. Rather, it assigns a weight to each signal according it relative importance, i.e. the PFC attaches the proper relevance to the incoming signal. This process is called gating.

 

Gating is abnormal in CFS/FMS and information that should be given low relevance is often instead given high relevance. In order to understand this, you must familiarize yourself with a crucial concept called signal to noise ratio. Your prefrontal cortex is

 

supposed to assign a high relevance to the signal and low relevance to any other sensory information. For example, the signal at the moment is your concentration on what you are now reading. Everything else is "noise". The television may be on in the other room--your PFC is supposed to assign that low relevance. The room may be a bit too cool--low relevance. There may be a fan running, again low relevance. The person next to you may be wearing perfume--so what! Instead, if your prefrontal cortex assigns all of these distractions high relevance, your concentration falters, or you may become overwhelmingly fatigued as you try to increase your concentration etc.

 

Abnormal gating makes walking a city block feel like you’ve walked ten miles; may make supposedly normal odors seem like you are awash in a sea of noxious chemicals; make you feel pain inappropriately; you may become worse when concentrating on the road at night, or experience a panic attack when you go to the mall, etc., etc.

 

Gating information is transmitted to your thalamus by a neurotransmitter called glutamate. Glutamate levels are abnormal in the CFS/FMS brain. Norepinephrine, a neurotransmitter that increases signal to noise ratio is low in the CFS/FMS brain, whereas substance P, a neurotransmitter which lowers signal to noise ratio is increased in the CFS/FMS brain. (Injection of substance P into the cerebrospinal fluid of healthy volunteers gives them diffuse body pain similar to that seen in FMS.)

 

So, the thalamus receives all this misinformation and has to modulate signals and transmit the message to various other brain centers. The thalamus is crucial to normal brain functioning. It modulates signals that control such things as pain information, appetite, mood, sleep, autonomic nervous system, libido, and the neuroimmunendocrine system. All these are abnormal in chronic fatigue/ fibromyalgia syndrome.

 

 

A Book Summary by Dr J A Skerkey - Betrayal By The Brain

 

 

There are four influences on how and why an individual will get CFS/FMS.

 

1)  Genetic Susceptibility. This tendency can be strong or weak or anything in between. If it is strong, a person will develop a neurosomatic illness no matter what, often beginning in childhood. Otherwise, expression of the trait is influenced by other factors i.e., childhood abuse, viral infections, anesthetics, pronounced physical or emotional stress, childbirth, trauma. There is an increased family history of panic disorder. There is often a history of psoriasis, allergies or asthma, sleep disturbances, irritable bowel syndrome, premenstrual syndrome, bruxism, or tinnitis.

 

2) Developmental Issues. While toddlers’ brains are still developing and forming neural network connections, it is important that the child be in a safe nurturing environment. If a child feels unsafe for a period of time from birth to puberty, his brain learns to be hypervigilant and to interpret the saliency of sensory input differently than a child who feels secure i.e., their brains learn to attach increased relevance to incoming stimuli instead of ignoring irrelevant stimuli. The prefrontal cortex, 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.

 

This also leads to elevated levels of substance P, enabling him to attend to a wide range of stimuli, as well as transiently elevated cortisol levels with consequent downregulation of the HPA axis. Central norepinephrine levels are low, contributing to dysautonomia.

 

3) Viral Infections. Viruses can produce persistent or hit & run infections which could alter neuronal transport as well as production of neurotransmitters in a genetically predisposed individual. More than one virus may be involved. Two viruses may interact with each other and enhance virulence. Viral gene products and host gene products may interact as well. Flu-like illnesses are known to deplete brain norepinephrine. Cognitive dysfunction in CFS/FMS may be caused by a similar mechanism as the gp120 glycoprotein in AIDS causes dementia.

 

4) Environmental triggers. The 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 reduction in neural plasticity, a decreased ability to re-regulate the brain’s response to stimuli. The synaptic density of neurons fluctuates depending on circulating levels of various neurotransmitters and hormones. In CFS there is decreased neural plasticity, therefore various stimuli (smells, increased concentration, exertion, shopping malls) make the individual sick.

 

 

 

 

SPECT scans show anterolateral and dorsolateral hypoperfusion, the right hemisphere worse than the left. The right hemisphere deals mostly with novel situations and uses norepinephrine. Norepinephrine is crucial to cognitive novelty. The left hemisphere deals mostly with repetitive, well-routined, pre-learned activities and uses mainly dopamine. Dopamine is critical to cognitive routinization. Flu-like illnesses are known to deplete brain norepinephrine.

 

Regional cerebral blood flow is consistantly found to decrease after exercise or any activity that makes the patient worse, for example doing calculations.

 

PET scans show activation of the dorsolateral prefrontal cortex along with decreased regional cerebral blood flow to the left angular gyrus, part of the neural network involved with tasks that require "willed action". Hypoperfusion and malfunctioning of the inferior parietal cortex leads to inappropriate sensations, behavior and emotions.

 

All stressors that require norepinephrine where the patient cannot produce enough, make the patient worse. If an individual is on the fence of norepinephrine signal to noise control and gets a flu, there is depletion of brain norepinephrine and the patient

 

can develop CFS/FMS if she/he is genetically programmed to have increased substance P, for example.

 

OK, let’s discuss the various symptoms one sees in CFS. Let’s start with PAIN.

 

The nucleus in the thalamus that deals with pain has two pathways coming into it, a pain pathway and a touch pathway. But they share a single pathway from the thalamus to the cerebral cortex, where the message is interpreted. When pain occurs, the touch pathway is inhibited by thalamic GABA production. Impairment of this GABA secretion would result in touch sensation being perceived by the cortex as pain, or in inappropriate pain interpretation (FMS).

 

 

 

 

Stimulation of the thalamus by electrodes in awake subjects causes them to experience pain they had years ago, a recurrence of pain in old scars etc. CFS patients experience this and complain of recurrence of pain and odd bodily sensations when the fatigue gets worse.

 

The basal ganglia neurons encode pain INTENSITY but NOT the LOCATION. Therefore, the basal ganglia are likely involved with a diffuse central pain disorder like FMS.

 

Case History: A 45 yr old immunologist with familial Parkinson’s disease, right side far worse than left, since age 38, developed CFS/FMS. A stereotactic left pallidotomy was performed. (The patient is awake during this procedure.) As soon as the left globus pallidus was cut the right-sided dyskinesia markedly decreased, and his right-sided fibromyalgia pain was reduced by 75%.

 

In summary then, dysfunctional sensory processing leads to inappropriate responses to a given stimulus. So, a patient may feel burning pain or severe weakness for no apparent reason, perspire profusely when he is not hot, or gain 30 lb in 6 weeks without changing eating habits.

 

The dorsolateral prefrontal cortex controls mood, organization, planning activities that require sequential tasks, motivation and drive, self-analysis. It is also involved in the making of new memories.

 

MEMORY: The prefrontal cortex regulates the hippocampus in new memory production. With prefrontal cortical dysfunction, situations are erroneously interpreted as novel i.e., that there is no cognitive repertoire for it. This leads to anxiety and other inappropriate responses.

 

 

 

 

Memory production occurs if post-synaptic neurons increase secretion of nitric oxide. Nitric oxide diffuses into the pre-synaptic neuron and increases glutamate production which strengthens the synaptic connection. If there is not enough nitric oxide, or enough glutamate, the individual cannot strengthen that synapse to make a new memory.

 

Since nitric oxide is anxiolytic, a decrease in nitric oxide leads to an increase in anxiety. Nitric oxide increases serotonin and norepinephrine and dopamine. If nitric oxide is low then dopamine is Iow, leading to fatigue, behavioral changes, decreased attention and decreased cognition.

 

SLEEP: Short-term memories are made in the hippocampus and are strengthened by repetitive hippocampal neural firing during slow-wave delta sleep. REM sleep is also vital for consolidation of new memories. THESE ARE BOTH DYSFUNCTIONAL IN CFS/FMS.

 

The reticular nucleus of the thalamus, via GABA inhibition, controls the transition from awake to sleep. Impairment here would impair sleep onset and sleep maintenance.

 

The cortex and the reticular nucleus also play a major role in the production of delta sleep. This is dysfunctional in CFS. Slow wave sleep is necessary to restore neuron glycogen stores that are progressively depleted during waking.

 

Substance P (which is increased in CFS) causes the release of excitatory neurotransmitters. This can lead to nightsweats, bruxism, nocturnal panic attacks, and nightmares.

 

The reticular formation in the brainstem projects to the thalamus and also projects to the hypothalamus and the cerebral cortex. Dysfunction here can cause insomnia. Sleep is a very complex phenomenon.

 

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.

 

Many neurochemicals are involved in sleep control; serotonin, GABA, adenosine, prostaglandins, insulin and many more.

 

EXERCISE: Exercise should cause an increase in norepinephrine, cortisol, B-endorphins, growth hormone, certain interleukins, adrenaline and noradrenaline, temperature, and regional cerebral blood flow, but doesn’t in CFS/FMS.

 

High levels of Substance P have repeatedly been found in CFS and may be responsible for the inappropriate post-exertional fatigue.

 

Exercise-induced temperature elevation is NOT the result of heat generated by increased activity, but is neurohormonally mediated. Similar mechanisms may be responsible for the temperature intolerance commonly experienced by CFS patients and in the often low basal body temperatures seen.

 

CHEMICAL SENSITIVITIES: Chemical sensitivities is a decreased signal to noise ratio phenomenon. Low level exposure to previously well tolerated foods and smells now make the patient sick. Olfactory information goes directly into the thalamus, which, as you already know by now, is dysfunctional!

 

FATIGUE: Fatigue is caused by dysfunctioning thalamic areas. In the 1930’s Dr. Wilder Penfield, working at The Montreal Neurological Institute, used direct electrode stimulation of various brain sites in wide-awake volunteers. Stimulation of one site would elicit a clear memory of a long ago event; of another site, perhaps the distinct odor of cooking, or the sound of a telephone ringing etc., etc. Some of the subjects, when being stimulated in the medial temporal lobe, reported a sudden onset of severe fatigue, "like someone turned on a faucet and drained all the energy out of me."

 

Dysfunction of the AUTONOMIC NERVOUS SYSTEM is manifested by low blood pressure and orthostatic hypotension, or, what is now being called neurally mediated hypotension (you don’t need a tilt table test to show this!), Reynaud’s phenomenon, rapid heart rate, temperature dysregulation, & weird skin sensations.

 

COGNITIVE & LANGUAGE TASKS: PET scans done while the subject is doing problem solving, calculations, explanations etc., show the neodentate lobe of the CEREBELLUM is involved in these tasks.

 

 

 

 

These areas are involved in the process of word finding. (often a problem in CFS/FM). The neodentate of the cerebellum acts as a computer to control prefrontal cortical symbolic representations of information, ideas and 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 CFS/FMS.

 

Waxing and waning of symptoms may be related to variable production of compensatory factors such as thyrotropin releasing hormone, corticotropin releasing hormone, nitric oxide, GABA or one of the subunits of the GABA receptor.

 

TREATMENT - Treatment is directed towards correcting a central deficiency of norepinephrine, nitric oxide, oxytocin (co-exists in the same cells that release CRH), Neuropeptide Y, etc.

 

Most of the medications on the protocol list work quickly and many patients who have been sick for years can show dramatic improvements within thirty to forty minutes after taking an effective medication. These medications have a good safety profile and Dr. Goldstein claims a 95% treatment success rate, meaning significant improvement in 95% of patients.

 

In my own practice, my success rate is approximately 50%, but that is because there are a few agents on the list that are not available in Canada, and a few, that I, so far, will not use.

 

Some of my patients have responded with an 80% plus improvement in symptoms to a single agent and have returned to work after absences of eight or more years. Most who respond, however, require two or three medications to achieve this level of improvement. For example, one of my patients, a 48 year old engineer who had been unable to work for eight years because of severe fatigue, severe fibromyalgia pain and severe cognitive dysfunction responded immediately 30 minutes after I gave her a 30mg capsule of nimodipine with about a 50% amelioration of her cognitive dysfunction. She had not been able to read so much as a magazine article for the past 8 years because by the time she got to the fifth line, she would lose the context. When I called her in from the waiting room 40 minutes after she had taken the medication, she had a big smile on her face and said she had been reading Newsweek in the waiting room and could tell me the content of the article. The nimodipine had done nothing, however, for her other symptoms. I sent her home on 30mg three times a day. Two weeks later I increased the dose to 60mg three times a day. She estimated that this improved her cognitive functioning to about 80% of normal. On a subsequent visit I gave her a tiny sliver of a nitroglycerine tablet under her tongue. This totally relieved her fibromyalgia pain in about three minutes. I gave her several single dose samples to try at home on different days. Several agents did nothing for her. Then she called me to say that mestinon 30mg totally relieved her fatigue for about 8 hours. She is now taking nimodipine 60mg tid, mestinon 60mg tid ( the dose later had to be increased to maintain freedom from fatigue), and nitroglycerine, approximately 1/4 of a 0.3mg tablet sublingually as required. She has returned to work and has remained virtually symptom free on this regimen for almost two years.

 

I include the treatment protocol here for your consideration. Perhaps your own doctor would feel comfortable trying you on samples of some of them if he/she is not comfortable with all these potentially useful medications. (His most useful medications are: nimodipine, gabapentin, oxytocin, baclofen and I.V. lidocaine.)

 

For those of you who are interested in obtaining the full text of Dr.Goldstein’s book, it has been published by The Haworth Medical Press and is available by calling 1-800-342-9678 .

 

I hope you find this information interesting. I wish you all a speedy recovery.

 

J. A. Sherkey M.D., C.C.F.P.

168 Annette Street, Toronto, Ontario, CANADA, M6P 1P4

FAX (416) 767-4898

 

 

 

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