Unexplained Chronic Illness Martin Pall's compelling conceptualization of the excitotoxic cascade and its pivotal role in both the initiation and the perpetuation of chronic multisystem illnesses one or more short-term stressors chemical sensitivity – pesticides and organic solvents chronic fatigue – bacterial and viral infections fibromyalgia – physical traumas PTSD – severe psychological traumas to which the body responds with an outpouring of excitotoxins (glutamate) inflammatory factors (cytokines and eicosanoids) free radicals (nitric oxide) stress-induced outpouring of endogenous excitotoxins, inflammatory cytokines, and free radicals sets in motion (in certain susceptible individuals) the nitric oxide / peroxynitrite cycle a viciously destructive, self-propagating cycle involving immune stimulation, inflammatory cytokines, membrane destabilization, synaptic overactivity, opening of calcium-permeable channels, massive calcium influx, etc. and culminating in chronic illness

1. EMFs
AND THE
EXCITOTOXIC
CASCADE
MARTHA STARK, MD
MarthaStarkMD@HMS.Harvard.edu
JUNE 4, 2010 – Dr. Rea

2. MUCH OF MY PRESENTATION
IS BASED UPON MY INTERPRETATION
OF THE GROUNDBREAKING IDEAS OF
MARTIN PALL AND RUSSELL BLAYLOCK
RUSSELL BLAYLOCK – SPEAKS TO THE CRITICAL ROLE
PLAYED BY THE BRAIN’S IMMUNE SYSTEM IN ITS VALIANT
EFFORTS TO MAINTAIN THE BRAIN’S HOMEOSTATIC BALANCE
IN THE FACE OF THE MYRIAD ENVIRONMENTAL STRESSORS
TO WHICH IT IS BEING CONTINUOUSLY EXPOSED –
INCLUDING, OF COURSE, EMFs
PALL ML. Explaining “Unexplained Illnesses.” New York, NY: The Haworth Press, 2007.
BLAYLOCK RL. Excitotoxins: The Taste That Kills. Santa Fe, NM: Health Press, 1997.
OSCHMAN JL. Energy Medicine: The Scientific Basis. New York, NY: Harcourt Publishers, 2000.
MATTHEWS EK. Calcium and membrane permeability. Brit Med Bull 1986;42:391-397.
ADEY W. Electromagnetic fields, cell membrane amplification, and cancer promotion.
In: Wilson B et al. (eds). Extremely Low Frequency Electromagnetic Fields:
The Question of Cancer. Columbus, OH: Battelle Press, 1990, pp 211-249.
CHOI DW. Glutamate neurotoxicity: A three-stage process. In: Neurotoxicity of
Excitatory Amino Acids. FIDA Research Foundation Symposium Series, Vol. 4,
Guidotti A (ed). New York: Raven Press, 1990, pp 235-242.

3. UNEXPLAINED CHRONIC ILLNESSES
MARTIN PALL’S COMPELLING CONCEPTUALIZATION
OF THE EXCITOTOXIC CASCADE
AND ITS PIVOTAL ROLE
IN BOTH THE INITIATION, AND THE PERPETUATION,
OF CHRONIC MULTISYSTEM ILLNESSES
ONE OR MORE SHORT-TERM STRESSORS
CHEMICAL SENSITIVITY – PESTICIDES AND ORGANIC SOLVENTS
CHRONIC FATIGUE – BACTERIAL AND VIRAL INFECTIONS
FIBROMYALGIA – PHYSICAL TRAUMAS
PTSD – SEVERE PSYCHOLOGICAL TRAUMAS
TO WHICH THE BODY RESPONDS WITH AN OUTPOURING OF
EXCITOTOXINS (GLUTAMATE)
INFLAMMATORY FACTORS (CYTOKINES AND EICOSANOIDS)
FREE RADICALS (NITRIC OXIDE)

4. ENDOGENOUS AND EXOGENOUS
EXCITOTOXINS
ENDOGENOUS EXCITOTOXINS –
GLUTAMATE, ASPARTATE, AND QUINOLINIC ACID
AND THEIR SYNTHETIC ANALOGUES –
NMDA, KAINATE, AND QUISQUALATE
EXOGENOUS EXCITOTOXINS –
ASPARTAME (NUTRASWEET) AND MONOSODIUM GLUTAMATE (MSG)
AND OTHER FLAVOR-ENHANCING NEUROTOXIC ADDITIVES –
NATURAL FLAVORING, SPICES, YEAST EXTRACT,
TEXTURED PROTEIN, SOY PROTEIN EXTRACT,
AND HYDROLYZED VEGETABLE PROTEIN
SMITH JD et al. Relief of fibromyalgia symptoms following discontinuation
of dietary excitotoxins. Ann Pharmacotherapy 2001;35:702-706.

5. PALL’S NO, OH NO! CYCLE
NITRIC OXIDE (NO) / PEROXYNITRITE (ONOO-)
STRESS-INDUCED OUTPOURING OF ENDOGENOUS EXCITOTOXINS,
INFLAMMATORY CYTOKINES, AND FREE RADICALS
SETS IN MOTION (IN CERTAIN SUSCEPTIBLE INDIVIDUALS)
THE NITRIC OXIDE / PEROXYNITRITE CYCLE
A VICIOUSLY DESTRUCTIVE, SELF-PROPAGATING CYCLE INVOLVING
IMMUNE STIMULATION – MICROGLIAL ACTIVATION
INFLAMMATORY CYTOKINES – FREE RADICALS – OXIDATIVE STRESS
MEMBRANE DESTABILIZATION – DYSREGULATED NEUROTRANSMISSION
SYNAPTIC OVERACTIVITY – GLUTAMATE EXCITOTOXICITY
NMDA, AMPA, VANILLOID, AND MUSCARINIC RECEPTOR UPREGULATION
OPENING OF CALCIUM-PERMEABLE CHANNELS
MASSIVE CALCIUM INFLUX – CALCIUM DYSHOMEOSTASIS
ACTIVATION OF CALCIUM-DEPENDENT SIGNAL CASCADES
INDUCTION OF NITRIC OXIDE SYNTHASE
ELEVATED PRODUCTION OF NITRIC OXIDE, SUPEROXIDE, AND PEROXYNITRITE
MITOCHONDRIAL DYSFUNCTION – ENERGY DEPLETION
ACTIVATION OF CALMODULIN, CALPAIN,
ENDONUCLEASES, PHOSPHOLIPASES, AND ATPases
CASPASE-DEPENDENT APOPTOSIS CASCADE
AND CULMINATING IN CHRONIC ILLNESS

6. EXCITOTOXICITY, INFLAMMATION,
AND OXIDATIVE STRESS
IN THE FACE OF ANY PERCEIVED THREAT
TO ITS HOMEOSTATIC BALANCE,
THE BRAIN WILL MOBILIZE WHATEVER RESOURCES IT CAN,
INCLUDING ITS SPECIALIZED IMMUNE SYSTEM
(CONSISTING OF MICROGLIA AND ASTROCYTES)
MICROGLIA – THE RESIDENT “MACROPHAGES” IN THE CNS
SERVE AS ITS FIRST, AND PRIMARY, FORM
OF INNATE IMMUNE DEFENSE
MICROGLIAL ACTIVATION PLAYS A CRTICAL ROLE
IN THE BRAIN’S RESPONSE TO ALL MANNER OF STRESSORS
PROMPTING THE OUTPOURING OF HIGH LEVELS
OF GLUTAMATE, QUINOLINIC ACID,
CYTOKINES, EICOSANOIDS, AND NITRIC OXIDE
OLNEY JW. Glutamate: A neurotoxic transmitter. J Child Neur 1989;4:218-226.

7. SYNERGY OF NOXIOUS STIMULI
DIRTY ELECTROMAGNETISM
INFECTIONS
PESTICIDES
VOLATILE ORGANIC COMPOUNDS
PHYSICAL TRAUMAS
HEAD INJURIES
PSYCHOLOGICAL TRAUMAS
CEREBRAL VASOSPASM
ISCHEMIA
EXCESSIVE EXERCISE
HYPOXIA
PROLONGED HYPOGLYCEMIA
HEAVY METALS
SYNERGY – TOXINS CAN MAKE EACH OTHER MORE TOXIC
MAKE A DOSE OF MERCURY THAT WILL KILL 1 OUT OF 100 RATS
MAKE A DOSE OF LEAD THAT WILL KILL 1 OUT OF 100 RATS
THEN COMBINE THE DOSES AND 100% OF EXPOSED RATS WILL DIE
Dr. Boyd Haley – Professor and Chair, Department of Chemistry, University of Kentucky
To Congress on August 13, 2002

8. HORMETIC DOSE-RESPONSE
THE SYSTEM’S RESPONSE TO ELECTROMAGNETIC ENERGY
WILL BE DETERMINED BY THE DOSE
THE HORMETIC (OR BIPHASIC) DOSE-RESPONSE
WHEREBY LOW DOSES MAY PROMPT
“MODEST OVERCOMPENSATION” AND A BENEFICIAL EFFECT
WHEREAS HIGHER DOSES MAY PROVE TOXIC
MY FOCUS TODAY IS NOT ON
THE THERAPEUTIC USE OF HEALING ENERGIES
TO PROMOTE TISSUE REPAIR
BY FACILITATING THE FLOW OF INFORMATION AND ENERGY
THROUGH THE VAST EXPANSE OF THE MINDBODYMATRIX
RATHER, MY FOCUS WILL BE ON
DIRTY ELECTROMAGNETISM AND THE SYNERGISTIC ROLE IT PLAYS
IN ACTIVATING THE EXCITOTOXIC CASCADE IN THE BRAIN

9. NONLINEAR SYSTEM
BRAIN – A COMPLEX NETWORK OF MULTIPLE
INTERCONNECTED PATHWAYS IN A TANGLE
OF COMPLICATED INTERDEPENDENCE
A NONLINEAR WEB OF INTERRELATED
CYCLES, CASCADES, CHAIN REACTIONS,
CIRCUITS, CIRCLES, AND LOOPS
WITH NODAL POINTS HAVING MULTIPLE INPUTS / MULTIPLE OUTPUTS
… ALL ROADS WILL LEAD US ULTIMATELY
TO THE SAME FINAL COMMON DESTRUCTIVE PATHWAY –
THE EXCITOTOXIC CASCADE
THE NORMALLY TIGHTLY REGULATED BALANCE
BETWEEN EXCITATORY AND INHIBITORY NEUROTRANSMISSION
BECOMES SO SKEWED IN THE DIRECTION
OF RUNAWAY “POSITIVE FEEDBACK” EXCITATION
THAT SOME OF THE NEURONS LITERALLY
EXCITE THEMSELVES TO DEATH
NEURAL SENSTIIZATION – THE KINDLING EFFECT
CUMULATIVE RESONANCE

10. POSITIVE FEEDBACK LOOPS
UNLIKE NEGATIVE FEEDBACK LOOPS,
WHICH SERVE TO “CORRECT” ANY DISCREPANCIES
BETWEEN ACTUAL AND DESIRED OUTPUT
BY CONTINUOUS ADJUSTMENTS TO THE ORIGINAL SIGNAL,
POSITIVE FEEDBACK LOOPS
PROGRESSIVELY INCREASE THE MAGNITUDE
OF ANY PARTICULAR ENVIRONMENTAL PERTURBATION,
SUCH THAT THE ORIGINAL SIGNAL
WILL BE CONTINUOUSLY AMPLIFIED –
THEREBY CREATING A RUNAWAY SITUATION
IN WHICH THE BRAIN LITERALLY BURNS ITSELF OUT
UNLESS WE CAN ZERO IN ON
THE UNDERLYING BIOCHEMICAL MECHANISMS
THAT ARE GENERATING THE EVER-ESCALATING “FIRE WITHIN”
AND INTERVENE WITH STRATEGIES
DESIGNED TO DOUSE THE FIRE
BY DOWNREGULATING THIS EXCITOTOXIC CYCLE

11. PHOSPHOLIPID BILAYER
THE CELL MEMBRANE OF THE POSTSYNAPTIC NERVE CELL
A PHOSPHOLIPID BILAYER
COMPOSED OF NEGATIVELY CHARGED MOLECULES
(THE PHOSPHATE GROUPS)
HELD TOGETHER BY POSITIVELY CHARGED IONS
(CALCIUM AND SODIUM)
IN DYNAMIC EQUILIBRIUM
WITH FREE (CALCIUM AND SODIUM) IONS
IN THE SYNAPTIC SPACE
THE DIVALENT CALCIUM IONS
(WITH THEIR TWO POSITIVE CHARGES)
DO A BETTER JOB OF
MAINTAINING THE STABILITY OF THE MEMBRANE
THAN DO THE MONOVALENT SODIUM IONS
(WITH THEIR ONE POSITIVE CHARGE)

12. CRITICAL EMF “AMPLITUDE WINDOWS”
IN 1975 – SUZANNE BAWIN FOUND THAT
EXPOSING BRAIN TISSUE TO WEAK VHF RADIO SIGNALS
MODULATED AT 16Hz (16 CYCLES PER SECOND)
SELECTIVELY REMOVED CALCIUM IONS
FROM THE MEMBRANE OF NERVE CELLS
THEREBY DISRUPTING THE INTEGRITY OF THE MEMBRANE
BAWIN S et al. Effects of modulated VHF fields on the central nervous system.
Ann NY Acad Sci 1975;247:74-81.
SUBSEQUENT EXPERIMENTS IN OTHER LABS
WITH A BROAD RANGE OF DIFFERENT FREQUENCIES
REPLICATED THESE RESULTS – BUT ALSO DEMONSTRATED
THAT DESTABILIZATION OF THE MEMBRANE
WAS RESTRICTED TO CERTAIN
CRITICAL “AMPLITUDE WINDOWS” –
ABOVE AND BELOW WHICH THERE WAS NO EFFECT!
BLACKMAN C. ELF effects on calcium homeostasis. In: Wilson B et al. (eds).
Extremely Low Frequency Electromagnetic Fields: The Question of Cancer.
Columbus, OH: Battelle Press, 1990, pp 189-208.

13. “AGITATION” OF THE MEMBRANE
THE “AMPLITUDE WINDOW” EFFECT
OCCURS PRIMARILY WITH LOW-FREQUENCY ALTERNATING FIELDS
OR WITH RADIO-FREQUENCY FIELDS THAT ARE
AMPLITUDE-MODULATED OR PULSED AT A LOW FREQUENCY
ALTERNATING ELECTROMAGNETIC FIELDS
CAN AGITATE THE CELL MEMBRANE
CAUSING THE NEGATIVELY CHARGED STRUCTURAL COMPONENTS
AND THE POSITIVELY CHARGED BINDING IONS
TO MOVE IN OPPOSING DIRECTIONS
ONLY IF THE FORCE IS “JUST RIGHT”
WILL THE MORE STRONGLY CHARGED IONS (CALCIUM)
BE AFFECTED AND SELECTIVELY REMOVED –
AND THE VACATED SPOTS THEN FILLED IN
BY THE IONS THAT WERE LESS AFFECTED (POTASSIUM)
Goldsworthy A (2006). Effects of electrical and electromagnetic fields on plants and related topics.
In: Volkov A (ed). Plant Electrophysiology – Theory and Methods. Berlin: Springer-Verlag.

14. EMF-INDUCED
MEMBRANE LEAKINESS
MEMBRANES THAT HAVE BECOME DESTABILIZED
BY THE LOSS OF THEIR CALCIUM BINDING IONS
ARE MORE PRONE TO ACCIDENTAL TEARING,
THE FORMATION OF TRANSIENT PORES,
AND MEMBRANE LEAKINESS
AS A RESULT, CHRONIC EXPOSURE
TO OSCILLATING LOW LEVEL EMFs,
THOUGH TOO WEAK TO GENERATE AN ACTION POTENTIAL,
MAY NONETHELESS PROVOKE A MASSIVE INFLUX
OF CALCIUM INTO THE CELL INTERIOR –
WITH POTENTIALLY DISASTROUS CONSEQUENCES
CONTI P et al. Electromagnetic Biology and Medicine. 1985, Vol. 4, No. 1, pp 227-236.
YU-HONG Z et al. Mechanism of permeation in calcium channels activated by
applied magnetic fields. Conf Proc IEEE Eng Med Biol Soc 2007:1391-3.
MATTHEWS EK. Calcium and membrane permeability. Brit Med Bull 1986;42:391-397.

15. INTRACELLULAR CALCIUM
LEVEL NORMALLY MANTAINED AT 0.1 – 0.2 MICROMOLES
LEVEL DETERMINED PRIMARILY
BY THE BALANCE BETWEEN
CALCIUM LEAKING INTO THE CYTOSOL
WHICH HAPPENS WHEN CALCIUM FLOODS IN
BECAUSE OF EMF-INDUCED MEMBRANE DESTABILIZATION
OR BECAUSE OF ACTIVATION OF NMDA RECEPTORS BY GLUTAMATE
WHICH THEN OPENS THE ASSOCIATED CALCIUM CHANNELS
TO ALLOW THE PASSIVE INFLUX OF CALCIUM IONS
DOWN THEIR CONCENTRATION GRADIENT
AND CALCIUM BEING PUMPED OUT
WHICH HAPPENS WHEN ION PUMPS
ACTIVELY TRANSPORT CALCIUM IONS OUT OF THE CELL
AGAINST THEIR CONCENTRATION GRADIENT
THE ENERGY FOR WHICH IS PROVIDED BY
EITHER MITOCHONDRIAL ATP
OR THE CONCENTRATION GRADIENT CREATED BY ANOTHER ION

16. CALCIUM-DEPENDENT ENZYMES
CALCIUM REGULATES MANY OF THE CELL’S
PHYSIOLOGICAL PROCESSES
BY ACTIVATING INTRACELLULAR SIGNAL CASCADES
CALMODULIN (CALcium MODULated proteIN)
CALPAIN, ENDONUCLEAES, PHOSPHOLIPASES, AND ATPases
EXCESS AMOUNTS OF WHICH DAMAGE VITAL COMPONENTS
IN THE COMPLEX AND SENSITIVE CIRCUITRY OF THE BRAIN
CALCIUM ALSO STIMULATES
THE PRODUCTION AND RELEASE OF GLUTAMATE
WHICH WILL, IN TURN, STIMULATE NMDA AND AMPA RECEPTORS
ALONG WITH THEIR ASSOCIATED CALCIUM-PERMEABLE CHANNELS
LEADING TO EVEN FURTHER CALCIUM INFLUX
WHICH WILL, IN TURN, EXCITE THE CELL EVEN MORE,
CAUSING ADDITIONAL OXIDATIVE DAMAGE,
AND FURTHER IGNITING THE ALREADY RAGING FIRE

17. CALCIUM-DEPENDENT
NITRIC OXIDE SYNTHASES
nNOS (NEURONAL NITRIC OXIDE SYNTHASE)
AND eNOS (ENDOTHELIAL NITRIC OXIDE SYNTHASE)
BOTH ARE CALCIUM-DEPENDENT ENZYMES
INVOLVED IN THE GENERATION OF NITRIC OXIDE –
A MESSENGER MOLECULE THAT (ALONG WITH GLUTAMATE)
IS RESPONSIBLE, IN LOW DOSES,
FOR THE LONG-TERM POTENTIATION (LTP)
THAT UNDERLIES BOTH SYNAPTIC PLASTICITY
AND LEARNING / MEMORY
BUT IN HIGHER DOSES BECOMES A KEY PLAYER
IN THE VICIOUS EXCITOTOXIC CASCADE
LOW DOSES STIMULATE PHYSIOLOGICAL PROCESSES,
WHEREAS HIGHER DOSES TRIGGER
PATHOPHYSIOLOGICAL PROCESSES
THE HORMETIC DOSE-RESPONSE

18. A SYNAPTIC MODEL OF MEMORY
IF THE DOSE IS RIGHT, NITRIC OXIDE AND GLUTAMATE,
IN THEIR ROLE AS EXCITATORY NEUROTRANSMITTERS,
CAN FUNCTION AS “OPTIMAL STRESSORS”
TO IMPROVE THE SENSITIVITY OF THE POSTSYNAPTIC CELL
TO SIGNALS RECEIVED FROM THE PRESYNAPTIC CELL
BY INCREASING BOTH
THE “ACTIVITY” OF EXISTING RECEPTORS
AND THE ACTUAL NUMBER OF THOSE RECEPTORS
THEREBY ENHANCING SIGNAL TRANSMISSION
ACROSS THE SYNAPSE,
PROMOTING SYNAPTIC PLASTICITY
AND LONG-TERM POTENTIATION,
AND MAKING POSSIBLE LEARNING AND MEMORY
Bliss T et al. (1993). A synaptic model of memory: Long-term potentiation
in the hippocampus. Nature Vol. 361, pp 31-39.
Bohme G et al. (1993). Altered synaptic plasticity and memory formation
in nitric oxide synthase inhibitor-treated rats.
Proc Natl Acad Sci 90(19):9191-9194.

19. EMF-INDUCED CALCIUM DYSHOMEOSTASIS
WHEN THERE IS MASSIVE CALCIUM FLOODING OF THE CELL
WHETHER TRIGGERED BY OSCILLATING LOW LEVEL EMFs
OR SOME OTHER STRESSOR
AND THE CIRCUITRY IN THE BRAIN GOES AWRY,
THE EXCESS PRODUCTION OF FREE RADICALS AND EXCITOTOXINS
WILL SIMPLY ADD FUEL TO THE ALREADY RAGING NO, OH NO! FIRE
CALCIUM DYSHOMEOSTASIS HAS BEEN IMPLICATED
AS A KEY PLAYER IN APOPTOSIS (PROGRAMMED CELL DEATH)
ORDINARILY AN ADAPTIVE MECHANISM THAT
RIDS THE BODY OF CELLS THAT HAVE OUTLIVED THEIR USEFULNESS
BUT A MECHANISM THAT, WHEN ACTIVATED TO EXCESS,
BECOMES MALADAPTIVE AND KILLS EVERYTHING IN SIGHT
IN SUM – CHRONIC EXPOSURE TO LOW LEVEL EMFs
BY DISRUPTING THE INTEGRITY OF THE CELL MEMBRANE
AND THEREBY TRIGGERING MASSIVE INFLUX OF CALCIUM
IS A STRESSOR THAT FUNCTIONS SYNERGISTICALLY WITH
OTHER STRESSORS TO INITIATE, AND PERPETUATE, EXCITOTOXICITY

20. TREATMENTS MUST DOWNREGULATE
THE EXCITOTOXIC CASCADE
LIGHTEN THE LOAD – TO CORRECT FOR TOXICITIES
REPLENISH THE RESERVES – TO CORRECT FOR DEFICIENCIES
MAGNESIUM
HYDROXOCOBALAMIN (VITAMIN B12)
1,25-DIHYDROXYVITAMIN D3 (1,25-DIHYDROXYCHOLECALCIFEROL)
BIOACTIVE FOLATE (5-MTHF)
REDUCED GLUTATHIONE
BUFFERED VITAMIN C
SELENIUM
ALPHA LIPOIC ACID
RIBOFLAVIN (VITAMIN B2)
SUPEROXIDE DISMUTASE – SOD
BETAINE (TRIMETHYLGLYCINE)
PHOSPHATIDYLCHOLINE
QUERCETIN
CURCUMIN (TURMERIC)

21. NO, OH NO! RUN-RUN-RUN-RUN-RUNAWAY!
DEDICATION TO MARTY PALL
CHRONIC INTOXICATION BY ELECTROMAGNETIC RADIATION
PROMPTS INITIATION AND PROPAGATION
OF MEMBRANE DESTABILIZATION AND CALCIUM ACCUMULATION
IN ADDITION – IMMUNE STIMULATION, CYTOKINE GENERATION,
MICROGLIAL ACTIVATION, NMDA UPREGULATION, FREE RADICAL FORMATION,
PHOSPHOLIPID PEROXIDATION, MITOCHONDRIAL DYSREGULATION,
SELF-PERPETUATING INFLAMMATION, AND NERVE CELL DEGENERATION
No, Oh No! – A FIERY CONFLAGRATION
OF EXCITOTOXIC AMPLIFICATION
A RUNAWAY SITUATION OF NEURAL SENSITIZATION
REMEDIATION FOR WHICH IS DETOXIFICATION AND SUPPLEMENTATION
TO INTERRUPT ESCALATION AND PROMOTE DOWNREGULATION
Yes, Oh Yes!
Martha Stark (2010)