autism and emf? plausibility of a pathophysiological link ... › file › 7520958031.pdfautism...

P

A

fi(oasoospeoflasAcoatsd©

KW

1

agc

0h

ARTICLE IN PRESSATPHY-777; No. of Pages 24

Pathophysiology xxx (2013) xxx–xxx

Autism and EMF? Plausibility of a pathophysiological link part II

Martha R. Herbert a,∗, Cindy Sage ba Massachussetts General Hospital Harvard Medical School Boston, TRANSCEND Research Program Neurology, Boston, MA, USA

b Sage Associates, Santa Barbara, CA, USA

bstract

Autism spectrum conditions (ASCs) are defined behaviorally, but they also involve multileveled disturbances of underlying biology thatnd striking parallels in the physiological impacts of electromagnetic frequency and radiofrequency radiation exposures (EMF/RFR). Part IVol 776) of this paper reviewed the critical contributions pathophysiology may make to the etiology, pathogenesis and ongoing generationf behaviors currently defined as being core features of ASCs. We reviewed pathophysiological damage to core cellular processes that aressociated both with ASCs and with biological effects of EMF/RFR exposures that contribute to chronically disrupted homeostasis. Manytudies of people with ASCs have identified oxidative stress and evidence of free radical damage, cellular stress proteins, and deficienciesf antioxidants such as glutathione. Elevated intracellular calcium in ASCs may be due to genetics or may be downstream of inflammationr environmental exposures. Cell membrane lipids may be peroxidized, mitochondria may be dysfunctional, and various kinds of immuneystem disturbances are common. Brain oxidative stress and inflammation as well as measures consistent with blood–brain barrier and brainerfusion compromise have been documented. Part II of this paper documents how behaviors in ASCs may emerge from alterations oflectrophysiological oscillatory synchronization, how EMF/RFR could contribute to these by de-tuning the organism, and policy implicationsf these vulnerabilities. It details evidence for mitochondrial dysfunction, immune system dysregulation, neuroinflammation and brain bloodow alterations, altered electrophysiology, disruption of electromagnetic signaling, synchrony, and sensory processing, de-tuning of the brainnd organism, with autistic behaviors as emergent properties emanating from this pathophysiology. Changes in brain and autonomic nervousystem electrophysiological function and sensory processing predominate, seizures are common, and sleep disruption is close to universal.ll of these phenomena also occur with EMF/RFR exposure that can add to system overload (‘allostatic load’) in ASCs by increasing risk, and

an worsen challenging biological problems and symptoms; conversely, reducing exposure might ameliorate symptoms of ASCs by reducingbstruction of physiological repair. Various vital but vulnerable mechanisms such as calcium channels may be disrupted by environmentalgents, various genes associated with autism or the interaction of both. With dramatic increases in reported ASCs that are coincident inime with the deployment of wireless technologies, we need aggressive investigation of potential ASC—EMF/RFR links. The evidence isufficient to warrant new public exposure standards benchmarked to low-intensity (non-thermal) exposure levels now known to be biologicallyisruptive, and strong, interim precautionary practices are advocated.

2013 Elsevier Ireland Ltd. All rights reserved.

eywords: Autism; EMF/RFR; Cellular stress; Oxidative stress; Mitochondrial dysfunction; Oscillatory synchronization; Environment; Radiofrequency;ireless; Children; Fetus; Microwave

dac

. Recap of part I and summary of part II

Part I of this two-part article previously documented

Please cite this article in press as: M.R. Herbert, C. Sage, Autism and EMF(2013), http://dx.doi.org/10.1016/j.pathophys.2013.08.002

series of parallels between the pathophysiological andenotoxic impacts of EMF/RFR and the pathophysiologi-al, genetic and environmental underpinnings of ASCs. DNA

∗ Corresponding author.E-mail address: [email protected] (M.R. Herbert).

caawdn

928-4680/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved.ttp://dx.doi.org/10.1016/j.pathophys.2013.08.002

amage, immune and blood–brain barrier disruption, cellularnd oxidative stress, calcium channel dysfunction, disturbedircadian rhythms, hormone dysregulation, and degradedognition, sleep, autonomic regulation and brainwavectivity—all are associated with both ASCs and EMF/RFR;nd the disruption of fertility and reproduction associated

? Plausibility of a pathophysiological link part II, Pathophysiology

ith EMF/RFR may also be related to the increasing inci-ence of ASCs. All of this argues for reduction of exposuresow, and better coordinated research in these areas. These

dx.doi.org/10.1016/j.pathophys.2013.08.002dx.doi.org/10.1016/j.pathophys.2013.08.002mailto:[email protected]/10.1016/j.pathophys.2013.08.002

ARTICLE IN PRESSPATPHY-777; No. of Pages 242 thophys

pdst

iipeibocaoetetlitoaotwatibmddcbcIEcamatndadadbcaIsi

2

2

phsesrifmddci

2

tfacsrmmac

cmtotbatmta(oagttTtd

M.R. Herbert, C. Sage / Pa

athophysiological parallels are laid out after identifying theynamic features of ASCs that could plausibly arise out ofuch pathophysiological dysregulation. The importance ofransduction between levels was also discussed in Part I.

Part II elucidates in much more detail the possiblenterfaces between the cellular and molecular pathophys-ology reviewed above and the higher-level disruption ofhysiological systems, brain tissue and nervous systemlectrophysiology. It addresses mitochondrial dysfunction,mmune system disregulation, neuroinflammation and brainlood flow alterations, altered electrophysiology, disruptionf electromagnetic signaling, synchrony, and sensory pro-essing, de-tuning of the brain and organism, and behavior asn emergent property. The emergence of ever larger amountsf data is transforming our understanding of ASCs from staticncephalopathies based on genetically caused brain damageo dynamic encephalopathies where challenging behaviorsmanate from physiologically disrupted systems. In parallel,he emergence of ever larger bodies of evidence supporting aarge array of non-thermal but profound pathophysiologicalmpacts of EMF/RFR is transforming our understanding ofhe nature of EMF/RFR impacts on the organism. At presentur policies toward ASCs are based on outdated assumptionsbout autism being a genetic, behavioral condition, whereasur medical, educational and public health policies relatedo treatment and prevention could be much more effective ife took whole-body, gene-environment considerations into

ccount, because there are many lifestyle and environmen-al modifications that could reduce morbidity and probablyncidence of ASCs as well. Our EMF/RFR standards are alsoased on an outdated assumption that it is only heating (ther-al injury) which can do harm. These thermal safety limits

o not address low-intensity (non-thermal) effects. The evi-ence is now overwhelming that limiting exposures to thoseausing thermal injury alone does not address the muchroader array of risks and harm now clearly evident withhronic exposure to low-intensity (non-thermal) EMF/RFR.n particular, the now well-documented genotoxic impacts ofMF/RFR, placed in parallel with the huge rise in reportedases of ASCs as well as with the de novo mutations associ-ted with some cases of ASCs (as well as other conditions),ake it urgent for us to place the issue of acquired as well

s inherited genetic damage on the front burner for scien-ific investigation and policy remediation. With the risingumbers people with ASCs and other childhood health andevelopmental disorders, and with the challenges to our priorssumptions posed ever more strongly by emerging evi-ence, we need to look for and act upon risk factors thatre largely avoidable or preventable. We argue that the evi-ence is sufficient to warrant new public exposure standardsenchmarked to low-intensity (non-thermal) exposure levelsausing biological disruption and strong, interim precaution-


ry practices are advocated. The combined evidence in Parts and II of this article provide substantial pathophysiologicalupport for parallels between ASCs and EMF/RFR healthmpacts.

e

oE

iology xxx (2013) xxx–xxx

. Parallels in pathophysiology

.1. Degradation of the integrity of functional systems

EMF/RFR exposures can yield both psychological andhysiological stress leading to chronically interruptedomeostasis. In the setting of molecular, cellular and tis-ue damage, one would predict that the organization andfficiency of a variety of organelles, organs and functionalystems would also be degraded. In this section we willeview disturbances from EMF/RFR in systems (includingnclude oxidative and bioenergetics metabolism, immuneunction and electrophysiological oscillations) that includeolecular and cellular components subject to the kinds of

amage discussed in the previous section. We will reviewisturbances that have been associated with EMF/RFR, andonsider the parallel disturbances that have been documentedn ASCs.

.1.1. Mitochondrial dysfunctionMitochondria are broadly vulnerable, in part because

he integrity of their membranes is vital to their optimalunctioning—including channels and electrical gradients,nd their membranes can be damaged by free radicals whichan be generated in myriad ways. Moreover, just about everytep in their metabolic pathways can be targeted by envi-onmental agents, including toxicants and drugs, as well asutations [1]. This supports a cumulative ‘allostatic load’odel for conditions in which mitochondrial dysfunction is

n issue, which includes ASCs as well as myriad other chroniconditions.

Mitochondria are commonly discussed in terms of the bio-hemical pathways and cascades of events by which theyetabolize glucose and generate energy. But in parallel with

his level of function there also appears to be a dimensionf electromagnetic radiation that is part of the activity ofhese organelles. For example, electromagnetic radiation cane propagated through the mitochondrial reticulum, whichlong with the mitochondria has a higher refractive indexhan the surrounding cell and can serve to propagate electro-

agnetic radiation within the network [2]. It is also the casehat “The physiological domain is characterized by small-mplitude oscillations in mitochondrial membrane potentialdelta psi(m)) showing correlated behavior over a wide rangef frequencies. . .. Under metabolic stress, when the bal-nce between ROS [reactive oxygen species, or free radicals]eneration and ROS scavenging [as by antioxidants] is per-urbed, the mitochondrial network throughout the cell lockso one main low-frequency, high-amplitude oscillatory mode.his behavior has major pathological implications because

he energy dissipation and cellular redox changes that occururing delta psi(m) depolarization result in suppression of


lectrical excitability and Ca2 + handling. . .” [3].These electromagnetic aspects of mitochondrial physiol-

gy and pathophysiology could very well be impacted byMF/RFR.

dx.doi.org/10.1016/j.pathophys.2013.08.002

ARTICLE IN PRESSPATPHY-777; No. of Pages 24thophys

mtrDatDemneoq

ca[tdo

tmanfadca

22scrdhpfosa

2eofopip

ft

pilsinwpde[aaatcattsltpm(iNiapt(adC

itrmAacre

2iteb


Other types of mitochondrial damage have been docu-ented in at least some of the studies that have examined

he impacts of EMF/RFR upon mitochondria. These includeeduced or absent mitochondrial cristae [4–6], mitochondrialNA damage [7], swelling and crystallization [5], alterations

nd decreases in various lipids suggesting an increase inheir use in cellular energetics [8], damage to mitochondrialNA [7], and altered mobility and lipid peroxidation after

xposures [9]. Also noted has been enhancement of brainitochondrial function in Alzheimer’s transgenic mice and

ormal mice [10]. The existent of positive as well as negativeffects gives an indication of the high context dependencef exposure impacts, including physical factors such as fre-uency, duration, and tissue characteristics [11].

By now there is a large amount of evidence for biochemi-al and other abnormalities in a large portion of children withutism that are consistent with mitochondrial dysfunction12–14]. Recently published postmortem brain tissue studieshat have added a new dimension of evidence for mitochon-rial abnormalities in ASCs will be reviewed in the sectionn alteration of brain cells below.

Secondary mitochondrial dysfunction (i.e. environmen-ally triggered rather than rooted directly in genetic

utations) [15–18] could result among other things from thelready discussed potential for EMF/RFR to damage chan-els, membranes and mitochondria themselves as well asrom toxicant exposures and immune challenges. In a meta-nalysis of studies of children with ASC and mitochondrialisorder, the spectrum of severity varied, and 79% of theases were identified by laboratory findings without associ-ted genetic abnormalities [16].

.1.2. Melatonin dysregulation

.1.2.1. Melatonin, mitochondria, glutathione, oxidativetress. Melatonin is well-known for its role in regulation ofircadian rhythms, but it also plays important metabolic andegulatory roles in relation to cellular protection, mitochon-rial malfunction and glutathione synthesis [19–21]. It alsoelps prevent the breakdown of the mitochondrial membraneotential, decrease electron leakage, and thereby reduce theormation of superoxide anions [22]. Pharmacological dosesf melatonin not only scavenge reactive oxygen and nitrogenpecies, but enhance levels of glutathione and the expressionnd activities of some glutathione-related enzymes [21,23].

.1.2.2. Melatonin can attenuate or prevent some EMF/RFRffects. Melatonin may have a protective effect in the settingf some EMF/RFR exposures, apparently in relation to theseunctions just described. EMF/RFR can impact melatonin;ne example is exposure to 900 MHz microwave radiationromoted oxidation, which reduced levels of melatonin andncreased creatine kinase and caspase-3 in exposed as com-


ared to sham exposed rats [24].Melatonin can attenuate or prevent oxidative damage

rom EMF/RFR exposure. In an experiment exposing ratso microwave radiation (MW) from a GSM-900 mobile

(omo

iology xxx (2013) xxx–xxx 3

hone with and without melatonin treatment to study renalmpacts [25], the untreated exposed rats showed increases ofipid peroxidation markers as reduction of the activities ofuperoxide dismutase, catalase and glutathione peroxidasendicating decrement in antioxidant status. However theseegative effects were inhibited in the exposed rats treatedith melatonin. Melatonin also inhibited the emergence ofreneoplastic liver lesions in rats exposed to EMFs [26]. Theevelopment of DNA strand breaks was observed in RFRxposed rats; this DNA damage was blocked by melatonin27]. Exposure of cultured cortical neurons to EMF led ton increase in 8-hydroxyguanine in neuronal mitochondria,

common biomarker of DNA oxidative damage, along with reduction in the copy number of mitochondrial DNA andhe levels of mitochondrial RNA transcripts; but these effectsould all be prevented by pretreatment with melatonin [7]. In

study of skin lesion induced by exposure to cell phone radia-ion, the skin changes in the irradiated group (which includedhicker stratum corneum, epidermal atrophy, papillamato-is, basil cell proliferation, increased epidermal granular cellayer and capillary proliferation, impaired collagen tissue dis-ribution and separation of collagen bundles in dermis) wererevented (except for hypergranulosis) by melatonin treat-ent [28]. Melatonin as well as caffeic acid phenyethyl ester

an antioxidant) both protected against retinal oxidative stressn rates exposed long-term to mobile phone irradiation [29].itric oxide (NO) was increased in nasal and sinus mucosa

n rats after EMF exposure, with this NO possibly acting as defense mechanism suggesting tissue damage; but this wasrevented by pretreatment with melatonin [30]. Melatoninreatment significantly prevented the increase in the MDAmalondyaldehyde, a marker of lipid peroxidation) contentnd XO (xanthine oxidase) activity in rat brain tissue after 40ays of exposure, but it was unable to prevent the decrease ofAT activity and increase of carbonyl group contents [31].

Of note, the melatonin production of infants in isolettesn neonatal intensive care units appears to be impacted byhe high ELF-EMF environment, in that when infants wereemoved from those exposures they showed an increase inelatonin levels [32]. There is an increased prevalence ofSCs in children who were born prematurely [33–43]. There

re many potential prematurity-associated factors that couldontribute to increased risk for ASCs, but proper melatoninegulation warrants EMF/RFR controls in the newborns’nvironment.

.1.2.3. Melatonin and autism. Regarding melatonin statusn people with ASCs, a recent meta-analysis summarizedhe current findings as indicating that “(1) Physiological lev-ls of melatonin and/or melatonin derivatives are commonlyelow average in ASC and correlate with autistic behavior,


2) Abnormalities in melatonin-related genes may be a causef low melatonin levels in ASD, and (3) . . . treatment withelatonin significantly improves sleep duration and sleepnset latency in ASD.” [44].



mmbg

ltstvmt[thmf

2PAatycdeiohilnettt[

2

ia[fgrifnawiit

h[taiEbEe

2ditctcdDeu(italoMcwtcaa

2niavpotawa[aiwii


The meta-analysis also showed that polymorphisms inelatonin-related genes in ASC could contribute to lowerelatonin concentrations or an altered response to melatonin,

ut only in a small percentage of individuals, since pertinentenes were found in only a small minority of those screened.

Based on the common presence of both sleep disorders andow melatonin levels, Bourgeron [45] proposed that synap-ic and clock genes are important in ASCs, and that futuretudies should investigate the circadian modulation of synap-ic function [45]. A number of melatonin-related geneticariants have been identified as associated with ASCs. Poly-orphisms and deletions in the ASMT gene, which encodes

he last enzyme of melatonin synthesis, have been found46–48], and variations have been found as well for mela-onin receptor genes [46,47,49]. CYP1A2 polymorphismsave been found in slow melatonin metabolisers, in whomelatonin levels are aberrant and initial response to melatonin

or sleep disappeared in a few weeks [50].

.1.2.4. Autism AND melatonin AND glutathione. WhereasubMed searches for “autism AND melatonin” and “autismND glutathione” each coincidentally yielded 72 citations,

nd “melatonin AND glutathione” yielded 803 citations,he search for “autism AND melatonin AND glutathione”ielded zero citations. This is interesting given the strongonnection of melatonin and glutathione metabolically, asiscussed above, alongside of the strongly established inter-st in both glutathione and melatonin in ASC research andncreasingly in clinical practice. Hopefully one contributionf an investigation of EMF/RFR links to ASCs will be toelp bring attention to this relationship, which may helpdentify potential environmental and physiological causes forow melatonin in those without pertinent mutations. Of perti-ence, tryptophan hydroxylase (TPH2) – the rate limitingnzyme in the synthesis of serotonin, from which mela-onin is derived – is extremely vulnerable to oxidation, andends to misfold when its cysteine residues are oxidized, withhe enzyme being converted to a redox-cycling quinoprotein51–54].

.1.3. Disturbed immune functionThere is by now a broad appreciation of the presence of

mmune disturbances in ASCs, to the point where there isn emerging discussion of ASCs as neuroimmune disorders55,56]. Research identifying immune features in ASCs spansrom genetics where risk genes have been identified to epi-enetics where altered expression of immune genes is beingeported as prominent in ASC epigenetics [57–59], and alsoncludes prenatal infectious and immune disturbances as riskactors for autism as well as other neurodevelopmental andeuropsychiatric diseases as well as other conditions such assthma [60–62]. Immune disturbances in infants and children


ith ASC are heterogeneous, with some but not all manifest-ng autoimmunity [63,64]. Anecdotally, recurrent infections common while on the other hand some get sick less oftenhan their peers. It is common for people with autism to

pobt


ave family members with immune or autoimmune diseases65]. The immune system is turning out to have an impor-ant role in brain development [66–68]. As mentioned, glialctivation associated with brain immune response has beendentified in a growing number of studies. Whether or notMF/RFR contributes to these features of ASCs causally,ased on the evidence below regarding immune impacts ofMF/RFR exposure [69], it is certainly plausible that suchxposures could serve as aggravating factors.

.1.3.1. Low-intensity exposures. The body’s immuneefense system is now known to respond to very low-ntensity exposures [70]. Chronic exposure to factorshat increase allergic and inflammatory responses on aontinuing basis is likely to be harmful to health, sincehe resultant chronic inflammatory responses can lead toellular, tissue and organ damage over time. Many chroniciseases are related to chronic immune system dysfunction.isturbance of the immune system by very low-intensity

lectromagnetic field exposure is discussed as a potentialnderlying cause for cellular damage and impaired healingtissue repair), which could lead to disease and physiologicalmpairment [71,72]. Both human and animal studies reporthat exposures to EMF and RFR at environmental levelsssociated with new technologies can be associated witharge immunohistological changes in mast cells as well asther measures of immune dysfunction and dysregulation.ast cells not only can degranulate and release irritating

hemicals leading to allergic symptoms; they are alsoidely distributed in the body, including in the brain and

he heart, which might relate to some of the symptomsommonly reported in relation to EMF/RFR exposure (suchs headache, painful light sensitivity, and cardiac rhythmnd palpitation problems).

.1.3.2. Consequences of immune challenges during preg-ancy. As mentioned, infection in pregnancy can alsoncrease the risk of autism and other neurodevelopmentalnd neuropsychiatric disorders via maternal immune acti-ation (MIA). Viral, bacterial and parasitic infections duringregnancy are thought to contribute to at least 30% of casesf schizophrenia [73]. The connection of maternal infec-ion to autism is supported epidemiologically, including in

Kaiser study where risk was associated with psoriasis andith asthma and allergy in the second trimester [65], and in

large study of autism cases in the Danish Medical registry74] with infection at any point in pregnancy yielding andjusted hazard ration of 1.14 (CI: 0.96 − 1.34) and whennfection occurred during second trimester the odds ratioas 2.98 (CI: 1.29 − 7.15). In animal models, while there

s much variation in study design, mediators of the immunempact include oxidative stress, interleukin-6 and increased


lacental cytokines [61,68,75]. Garbett et al. [76] commentedn several mouse models of the effects of MIA on the fetalrain that “The overall gene expression changes suggest thathe response to MIA is a neuroprotective attempt by the



dcgh

EEtstdhbp

2vanlmai

iswmtsiil2hfiimeutfTaib[ctcp

tsc

Snow

iurhtoim[ra

2

ramdastcewaotcbE

2betseduad[iwtaG


eveloping brain to counteract environmental stress, but at aost of disrupting typical neuronal differentiation and axonalrowth.” [76]. Maternal fetal brain-reactive autoantibodiesave also been identified in some cases [62,77–82].

Although we have evidence of immune impacts ofMF/RFR, the impact of repeated or chronic exposure toMF and RFR during pregnancy is poorly studied; could this

rigger similar immune responses (cytokine production) andtress protein responses, which in turn would have effects onhe fetus? Although this has been poorly studied, we do haveata that very low cell phone radiation exposures during bothuman and mouse pregnancies have resulted in altered fetalrain development leading to memory, learning, and attentionroblems and behavioral problems [83].

.1.3.3. Potential immune contributions to reactivity andariability in ASCs. Immune changes in ASCs appear to bessociated with behavioral change [84–88], but the mecha-isms are complex and to date poorly understood [89] andikely will need to be elucidated through systems biology

ethods that capture multisystem influences on the inter-ctions across behavior, brain and immune regulation [90],ncluding electrophysiology.

Two of the particularly difficult parts of ASCs are thentense reactivity and the variability in assorted symptomsuch as tantrums and other difficult behaviors. Childrenith ASCs who also have gastrointestinal symptoms andarked fluctuation of behavioral symptoms have been shown

o exhibit distinct innate immune abnormalities and tran-criptional profiles of peripheral blood monocytes [91]. Its worth considering EMF/RFR exposures could be operat-ng through related mechanisms so as to add to ‘allostaticoading’ in ways that exacerbate behavior. In Johansson006 and 2007 a foundation is provided for understandingow chronic EMF/RFR exposure can compromise immuneunction and sensitize a person to even small exposuresn the future [72,92]. Johansson discusses alterations ofmmune function at environmental levels resulting in loss ofemory and concentration, skin redness and inflammation,

czema, headache, and fatigue. Mast cells that degranulatender EMF and RFR exposures and substances secreted byhem (histamine, heparin and serotonin) may contribute toeatures of this sensitivity to electromagnetic fields [92].heoharides and colleagues have argued that environmentalnd stress related triggers might activate mast cells, causingnflammatory compromise and leading to gut–blood–brainarrier compromise, seizures and other ASC ASC symptoms93,94], and that this cascade of immune response and itsonsequences might also be triggered in the absence of infec-ion by mitochondrial fragments that can be released fromells in response to stimulation by IgE/anti-IgE or by theroinflammatory peptide substance P [95].


Seitz et al. [96] reviewed an extensive literature on elec-romagnetic hypersensitivity conditions reported to includeleep quality, dizziness, headache, skin rashes, memory andoncentration impairments related to EMF and RFR [96].

aFhg


ome of these symptoms are common in ASCs, whether orot they are due to EMF/RFR exposure, and the experiencef discomfort may be hard to document due to difficultiesith self-reporting in many people with ASCs.Johansson [72] also reports that benchmark indicators of

mmune system allergic and inflammatory reactions occurnder exposure conditions of low-intensity non-ionizingadiation (immune cell alterations, mast cell degranulationistamine-positive mast cells in biopsies and immunoreac-ive dendritic immune cells) [71,72]. In facial skin samplesf electro-hypersensitive persons, the most common findings a profound increase in mast cells as monitored by various

ast cell markers, such as histamine, chymase and tryptase97]. In ASCs, infant and childhood rashes, eczema and pso-iasis are common, and they are common in family memberss well [98].

.1.4. Alteration of and damage to cells in the brainBrain cells have a variety of ways of reacting to envi-

onmental stressors, such as shape changes, metaboliclterations, upregulation or downregulation of neurotrans-itters and receptors, other altered functionality, structural

amage, production of un-metabolizable misfolded proteinsnd other cellular debris, and apoptosis; these range along apectrum from adaptation to damage and cell death. Theseypes of alterations can be looked at in animals underontrolled conditions, but in human beings direct cellularxamination can only be done on surgical biopsy tissue –hich is hardly ever available in people with ASCs – or

fter death, at which point there has been a whole lifetimef exposures that are generally impossible to tease apart ifhere were even motivation to do so. This complicates theomparison of brain cell and tissue-related pathophysiologyetween what is seen in ASCs and what is associated withMF/RFR exposures.

.1.4.1. Brain cells. Impact of EMF/RFR on cells in therain has been documented by some of the studies that havexamined brain tissue after exposure, although the interpre-ation of inconsistencies across studies is complicated byometimes major differences in impact attributable to differ-nces in frequencies and duration of exposure, as well as toifferences in resonance properties of tissues and other poorlynderstood constraints on cellular response. These studiesnd methodological considerations have been reviewed inepth in several sections of the 2012 BioInitiative Report11,99]. A few examples of observations after exposure havencluded dark neurons (an indicator of neuronal damage), asell as alteration of neuronal firing rate [100], and upregula-

ion of genes related to cell death pathways in both neuronsnd astrocytes [101]. Astrocytic changes included increasedFAP and increased glial reactivity [102–105], as well as


strocyte-pertinent protein expression changes detected byragopoulou et al. [322] as mentioned above. Also observedas been a marked protein downregulation of the nerverowth factor glial maturation factor beta (GMF) which is



cagtdioc

hrtfiemadsfplbtbwd[

2ilaoslabirdfiawaratbaqattrw

Giccfnwwwcbm

lbfplhoeinhobAfhts

titttdra

pwrdrawrrt[


onsidered as an intracellular signal transduction regulator instrocytes, which could have significant impact on neuronal-lial interactions as well as brain cell differentiation andumor development. Diminution of Purkinje cell number andensity has also been observed, [106] including in two stud-es of the impacts of perinatal exposure [107,108]. Promotionf pro-inflammatory responses in EMF-stimulated microglialells has also been documented [109].

Neuropathology findings in ASCs have been varied andave been interpreted according to various frameworksanging from a regionalized approach oriented to iden-ifying potential brain relationships to ASC’s behavioraleatures [110] to identifying receptor, neurotransmitter andnterneuron abnormalities that could account for an increasedxcitation/inhibition ratio [111–115]. Studies have docu-ented a range of abnormalities in neurons, including

ltered cellular packing in the limbic system, reduced den-ritic arborization, and reductions in limbic GABAergicystems [116]. Over the past decade a shift has occurredrom presuming that all pertinent brain changes occurredrior to birth, to an acknowledgement that ongoing cellu-ar processes appear to be occurring not only after birthut well into adulthood [117]. One of the reasons forhis shift was the observation that head size (as well asrain weight and size) was on average larger in childrenith autism, and the head sizes of children who becameiagnosed with autism increased in percentile after birth118].

.1.4.2. Neuroinflammation, glial activation and excitotox-city. Although much attention has been paid in ASC brainiterature to specific regions manifesting differences in sizend activity in comparison to those without ASCs, there arether observations that are not strictly regional in nature,uch as more widely distributed scaling differences (e.g.arger brains, wider brains, increased white matter volume,long with altered functional connectivity and coherence toe discussed below). Recently more studies have appeareddentifying pathophysiological abnormalities such as neu-oinflammation, mitochondrial dysfunction and glutathioneepletion in brain tissue. Neuroinflammation was first identi-ed in a study of postmortem samples from eleven individualsged 5–44 who had died carrying an ASC diagnosis, inhich activated astrocytes and microglial cells as well as

bnormal cytokines and chemokines were found. Otheresearch has identified further astrocyte abnormalities suchs altered expression of astrocyte markers GFAP abnormali-ies, with elevation, antibodies, and altered signaling havingeen documented [119–121]. Increased microglia activationnd density as well as increased myeloid dendritic cell fre-uencies have also been documented [87,122,123], as hasbnormal microglial-neuronal interactions [124]. Recently,


hrough use of the PET ligand PK11105, microglial activa-ion was found to be significantly higher in multiple brainegions in young adults with ASCs [125]. Genes associatedith glial activation have been documented as upregulated.

smon


arbett et al measured increased transcript levels of manymmune genes, as well as changes in transcripts related toell communication, differentiation, cell cycle regulation andhaperone systems [126]. Voineaugu and colleagues per-ormed transcriptomic analysis of autistic brain and found aeuronal module of co-expressed genes which was enrichedith genetically associated variants; an immune-glial modulehich showed no such enrichment for autism GWAS signalsas interpreted as secondary [127], but this seems to involve

ircular thinking, since it implies that the primary cause muste genetic, which is an assumption deriving from a dominantodel, but is not a proven fact.Neuroinflammation also does not appear to be strictly

ocalized in a function-specific fashion, and it may contributeoth to more broadly distributed and more focal featuresor tissue-based reasons. It may be that brain regions witharticular prominence in ASCs may have distinctive cellu-ar characteristics—e.g. the amygdala [128–138], which mayave a larger or more reactive population of astrocytes [139]r the basal ganglia which may have greater sensitivity toven subtle hypoxia or perfusion abnormalities. In this caset may be the histology of these areas that makes them vul-erable to environmental irritants, and this may contribute toow environmental factors such as EMF/RFR might triggerr aggravate some of ASC’s features. More widely distributedrain tissue pathology be part of what leads to differences inSCs in brain connectivity. However these types of tissue-

unction relationships have been poorly investigated. Belyaevas intensively reviewed physical considerations includinghe contribution of tissue differences to variability in mea-ured EMF/RFR impacts [11].

Various signs of mitochondrial dysfunction and oxida-ive stress have also been identified in the brain. Findingsnclude downregulation of expression of mitochondrial elec-ron transport genes [140] or deficit of mitochondrial electronransport chain complexes [141], brain region specific glu-athione redox imbalance [142], and evidence of oxidativeamage and inflammation associated with low glutathioneedox status [143]. Oxidative stress markers were measureds increased in cerebellum [144].

Additional support for the presence of tissueathophysiology-based changes in brains of peopleith ASCs comes from the various studies documenting

eduction in Purkinje cell numbers [117,145–150], possiblyue to oxidative stress and an increased excitation/inhibitionatio that could potentially be acquired [150]. Also of notere changes in the glutamatergic and GABAergic systems,hich when imbalanced can disturb the excitation/inhibition

atio and contribute to seizure disorders; reductions in GABAeceptors as well as in GAD 65 and 67 proteins that catalysehe conversion of glutamate into GABA have been measured151–153]. A consensus statement on the cerebellum in ASCs


tated that, “Points of consensus include presence of abnor-al cerebellar anatomy, abnormal neurotransmitter systems,xidative stress, cerebellar motor and cognitive deficits, andeuroinflammation in subjects with autism” [150].



ftpoqrT(siafdcsttt6itwshdstt

eohbnsastmmia

ccidiciw

2aE

ttgdptesaicvcweuatldsdr

iiuoistfopoe

hdqetiowscnAips


Some indirect corroboration for these findings has comerom neuroimaging, where the initial hypothesis regardinghe tissue basis of the larger size of brains in so manyeople with autism – that it was due to a higher densityf neurons and more tightly packed axons – came underuestion with the emergence of contradictory findings, welleviewed a few years ago by Dager and colleagues [154].hese include reduced rather than increased density of NAA

n-acetylaspartate, a marker of neuronal integrity and den-ity that is produced in the mitochondria), reduced rather thanncreased fractional anisotropy suggesting less tightly packedxonal bundles [155–161] and greater rather than lower dif-usivity, all of which may be more consistent with lowerensity of tissue and tissue metabolites and more fluid, whichould be consistent with neuroinflammation and/or oxidativetress. The early postnatal development of such lower frac-ional anisotropy and increased diffusivity was measured inhe process of occurring recently, in the first large prospec-ive longitudinal imaging study of infants, who trended from

months to 2 years in the direction of these findings becom-ng more pronounced—but still with substantial overlap withhose infants who did not develop autism [160]. This trendas consistent with prior studies showing increase in head

ize after birth, and added some information about what wasappening in the brain to drive this size increase, althoughue to its methods it could only indirectly address the pos-ibility that emergence during the first few years of life ofissue pathophysiology disturbances such as neuroinflamma-ion might be contributing to these trends [162].

There is also substantial variability across many differ-nt types of brain findings. Of interest is that a numberf functional brain imaging and electrophysiology studiesave identified greater heterogeneity in response to stimulietween individuals in the ASC group than individuals in theeurotypical control group [163,164]. This may make moreense from the point of view of non-linear response—i.e.

disproportionality between output and input (as well astate and context sensitivity), in a pathophysiologically per-urbed brain system. Nonlinearity has also been a significant

ethodological issue in EMF/RFR research because linearethods of study design and data analysis have often been

nsensitive to effects, whereas nonlinear methods have beenrgued to show greater sensitivity [165–175].

It is important to entertain how environmental agentsould contribute individually and synergistically to brainhanges in ASCs, how different exposures may disturb phys-ology similarly or differently, and how these changes mayevelop over progress over time after the earliest periodsn brain development. EMF/RFR exposures could be pre-onceptional, prenatal or postnatal—or all of the above;t is conceivable that this could be the case in ASCs asell.


.1.4.3. Altered development. There is some evidence forltered brain and organism development in relation toMF/RFR exposure. Aldad et al. [83] exposed mice in-utero

bsuC


o cellular telephones, with resultant aberrant miniature exci-atory postsynaptic currents, and dose-responsive impairedlutamatergic synaptic transmission onto layer V pyrami-al neurons of the prefrontal cortex [83]. Lahijani exposedreincubated chicken embryos to 50 Hz EMFs, and madehe following morphological observations: “exencephalicmbryos, embryos with asymmetrical faces, crossed beak,horter upper beak, deformed hind limbs, gastroschesis,nophthalmia, and microphthalmia. H&E and reticulin stain-ngs, TEMS, and SEMs studies indicated EMFs wouldreate hepatocytes with fibrotic bands, severe steatohepatitis,acuolizations, swollen and extremely electron-dense mito-hondria, reduced invisible cristae, crystalized mitochondriaith degenerated cristae, myelin-like figures, macrophagesngulfing adjacent cells, dentated nuclei, nuclei with irreg-lar envelopes, degenerated hepatocytes, abnormal lipidccumulations, lipid droplets pushing hepatocytes’ nuclei tohe corner of the cells, abundant cellular infiltrations cel-ular infiltrations inside sinusoid and around central veins,isrupted reticulin plexus, and release of chromatin into cyto-ol, with partially regular water layers, and attributed cellamage to elevated free radical induced cell membrane dis-uptions” [5].

Although it is of great interest to characterize the changesn development associated with ASCs, it is also difficult to don human beings because at present diagnosis is not possiblentil at least 2–3 years after birth. By now there have been a lotf prospective studies of infants at high risk for autism, but then vivo brain imaging and electrophysiology data from thesetudies is only starting to be published, and so the for nowhe main sources of information are still inference backwardsrom post-mortem or imaging data, and animal models, bothf which have clear limitations. Thus it is impossible to seekrecise parallels here between what we know about the devel-pment of ASCs compared with the impacts of EMF/RFRxposures.

Nevertheless it is of real concern that such exposuresave elicited some of the brain tissue changes that have beenocumented in ASCs, both in early development and subse-uently. Already noted above is the question of whether highxposures of neonates to monitoring equipment may affecthe melatonin levels of neonates [32]; these exposures alsompact heart rate variability [258]. There are no studies yetn infants exposed to baby surveillance monitors or DECTireless phones. However there are good laboratory testing

tudies yielding actual measurements of these devices thatonclude: “Maximum incident field exposures at 1 m can sig-ificantly exceed those of base stations (typically 0.1–1 V/m).t very close distances the derived or reference exposure lim-

ts are violated for baby surveillance monitors and DECThones. Further, the authors conclude that, based on verytrictly controlled laboratory testing of everyday devices like


aby monitors and some cordless phones (W)orse case peakpatial SAR values are close to the limit for the public orncontrolled environments, e.g., IEEE 802.11b and Bluetoothlass I” [176].



ehct

2fiCifts[anmtscmbitomb

beuVoStifimtwneu

mfVlttvcuia

ari

2

wtantatmn

tltsibag[

lWntrk[pa

2aEpnlaosshwodoo


Even exposure of the fetus to laptop computer wirelessmissions through the pregnant mother’s use of this device oner lap may involve induction of strong intracorporeal electricurrent densities from the power supply possibly even morehan the device itself [177].

.1.4.4. Brain blood flow and metabolism. Cerebral per-usion and metabolism abnormalities have been identifiedn close to two dozen papers studying autistic cohorts.erebral perfusion refers to the quantity of blood flow

n the brain. Abnormal regulation of cerebral perfusion isound in a range of severe medical conditions includingumors, vascular disease and epilepsy. Cerebral hypoperfu-ion has also been found in a range of psychiatric disorders178]. Neurocognitive hypotheses and conclusions, as wells localization of perfusion changes, have been heteroge-eous across these papers. Hypoperfusion or diminishedetabolism has been identified in frontal regions [179–184],

emporal lobes [179,181,183–190], as well as a variety ofubcortical regions including basal ganglia [181,188,189],erebellum [188], limbic structures [184,191] and thala-us [188,189,191]—i.e. in a widely distributed set of

rain regions. Possibly because virtually all of these stud-es were oriented toward testing neuropsychological ratherhan pathophysiological hypotheses, there were no probesr tests reported to unearth the tissue level alterations thatight be underlying these reductions in blood flow in these

rains.While a large number of animal studies have documented

lood–brain barrier (BBB) abnormalities from EMF/RFRxposures, only a few PET studies have been performed eval-ating EMF exposure effects upon brain glucose metabolism.olkow et al. performed PET scans both with and with-ut EMF exposure (50 min of GSM-900 with maximumAR of 0.901 W/kg), and the participants were blinded to

he exposure situation [192]. A 7% increase in metabolismn the exposure situation compared to controls was identi-ed regionally on the same side of the head as where theobile phone was placed. The strength of the E-field from

he phones correlated positively with the brain activation,hich the authors hypothesized was from an increase in braineuron excitability. A subsequent smaller study by Kwont al. demonstrated not increased but decreased brain 18FDGptake after GSM-900 exposure [193].

Many possible mechanisms could be involved in theetabolic and perfusion abnormalities identified, ranging

rom altered neuronal activity that was hypothesized in theolkow et al. [192] 8FDG PET study to narrowing of vascu-

ar lumen in the setting of reduced perfusion. Underlyingissue pathophysiology-based phenomena could influencehe measurable metabolism and perfusion abnormalities,ia mechanisms such as excitotoxicity, cell stress response,


onstriction of capillary lumen by activated astrocytes, vol-me effects of vascular extravasation, subtle alterationsn blood viscosity due to immune or oxidative stress-ssociated blood chemical changes, with other possibilities

c[fE


s well. Differences in findings between papers couldelate at least in part to study design and nonlinearityssues.

.1.5. Electrophysiology perturbationsAt this stage the argument we hit a key pivot point, where

e look at how the alterations in molecular, cellular and sys-ems physiological function, which occur in the brain as wells in the body, impact the transduction into the electrical sig-aling activities of the brain and nervous system. Certainlyhe cells and tissues whose physiological challenges we havelready discussed provide the material substrate for the elec-rical activity. Although ASC behaviors are influenced by

any factors, they must in principle be mediated throughervous system electrophysiology.

If the cells responsible for generating synapses and oscilla-ory signaling are laboring under cellular and oxidative stress,ipid peroxidation, impaired calcium and other signaling sys-em abnormalities, then mitochondrial metabolism will fallhort, all the more so because of the challenges from themmune system which in turn be triggered to a major extenty environment. How well will synaptic signals be gener-ted? How well will immune-activated and thereby distractedlial cells be able to modulate synaptic and network activity?194–197].

At present we are in the early stages of being able to formu-ate these questions well enough to address them empirically.

e do know that microglial activation can impact excitatoryeurotransmission mediated by astrocytes [198]. We do knowhat the cortical innate immune response increases local neu-onal excitability and can lead to seizures [199,200]. We donow that inflammation can play an important role in epilepsy201]. We know less about lower levels of chronic or acuteathophysiological dysfunction and how they may modulatend alter the brain’s electrophysiology.

.1.5.1. Seizures and epilepsy. EEG signals in ASCs arebnormal on a variety of levels. At the most severe level,EGs show seizure activity. Although less than 50% of peo-le with ASCs clearly have seizures or epilepsy a much largerumber have indications of epileptiform activity, and an evenarger percent have subclinical features that can be noted by

clinical epileptologist though not necessarily flagged asf clinical concern. In addition to the association of someevere epilepsy syndromes (e.g. Landau Kleffner, tuberousclerosis) with autism, the risk of epilepsy is substantiallyigher in people with ASCs than in the general population,ith a large subset of these individuals experiencing seizurenset around puberty, likely in relation to aberrations in theramatic and brain-impactful hormonal shifts of that phasef life. Epileptic seizures can be both caused by and causexidative stress and mitochondrial dysfunction. Seizures


an cause extravasation of plasma into brain parenchyma202–206] which can trigger a vicious circle of tissue damagerom albumin and greater irritability, as discussed above.vidence suggests that if a BBB is already disrupted, there



wBc

iiemfoivfmh

pedbscescdl

2eiioatlcnarap

ucMw[dw(

umlv

insatnoiE

2rosaosapiioabocwrmbamc

mdba[aasduhs

2siti


ill be greater sensitivity to EMF/RFR exposure than if theBB were intact [207,208], suggesting that such exposuresan further exacerbate vicious circles already underway.

The combination of pathophysiological and electrophys-ological vulnerabilities has been explored in relation to thempact of EMF/RFR on people with epilepsy EMF/RFRxposures from mobile phone emissions have been shown toodulate brain excitability and to increase interhemispheric

unctional coupling [209,210]. In a rat model the combinationf picrotoxin and microwave exposure at mobile phone-likentensities led to a progressive increase in neuronal acti-ation and glial reactivity, with regional variability in theall-off of these responses three days after picrotoxin treat-ent [211], suggesting a potential for interaction between a

yperexcitable brain and EMF/RFR exposure.One critical issue here is nonlinearity and context and

arameter sensitivity of impact. In one study, rat brain slicesxposed to EMF/RFR showed reduced synaptic activity andiminution of amplitude of evoked potentials, while wholeody exposure to rats led to synaptic facilitation and increasedeizure susceptibility in the subsequent analysis of neo-ortical slices [212]. Another study unexpectedly identifiednhanced rat pup post-seizure mortality after perinatal expo-ure to a specific frequency and intensity of exposure, andoncluded that apparently innocuous exposures during earlyevelopment might lead to vulnerability to stimuli presentedater in development [213].

.1.5.2. Sleep. Sleep involves a profound change in brainlectrophysiological activity, and EEG abnormalities includ-ng disrupted sleep architecture figure in sleep challengesn ASCs. Sleep symptoms include bedtime resistance, sleepnset delay, sleep duration and night wakings; and sleeprchitecture can involve significantly less efficient sleep, lessotal sleep time, prolonged sleep latency, and prolonged REMatency [214,215], with these sleep problems being worse inhildren with ASCs who regressed than in those who didot regress into their autism [215]. EEG abnormalities havelso been associated with EMF/RFR exposure, including dis-upted sleep architecture as well as changes in sleep spindlesnd in the coherence and correlation across sleep stages andower bands during sleep [216,217].

Sleep disturbance symptoms are also common in both sit-ations. Insomnia is commonly reported in people who arehronically exposed to low-level wireless antenna emissions.ann and Rosch reported an 18% reduction in REM sleep,hich is key to memory and learning functions in humans

321]. In ASCs sleep difficulties are highly pervasive andisruptive not only to the affected individual but also to theirhole family due to the associated problems such as noise

e.g. screaming at night) and the need for vigilance.The multileveled interconnections involved in the mod-


lation of sleep exemplify the interconnectedness of theany levels of pathophysiology reviewed here: “Extracellu-

ar ATP associated with neuro- and glio-transmission, actingia purine type 2 receptors, e.g., the P2X7 receptor, has a role

spsp


n glia release of IL1 and TNF. These substances in turn act oneurons to change their intrinsic membrane properties andensitivities to neurotransmitters and neuromodulators suchs adenosine, glutamate and GABA. These actions changehe network input-output properties, i.e., a state shift for theetwork” [218]. With disturbance simultaneously at so manyf these levels, it is not surprising that sleep dysregulations nearly universal in ASCs, and common in the setting ofMF/RFR exposures.

.1.5.3. Quantitative electrophysiology. While clinicaleading of EEG studies is done visually, a growing numberf studies are examining EEG and MEG data using digitalignal processing analysis to find not only epilepsy, but alsobnormalities in the power spectrum, i.e. the distributionf power over the different frequencies present, withome studies showing impaired or reduced gamma-andctivity [219–221] and others showing reduction of spectralower across all bands [222] while still others showedncreased high-frequency oscillations [223]. Abnormalitiesn coherence and synchronization between various partsf the brain have been found [224–226], comparable tobnormal functional connectivity measured by fMRI [227]ut measurable with higher temporal resolution using EEGr MEG [228–232]. Several studies have identified reducedomplexity and increased randomness in EEGs of peopleith ASCs [233,234], as well as an increase in power but a

eduction in coherence [229,235]. Some electrophysiologicaletrics are emerging as potential discriminators between

rain signal from individuals with ASCs and those whore neurotypical, such as a wavelet-chaos-neural networkethodology applied to EEG signal [236] and reduced

ross-frequency coupling [237].EMF/RFR also has impacts at levels of brain function

easurable by these techniques. At various frequencies andurations of exposure it has been noted to impact alpha andeta rhythms [238], to increase randomness [170,239], tolter power, to modulate interhemispheric synchronization240], to alter electrical activity in brain slices [241] and tolter the patterns of coordination (spectral power coherence)cross the major power bands [242]. Bachman et al. [243]howed statistically significant changes in EEG rhythms andynamics occurred in between 12% and 20% of healthy vol-nteers [243]. In children, exposures to cell phone radiationave resulted in changes in brain oscillatory activity duringome memory tasks [97,102].

.1.5.4. Sensory processing. Symptomatic level issues withensory processing are highly prevalent in ASCs and cannclude hypersensitivity to external stimuli, hyposensitivityo internal sensations and difficulty localizing sensationncluding pain, and difficulty processing more than one


ensory channel at one time [244–246]. There is now electro-hysiological evidence of abnormalities at early (brainstem)tages of sensory processing, as well as in later stages ofrocessing that occur in the cortex [247]. Some studies have



sapn.

mtdAod

bicpi

odi[bm[e[nnu[

2neH[Gbsndat

[awtamsip

l

wsa

ibheaasmoetEds

(poMnwBtcaaibmt

2

2s

oa

ftofipm

ti

0 M.R. Herbert, C. Sage / Pa

hown lower and some longer latencies of response to anuditory stimulus [247]. Domains of perception where theerformance of people with ASCs is superior to that ofeurotypical individuals have been identified [248]. “It is

. . probable that several mechanisms and neuronal abnor-alities, most likely at multiple levels (from single neurons

hrough to inter-area connections), all contribute to varyingegrees to the abnormal sensory processing observed inSD. It is also likely that no single mechanism is unique tone sensory modality, which is why we see such a widelyistributed range of abnormalities across modalities” [247].

It is also possible that the mechanisms may not simplye neural—they may also be modulated by glial, metabolic,mmune, perfusional and other physiological processes byommon underlying cellular abnormalities, and by physicalroperties as well. Yet there are few studies focusing upon thenterface of tissue pathophysiology with electrophysiology.

Kenet et al. demonstrated environmental vulnerabilityf sensory processing in the brain by the exposure of ratams to noncoplanar polychlorinated biphenyls (PCBs), dur-ng gestation and for three subsequent weeks of nursing247]. The rat pups showed normal hearing sensitivity andrainstem auditory responses, but their tonotopic develop-ent of the primary auditory cortex was grossly distorted

249]. This study may be particularly relevant for EMF/RFRxposures, as Pessah, a co-author on this Kenet et al.249] paper, was cited earlier as documenting how theoncoplanar PCBs used in this experiment target calcium sig-aling as do EMF/RFR exposures—i.e. they both convergepon a common particularly critical cellular mechanism250,251].

.1.5.5. Autonomic dysregulation. Although there are a fairumber of negative studies regarding the impact of EMF/RFRxposure on the autonomic nervous system, increasedRV and autonomic disturbances have been documented

252–256]. Buchner and Eger [257], in a study in ruralermany of the health impacts of exposures from a newase station yielding novel exposure to EMF/RFR, saw aignificant elevation of the stress hormones adrenaline andoradrenaline during the first six months with a concomitantrop in dopamine, with a failure to restore the prior levelsfter a year and a half. These impacts were felt by the young,he old and the chronically ill, but not by healthy adults [257].

Neonate vulnerability was documented by Bellieni et al.258] who found that heart rate variability is adverselyffected in infants hospitalized in isolettes or incubatorshere ELF-EMF levels are in the 0.8 to 0.9 �T range (8

o 9 mG). Infants suffer adverse changes in heart rate vari-bility, similar to adults [258]. This electromagnetic stressay have lifelong developmental impacts, based on a study

howing that in-utero beta 2 agonist exposure can potentially


nduce a permanent shift in the balance of sympathetic-to-arasympathetic tone [259].

Meanwhile clinical observation and a growing body ofiterature support a major role for stress in ASCs [260–263],

ifipl


ith variability amongst individuals in the severity of thetress response but a tendency to have high tonic sympatheticrousal at baseline [264–269].

The impact of EMF/RFR exposure can also be greatlynfluenced by the stress system status of the individualeing exposed. Tore et al. sympathecotomized some ofis rats before exposure to GSM, to simulate cell phonexposure [207,208]. Sympathectomized rats, which were in

chronic inflammation-prone state, had more prominentlbumin leakage than sham-exposed rats. However in theympathecotmized rats who were exposed to GSM, albu-in leakage was greatly increased, to levels resembling those

bserved in positive controls after osmotic shock. Salfordt al. [99] suggest that “. . .more attention should be paido this finding, since it implicates that the sensitivity toMF-induced BBB permeability depends not only on powerensities and exposure modulations, but also on the initialtate of health of the exposed subject” [99].

The interconnection between stress and brain connectivityor coherence) in ASCs is brought out by Narayanan et al. in ailot study testing the impact of the beta blocker propranololn brain functional connectivity measured using functionalRI [270]. A fairly immediate increase in functional con-

ectivity was noted from propranolol—but not from nadololhich has the same vascular effects but does not cross theBB. Propranolol decreases the burden of norepinephrine,

hereby reducing the impact of stress systems on brain pro-essing, and the authors interpreted these effects as creatingn improvement of the brain’s signal-to-noise ratio [271],llowing it to utilize and coordinate more remote parts ofts networks. This suggests that stressors such as EMF/RFR,y adding biologically non-meaningful noise to the system,ight have the opposite effects, degrading coherent integra-

ion.

.2. De-tuning of the brain and organism

.2.1. Electromagnetic signaling, oscillation andynchrony are fundamental, and vulnerable

While electrophysiological activity is an intrinsic propertyf the nervous system, electromagnetic signaling is a vitalspect of every cell and of molecular structure.

All life on earth has evolved in a sea of natural low-requency electromagnetic (EM) fields. They originate inerrestrial and extraterrestrial sources. The ever-growing usef electric power over the last century has sharply modi-ed this natural environment in urban settings. Exposure toower-frequency fields far stronger than the natural environ-ent is now universal in civilized society. [272]Adey published some of the earliest scientific studies on

he “cooperativity” actions of cells in communication. Stud-es showing us that the flux of calcium in brain tissue and


mmune cells is sensitive to ELF-modulated radiofrequencyelds is actually telling us that some of the most fundamentalroperties of cells and thus of our existence can be modu-ated by EMF/RFR. “. . .in first detection of environmental



Esotctfwrt

itptfTconfpsaUt“oegimaipbslotmt

tsaacoaitaeem

oc(tml

umiao

vcc[

cantbatap

aoimccdmcbbw[ed

2

hsfbFt


M fields in tissues, there appears to be a general consen-us that the site of field action is at cell membranes. Strandsf protein are strategically located on the surface of cells inissue, where they act as detectors of electrical and chemi-al messages arriving at cell surfaces, transducing them andransmitting them to the cell interior. The structural basisor this transductive coupling by these protein strands isell known. Through them, cell membranes perform a triple

ole, in signal detection, signal amplification, and signalransduction to the cell interior” [272].

Oscillation is also a universal phenomenon, and biolog-cal systems of the heart, brain and gut are dependent onhe cooperative actions of cells that function according torinciples of non-linear, coupled biological oscillations forheir synchrony, and are dependent on exquisitely timed cuesrom the environment at vanishingly small levels [273,274].he key to synchronization is the joint actions of cells thato-operate electrically - linking populations of biologicalscillators that couple together in large arrays and synchro-ize spontaneously according to the mathematics describedor Josephson junctions (Brian Josephson, the 1993 Nobelrize winner for this concept). This concept has been profes-ionally presented in journal articles and also popularized in

book by Prof. Steven Strogatz, a mathematician at Cornellniversity who has written about ‘sync’ as a fundamen-

al organizing principle for biological systems [274,275].Organisms are biochemically dynamic. They are continu-usly subjected to time-varying conditions in the form of bothxtrinsic driving from the environment and intrinsic rhythmsenerated by specialized cellular clocks within the organismtself. Relevant examples of the latter are the cardiac pace-aker located at the sinoatrial node in mammalian heartsnd the circadian clock residing at the suprachiasmatic nuclein mammalian brains. These rhythm generators are com-osed of thousands of clock cells that are intrinsically diverseut nevertheless manage to function in a coherent oscillatorytate. This is the case, for instance, of the circadian oscil-ations exhibited by the suprachiasmatic nuclei, the periodf which is known to be determined by the mean period ofhe individual neurons making up the circadian clock. Theechanisms by which this collective behavior arises remain

o be understood” [274].The brain contains a population of oscillators with dis-

ributed natural frequencies, which pull one another intoynchrony (the circadian pacemaker cells). Strogatz hasddressed the unifying mathematics of biological cyclesnd external factors disrupt these cycles. Others have dis-ussed how this also applies to mitochondria: “Organisationf mitochondrial metabolism is a quintessential example of

complex dissipative system which can display dynamicnstabilities. Several findings have indicated that the condi-ions inducing instabilities are within the physiological range


nd that mild perturbations could elicit oscillations. Differ-nt mathematical models have been put forth in order toxplain the genesis of oscillations in energy metabolism. Oneodel considers mitochondria as an organised network of

wrpt


scillators and indicates that communication between mito-hondria involves mitochondrial reactive oxygen speciesROS) production acting as synchronisers of the energy sta-us of the whole population of mitochondria. An alternativeodel proposes that extramitochondrial pH variations could

ead to mitochondrial oscillations” [276].Mitochondrial dysfunction is important in ASCs but is

sually conceptualized in purely biochemical terms withoutentioning any oscillatory dimension to mitochondrial activ-

ty; it is conceivable that the interplay between biochemistrynd oscillation could figure significantly in the mechanismsf impact of EMF/RFR in ASCs.

The field of bioelectromagnetics has studied exposure toery low levels of electromagnetic frequencies. Exposuresan alter the magnetokinetics of the formation of a chemi-al bond, shifting the rate and amount of product produced272].

Not just chemical reactions but synchronous biologi-al oscillations in cells (pacemaker cells) can be disturbednd disrupted by artificial, exogenous environmental sig-als, which can lead to desynchronization of neural activityhat regulates critical functions (including metabolism) in therain, gut and heart and circadian rhythms governing sleepnd hormone cycles [277]. Buzsaki in his book Rhythms ofhe Brain says “rhythms can be altered by a wide variety ofgents and that these perturbations must seriously alter brainerformance.” [273].

Disturbance can get increasingly disruptive as more dam-ge occurs and more systems are thrown out of kilter andut of cooperativity. One can think of the kindling modeln which repeated induction of seizures leads to longer andore severe seizures and greater behavioral involvement. The

ombination of disruptive and stimulatory effects of biologi-ally inappropriate EMF/RFR exposures could contribute toisruption of synchronized oscillation and cooperativity at ayriad of levels but particularly in the brain, and this may

ontribute to the loss of coherence and complexity in therain in autism, as well as dysregulation of multiple otherodily systems. Strogatz points out that there are many moreays of being desynchronized than of being synchronized

274] (which may relate to ASC’s great heterogeneity). It hasven been suggested that autism itself could be due to brainesynchronization [278].

.2.2. Behavior as an “emergent property”From a pathophysiological point of view one might

ypothesize that a brain with greater indications of oxidativetress along with immune activation and mitochondrial dys-unction might generate different oscillatory activity than arain in which those pathophysiological features were absent.rom this vantage point it would make sense to propose that

he compromised whole body health status of at least many


ith ASCs would make it harder for them to maintain theesilience of their brain cells and brain activities in the face ofotentially disruptive exposures. Yet the investigation of howhis might occur remains a largely unexplored frontier. But



foE

wmIewios[baos

csecE[

tcw(yiw

faweaptmsa[la

3

3

tRd

ofgtamemm

3

Ectouvttnlwcalt

amHbttdldpflal

3

fdsi

tgo


rom the point of view of making sense of the brain impactf environmental challenges – including but not limited toMF-RFR – this investigation is crucial.

The pathophysiological perspective that guides this reviewould suggest a move away from considering the behavioralanifestations of ASCs as core, intrinsic, ‘hard-wired traits.’

nstead behaviors may be better understood as ‘outputs’ ormergent properties – what the brain and body produce –hen their physiological attributes are altered in these fash-

ons for whatever reasons—be they genetic, environmentalr many combinations of both [279–284]. Sleep and con-ciousness have also been considered ‘emergent properties’285,286]. Brain oscillatory activity is critical for organizingehavior, and it arises from cells and subcellular features thatre shaped by the environment and can act differently basedn their functional status as well as on account of externalensory or psychosocial stimuli.

In particular, (a) brain oscillatory activity is intimatelyonnected with underlying cellular, metabolic and immunetatus, (b) EMF/RFR is capable of perpetrating changes atach of these levels, and (c) problems at each of these levelsan make other problems worse. And as mentioned earlier,MF/RFR and various toxicants can co-potentiate damage

287–294], amplifying ‘allostatic load’.Put together, all of this implies that the combination of

hese EMF/RFR impacts may quite plausibly significantlyontribute both to how ASCs happen in individuals and tohy there are more reported cases of ASCs than ever before

1200–1500% increase in reported cases over the past 15–20ears, with studies showing that a substantial portion of thisncrease (45–65%) cannot be written off as artifact and mayell represent true increases [295,296]).The hopeful side of this framing of the problem comes

rom moving beyond the increasingly anachronistic idea thatutism is determined overwhelmingly by genetic code abouthich we can do little or nothing. An emerging model that

xplains much more of what we now know frames ASCss the dynamic, active outcomes of perturbed physiologicalrocesses – again, more like a chronic but changeable ‘state’han a ‘trait.’ In the latter model, one is empowered – and

otivated – to strongly reduce exposures and to make aggres-ive constructive environmental changes – particularly in dietnd nutrition, given their protective potency discussed above297]. In this way ‘allostatic load’ can be reduced, physio-ogical damage can be repaired, homeostasis can be restorednd resilience and optimal function can be promoted.

. Implications

.1. Exposures and their implications


Several thousand scientific studies over four decades pointo serious biological effects and health harm from EMF andFR [298,299]. These studies report genotoxicity, single-andouble-strand DNA damage, chromatin condensation, loss

3i2[


f DNA repair capacity in human stem cells, reduction inree-radical scavengers (particularly melatonin), abnormalene transcription, neurotoxicity, carcinogenicity, damageo sperm morphology and function, effects on behavior,nd effects on brain development in the fetus of humanothers that use cell phones during pregnancy. Cell phone

xposure has been linked to altered fetal brain develop-ent and ADHD-like behavior in the offspring of pregnantice [83].

.1.1. Exposures have outpaced precautionsThere is no question that huge new exposures to

MF/RFRs have occurred over the past few decades. As dis-ussed extensively in the BioInitiative 2012 update [299],here is much concern that regulations to date have been basedn a very limited sense of the pertinent biology, and partic-larly that limiting concern to thermal impacts is no longeralid since there is a wealth of evidence by now that non-hermal impacts can be biologically very powerful. Only inhe last two decades have exposures to RFR and wireless tech-ologies become so widespread as to affect virtually everyiving space, and affect every member of societies around theorld. Even as some disease patterns like brain tumors from

ell phone use have become ‘epidemiologically visible’, therere no comprehensive and systematic global health surveil-ance programs that really keep up to report EMF/RFR healthrends [300].

The deployment of new technologies is running ahead ofny reasonable estimation of possible health impacts and esti-ates of probabilities, let alone a solid assessment of risk.owever, what has been missing with regard to EMF/RFR haseen an acknowledgement of the risk that is demonstrated byhe scientific studies. There is clear evidence of risk, althoughhe magnitude of the risk is uncertain, and the magnitude ofoing nothing on the health effects cost to society is simi-arly uncertain. This situation is very similar to our history ofealing with the hazards of smoking decades ago, where theower of the industry to influence governments and even con-icts of interest within the public health community delayedction for more than a generation, with consequent loss ofife and enormous extra health care costs to society. [301].

.1.2. The population’s exposure has increasedThe very rapid global deployment of both old and new

orms of emerging wireless technologies in the last twoecades needs aggressive evaluation from a public health per-pective, given the range of physiological impacts describedn Section 2.

In the United States, the deployment of wireless infrastruc-ure (cell tower sites) to support cell phone use has acceleratedreatly in the last decades. The Cellular Telephone Institutef America (CTIA) estimated that in 1997 there were only


6,650 cell sites in the US; but increased rapidly to 131,350n June 2002; 210,350 in June 2007 and 265,561 in June012 [302,303]. About 220,500 cell sites existed in 2008303–305]. These wireless facilities for cellular phone voice



amwRpce

gpect1m1jsi

tiwm

h[2TapR

(t(ehco

3h

othesla[heCa

aw

ilfhleaefivea[

l[mo

fiacaRa

mtnppDamhfa

3g

hdlbwb“


nd data transmission produce RFR over broad areas in com-unities and are an involuntary and unavoidable source ofhole-body radiofrequency radiation exposure. Other newFR exposures that did not exist before are from WI-FI accessoints (hotspots) that radiate 24/7 in cafes, stores, libraries,lassrooms, on buses and trains, and from personal WI-FInabled devices (iPads, tablets, PDAs, etc).

Not surprisingly, the use of cell phones has a parallelrowth trend. In the late 1980s and early 1990’s, only a fewercent of the US population were cell phone users. By 2008,ighty-four percent (84%) of the population of the US ownedell phones. CTIA reports that wireless subscriber connec-ions in the US increased from 49 million in June 1997 to35 million in June 2002 to 243 million in June 2007 to 322illion in June 2012 [302,303]. This represents more than a

00% penetration rate in the US consumer market, up fromust a few percent in the early 1990’s. The number of wirelessubscribers in June 1997 was 18%; in June 2002 it was 47%;n June 2007 it was 81% and in June 2012 it was 101%.

The annualized use of cell phones in the US was estimatedo be 2.23 trillion minutes in 2008 and 2.296 trillion minutesn 2010 [303]. There are 6 billion users of cell phones world-ide in 2011 up from 2.2 billion in 2008 and many millionore users of cordless phones.The number of US homes with only wireless cell phones

as risen from 10.5% in 2007 to 31.6% in June of 2012302,303]. There are no statistics for June 1997 nor for June002, since landline (non-wireless) phone use predominated.he shift to wireless communications, more minutes of use,nd reliance on cell and cordless phones rather than cordedhones is an extremely revealing measure of new EMF andFR exposures for both adults and children.

The prevalence of autism has risen in parallel from one1) in 5000 (1975) to 1 in 2500 (1985) to 1 in 500 (1995)o 1 in 250 (∼2001) to 1 in 166 (∼2004) to 1 in 88∼2008) to 1 in 50 (∼2013). All reflected birth cohorts bornarlier1,2. Further research into autism prevalence studiesave debunked the initial contention that higher numbersould be explained away by better diagnosis and broadeningf diagnostic criteria3-6.

.1.3. Infants, children and childbearing families areighly exposed and vulnerable

The spread of cell towers in communities, often placedn pre-school, church day-care, and school campuses, meanshat young children may have hundreds of thousands of timesigher RFR exposures in home and school environments thanxisted even 20–25 years ago. In addition, the nearly universalwitch to cordless and cell phones, and away from cordedandline phones, means that people are experiencing closend repetitive exposures to both EMF and RFR in the home306]. Wireless laptops and wireless internet in schools, and


ome offices and for homework mean even more chronicxposures to RFR, a designated IARC 2B Possible Humanarcinogen [307,308]. The great utility of handheld devicess communication aids and engaging sources of information

taiv


nd satisfaction for people on the autism spectrum may comeith a concerning biologically harmful underbelly.Exposures prior to conception or during pregnancy and

nfancy can come from faulty wiring, proximity to powerines, or high-frequency transients from a proximate trans-ormer on a utility pole. Sources of pulsed RFR inside theome include an electronic baby monitor in the crib, a wire-ess router in the next room, a DECT phone that pulses highmissions of RFR on a continuous basis 24/7, or conversion toll compact fluorescent bulbs that produce significant ‘dirtylectricity’ for occupants due to low-kilohertz frequencyelds on electrical wiring and in ambient space. Sick andulnerable infants in neonatal intensive care units are heavilyxposed from being surrounded by equipment, with neg-tive metabolic and autonomic consequences documented32,258].

Wireless phones and laptops exposures produce extremelyow frequency pulses from the battery of the wireless device301,306,309] and the exposures to pulsed radiofrequencyicrowave radiation when the wireless device is transmitting

r receiving calls and emails.Especially since EMF/RFR exposures are already classi-

ed as IARC 2B Possible Human Carcinogens, we should bectively investigating these sources of damage to DNA thatould reasonably result in ‘de novo mutations’ but also beware that common environmental exposures from EMF andFR might play a role in the higher rates of concordance forutism (ASD) among twins and siblings.

Researchers also should be aware that common environ-ental exposures from EMF and RFR might play a role in

he higher rates of autism (ASD) among twins and siblings,ot solely because of maternal use of wireless devices duringregnancy and paternal sperm exposure to wireless deviceseri-conception; but also because such oxidative damage toNA can occur at levels introduced into the world of the fetus,

nd young developing infant and child via baby surveillanceonitoring devices in the crib and wireless devices in the

ome. The deployment of technologies poses risks to humanertility and reproduction capacity, to the fetus, to childrennd adults [301].

.1.4. ASC risk and genomic damage to futureenerations

Barouki and Grandjean make a persuasive case that publicealth interventions are critically needed in early childhoodevelopment to prevent adult diseases that appear decadesater [310]. Although they do not include EMF or RFRut only chemicals, they do say that physiological stressors,hich EMF and RFR certainly have been established, shoulde reduced during critical development windows. They say:The current pandemic of non-communicable diseases and


he increased prevalence of important dysfunctions demandn open interrogation of why current interventions appearnsufficient. We now know that disease risk can be inducedery early in the life course and that it is modifiable by



nd

toardpc

3

iapsc

aeoaotebmaodaimEihwompd

rmtapdsnsmlp

ba

3

cpsmaAbtifim(iasabbmfkabibpahbhEpmpotwp

ailP[li


utrients and environmental chemical exposures (along withrugs. infections, and other types of stresses)” [310].

Public health interventions are warranted now to protecthe genetic heritage of humans, as well as the other stocksf genetic material in wildlife and plants in the face of whatppears to be on-going impairment of these genomes. Theisk of genomic damage for future generations is sufficientlyocumented to warrant strong preventative action and newublic safety limits that observe EMF/RFR levels shown toause adverse effects.

.1.5. De-tuning the organismGenetic mutations may lead to cancer and other diseases

n the present and future generations, but the exposures thatre capable of creating genotoxic impacts also compromisehysiological function. Even genotoxicity can have not onlypecific but also non-specific effects due to molecular ineffi-iencies, misfolded proteins, and cellular debris [311,312].

In the setting of autism, a baby gestated or developings a neonate in a milieu with excessively elevated EMF/RFRxposures is vulnerable to interference with the normal devel-pment processes, including the organization of informationnd experience in the brain. This baby’s environment alsoften includes nutritional insufficiencies (processed dena-ured pesticide-laden food low in antioxidants, minerals andssential fatty acids essential to cellular protection). Theaby’s gestational period may have been complicated by theother’s own health issues such as conditions like obesity

nd diabetes [313] which converge upon on inflammation,xidative stress and other common forms of physiologicalysregulation. The exquisite ‘tuning up’ of the brain and bodys it develops will integrate and respond to the environmentalnputs it receives, and is particularly sensitive to environ-

ental miscues (whether chemical like endocrine disruptors,MF/RFR which can be both chemically and electromagnet-

cally disruptive, or other environmental conditions whetherostile or nurturing). To the extent that the baby is burdenedith more disorganized or hostile cues than nurturing andrganizing cues, that baby may lose resiliency and becomeore physiologically vulnerable –perhaps approaching a tip-

ing point into decompensation such as autistic regression orevelopment of other chronic disease processes.

From a systems point of view, the phenomenon of ‘autisticegression’ can be understood as occurring after an accu-ulation of multisystem signaling interference leading to a

ipping point of loss of some vital systems synchronizationnd increase in randomization. EMF/RFR exposures couldlausibly contribute both to this vulnerability and to theecompensation/desynchronization process – as could othertressors s

autism and emf? plausibility of a pathophysiological link ... › file › 7520958031.pdfautism...

Documents