US010335396B2

(12) United States Patent ( 10) Patent No.: US 10 ,335 ,396 B2

Nemechek (45) Date of Patent: Jul. 2 , 2019
(54 ) METHODS OF REVERSING AUTONOMIC (56 ) References Cited
NERVOUS SYSTEM DAMAGE U . S . PATENT DOCUMENTS
(71 ) Applicant: Patrick M . Nemechek , Buckeye , AZ 6 , 838 ,471 B2 1/2005 Tracey
(US) 7 ,079 ,888 B2 7 /2006 Dung et al.
7 ,499 ,748 B2 3 / 2009 Moffitt et al.
( 72 ) Inventor : Patrick M . Nemechek , Buckeye, AZ 7 ,529 , 579 B2 5 /2009 Colombo et al.
8 ,676 , 324 B2 3 /2014 Simon et al.
(US ) 8 ,706 , 223 B2 4 /2014 Zhou et al.
8 ,788,034 B2 7 /2014 Levine et al.
( * ) Notice : Subject to any disclaimer, the term of this 8 , 868, 177 B2 10 /2014 Simon et al.
patent is extended or adjusted under 35 8 ,914 , 114 B2 12 /2014 Tracey et al.
9 , 162 ,064 B2 10 /2015 Faltys et al.
U .S .C . 154 (b ) by 1 day . 9 ,211,409 B2 12 / 2015 Tracey et al.
9 ,211 ,410 B2 12 / 2015 Levine et al.
( 21 ) Appl. No.: 15 /336 ,518 9 ,414 ,219 B2 8 /2016 Shao et al.
9 ,415 ,220 B1 * 8 /2016 Spinelli ...... A61N 1/ 36032
9 ,457 , 187 B2 10 / 2016 Zhao et al.
(22) Filed : Oct. 27, 2016
OTHER PUBLICATIONS
(65 ) Prior Publication Data
US 2018 /0117017 A1 May 3, 2018 Nemechek , Paul, “ Fatty Liver or NAFLD — What is Fatty Liver ?"
Apr. 21, 2011 https:// www .nemecheckconsultativemedicine . com /
blog /fatty -liver-or -nafld /.*
(51 ) Int . CI. (Continued )
A61N 1/ 04 ( 2006 .01 )
A61K 31/437 ( 2006 .01 ) Primary Examiner — Eric D . Bertram
A61K 31/ 202 ( 2006 .01) (74 ) Attorney , Agent, or Firm — Procopio , Cory,
A61K 31/201 ( 2006 .01) Hargreaves & Savitch LLP
A6IK 36 /63 ( 2006 .01)
A61N 1/ 36 ( 2006 .01 ) (57) ABSTRACT
(52) U .S . CI. Provided herein are methods for preventing , reducing or
CPC .......... A61K 31/437 ( 2013.01); A61K 31/201 reversing acute and /or chronic autonomic damage by the
( 2013 .01); A61K 31/ 202 ( 2013 .01) ; A61K suppression of pro -inflammatory cytokines in a subject in
36 /63 ( 2013 .01) ; A6IN 1 /0456 ( 2013 .01) ; need thereof, which methods comprise administering to said
A61N 1 / 36014 (2013 . 01) ; YO2A 50 / 385 subject an effective amount of an antibiotic ; polyunsaturated
(2018 .01 ); YO2A 50 /411 ( 2018 .01) omega -3 fatty acid ; and oleic acid ; providing VNS (vagal
nerve stimulation ) to the subject; and placing said subject on
(58 ) Field of Classification Search an intermittent fasting regimen .
CPC ... ............. ..... ........... A61N 1 /0456
See application file for complete search history . 15 Claims, 6 Drawing Sheets
Peripheral Sources of Pro -Inflammatory Cytokines
Feed the Inflammatory Burden within the CentralNervous System

Excessive dietary linoleic acid & palmitic acid .

Deficient dietary omega - 3 fatty acids. Damage to the Parasympathetic Branch of the Autonomic
Excessive carbohydrate intake . Nervous System , and loss of Inflammatory Control via
Excessive AGE intake. Cholinergic Anti-Inflammatory Pathway
Excessive calorie intake.

Supplementation with
ALA EPA , DHA, Oleic Autoimmune and Other
Bacterial Acid , Low Temp. Chronic Inflammatory
Intestinal Cooking & Disorders
Overgrowth Intermittent Fasting .
VNS , DHA ,
EPA & ALA

Antibiotic Supplementing the pool

of pro - inflammatory
Total Peripheral Burden of cytokines within the
Pro - inflammatory Cytokines Central Nervous System
and impairs brain
recovery ,

LPS - Lipopolysaccharide Enters Brain via

VNS - Vagal Nerve Stimulation Blood Brain Barrier &
ALA - Alpha -Linolenic Acid Circumventricular Organs
EPA - Eicosapentaenoic Acid
DHA - Docosahexaenoic Acid
 US 10 ,Page
335 ,2396 B2

(56 ) References Cited Marwan A . Maalouf, “ The neuroprotective properties of calorie

restriction , the ketogenic diet, and ketone bodies ,” Brain Res Rev .
Mar. 2009 ; 59 ( 2 ): 293 -315 .
OTHER PUBLICATIONS Christopher T. Ford , “ Identification of (polyphenol treatments that
modulate the release of pro -inflammatory cytokines by human
Nemechek , Paul , “ Fish Oil and Flax Improves Your Metabolism ,” lymphocytes,” British Journal of Nutrition (2016 ), 1699 - 1710 .
Shannon Levesque, “ Diesel exhaust activates and primes microglia :
Nov . 3 , 2013 , https://www .nemecheckconsultativemedicine.com / Air pollution , neuroinflammation , and regulation of dopaminergic
blog / fish - oil -and - flax -improves -your-metabolism /.* neurotoxicity ,” Environmental Health Perspectives , vol. 119 , No . 8 ,
Nemechek , Paul, “ Breakfast is Not Your Friend ,” Aug. 7 , 2015 , Aug. 2011.
https://www .nemecheckconsultativemedicine .com /blog/breakfast-is Andre C ., “ Diet-induced obesity progressively alters cognition ,
not -your- friend/. * anxiety - like behavior and lipopolysaccharide-induced depressive
Nemechek , Paul, “ Inflammation and Depression ,” 2014 , https:// like behavior : Focus on brain indoleamine 2 , 3 -dioxygenase activa
www .nemecheckconsultativemedicine.com /blog /inflammation -and tion ,” Brain Behav Immun . Oct. 2014 ; 41: 10 -21.
depression -new -answers/ . * Christine M . Sandiego , “ Imaging robust microglial activation after
lipopolysaccharide administration in humans with PET,” PNAS ,
Nemechek , Paul, “ Olive Oil Tastes Like ‘Skinny Jeans’,” Aug. 30 , Oct. 6 , 2015 , 12468-12473 , vol. 112 , No. 40 .
2014 , https ://www .nemecheckconsultativemedicine.com /blog/olive Dennys E . Cintra “Unsaturated fatty acids revert diet-induced
oil -tastes-like -skinny -jeans/.* hypothalamic inflammation in obesity ," PloS ONE, Jan . 2012 , vol.
Guixiang Zhao , “ Dietary a - linolenic acids inhibits proinflammatory 7 , Issue 1 .
cytokine production by peripheral blood monouclear cells in Anthony F . Domenichiello , “Whole body synthesis rates of DHA
hypercholesterolemic subjects,” Am J Clin Nutr 2007;85: 385-91, from « -linolenic acid are greater than brain DHA accretion and
2007 American Society for Nutrition . uptake rates in adult rats,” Journal of Lipid Research , vol. 55 , 2014 .
Simon C . Dyall, “ Long - chain omega - 3 fatty acids and the brain : A Philip K - Y Chang, “ Docosahexaenoic acid (DHA ): A modulator of
review of the independent and shared effects of EPA , DPA and microglia activity and dendritic spine morphology,” Journal of
DHA ,” Frontiers in Aging Neuroscience , Apr. 2015. Neuroinflammation ( 2015 ) 12 :34 .
George E . Billman , “ Effect of dietary omega - 3 polyunsaturated Lloyd D . Harvey , “ Administration of DHA reduces endoplasmic
fatty acids on heart rate and heart rate variability in animals reticulum stress- associated inflammation and alters microglial or
susceptible or resistant to ventricular fibrillation ,” Frontiers in macrophage activation in traumatic brain injury ,” ASN Neuro
Physiology, Mar. 2012 , vol. 3 . Nov .-Dec . 2015 : 1 -15 .
Wu A , “ Dietary strategy to repair plasma membrane after brain Imanuel Lerman , “ Noninvasive transcutaneous vagus nerve stimu
trauma: implications for plasticity and cognition ," Neurorehabil lation decreases whole blood culture -derived cytokines and chemokines:
Neural Repair , Aug. 2013 . a randomized , blinded , health control pilot trial,” Neuromodulation ,
Kazuhiro Tanaka , “ Effects of docosahexaenoic acid on neurotransmis Mar. 2016 .
sion ” , Biomolecules & Therapeutics 20 ( 2 ), 152 - 157 (2012 ). Colm Cunningham , “ Microglia and Neurodegeneration : The role of
Jeppe Hagstrup Christensen , " Omega -3 polyunsaturated fatty acids systemic inflammation ," GLIA 61:71- 90 , ( 2013 ) .
and heart rate variability,” Frontiers in Physiology, Nov. 2011, vol. J. Thomas Brenna , “ a -Linolenic acid supplementation and conver
2 , Article 84 . sion to n - 3 long chain polyunsaturated fatty acids in humans,"
Barbara S . Beltz , “ Omega -3 fatty acids upregulate adult neurogenesis," ISSFAL Official Statement No. 5 .
NIH Public Access Author Manuscript, Neurosci Lett . Mar. 26 , Zhenying Han , “ Activation of a -7 nicotinic acetylcholine receptor
2007; 415 ( 2 ): 154 - 158 . reduces ischemic stroke injury through reduction of pro
" Omega - 3 fatty acids supplementation restores mechanisms that inflammatory macrophages and oxidative stress,” PLOS One, Aug.
maintain brain homeostasis in traumatic brain injury,” Abstract. 2014 , vol. 9 , Issue 8 .
Miki Igarashi, “ Dietary N -6 polyunsaturated fatty acid deprivation Margaret F. Gregor, “ Inflammatory mechanisms in obesity,” Annu .
increases docosahexaenoic acid metabolism in rat brain ,” J Neurochem Rev . Immunol. 2011, 29 :415 - 445 .
Mar. 2012 ; 120 (6 ): 985 - 997 . Trent Grundy, “ Long-term omega -3 supplementation modulates
Nicolas Blondeau ,“ Subchronic alpha -linolenic acid treatment enhances behavior hippocampal fatty acid concentration, neuronal progenitor
brain plasticity and exerts an antidepressant effect: a versatile proliferation and central TNF- a expression in 7 month old unchal
potential therapy for stroke," Neuropsychopharmacology : official lenged mice,” Frontiers in Cellular Neuroscience , Nov. 2014 , vol. 8 ,
publication of the American College ofNeuropsychopharmacology , Article 399 .
Aug. 2009. Pnina Green , “ Pathways of polyunsaturated fatty acid utilization :
Bronwen Martin , " Caloric restriction and intermittent fasting : Two Implications for brain function in neuropsychiatric health and
potential diets for successful brain aging," Ageing Res Rev . Aug . disease ,” Brain Research , Dec . 2014 .
2006 ; 5 ( 3 ); 332 - 353. Andrea R . Vasconcelos, “ Intermittent fasting attenuates lipopolysac
Ameer Y. Taha , “ Dietary omega -6 fatty acid lowering increases charide-induced neuroinflammation and memory impairment,” Jour
bioavailability of omega - 3 polyunsaturated fatty acids in human nal of Neuroinflammation, 2014 , 11: 85 .
plasma lipid pools ,” Prostaglandins Leukot Essent Fatty Acids,May Diana M . Norden , “Microglia of the aged brain : Primed to be
2014 ; 90 ( 5 ): 151- 157 . activated and resistant to regulation ," Neuropathol Appl. Neurobiol.
Xiao -Guang Luo , “ The changing phenotype of microglia from Feb . 2013 ; 39( 1 ): 19 -34 .
homeostasis to disease ,” Lou and Chen Translational Neurodegenera
tion 2012 , 1: 9 . * cited by examiner
Us. Patent atent Jul. 2 , 2019
?? Sheet 1 of 6 US 10,335,396 B2

SPeoriuphecralPro-InflamatoCytokines PofNreoductnioalCSPreotglenitmsor
Central Nervous System
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Inflamtion
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SNVNS-Vtieamurglavtielna-DocsHheixaAndoic
-LipoPlysacShride
Nreopamirl .proces
 atent Jul. 2 , 2019 Sheet 2 of 6 US 10 ,335, 396 B2

ptSuolhemnetlig thewcyitokhinesSNCeyrnsvtoeuamslbandirpairns.recovery
oftheABtoPDaurtsoyamnptmhcgeiviaCof,andlSNnoeyfrsamtvroeusmlyP-IACnhafoltimhnewartgoiyc OaAutonhimedurn ICnhflramontircyDsordes ofpro-inflam atory

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BacterialIntesinalOvergowth Antibo c Li-po lPysachSride
U . S . Patent Jul. 2, 2019 Sheet 3 of 6 US 10 ,335 ,396 B2

Use of Spectral Analysis and Autonomic Recovery to Determine

Pro -Inflammatory Suppression Within Central Nervous System

Measure Baseline Autonomic Function via

Spectral Analysis
Initiate Autonomic Recovery Protocol

Return to Clinic in 2 Months for Repeat

Spectral Analysis

Improvement in Autonomic Function Inadequate Improvement in

Autonomic Function

Assess Patient Adherence

To Autonomic Recovery Protocol

If Poor compliance ,
Continue Protocol Re-Educate Patient If Good Compliance ,
and Continue Same Consider Addition of
Follow -up in 2 -3 Protocol Curcumin , Intermittent
Months for Repeat Fasting or Carbohydrate
Spectral Analysis Repeat Spectral Reduction Depending on
Analysis in 2 Months Other Clinical Factors.
Repeat Spectral Analysis
in 2 Months

Figure 3
 atent Jul. 2 , 2019 Sheet 4 of 6 US 10 ,335, 396 B2

.... ..... ...... ..... .... ..... ...... ..... .... ..... ...... ..... .... ..... ... ... ..... ..... ..... ..... ...... ..... ..... ..... ...... ..... ..... ..... ...... ..... ..... ..... ...... ..... .... .......... .... ..... ..... ...... .... ..... ..... ...... .... ..... ..... ...... .... ..... ..... ..... ..... ..... ..... ..... .... ...... ..... ...... .... ...... ..... ...... .... ...... ..... ...... . .

Day 1 Day 2 Day 3 Day 4 Day 5 .

Day 6 Day 7
Normal Normal Fasting Normal Fasting .

Normal Normal
TDEE TDEE 500 -female TDEE 500 -female .

TDEE TDEE
600 -male 600 -male

Calories (per day)

TDEE = total daily energy expenditure

Figure 4
 atent Jul. 2 , 2019 Sheet 5 of 6 US 10,335,396 B2

Proper Balance of Omega-6 and Omega-3 Fatty Acids

Omega -6 Omega -3
Linoleic Acid Alpha -Linolenic Acid
LA C18 :2 n6 ALA C18 : 3 n3

Gamma-Linolenic Acid Stearidonic Acid

GLA C18 :3 n6 C18 :4 n3

Dihomo Eicosapentaenoic Acid

C20:3n6 EPA C20 :3n3

Arachidonic Acid Docosahexaenoic Acid

AA C20:4n6 DHA C22:6 n3

Production of Production of
Inflammation Anti- Inflammation
Causing Chemicals Chemicals

Healthy 1 -3
Omega 6 :3 Ratio
Hunter Gathers

Figure 5
atent Jul. 2 , 2019 Sheet 6 of 6 US 10 ,335 , 396 B2

Parasympathetic
Branch of ANS

Auricular (Ear)
Brancho
Vagus Nerve

Vagus
Nerve

Controls
Inflammation via
Spleen , Liver and
Intestine

Figure 6
 US 10 ,335 ,396 B2
METHODS OF REVERSING AUTONOMIC treatment resistant epilepsy, autism , developmental delay
NERVOUS SYSTEM DAMAGE and sensory perception disorder.
TECHNICAL FIELD INCORPORATION BY REFERENCE
The invention relates to methods for reversing acute Herein , all issued patents, published patent applications,
and /or chronic autonomic damage by the suppression of and non -patent publications that are mentioned in this speci
pro -inflammatory cytokines . fication are herein incorporated by reference in their entirety
for all purposes , to the same extent as if each individual
INTRODUCTION 10 issued patent, published patent application , or non - patent
publication were specifically and individually indicated to
The automatic nervous system (ANS) regulates “ invol - be incorporated by reference .
untary ” organs. The ANS includes the sympathetic nervous BRIEF DESCRIPTION OF THE DRAWINGS
system and the parasympathetic nervous system . The sym 15
pathetic nervous system is affiliated with stress and the “ fight FIG . 1 shows a diagram of Microglia Activation within
or flight response ” to emergencies . The parasympathetic
nervous system is affiliated with relaxation and the “ rest and the Central Nervous System .
digest response .” The ANS maintains normal internal FIG . 2 shows a diagram depicting that Peripheral Sources
of Pro - Inflammatory Cytokines Feed the Inflammatory Bur
homeostasis and works with the somatic nervous system . 20 den within the Central Nervous System
Autonomic balance reflects the relationship between para FIG . 3 shows the Use of Spectral Analysis and Autonomic
sympathetic and sympathetic activity . Recovery to Determine Pro - Inflammatory Suppression
Vertebrates achieve internal homeostasis during infection Within the Central Nervous System .
or injury by balancing the activities of proinflammatory and FIG . 4 shows the depiction of a 5 :2 Intermittent Fasting
anti -inflammatory pathways. However , in many disease 25 Regimen .
conditions , this internal homeostasis becomes out of bal FIG . 5 shows the Proper Balance of Omega -6 and
ance. For example , endotoxin ( lipopolysaccharide, LPS ) Omega -3 Fatty Acids.
produced by all Gram -negative bacteria activates macro - FIG . 6 shows the Transcutaneous vagus nerve stimulation
phages to release cytokines that are potentially lethal. ( VNS) of the Auricular Branch of the Vagus Nerve ; and
Inflammation and other deleterious conditions (such as 30 depicts that electrical stimulation of the auricular branch of
septic shock caused by endotoxin exposure ) are often the Vagus nerve at the tragus will trigger an anti-inflamma
induced by pro - inflammatory cytokines , such as tumor tory response via the spleen , liver and intestinal tract.
necrosis factor ( TNF ; also known as TNF -alpha or cachec
tin ), interleukin ( IL )- 1.alpha., IL - 1.beta ., IL -6 , IL - 8 , IL - 18 , DETAILED DESCRIPTION
interferon , platelet-activating factor (PAF ), macrophage Provided herein are methods for preventing, reducing or
migration inhibitory factor (MIF ), and other compounds. reversing acute and / or chronic autonomic damage by the
These pro - inflammatory cytokines are produced by several suppression of pro -inflammatory cytokines in a subject in
different cell types, and contribute to various diseases and need thereof, which methods comprise administering to said
disorders through their release during an inflammatory 40 subject an effective amount of an antibiotic ; an effective
cytokine cascade. amount of polyunsaturated omega -3 fatty acid ; and an
Accordingly , there is a need in the art for suppressing the effective amount of oleic acid ; providing VNS (vagal nerve
production of pro -inflammatory cytokines from each of their stimulation ) to the subject; and placing said subject on an
various sources . intermittent fasting regimen . These invention methods are
45 also referred to herein collectively as the Nemechek Proto
SUMMARY col, and these methods are useful for treating and /or revers
ing various disease states that are mediated by autonomic
Provided herein are the Nemechek Protocolmethods for damage caused by pro -inflammatory cytokines .
preventing, reducing or reversing acute and/or chronic auto - Generally speaking, the Nemechek Protocol methods of
nomic damage by the suppression of pro - inflammatory 50 treatment set forth herein reverse autonomic nervous system
cytokines in a subject in need thereof, which methods damage through a combination of supplements , vitamins ,
comprise administering to said subject an effective amount chemical compounds, pharmaceutical agents, dietary restric
of an antibiotic ; an effective amount of polyunsaturated tions and neuromodulation of the vagus nerve , and the like .
omega -3 fatty acid ; and an effective amount of oleic acid ; The combined effect of these treatments is to substantially
providing VNS ( vagal nerve stimulation ) to the subject; and 55 reduce the levels of pro - inflammatory cytokines within the
placing said subject on an intermittent fasting regimen . The central nervous system such that natural repair mechanisms
invention methods are useful for reducing the levels of are activated and autonomic nervous system function recov
pro - inflammatory cytokines within the central nervous sys - ers . Autonomic recovery is detected by sequential spectral
tem such that natural repair mechanisms are activated and analysis monitoring of the autonomic nervous system . If no
autonomic nervous system function recovers . Such reduc - 60 recovery is initially noted , the treatment regimen can be
tion in the levels of pro -inflammatory cytokines within the supplemented further.
centralnervous system is also useful for treating a variety of The invention Nemechek Protocol methods provided
neuroinflammatory diseases and /or conditions including herein are believed to be safe , non - invasive , portable , and do
traumatic brain injury, concussion , chronic traumatic not require certified technicians . The invention methods are
encephalopathy (CTE ), post-concussion syndrome (PCS), 65 extremely effective for recovery of autonomic function from
Alzheimer 's disease, Parkinson 's disease , essential tremor, a variety of neuroinflammatory conditions including trau
post-traumatic stress disorder (PTSD ), chronic depression , matic brain injury, concussion , chronic traumatic encepha
 US 10 ,335 ,396 B2
lopathy (CTE ), post-concussion syndrome (PCS ), Alzheim stem cells increase in number and functionality , and the
er's disease , Parkinson 's disease, essential tremor, post microglial populations shifts toward the M2- phenotype
traumatic stress disorder (PTSD ), chronic depression , which repair neuronal damage and start producing anti
treatment resistant epilepsy, autism , developmental delay, inflammatory cytokines (i.e., IL -4 , IL - 10 , TNF -beta ).
sensory perception disorder , and the like. The consequence is the broad -based repair of damaged
In certain embodiments, the present invention methods neurons throughout the brain , and is reflected in the recovery
relate to the reversal of acute and chronic autonomic damage of autonomic function as noted on the sequential spectral
by the suppression of pro - inflammatory cytokines, namely analysis tests as well as reversal of patient' s symptoms of
interleukin - 1 (IL - 1 ), interleukine-6 (IL -6 ) and tumor necro - dysautonomia ( e. g ., dizziness , fainting, urinary hesitation ,
sis factor -alpha ( TNF - alpha ). The pro - inflammatory cytok - 10 urinary incontinence , urinary retention , dysfunction of erec
ines are reduced through the cumulative effect of reversing tion or ejaculation , early satiety , loss of appetite, diarrhea ,
intestinal bacterial overgrowth , normalizing dietary intake constipation , abdominal bloating, nausea , vomiting, diffi
of omega -6 and omega - 3 fatty acids, supplementation with culty swallowing , heartburn , excessive of deficient sweat
oleic acid , intermittent restriction of caloric intake, and ing, intolerance to light, poor vision at night, or exercise
stimulation of the acetylcholine inflammatory reflex by 15 intolerance ).
transcutaneous vagal nerve stimulation ( VNS). If this An additional consequence is the clinical improvement
proves initially inadequate , additional steps to reduce pro - through the amelioration or alleviation of other chronic
inflammatory cytokines include supplementation with cur- neuroinflammatory disorders such as chronic depression ,
cumin and/ or the introduction of carbohydrate restriction post -traumatic stress disorder, epilepsy , autism spectral dis
and / or intermittent fasting . 20 orders, developmental delay, Alzheimer 's disease , Parkin
The accurate measurement of pro - inflammatory cytokines son 's disease and chronic traumatic encephalitis . After the
within the central nervous system is believed to be unavail- baseline test is performed as set forth in Example 1, the
able in the clinical setting so recovery of autonomic function treatment regimen components provided herein are initiated
as measured by spectral analysis is used herein as a surrogate and spectral analysis is repeated within a suitable timeframe,
marker for cytokine suppression and normalization of natu - 25 preferably approximately 2 months later, and the like ( see
ral repair mechanisms. If cytokine concentrations are FIG . 3 ). Once the spectral analysis is repeated and the
reduced to a healthy physiological range , normal repair relative change in the autonomic test results is assessed ,
mechanisms are activated (i.e ., phenotypic shift ofmicroglia additional steps can be taken to increase the potential
to the reparative , restorative M2- phenotype , and increased inflammation suppression effect of the regimen , if improve
progenitor stem cell production and functionality ), recovery 30 ment is not noted .
of autonomic strength and function as measured by spectral Methods for spectral analysis are well- known in the art
analysis returns to normal. and include the methods set forth in U . S . Pat. Nos . 7 ,079, 888
Sequential testing of the autonomic nervous system with and 7 ,529 ,579 , incorporated herein by reference in their
spectral analysis is particularly preferred in the recovery entirety .
process because the detection of a reduction in inflammation 35 As used herein , the term “ antibiotic ” refers to a naturally
within the peripheral circulation does not mean there is occurring substance produced by a microorganism , such as,
improvement within the central nervous system . The reduc - without limitation , a fungus or a yeast, the substance being
tion in pro - inflammatory cytokines within the blood stream useful in the treatment of infectious disease . Antibiotic also
may correlate with symptomatic improvements but has little refers to semi-synthetic substances wherein a molecular
impact on restoring autonomic nervous system function . 40 version produced by a microorganism is subsequently modi
This is a common scenario in the recovery from minor fied to achieve desired properties . Preferred antibiotics for
traumatic brain injuries, commonly referred to as a concus - use herein include the well know class of compounds useful
sion . for reversing bacterial overgrowth in the intestinal track .
Prior to initiating the invention Nemechek Protocol meth - Exemplary antibiotic for use herein include the antibiotic
ods set forth herein , the subject is sequentially monitored to 45 class including one or more of pyrimidine derivative , sul
ascertain the base -level of autonomic nervous system health fonamide, quinolone, glycopeptides, beta -lactam , ampheni
via spectral analysis . In one embodiment, monitoring of cols , aminoglycoside and amino acid derivative . In yet other
autonomic function via spectral analysis is performed at aspects , one or more antibiotics are selected from the group
baseline and again every 1 -3 months depending on the including one or more of rifaximin , chloramphenicol, peni
severity of the patient' s condition , their clinical status, and 50 cillin G , vancomycin , carbenicillin , ciprofloxacin , mafenide ,
overall rate of recovery (see FIG . 3 ). Because the measure - kanamycin , sisomicin , amikacin , trimethropin , D - cycloser
ment of neuroinflammation from pro - inflammatory cytok ine, gentamicin , dicloxacillin , nalidixic acid , thiamphenicol,
ines (i.e ., IL - 1 , IL -6 , TNF -alpha, INF- gamma) is unavailable levofloxacin , sulfamethizole and sulfisoxazole . In a pre
in the clinical setting, improvement in autonomic function as ferred embodiment, the subject is treated with rifaximin at a
measured by spectral analysis is used as a surrogate marker 55 dosage of 550 mg, 1 tablet by mouth 2 - 3 times daily for
for the suppression of the cytokine production . See , for 10 - 14 days . This antibiotic treatment step is repeated as
example, the results of a spectral analysis set forth in often as necessary based upon the suspicion of relapse of
Example 1 herein . The level of intracranial cytokines comes bacterial overgrowth .
from sources within the central nervous system ( e. g ., clas - In other embodiments, concomitant use of a second
sically activated microglia , imbalances cellular membrane 60 antibiotic such as metronidazole or neomycin may be
omega -3 : omega -6 fatty acid composition , toxic exposure , required to adequately reverse small intestine bacterial over
ischemia , hypoxia , inflammatory conditions , and infections ) growth . In addition , because of the high rate ofrelapse that
as well as from the periphery (e .g., chronic infections, has been observed , treatment with antibiotics is preferably
bacterial translocation of LPS, autoimmune disorders , repeated every 12 months in all patients in order to reverse
tobacco smoke inhalation , toxic exposures, vaccinations, 65 any low grade, subclinical bacterial overgrowth that may be
chronic inflammatory conditions ). It has been found that if recurring . It has been found that treatment with rifaximin
cytokines are reduced substantially, neuronal progenitor with or without metronidazole or neomycin or any other
 US 10 ,335 ,396 B2
antibiotic combination deemed necessary will reverse the EPA , although these other dietary sources of DHA are also
excessive quantity of bacteria within the small intestine . The contemplated herein for use in the invention methods.
reduction of small intestinal bacterial load by using the In preferred embodiments, DHA may be obtained from
antibiotics results in decreased pro - inflammatory cytokine various sources , including natural sources and artificial
production from translocation ( i. e ., leakage ) of lipopolysac - 5 sources. Natural sources include, without limitation , oils and
charide (LPS ) into the surrounding tissue . It has been found fats from cold -water fish , such as shellfish , tuna , salmon ,
that leakage of LPS is a major element shown to result in the mackerel, herring , trout, and swordfish , anchovy , sardines ,
priming and activation of microglia within the brain . Micro - and possibly including certain types of algae . Fish are able
glia are generally in a resting or M2 phenotype, monitor to convert an omega -6 fatty acid , linolenic acid , in the algae
neurons for signs of damage /distress , and actively engage in 10 to DHA to a reasonably fruitful degree whereas humans are
the repair of damaged neurons. Once activated (often only able to do so to a limited degree . Artificial sources
referred to as priming ) by substances such as LPS , the include man -made DHA produced synthetically in the labo
morphology and function of the M2-microglia changes ratory or by other suitable means, typically in the form of
significantly , and are often referred to as “ primed ”, “ classi synthetic oils , waxes and fats, for inclusion into the present
cally activated ” or M1-microglia . 15 composition . Further non - limiting exemplary natural
M1-microglia produce excessive quantities of pro -inflam - sources of DHA includes seed oil such as flaxseed oil, canola
matory cytokines in response to brain injury, and contribute oil, vegetable oil, safflower oil, sunflower oil, nasturtium
to progressive damage from neurodegenerative disorders seed oil, mustard seed oil , olive oil , sesame oil , soybean oil ,
( e. g ., Alzheimer' s disease , Parkinson ' s disease , chronic trau - corn oil, peanut oil , cottonseed oil, rice bran oil, babassu nut
matic encephalopathy ) or incomplete recovery from trauma 20 oil, palm oil , low erucic rapeseed oil, palm kernel oil, among
( e . g ., post -concussion syndrome, post -traumatic stress dis others .
order, chronic depression ). The excessive pro - inflammatory It has also been found that DHA supplementation results
cytokine production ofM1-microglia impair the ability of in shifting the pro -inflammatory, neuron - damaging M1-mi
normal repair mechanisms (i. e ., stem cell , astrocytes and croglia back to the anti- inflammatory , restorative M2-mi
M2-microglia ) to repair damage to neurons and surrounding 25 croglia . This results in the reduction of damage -promoting,
tissues. See FIGS. 1 and 2 ; and Table 1 of Luo, et al., Trans1 and repair -inhibiting pro - inflammatory cytokines. In par
Neurodegener. 2012 ; 1 :9 , incorporated herein by reference ticular embodiments ,high concentrations of DHA within the
in its entirety. brain are employed to re - establish the function of natural
As used herein , the phrase docasahexaeonic acid or repair mechanisms, and as a consequence , results in the
“ DHA ” refers to the well-known polyunsaturated omega -3 30 reversal of underlying brain injury . In a particularly pre
fatty acid . Fish oil contains 2 important polyunsaturated ferred embodiment, the source of DHA employed herein
omega -3 fatty acids EPA (Eicosapentaenoic acid ) and DHA includes the high concentrations of DHA that can be found
which can also be found in a variety of other dietary animal in liquid fish oils ( e . g ., in doses of 1 - 2 tablespoons per day
meats. Omega - 3 fatty acids are often referred to as “ essen - depending on the brand and concentration ), as well as in
tial” fatty acids because they are needed for human health 35 capsule form . See , e .g ., U .S . Pat. No. 9 ,458 ,409, which is
but are not sufficiently produced by the body alone. EPA and incorporated herein by reference in its entirety.
DHA are naturally found in certain cold -water fatty fish such As used herein , " high concentrations of DHA” refers to
as salmon , tuna , and mackerel. They can also be derived in DHA in the range of about 1,000 -5 ,000 mg, more preferably
the body from alpha - linolenic acid (ALA ), which is an about 2 , 000 -4 ,000 mg of DHA . In a preferred embodiment
omega - 3 fatty acid found in certain seeds, plant-based oils , 40 of the invention methods, about 3 ,000 mg of DHA daily
and animal-based oils . supplement is employed herein .
The modern diet is typically deficient in omega - 3 essen - In another embodiment, daily dietary supplementation
tial fatty acids and has become overloaded with pro -inflam - with ALA (alpha linolenic acid ) containing foods or supple
matory omega -6 fatty acids, especially arachidonic acid . ments is contemplated herein . As used herein the term
This heavy imbalance of omega -6 to omega - 3 fatty acids in 45 “ alpha - linolenic acid ” refers to 9 , 12 , 15 octadecatrienoic
the modern diet is thought to lead to an overall inflammatory acid , which has a short hand desimation of 18 : 3 ( n - 3 ) and a
state that contributes to several diseases . The increased molecular weight of 278 .4 . Throughout the specification
consumption of vegetable oils and shortenings , beef, and alpha - linoienic acid is referred to as either alpha- linolenic
dairy is one of the major reasons for the high amount of acid or “ ALA " . This is a plant derived omega - 3 fatty acid ,
omega -6 fatty acids in the diet and the imbalance between 50 which is commonly found in plants such as nuts , flax , hemp
omega -6 to omega - 3 fatty acids. The North American popu - and chia . In accordance with a particular embodiment of the
lation , in particular, has among the lowest dietary intake of present invention , supplementation with approximately a
omega - 3 fatty acids in the world and the highest intake of the 1/4 - 1/2 cup of these food sources per day or 1000 mg of flax
pro - inflammatory omega -6 fatty acids . seed oil per day. Although ALA does not readily penetrate
For the invention methods provided herein , adequate 55 the brain , it has been found that supplementation reduces
amounts of omega- 3 fatty acids, including EPA and DHA , peripheral sources of pro - inflammatory cytokines which are
are preferred and can be obtained in the diet from cold -water capable of passing through the blood brain barrier, and
fatty fish such as salmon , tuna, and mackerel. It has been worsening brain damage recovery . ALA has also been found
found that these omega - 3 fatty acids are important precur- to increases neurogenesis, synaptogenesis , and synaptic
sors for a variety of inflammation - suppressing chemicals 60 function in the rodent brain . It has also been found that ALA
within the body . For example, DHA is the predominant also increases tissue levels of DHA even in the brain .
omega - 3 fatty acid within the nervous system , and has been As used herein , " oleic acid ” refers to an omega - 9 fatty
found to be associated with reductions in the production of acid that is typically present in olive oil, preferably extra
pro -inflammatory cytokines. Dietary sources of DHA are virgin olive oil (EVOO ). A suitable amount of oleic acid for
preferred , as they more readily penetrate and contribute to 65 use herein contains enough oleic acid necessary to reduce
the needs of the central nervous system than are supplies of tissue concentrations of linoleic acid and arachidonic acid ,
DHA converted from other dietary sources such as ALA or which are omega -6 fatty acids involved in the production of
 US 10 ,335, 396 B2
pro -inflammatory mediators . In a preferred embodiment, a needle , ultrasound , or vibration . Mechanical stimulation can
daily supplement of a suitable amount of extra virgin olive also be carried out by carotid massage, oculocardiac reflex ,
oil is consumed . In some embodiments, the range of EVOO dive reflex and valsalva maneuver. The efferent vagal nerve
is from about 5 mlto about 100 ml, about 10 ml to about 75 fibers can also be stimulated by electromagnetic radiation
ml, about 15 ml to about 50 ml, about 20 ml to about 40 ml, 5 such as infrared , visible or ultraviolet light; heat, or any
with about 25 ml daily of EVOO being particularly pre other energy source . The efferent vagus nerve can be stimu
ferred . It has been found that the reduced levels of pro lated by stimulating the entire vagus nerve (i. e ., both the
inflammatory mediators within the brain have been linked to
the reversal of neuronal damage . It is also believed that the afferent and efferent nerves), or by isolating efferent nerves
and stimulating them directly . The latter method can be
phenolic compounds contained within extra virgin olive oil 10 accomplished by separating the afferent from the efferent
have a variety of other anti-inflammatory and health pro fibers in an area of the nerve where both types of fibers are
moting effects including improvements in cellular function , present . Alternatively, the efferent fiber is stimulated where
oxidation , reduced microbial activity , and a reduction in the no afferent fibers are present, for example close to the target
level of pro - inflammation mediators.
In the methods utilized herein , it is preferable to restrict 15 organ served by the efferent fibers .
the consumption of cooking oils containing high ratios of The efferent vagus nerve fibers can also be stimulated by
omega -6 to omega -3 fatty acids. For example , it has been stimulating the target organ directly , e .g., electrically, thus
found that a healthy balance of cellular omega -6 and stimulating the efferent fibers that serve that organ . In other
omega -3 fatty acids is required to maintain inflammation embodiments, the ganglion or postganglionic neurons of the
homeostasis within the brain and body . Consequently , pre - 20 vagus nerve can be stimulated . In preferred embodiments set
ferred cellular and dietary fatty acid ratios of omega -6 to forth herein , the vagus nerve is stimulated electrically , using
omega -3 fatty acids are in the 1 - 3 to 1 range ( e . g., within any electrical means known to those of skill in the art. For
1- 3 :1 omega-6 :omega -3 ; see FIG . 5 ). example , commercial vagus nerve stimulators for use herein
It has also been found that restriction of inflammation include the Cyberonics NCPR , the NEMOS device for
promoting omega -6 fatty acids , linoleic acid and arachidonic 25 t- VNS, or a transcutaneous electrical nerve stimulation
acidomega-6 fatty has the combined effect of reducing the (TENS ) unit, such as the TENS 7000 (Roscoe Medical,
production of inflammation -promoting mediators ; and also Strongsville , Ohio ), and the like .
has the consequence of increasing levels of DHA within the In combination with the methods provided herein , the
brain . Dietary linoleic acid is most commonly consumed in amount of stimulation useful to inhibit inflammatory cytok
the form of plant oils such as soy oil , corn oil , safflower oil, 30 ines, such as in an inflammatory cytokine cascade , can be
sunflower oil, vegetable oil, grapeseed oil , margarine and determined by the skilled artisan without undue experimen
shortenings. These oils are to be preferably avoided and are tation for any condition to be treated . In one embodiment, to
commonly consumed as an ingredient in prepared commer - inhibit a systemic inflammatory cytokine cascade , a constant
cial foods. voltage stimuli of about 1 to 5 V , at 2 ms and 1 Hz, for 10
In the methods utilized herein it is preferred to consume 35 minutes is contemplated herein to inhibit the systemic
cooking oils containing evenly balanced ratios of omega -6 inflammatory cytokines sufficiently .
to omega - 3 fatty acids . As set forth above , preferred cellular In certain embodiments, the electrical stimulation is
and dietary fatty acid ratios are in the 1 - 1 to 3 - 1 (omega -6 : achieved by clipping electrodes across the tragus of the ear,
omega - 3 ) range. Exemplary oils having the desired 1 - to - 1 inducing an electrical current with a TENS (transcutaneous
omega - 3 :omega -6 ratios, include for example , canola , but- 40 electrical nerve stimulation ) unit with the frequency in the
ter, palm kernel oil, and the like. It has been found that the range selected from about 0 . 1 Hz to about 30 Hz, about 0 .3
reduction in dietary omega -6 acid intake increases bioavail- Hz to about 25 Hz, about 0 .5 Hz to about 20 Hz, about 0 .7
ability of omega -3 polyunsaturated fatty acids in the blood Hz to about 15 Hz, about 0 .9 Hz to about 10 Hz, about 1.0
stream . Accordingly , switching prepared food items to those Hz to about 9 Hz, about 1 .2 Hz to about 8 Hz, about 1 . 4 Hz
with 1 -to - 1 ratios is highly preferable to reduce inflamma- 45 to about 7 Hz, about 1.6 Hz to about 6 Hz, or about 2 Hz to
tion within the brain . about 5 Hz. In these embodiments the pulse width can be in
As used herein , the phrase " vagus nerve stimulation ” or the range selected from about 20 to about 1000 uS, about 30
“ VNS ” refers to the stimulation of the auricular branch of to about 900 us , about 40 to about 800 us , about 50 to about
the vagus nerve . The vagus nerve can be stimulated using 700 us , about 60 to about600 us , about 70 to about 500 uS ,
methods well known in the art, including internally via a 50 about 80 to about 450 us , about 90 to about 400 us , about
transplanted device (e . g ., U .S . Pat. No . 9 ,211 ,410 ; incorpo - 100 to about 350 us , about 110 to about 325 us , about 120
rate herein by reference in its entirety), mechanically , or to about 300 us, about 130 to about 275 us , about 140 to
transcutaneously . Transcutaneous vagus nerve stimulation about 260 us, or about 150 to about 250 S . In these
( VNS ) of the auricular branch of the Vagus nerve (FIG . 6 ) embodiments, the current can be in a range selected from
results in the reduction of pro - inflammatory cytokines via 55 about 0 . 1 to about 5 . 0 , about 0 . 2 to about 4 . 0 , about 0 . 3 to
the cholinergic anti- inflammatory pathway (Lerman et al., about 3 .0 , about 0 .4 to about 2. 0 , or about 0 .5 to about 1 .0
Neuromodulation 19 : 283 - 291 , 2016 ; incorporated herein by mAmps (see FIG . 6 ). In a particularly preferred embodi
reference in its entirety ) . As used herein , the term " vagus ment, the electrical stimulation is achieved by inducing an
nerve” is used in its broadest sense , and includes any nerves electrical current with a TENS (transcutaneous electrical
that branch off from the main vagus nerve, as well as 60 nerve stimulation ) unit with the frequency at 2 - 5 Hz, pulse
ganglions or postganglionic neurons that are connected to width at 150 - 250 uS and 0 .5 - 1 .0 mAmps (see FIG . 6 ). It is
the vagus nerve . The vagus nerve is also known in the art as contemplated herein , that the tVNS is employed for an
the parasympathetic nervous system and its branches , and amount of time sufficient to adequately reduce the pro
the cholinergic nerve. inflammatory cytokines via the cholinergic anti -inflamma
In certain embodiments , the vagus nerve can be stimu- 65 tory pathway . Suitable times for use herein include about 30
lated by any means known to those of skill in the art . minutes up to about 8 hours per day, more preferably 45
Nonlimiting examples include: mechanical means such as a minutes up to about 7 hours , more preferably 1 hour up to
 US 10 ,335 ,396 B2
10
about 6 hours, more preferably 1. 5 hours up to about 5 hours, intake is reduced to less than 500 calories per fasting- day for
with about 2 hours up to about 4 hours per day being women and less than 600 calories per fasting- day for men .
particularly preferred . In certain embodiments , the intermittent fasting regimen
Over-nutrition refers to the toxic cellular effects excessive may be initiated at the baseline visit , when the administra
nutrients inflict on the body . The voluntary or involuntary 5 tion of the antibiotic , polyunsaturated omega - 3 fatty acid ,
(i.e ., increased levels of hunger from autonomic dysfunction oleic acid and the vagus nerve stimulation are initiated , if the
or intestinal bacterial overgrowth ) of excess calories will patient does not exhibit any symptoms suggestive of cere
initially result in the growth of adipose tissue . As long as the bral hypoperfusion such as orthostasis , occipital headaches
excessive calories can be stored within subcutaneous adi 10 or neck tightness. If these symptoms are present, it is
preferable to wait until the 2nd or 3rd clinical visit to initiate
pose tissue , they are for the most part harmless to metabolic the intermittent fasting regimen otherwise the patient may
function and overall heath .However, for a variety ofreasons experience increases in hunger, anxiety , headaches and
known and unknown , many individuals reach a point where orthostasis .
they are unable to store calories within adipose . The exces In another embodiment, the basic format of intermittent
sively ingested calories then flow within cells of the brain
brain 15 fasting regimen is to alternate days of ' normal' calorie
and other organs, and the cells begin to function abnormally . consumption with fasting -days when calorie consumption is
These cells are being damaged due to over-nutrition from severely restricted . This can either be doneon an alternating
excessive caloric intake. day basis as set forth herein , or using the well-known 5 : 2
The endoplasmic reticulum (referred to as ER ; an internal strategy in which 2 days each week are classed as fasting
organelle responsible for the production of proteins and 20 days (see FIG . 4 ). It has been found that the excessive
lipids ) is the portion of the cell most adversely affected by consumption of calories results in a form of cellular stress
over- nutrition . Endoplasmic reticular stress (ER stress ) is a known as endoplasmic reticular stress , and also results in
common component of the major neurodegenerative disor- increases in pro - inflammatory cytokines within the central
ders ( Alzheimer' s Disease , Parkinson ' s Disease , Amyo - nervous system as well as peripheral tissues . It has also been
trophic Lateral Sclerosis, Lewy Body Dementia , Age -Re - 25 found that intermittent fasting regimens limit neuronal dam
lated Macular Degeneration ), and is responsible for the age and improve recovery after stroke, Parkinson ' s disease
pathological development of inclusion bodies. ER stress and Huntington 's disease ; and also attenuate pro - inflamma
from overnutrition impairs autophagy (the ability of brain tory cytokine production in response to LPS exposure from
cells to remove damaged or unneeded proteins and lipids intestinal bacterial overgrowth .
collecting within the cells ). The build -up of intracellular 30 Many patients with autonomic damage are unable to
proteins within the cell in the intracytoplasmic inclusion regulate the proper amount of arterial blood flow and oxygen
bodies (e.g ., tau, alpha -synuclein , Lewy Bodies ) which are delivery to the brain . Cerebral hypoperfusion is the primary
common features in neurodegenerative disorders. cause of symptoms (i.e ., headaches, neck tightness , anxiety ,
The use of intermittent fasting in the Nemechek Protocol lightheaded/dizziness , decreased cognitive function ) in a
invention methods provided herein creates a health -promot- 35 concussed individual. Patients with cerebral hypoperfusion
ing level of cellular stress that causes cells to repair them - often experience an increased level of hunger and thirst
selves and restore function . This positive stress is known as because the subconscious mind sense learns that by increas
hormesis, and it can restore normal cell function , reduce ing the intake of liquids or foods with contain salt and sugar ,
levels of pro - inflammatory cytokines, and repair damaged cerebral perfusion and oxygen delivery is temporarily
cells within the brain as well as in peripheral organs. 40 improved .
Importantly , hormesis will increase autophagy. Autophagy is The significantdecline ofcalories required by intermittent
the key feature required to reverse the build -up of intracy - fasting ( e. g , the total intake of only 500 -600 calories , and the
toplasmic inclusion bodies that is a central pathological like ) reverses the beneficial effect of food and drink on
component of the neurodegenerative disorders. cerebral perfusion . As set forth herein , the use of the
For example , the neurological benefits of using the Inter - 45 intermittent fasting step is contemplated in the invention
mittent Fasting step in the Nemechek Protocol invention methods at the onset of the Nemechek Protocol invention
methods provided herein , include : improved Autophagy ; methods provided herein . However , if intermittent fasting is
improved Mitochondrial Function ; reduced LPS - Induced initiated at the onset of the Nemechek Protocol, it can result
Neuroinflammation ; neuroprotection following Traumatic in the worsening of symptoms (headaches , fatigue , anxiety ,
Brain Injury ; improved Endoplasmic Reticular Function ; 50 poor concentration , altered balance and lightheadedness ).
increased Brain Stem Cell Production ; increases Resistance Accordingly , in a preferred embodiment for use with the
to Brain Damage ; improvement in Cognitive Functioning; invention methods , intermittent fasting is not implemented
and reversing cellular changes of Alzheimer 's Disease and in a range selected from until about 0 - 12 months, about 1 - 10
of Parkinson 's Disease . months , about 2 - 8 months , about 3 -6 months, or about 3 - 4
As used herein , the phrase " placing said subject on an 55 months, after initiation of administering the antibiotic, poly
intermittent fasting regimen ” refers to requiring and/or unsaturated omega - 3 fatty acid , and oleic acid with or
scheduling the subject for the significant reduction of caloric without vagal nerve stimulation , when symptomatic
intake, preferably at least once weekly ( e. g., one fasting- day improvement of cerebral hypoperfusion has been achieved .
per week ); to up to 3 non -consecutive fasting -days per week . In a particularly preferred embodiment for use with the
In certain embodiments contemplated herein , on a “ fasting - 60 invention methods, intermittent fasting is not implemented
day” as referred to herein , total dietary caloric intake is until about 3 -4 months after initiation of administering the
reduced to less than 1000 , less than 900 , less than 800 , less antibiotic , polyunsaturated omega -3 fatty acid , and oleic
than 700 , less than 600 or less than 500 calories per acid with or without vagal nerve stimulation, when symp
fasting - day for women and less than 1200 , less than 1100 , tomatic improvement of cerebral hypoperfusion has been
less than 1000 , less than 900 , less than 800 , less than 700 , 65 achieved .
or less than 600 calories per fasting - day for men . In a In some embodiments , daily supplementation with cur
particularly preferred embodiment, total dietary caloric cumin is optionally employed in the methods described
 US 10 ,335 ,396 B2
JI 12
herein . In particular embodiments, curcumin supplementa - In preferred embodiments, the diseases or conditions
tion can occur either once or twice daily . The amount of treated herein by the suppression of pro -inflammatory cytok
curcumin taken daily can range from about 100 mg up to ines are traumatic brain injury , concussion , chronic trau
about 5000 mg, about 200 mg up to about 4500 mg, about matic encephalopathy (CTE ), post- concussion syndrome
300 mgup to about 4000 mg, about 400 mg up to about 3500 5 (PCS), Alzheimer 's disease , Parkinson' s disease , autism ,
mg, about 400 mg up to about 3000 mg, about 500 mg up essential tremor, post -traumatic stress disorder (PTSD ),
to about 2500 mg, about 600 mg up to about 2000 mg, about chronic depression , treatment resistant epilepsy, autism ,
700 mg up to about 2000 mg, about 800 mg up to about 1500 developmental
The disease
delay and sensory perception disorder.
or condition can be one where the pro
mg, with about 1000 mg taken twice daily being especially 10 inflammatory cytokines cause a systemic reaction . Alterna
preferred . tively, the condition can be mediated by a localized pro
Curcumin is derived from the spice turmeric, and is a inflammatory cytokines, such as in rheumatoid arthritis , and
potent anti -inflammatory agent that is added to the initial the like . Additional non - limiting
regimen if an individual is believed to have a significant disorders or diseases which can beexamples of inflammatory
treated using the present
inflammatory component from a comorbid autoimmune 15 invention include appendicitis, peptic , gastric or duodenal
disorder . In one embodiment, curcumin may be added to any ulcers, peritonitis , pancreatitis , ulcerative, pseudomembra
patient's regimen if there is inadequate clinical or autonomic nous , acute or ischemic colitis, diverticulitis, epiglottitis,
improvement after about 2 months of treatment without the achalasia , cholangitis, cholecystitis, hepatitis, Crohn 's dis
use of curcumin . ease, enteritis, Whipple 's disease , asthma, allergy , anaphy
Any form of curcumin known to those of skill in the art 20 lactic shock , immune complex disease , organ ischemia ,
can be utilized herein . For example , curcumin in the form of reperfusion injury , organ necrosis, hay fever, sepsis , septi
colloidal, nanoparticles , oil emersions or special blends are cemia, endotoxic shock , cachexia, hyperpyrexia , eosino
contemplated herein for use in reducing inflammation . philic granuloma, granulomatosis , sarcoidosis , septic abor
Nearly 80 % of the cells of immune system are located within tion , epididymitis , vaginitis , prostatitis , urethritis ,
the tissues immediately surrounding the lumen of the small 25 bronchitis , emphysema, rhinitis , cystic fibrosis, pneumoni
intestine often referred to as Peyer ' s patches. It has been tis , pneumoultramicroscopicsilicovolcanoconiosis -, alveali
found that curcumin is able to readily saturate this area tis, bronchiolitis , pharyngitis, pleurisy, sinusitis, influenza ,
without entering the blood stream , and in doing so comes in respiratory syncytial virus, herpes, disseminated bacteremia ,
contact with a large proportion of the immune system and Dengue fever, candidiasis , malaria , filariasis , amebiasis ,
results in the reduction in the production of pro - inflamma- 30 hydatid cysts, burns, dermatitis , dermatomyositis , sunburn ,
tory cytokines. urticaria , warts , wheals , vasculitis , angiitis , endocarditis ,
In another embodiment of the methods herein , the reduc arteritis , atherosclerosis, thrombophlebitis , pericarditis,
tion of total dietary carbohydrate intake to less than about myocarditis , myocardial ischemia , periarteritis nodosa ,
40 - 100 grams per day is optionally employed . It has been rheumatic fever, Alzheimer' s disease , coeliac disease, con
found that reduction in dietary carbohydrates to less than 35 gestive heart failure , adult respiratory distress syndrome,
100 gramsper day decreases hunger and total caloric intake meningitis , encephalitis, multiple sclerosis, cerebral infarc
as well as the level of pro - inflammatory cytokines produc t ion , cerebral embolism , Guillain -Barre syndrome, neuritis ,
tion . In addition to a reduction in hunger, it has also been neuralgia , spinal cord injury , paralysis , uveitis , arthritides ,
found that reducing caloric intake and dietary carbohydrates arthralgias, osteomyelitis, fasciitis, Paget' s disease, gout,
to less than 40 grams per day increases ketone production 40 periodontal disease , rheumatoid arthritis , synovitis, myas
making this alternative cellular fuel available for neurons, thenia gravis , thryoiditis , systemic lupus erythematosus ,
while providing additional protection from injury . Goodpasture's syndrome, Bechet's syndrome, allograft
In other embodiments of the methods set forth herein for rejection , graft -versus -host disease, Type I diabetes, anky
individuals intolerant to omega -3 intake from fish or indi- losing spondylitis , Berger 's disease , Reiter 's syndrome, or
viduals who choose not consume fish -derived products ( e . g ., 45 Hodgkin 's disease . In more preferred embodiments , the
vegetarians ), individuals can optionally consume other oils condition is appendicitis, peptic , gastric or duodenal ulcers ,
or foods that have high concentrations of alpha-linolenic peritonitis , pancreatitis , ulcerative, pseudomembranous,
acid (ALA ). Exemplary foods having high ALA concentra - acute or ischemic colitis, hepatitis, Crohn 's disease , asthma,
tions include , for example , flax oil, chia , kiwifruit seeds, allergy , anaphylactic shock , organ ischemia , reperfusion
perilla , lingonberry , purslane, sea buckthorn , and the like . In 50 injury , organ necrosis , hay fever, sepsis , septicemia , endo
a particular embodiment, supplementation with 3 ,000 mg of toxic shock , cachexia , septic abortion , disseminated bacte
flax seed oil twice daily is contemplated herein . It has been remia, burns, Alzheimer 's disease, coeliac disease , conges
found that high concentrations of alpha -linolenic acid can tive heart failure , adult respiratory distress syndrome,
increase the production of DHA and increase accretion of cerebral infarction , cerebral embolism , spinal cord injury ,
DHA within the brain . 55 paralysis , allograft rejection or graft- versus-host disease .
The treatment of any condition mediated by the suppres - Other diseases contemplated herein for treatment using
sion ofpro - inflammatory cytokines is within the scope of the the invention methods provided herein include hay fever,
invention methods provided herein . As used herein , the atherosclerosis , arthritis (rheumatoid , bursitis , gouty arthri
phrase “ suppression of pro - inflammatory cytokines” refers tis, polymyalgia rheumatic, etc .), asthma, autoimmune dis
to the combined effect of the invention treatmentmethods to 60 eases , chronic inflammation , chronic prostatitis , glomerulo
substantially reduce the levels of pro - inflammatory cytok - nephritis , nephritis, inflammatory bowel diseases, pelvic
ines within the central nervous system such that natural inflammatory disease, reperfusion injury, transplant rejec
repair mechanisms are activated and autonomic nervous tion , vasculitis , myocarditis , colitis, and the like .
system function recovers . As set forth herein , autonomic Also provided herein , are methods for preventing, reduc
recovery is detected by sequential spectral analysis moni- 65 ing or reversing acute and / or chronic autonomic damage by
toring of the autonomic nervous system . If no recovery is suppression of pro -inflammatory cytokines in a subject in
noted , the treatment regimen can be supplemented further. need thereof, comprising administering to said subject an
 US 10 ,335 , 396 B2
13 14
effective amount of an antibiotic ; an effective amount of -continued
polyunsaturated omega -3 fatty acid ; and an effective amount
of oleic acid ; and providing VNS ( vagal nerve stimulation ) carefully for signs of dizziness or loss of
to the subject. balance.
NOTE :
EXAMPLES If a patient is not able to perform the Stand challenge ( for whatever reason ), the test should
be performed in a supine position for the first five (5 ) phases. However, at the Stand portion
of the test, the patient should be instructed to sit up from the supine position . The patient
may be assisted in doing so , if necessary.
Example 1 — Spectral Analysis of Normal Baseline 10
Subjects And Subjects Treated with Various B . Nemechek Protocol Treatment:
Combinations of Antibiotic , DHA Supplement, Briefly, there was a ControlGroup (Normal) and 3 Groups
Oleic Acid and Vagal Nerve Stimulation Therapy of patients who were treated with either: antibiotic and DHA
supplement (referred to herein as the “ SD ” group; 116
A . Spectral Analysis: 15 patients ); antibiotic , DHA supplement and oleic acid ( re
Prior to initiating the Nemechek Protocol employing the
the ferred to herein as the “ SDE ” group ' 212 patients ); or
invention methods, autonomic monitoring is performed on antibiotic , DHA supplement, oleic acid , and vagal nerve
each prospective patient via a baseline spectral analysis stimulation (referred to herein as the “ SDEV ” group ; 77
using the ANX Version 3.0 Autonomic Nervous System patients ). The results of these treatments are provided below .
Monitor , available from ANSAR Medical Technologies Inc. More specifically , to the patients of the SD group , 550 mg
(Philadelphia Pa .). of the antibiotic rifaximin was administered 2 - 3 times daily
Briefly , as described in the ANX monitor protocol, the for 10 - 14 days . To this same SD patient group, 3 ,000 mg of
at patient in a comfortable chair with DHA supplement was administered daily.
sufficient back support. The chair should be stationary and 25 To the SDE patient group , in addition to antibiotic and
not swivel, tilt, rock , or have wheels/casters . Next, place the DHA supplement administered as above with the SD group ,
Blood Pressure (BP ) cuff on patient's upper left arm . Follow oleic acid in the form of extra virgin olive oil was admin
the instructions on the cuff to insure proper placement. Note istered by giving the SDE patients 25 mlof extra virgin olive
that you may manually start and stop the BP monitor by oil (EVOO ) per day .
clicking on the NIBP Start /Stop toggle switch on the front of 30 For the SDEV patient
pat group , in addition to being admin
the data acquisition screen . Next, the white and black leads istered antibiotic , DHA supplement and oleic acid in the
are placed on patient's upper chest just below the clavicle , form of EVOO , the SDEV group was subjected to electrical
each approximately 1. 5 - 2 inches out from the sternum . The vagal nerve stimulation by clipping electrodes across the
white lead is placed on the right, the black on the left. The 35 tragus of the left ear, inducing an electrical current with a
red lead is placed at the base of patient's rib cage on patient's TENS (transcutaneous electrical nerve stimulation ) 7000
left . As a final step , instruct the patient that throughout the unit (available from Roscoe Medical, Strongsville, Ohio ),
test she/he should remain as still as possible with feet flat on with the frequency at 2 -5 Hz. pulse width at 150 - 250 US and
the floor, not talk , and simply breathe freely at a comfortable 0 .5 - 1. 0 mAmps ( see FIG . 6 ).
pace unless instructed to do otherwise (e.g., during the Deep 40
Breathing and Valsalva challenges). TABLE 1
Testing Phases: Population Averages
N %F Age (yrs ) BMI (# /in ?)
Baseline Instruct patient to breathe at a relaxed , normal 5 minutes 45
pace . Normal 334 25 . 9
Deep Instruct patient to breathe 5 seconds in , 5 1 minute SD 116 29 .0
Breathing seconds out, and to breathe at a slow and easy SDE 212 29 .0
pace . This should be done correctly to SDEV 77 53 64 34 . 4
accurately challenge the parasympathetic
nervous system . 50
Baseline Instruct patient to breathe at a relaxed , normal 1 minute
pace .
Valsalva Patient should perform the first Valsalva with a 95 seconds TABLE 2
15 -second hold , then relax until the clock reads Data independence:
1:00 . Patient should then do 4 Valsalva 's, one
every 15 seconds. Instruct patient to take a 55 SD vs SD vs SDE vs SD vs SDE vs SDEV vs
quick breath in and hold it . Then , like inflating SDE SDEV SDEV Nml Nml Nml
a hard balloon , tell patient to create pressure in
her/his chest, pushing out and down on the Bx LFa 0 . 04 - 0 . 02 0 .00 0 .02 0 .05 0 .02
stomach while holding and bearing down on Bx RFA 0 .05 - 0 .04 0 .05 0 .03 -0 . 01 0 .01
the breath . (This feeling is also compared with
straining while having a bowelmovement.)
Bearing down on the breath is the single most
important part of this challenge . Discontinue When comparing the three patient groups ' Sympathetic
Valsalva if patient feels chest pain . (LFa) and Parasympathetic (RFa ) responses , all three groups
Baseline Instruct patient to breathe at a relaxed , normal 2 minutes
pace.
are found to be independent ( statistically , significantly dif
Stand Instruct patient to stand as quickly as possible. 5 minutes ferent: ps0 .05 , see Table above ). When comparing the three
Patients requiring assistance may be helped 65 patient groups with a normal subject population , at the
without compromising the test. Watch baseline study, all groups are statistically , significantly dif
ferent (ps0 .05 ).
 US 10 , 335, 396 B2
15
TABLE 3 After anti - biotic and DHA supplement (SD ) therapy, there
was no significant change in the average resting , Sympa
Resting Baseline StatisticalMeans Baseline ( Test 1) Responses
thetic ( Bx LFa ) responses (A = 0 .02 bpm², p = 0 .56 ) or Sym
compared with normal subjects :
pathovagal Balance (SB ) responses (4 = - 0 .01 bpm ” ,
?? Bx DB V V, PE PC PC, PE 5 p = 0 .36 ), while the average, resting Parasympathetic (Bx
LFA RFa SB Ria LFa ( % ) LFa % ) RFa ) increased by 45 .6 % (4 = 1.29 bpm², p = 0 .03 ). The
Normal 3.27 3.55 1. 30 42 .00 53. 10 0 .00 5 . 20 0 .00 changes in the dynamic responses to SD therapy included
SD 3.81 2. 83 2. 10 34 .43 61.29 90 .18 7 .06 61.61 insignificant decreases in deep breathing Parasympathetic
SDE 2 .46 2.40 1. 99 32. 59 54 . 89 89 .81 5 .33 68.93 activity (DB RFa : A = - 1.77 bpm², p = 0 . 83 ), Valsalva Sym
SDEV 2.06 1. 90 2 .24 25 .57 43. 93 92. 86 21. 28 71.43 10
pathetic activity (V LFa: A = - 9 .79 bpm², p = 0 .44), and stand
NOTE :
1 ) SB is the average of ratios, not the ratio of averages, therefore it is not always equal to
Sympathetic activity (PC LFa : A = - 0 .61 bpm², p = 0 .67 ).
the simple ratio of the average Bx LFa to Bx RFa. However, the prevalence of the abnormal, dynamic PEs both
Abbreviations:
LFa — Sympathetic Response , decreased significantly : V , PE decreased by 40 .2 % (p = 0 .04 )
RFa — Parasympathetic Response Bx — Baseline , 15 and PC , PE decreased by 21.4 % (p = 0 .01).
DB - Deep Breathing, After adding oleic acid with SD therapy (SDE therapy),
V — Valsalva , there was no significant change in the average resting,
PE — Parasympathetic Excess, Sympathetic responses (A = - 0 .43 bpm², p = 0 .57 ) or Sym
PC - Postural Challenge.
pathovagal Balance (SB ) responses (4 = - 0 .02 bpm >,
Dynamic Parasympathetic Excess (PE ) in response to 20 p = 0 .37). The average , resting Parasympathetic response
both Valsalva (V , PE ) and stand (postural change , or PC , PE ) increased , but not significantly ( 4 = 0 .30 bpm², p = 0 . 14 ). The
are prevalent in all patient populations at baseline testing. PE changes in the dynamic responses to SDE therapy included
( whether Valsalva or stand ) is associated with the following : an insignificant increase in deep breathing Parasympathetic
difficult to control BP, blood glucose , or hormone level, activity (4 = 6 .42 bpm², p = 0 . 99 ), an insignificant decrease in
difficult to describe pain syndromes (including CRPS ), dif- 25 Valsalva Sympathetic activity (A = - 11. 13 bpm², p = 0 .81),
ficult to manage weight- loss , unexplained arrhythmia (pal- and an insignificant increase in stand Sympathetic activity
pitations )or seizure, and symptoms of depression or anxiety, (4 = 1. 36 bpm², p = 0 .79 ). However, the prevalence of the
fatigue , exercise intolerance , sex dysfunction , sleep or GI abnormal, dynamic PEs both decreased significantly : V , PE
disturbance , lightheadedness, or frequent headache or decreased by 24 . 3 % ( p = 0 . 04 ) and PC , PE decreased by
migraine. PE with stand may also mask Sympathetic With - 30 16 . 5 % (p = 0 .02 ).
drawal (SW ) which underlies Orthostatic Dysfunction . After adding Vagal N . stimulation with SDE therapy
Regarding therapy , Valsalva Sympathetic Excess is consid - (SDEV therapy ), there were significant changes in the
ered secondary to Valsalva PE . average resting, Sympathetic responses (A = 2 .34 bpm ” ,
Low HRV is associated with low Parasympathetic (P ) p = 0 . 01 ) and average, resting Parasympathetic responses
activity, which is associated with increased levels of pro - 35 (4 = 1. 34 bpm², p = 0 .05). Sympathovagal Balance (SB )
inflammatory cytokine, which is associated with impairment responses also increased , but not significantly (4 = 0 .95
of the vagal-mediated acetylcholine inflammatory reflex . bpm², p = 0 . 33 ). The changes in the dynamic responses to
Total Spectral Power ( TSP ) is a measure of HRV . TSP is the SDEV therapy included an insignificant decrease in deep
sum ofLFa + RFa. As compared with normal subjects , (LFat breathing Parasympathetic activity ( A = - 2 .01 bpm²,
RFa = 6 .82 bpm²), the average HRV (or TSP ) response for the 40 p = 0 .87 ), an insignificant decrease in Valsalva Sympathetic
three study populations are all lower as compared with activity ( A = - 2 . 12 bpm², p = 0 .76 ), and an insignificant
normal: SD , TSP = 6 .64 bpm (p = 0 .02); SDE , TSP = 2. 86 decrease in stand Sympathetic activity (A = - 0 . 26 bpm ?,
bpm² (p = 0.01); SDEV, TSP = 3.96 bpm² (p = 0.01). p = 0 .63 ). However, the prevalence ofthe abnormal, dynamic
Pre -existing low HRV , from an inflammatory perspective , PEs both decreased significantly : V , PE decreased by 48 .6 %
correlates with the risk of developing PTSD . The prevalence 45 (p = 0 .01) and PC , PE decreased by 32.9 % (p = 0 .01 ).
of PTSD was higher in subjects with high pre -incidence In summary and on average among the three therapy
LFa /RFa ratios (SB ). The normal range for SB is modified modalities , SDEV therapy produced the most significant
by age. Patients younger than 65 years normally have a change in Parasympathetic activity , followed by SD , with
higher normal SB : 1 .0 < SB < 3 .0 ; otherwise they tend to be SDE having the least average effect on Parasympathetic
depressed . Older patients are recommended to normally 50 activity. SDEV therapy also produced the most significant
have a lower normal SB : 0 .4 < SB < 1 . 0 ; to afford a “ little
change in Sympathetic activity , with SD having essential no
more ” parasympathetic activity as cardio -protective [Singer, effect on Sympathetic activity, and SDE having a depressing
JACC , 1998 ].Based on these ranges and the average ages of effect on Sympathetic activity . The significant increase in
the study populations, the SDE & SDEV populations dem Sympathetic activity in response to SDEV , over that in
onstrate high pre -incident SB and the SD populations dem response to SD or SDE , is a result of direct stimulation of the
onstrate normal (p < 0 . 05 ). Parasympathetic activity and the feedback relationship
TABLE 4
Resting Baseline StatisticalMeans Follow -up (Test 2) Responses :
F /U Bx LFa Bx RFa SBError! Bookmark not defined . DB RFA V LFa V , PE (% ) PC LFa PC, PE (% )
SD 3 .83 4 .12 2 .09 33.41 55 .20 50 .00 6 .60 40 .18
SDE 2 .03 2 .70 1 . 97 39 .02 52 .29 65 .53 7 .77 52 . 43
SDEV 4 .40 3.24 3 .19 23 .56 50 .41 44 . 29 4 .87 38 .57
 US 10 ,335 ,396 B2
17 18
between the two nervous systems. The other two therapy made therein without departing from the spirit and scope of
modalities are indirect, systemic therapies which do not the present embodiments as defined by the following claims.
affect the feedback relationship as strongly. What is claimed is :
Given the mixed results , consider the SB responses. SDE 1. A method for reducing parasympathetic excess ( PE ) in
changed SB most in the direction of increasing relative 5 a subject in need thereof, comprising:
Parasympathetic activity (A = - 0 .02 ), SD averaged no (net ) administering to said subject rifaximin , wherein rifaximin
change in P & S balance and SDEV changed SB least in the is administered for 10 - 14 days ; a polyunsaturated
direction of increasing relative Parasympathetic activity omega - 3 fatty acid , wherein the polyunsaturated
(4 = 0 . 95 ). omega - 3 fatty acid comprises DHA in a daily concen
In general, by increasing resting Parasympathetic activity , 10 tration range selected from : about 2 ,000 -4 ,000 mg, or
the ( abnormal) dynamic Parasympathetic responses (leading about 3 ,000 mg; and olive oil, wherein the olive oil is
to PE ) were reduced . Reducing the dynamic , excess Para administered daily in an amount selected from : about 5
sympathetic responses also reduced morbidity risks, appar ml to about 100 ml, about 10 ml to about 75 ml, about
ently including excess levels of pro - inflammatory cytokines 15 ml to about 50 ml, about 20 ml to about 40 ml, or
within the CNS; thereby improving patient outcomes. 15 about 25 ml;
These results indicate that the invention methods provided providing VNS (vagal nerve stimulation ) to the subject,
herein reduce the excess levels of pro -inflammatory cytok wherein the VNS is provided transcutaneously using
ines within the CNS ; thereby reversing autonomic nervous electrical stimulation, wherein the electrical stimula
system damage . tion is achieved by clipping electrodes across the tragus
20 of an ear and inducing an electrical current with a
Example 2 — the Nemechek Protocol Including transcutaneous electrical nerve stimulation ( TENS )
Intermittent Fasting unit; and
placing said subject on an intermittent fasting regimen ,
A . Treatment Protocol: wherein the intermittent fasting regimen comprises
From an autonomic dysfunction perspective, patients 25 fasting for multiple days but not on consecutive days ;
most commonly requiring intermittent fasting (IF ) are often and
those who have suffered significant traumatic brain injuries wherein the prevalence of parasympathetic excess (PE ) is
( TBI), as compared to emotional trauma, pregnancy or decreased .
chronic inflammatory damage . Traumatic brain injuries are 2 . The method claim 1 , wherein rifaximin is administered
more of a challenge to reverse because the physical shearing 30 at a dosage of 550 mg, 1 tablet by mouth 2 - 3 times daily .
forces associated with TBIwill tear or snap neurons in half 3 . The method of claim 1 , wherein a second antibiotic is
whereas this is not known to occur with emotional or administered to the subject .
inflammatory neuronal disruption . Other patients with obe - 4 . The method of claim 3 , wherein the second antibiotic
sity , diabetes, sleep apnea , fatty liver disease, intra - abdomi- is selected from metronidazole or neomycin .
nal adiposity and organ failure (cardiomyopathy, chronic 35 5 . The method of claim 1 , wherein the olive oil is extra
kidney disease , neurodegenerative disorders ) are also placed virgin olive oil.
on an intermittent fasting regimen either for the removal of 6 . The method of claim 1 , wherein the electrical current
ectopic adipose or for the cellular reparative effect ( i.e . has a frequency in the range selected from : about 0 . 1 Hz to
hormesis ) that intermittent fasting has on their organs. about 30 Hz, about 0 . 3 Hz to about 25 Hz, about 0 .5 Hz to
All patients (regardless of trauma type) begin with the 40 about 20 Hz, about 0 .7 Hz to about 15 Hz, about 0 .9 Hz to
SDEV regimen , and are informed that a change to their about 10 Hz, about 1. 0 Hz to about 9 Hz, about 1. 2 Hz to
eating routine will be implemented around the 4 month about 8 Hz, about 1 .4 Hz to about 7 Hz, about 1 .6 Hz to
mark . At the 4 -6 month mark after initiating Nemechek about 6 Hz, or about 2 Hz to about 5 Hz ; has a pulse width
Protocol SDEV regimen (e . g ., being administered antibiotic , in the range selected from : about 20 to about 1000 us, about
DHA supplement and oleic acid in the form of EVOO , and 45 30 to about 900 us, about 40 to about 800 us , about 50 to
VNS as described for the SDEV patient group in Example about 700 us , about 60 to about 600 us , about 70 to about
1), patients are started on a 1 :6 intermittent fasting regimen 500 uS , about 80 to about 450 us, about 90 to about 400 US ,
as a long term recommendation and are encouraged to utilize about 100 to about 350 us , about 110 to about 325 us , about
the 2 :5 intermittent fasting regimen . 120 to about 300 us, about 130 to about 275 us, about 140
It is believed that patients with higher levels of pro - 50 to about 260 us , or about 150 to about 250 uS ; and a current
inflammatory cytokines within the central nervous system or in a range selected from : about 0 . 1 to about 5 .0 , about 0 .2 to
periphery have a slower and potentially incomplete recovery about 4 .0 , about 0 . 3 to about 3 .0 , about 0 . 4 to about 2 . 0 , or
of autonomic function . The addition of intermittent fasting about 0 .5 to about 1 . 0 Amps.
in the Nemechek Protocol invention methods provided 7 . The method of claim 6 , wherein the electrical current
herein , after 4 to 6 months of initiating the SDEV regimen , 55 has a frequency at 2 -5 Hz, pulse width at 150 - 250 us and
improves the rate and completeness of autonomic damage 0 .5 - 1.0 mAmps .
recovery as measured on spectral analysis , as well as broad 8 . The method of claim 1, wherein the electrical stimu
ens the degree of symptomatic and clinical improvement. lation is used for a time selected from the group consisting
Since many patients with autonomic dysfunction have of: about 30 minutes up to about 8 hours , about 45 minutes
increased caloric consumption in response to cerebral 60 up to about 7 hours, about 1 hour up to about 6 hours , about
hypoperfusion, intermittent fasting reduces excessive adi- 1. 5 hours up to about 5 hours, and about 2 hours up to about
posity especially in ectopic sites such as the intra -abdominal 4 hours ; per day .
cavity , buttocks and the head and neck . 9 . The method of claim 8 , wherein the electrical stimu
While the present embodiments have been particularly lation is used about 2 hours up to about 4 hours per day .
shown and described with reference to example embodi- 65 10 . The method of claim 1 , wherein total dietary caloric
ments herein , it will be understood by those of ordinary skill intake is reduced to an amount selected from the group
in the art that various changes in form and details may be consisting of less than 1000 , less than 900 , less than 800 , less
 US 10 , 335 ,396 B2
19 20
than 700 , less than 600 or less than 500 calories per cardial ischemia , periarteritis nodosa , rheumatic fever,
fasting - day for women ; and less than 1200 , less than 1100 , Alzheimer 's disease , coeliac disease , congestive heart
less than 1000 , less than 900 , less than 800 , less than 700 , failure , adult respiratory distress syndrome, meningitis,
or less than 600 calories per fasting- day for men . encephalitis , multiple sclerosis, cerebral infarction ,
11 . The method of claim 1, wherein a condition treated 5 cerebral embolism ,Guillame-Barre syndrome, neuritis,
herein is selected from the group consisting of: traumatic neuralgia , spinal cord injury, paralysis , uveitis , arthri
brain injury , concussion , chronic traumatic encephalopathy tides , arthralgias, osteomyelitis , fasciitis , Paget' s dis
(CTE ), post-concussion syndrome ( PCS), Alzheimer's dis ease, gout, periodontal disease , rheumatoid arthritis ,
ease , Parkinson 's disease , essential tremor, post-traumatic synovitis , myasthenia gravis, thryoiditis, systemic
stress disorder (PTSD ), chronic depression , treatment resis - 10 lupus erythematosus, Goodpasture 's syndrome, Beh
tant epilepsy , autism , developmental delay and sensory cets 's syndrome, allograft rejection , graft- versus-host
perception disorder . disease, Type I diabetes, ankylosing spondylitis, Berg
12 . The method of claim 1, wherein a condition treated er ' s disease , Reiter 's syndrome, or Hodgkin ' s disease .
herein is selected from the group consisting of:
rheumatoid arthritis, appendicitis, peptic , gastric or duo - 15 13 . The method of claim 1, wherein a condition treated
denal ulcers, peritonitis , pancreatitis, ulcerative , herein is selected from the group consisting of: hay fever,
pseudomembranous, acute or ischemic colitis , diver atherosclerosisrheumatic , rheumatoid arthritis , bursitis, gouty arthritis ,
ticulitis, epiglottitis , achalasia , cholangitis, cholecysti polymyalgia
eases , chronic
arthritis, asthma, autoimmune dis
inflammation , chronic prostatitis, glomerulo
tis, hepatitis, Crohn 's disease , enteritis , Whipple’s dis nephritis , nephritis , inflammatory bowel diseases, pelvic
ease, asthma, allergy , anaphylactic shock , immune 20 inflammatory disease, reperfusion injury , transplant rejec
complex disease , organ ischemia , reperfusion injury,
organ necrosis , hay fever, sepsis , septicemia , endotoxic tion , vasculitis , myocarditis, and colitis.
shock , cachexia , hyperpyrexia , eosinophilic granu 14 . The method of claim 1, wherein the prevalence of
postural change (PC ) PE is decreased by approximately
loma, granulomatosis , sarcoidosis, septic abortion , epi
didymitis , vaginitis, prostatitis , urethritis , bronchitis , 25 32 % .
emphysema, rhinitis , cystic fibrosis, pneumonitis , nomic 15 . A method for reversing acute and /or chronic auto
pneumoultramicroscopicsilicovolcanoconiosis -, damage in a subject in need thereof, comprising :
alvealitis , bronchiolitis , pharyngitis , pleurisy, sinusitis, administering to said subject an effective amount of an
influenza , respiratory syncytial virus, herpes, dissemi antibiotic; an effective amount of polyunsaturated
nated bacteremia , Dengue fever, candidiasis, malaria , 30 omega - 3 fatty acid ; and an effective amount of oleic
filariasis , amebiasis , hydatid cysts, burns , dermatitis , acid ; providing VNS (vagal nerve stimulation ) to the
dermatomyositis, sunburn , urticaria , warts , wheals, subject, and decreasing the prevalence of Valsalva ( V )
vasulitis , angiitis , endocarditis , arteritis , atherosclero PE by approximately 48 % .
sis , thrombophlebitis , pericarditis, myocarditis, myo