's thoughts about XMRV=0A=0AHow XMRV Retrovirus Findings May Fit With=0AThe=
Amygdala Hyperarousal Model For ME/CFS=0A =0AAshok Gupta MA(Cantab), MSc =
=0A =0Ainfo@guptaprogramme.com =0A =0AABSTRACT=0A =0ABackground=0A =0ARecen=
tly=0Ascientists from the Whittemore=0APeterson Institute (WPI) led by Dr M=
ikovits, claim to have discovered a=0Aretroviral link to ME/CFS. This paper=
reviews the literature to show how these=0Afindings may fit with the Amygd=
ala Hyperarousal Model for ME/CFS.=0A =0AMethods=0A =0AA=0Ageneral review o=
f the evidence on XMRV was conducted, as well as evidence on=0Aopportunisti=
c infections. This evidence was then rationalised with the evidence=0Aon Am=
ygdala Hyperarousal in ME/CFS as well as other disorders.=0A =0AResults =0A=
=0AThe=0Areview tentatively asserts that XMRV may simply represent one of =
many=0Aopportunistic infections, and that immune system abnormalities may a=
ctually be=0Acaused by Th1/Th2 imbalance caused by autonomic dysfunction, r=
ather than by=0AXMRV directly.=0A =0AConclusions=0AFurther=0Aresearch is re=
quired to validate the idea that XMRV actually contributes to=0AME/CFS, rat=
her than simply being one of many opportunistic infections found in=0AME/CF=
S.=0A =0AIntroduction=0A =0ARecently=0Ascientists from the Whittemore=0APet=
erson Institute (WPI) led by Dr Mikovits, claim to have discovered a=0Aretr=
oviral link to ME/CFS (1). This pioneering research has identified a=0Aretr=
ovirus called XMRV, shown to be active in two-thirds of patients, and=0Aant=
ibodies for the virus were present in 95% of patients. =0A =0AMikovits'=0At=
eam said further research must now determine whether XMRV directly causes C=
FS,=0Ais just a passenger virus in the suppressed immune systems of suffere=
rs, or a=0Apathogen that acts in concert with other viruses that have been =
implicated in=0Athe disorder by previous research.=0A =0AThe=0Apurpose of t=
his paper is to hypothesise how these findings may fit with the=0AAmygdala =
Hyperarousal Model for ME/CFS (2). =0A =0AMethods=0A =0AA=0Ageneral review =
of the evidence on XMRV was conducted, as well as evidence on=0Aopportunist=
ic infections. This evidence was then rationalised with the evidence=0Aon A=
mygdala Hyperarousal in ME/CFS as well as other disorders. There were three=
=0Abroad hypotheses developed, and the review of the literature was designe=
d to=0Acome to a conclusion as to which hypothesis was most supported.=0A =
=0AThree Potential Hypotheses =0A =0AOverall=0Athere are three broad hypoth=
eses that we can infer from the findings so far, as=0Aper Mikovits=E2=80=99=
statement:=0A =0A=091. The XMRV virus directly causes the symptoms of ME/C=
FS=0A=092. The XMRV virus indirectly causes ME/CFS by suppressing the immun=
e system in concert with other pathogens, allowing opportunistic viruses to=
flourish causing the symptoms of ME/CFS=0A=093. The XMRV virus is simply a=
n opportunistic infection which establishes itself due to general suppressi=
on and dysfunction of the immune system from another source. This general i=
mmune dysfunction may be caused by autonomic dysfunction as a result of amy=
gdala hyperarousal. =0A =0ADiscussion=0A =0AThere=0Aare two broad aspects t=
o the immune system, TH1 and TH2. TH1 involves Natural=0AKiller (NK) cells =
whose job it is to identify and destroy viruses. The TH2 side=0Aof the immu=
ne system involves, amongst other things, antibodies which respond=0Ato thr=
eats. There is evidence in the literature that patients with ME/CFS are=0A=
=E2=80=9CTH2=E2=80=9D biased, i.e. the TH2 aspect of the immune system is o=
ver-activated, causing=0Asuppression of the TH1 side and high levels of inf=
lammatory cytokines; patients=0Ahave lower Natural Killer (NK) cell immunit=
y. This bias may mean that=0Aopportunistic viruses and bacterial infections=
can no longer be kept at bay=0Aeffectively by the TH1 side of the system. =
=0A =0ARNase=0AL conducts a function of holding the virus at bay until NK c=
ells are available=0Ato eradicate the pathogen, however even the RNase L=E2=
=80=99s ability to perform this=0Afunction can be compromised over time if =
TH2 dominates for too long. RNase L=0Adysfunction was also reported in the =
prostate cancer cases of XMRV, although=0Alater research has not found a ge=
netic link. In ME/CFS, any suspected Rnase L=0Adeficiency many simply be du=
e to chronic TH2 dominance. If TH2 dominates for=0Atoo long, it can be hypo=
thesised that viruses such as HHV-6, Epstein Barr Virus=0A(EBV), CMV and Pa=
rvovirus B19 can flourish, as well as bacterial infections=0Asuch as mycopl=
asma and chlamydia=0Apneumonia. =0A =0AIt has been=0Aestablished that the m=
ajority of neurodegenerative disease, fatiguing illnesses=0Aand neurobehavi=
oral disease patients have chronic bacterial and viral=0Ainfections. (3). I=
n fact the WPI research claimed to have found higher levels=0Aof XMRA in =
=E2=80=9Catypical=E2=80=9D MS and Autism.=0A =0AThe XMRV virus may=0Asimply=
represent one of many viral and bacterial infections present in the=0Abloo=
d of ME/CFS patients, and that many of these previous infections (including=
=0AEBV) had been previously prematurely suspected as the root cause of ME/C=
FS.=0AThere have been many previous studies which have shown similar result=
s to those=0Afound for XMRV. As an example, a 2002 study found that out of =
261 patients with=0AME/CFS, 68.6% of patients had active mycoplasma bacteri=
al infection present=0Acompared to 5.6% of controls, a similar result to th=
at found for XMRV (4). A=0A2003 study found that 30.5% of CFS patients had =
active HHV-6 virus present, but=0Aonly 9% of controls (5). For Chlamydia pn=
eumoniae it was 7.8% of CFS patients=0Acompared to 1% of controls (5). For =
Parvovirus B19, it was detected in 40% of=0ACFS patients but only 15% of co=
ntrols (6). =0A =0AWhat=0Awas interesting in the 2003 (5) study was that ha=
ving one particular infection=0Adid not predict the likelihood of having an=
other infection. This may indicate=0Athat the infections themselves are not=
cumulatively affecting the strength of=0Athe immune system to fight off op=
portunistic infections, but that a general=0Aimmune deficiency is allowing =
particular types of infections to establish=0Athemselves in a pattern uniqu=
e to each patient. =0A =0AAccording=0Ato the WPI research, 4% of healthy co=
ntrols had active XMRV virus in their=0Ablood (versus 67% of ME/CFS patient=
s), which is similar to the levels of active=0Amycoplasma infection in heal=
thy controls. Therefore presence of active XMRV=0Adoes not necessarily pred=
ict ME/CFS, and would not support the first=0Ahypothesis. If 4% of the US =
=0Apopulation were found to have active XMRV pathogen in their blood, this =
would=0Aamount to over 10 million people. Yet there is no evidence that XMR=
V causes=0Acancer where it is active, or that it has any effect on health. =
It is merely a=0Asuspected link in 23% of prostate cancer cases where it is=
found in 1% of=0Asurrounding tissue, with no causal link established at th=
is stage; one=0Ahypothesis is that its presence is simply linked to immune =
deficiency. Once=0Aagain, the XMRV virus was found in 6% of benign biopsies=
showing that its=0Apresence may be widespread in the general USA populatio=
n. Further research=0Ahowever is critical. =0A =0AIt may=0Abe that XMRV may=
be a localised virus to the USA, especially since a recent=0Areport from G=
ermany (7) found that out of 589 biopsies carried out on prostate=0Acancer =
cases, not a single patient showed any evidence of XMRV. They conclude tha=
t =E2=80=9COne possible reason for=0Athis could be a geographically restric=
ted incidence of XMRV infections.=E2=80=9D (7)=0AThe WPI research was carri=
ed out on documented ME/CFS outbreaks which represent=0Aa very small percen=
tage of ME/CFS cases.=0A =0AIf 95%=0Aof ME/CFS patients show antibodies to =
XMRV (yet unpublished data from Mikovits=E2=80=99=0Ateam), yet only 67% sho=
w active virus, this could indicate that a third of=0AME/CFS patients no lo=
nger had the active XMRV virus, yet still were suffering=0Afrom ME/CFS. If =
this is confirmed to be true, then the first hypothesis would=0Aseem redund=
ant, and XMRV could only be the root cause of ME/CFS if the second=0Ahypoth=
esis were correct, i.e. that XMRV had adversely affected the long term=0Ape=
rformance of the immune system. Alternatively the presence of antibodies=0A=
could imply that the virus is still active in more that 67% of patients, bu=
t=0Ahad not been picked up through previous methods. It would also be inter=
esting=0Ato know the percentage of healthy controls that tested positive fo=
r XMRV=0Aantibodies which has not been revealed.=0A =0AOne=0Away the link w=
ithin the second hypothesis could be established, is to test=0Awhether the =
presence of active XMRV predicted higher levels of other=0Aopportunistic vi=
ruses and bacterial infections. According to the second=0Ahypothesis, prese=
nce of active XMRV should predict suppression of the immune=0Asystem and fu=
rther opportunistic pathogens. However, as previously mentioned,=0Athere is=
little evidence that having one opportunistic pathogen in ME/CFS=0Apredict=
s the likelihood of having another, therefore cumulative immune=0Adeficienc=
y caused by XMRV attack is unlikely, otherwise previous studies would=0Ahav=
e highlighted this finding in the blood of ME/CFS patients. This once again=
=0Aseems to tentatively support the third hypothesis, in that XMRV may simp=
ly be a=0Apassive opportunistic virus similar to other herpes viruses such =
as HHV-6 and=0AEBV. Even if presence of XMRV did predict the likelihood of =
secondary=0Ainfection, it would still be difficult to infer causality. =0A =
=0A =0AThe Amygdala Hyperarousal Model and XMRV=0A =0AThe=0AAmygdala Hypera=
rousal model states that ME/CFS and Fibromyalgia may becaused by a=0Acondit=
ioned trauma in the amygdala following an acute viral, bacterial or=0Aphysi=
cal insult, combined with psycho-social distress (2). Once the classical=0A=
and operant conditioning has occurred, the amygdala in association with the=
=0Ainsula, become hyper-sensitive to signals from both the body and externa=
l=0Astimuli, and magnify both the extent and frequency of the incoming stim=
uli in=0Athe sensory thalamus and cortex. This then produces the ME/CFS vic=
ious circle,=0Awhere an unconscious sensitivity reaction to symptoms causes=
chronic stimulation=0Aof the HPA axis, immune reactivation/dysfunction, ch=
ronic sympathetic=0Astimulation leading to autonomic dysfunction, mental an=
d physical exhaustion,=0Aallergies, compromised detoxification, mitochondri=
a dysfunction, oxidative=0Astress and a host of other distressing symptoms =
and secondary complications.=0AAnd these are exactly the symptoms that the =
amygdala, the insula, and=0Aassociated limbic structures are trained to mon=
itor and respond to,=0Aperpetuating a vicious circle. =0A =0AThe=0AAmygdala=
model predicts that there is likely to be TH2 dominance over TH1 due=0Ato =
overstimulation of the sympathetic nervous system. This has already been=0A=
extensively documented in many studies of sympathetic overactivity due to a=
cute=0Astress and anxiety (8, 9, 10). Although an ME/CFS patient may not ne=
cessarily=0Amentally experience acute stress or anxiety, the model predicts=
that the=0Aphysiological aspects of the stress response are chronically en=
gaged, thereby=0Acausing disruption in various systems of the body includin=
g the immune system.=0ATH2 will dominate over TH1, causing a likely increas=
e in opportunistic viral=0Aand bacterial pathogens such as XMRV, as well as=
an increase in allergic=0Aresponses due to TH2 over-sensitivity, as well a=
s increased propensity to=0Aproduce antibodies. There is extensive evidence=
of increased chemical and=0Aphysical sensitivities in patients. The parasy=
mpathetic system is suppressed,=0Acompromising digestive and detoxifying pr=
ocesses in the body.=0A =0AOnce=0Athe sympathetic autonomic system is condi=
tioned to be chronically activated, it=0Ais very difficult for autonomic an=
d Th1/Th2 balance to be restored.=0AOpportunistic viruses and bacterial inf=
ections flourish, in themselves causing=0Afurther symptoms in addition to t=
he ones caused directly by amygdala=0Ahyperarousal. =0A =0AIn the field of =
Psychoneuroimmunology,=0Amany studies have shown that excessive sympathetic=
activity can have an=0Aimmuno-suppressive effect on the body via Neuropept=
ide Y release, thereby=0Apointing to another pathway by which excessive sym=
pathetic stimulation may=0Acompromise immune function. A study by Fletcher =
et al (11) seems to model this=0Aeffect in ME/CFS patients. ME/CFS patients=
tend to show low natural killer cell=0Acytotoxicity, (NKCC), and it is kno=
wn that Neuropeptide Y (NPY) suppresses=0ANKCC. NPY is concentrated in the =
sympathetic nerve endings, and following=0Astress, is released together wit=
h adrenaline and noradrenalin. Fletcher et al=E2=80=99s=0Astudy tested the =
hypothesis that elevation of NPY occurs in ME/CFS and that the=0Aelevation =
of NPY is associated with severity of clinical symptoms. They found=0Athat =
NPY was significantly associated with severity of clinical symptoms, and=0A=
that NPY could be a potential bio-marker for ME/CFS. This shows a direct li=
nk=0Abetween levels of symptoms, and sympathetic overactivity where the mos=
t likely=0Aculprit is amygdala hyperarousal. =0A =0AThe WPI team are=0Awork=
ing on the hypothesis that many of the symptoms of ME/CFS may be caused by=
=0AXMRV attacking the cells of the immune system, thereby compromising immu=
nity.=0AHowever, there is potentially another culprit for reduced immunity =
as=0Adiscussed: chronic sympathetic activity. This has already been shown t=
o=0Asuppress general immunity and especially TH1 function, whilst at the sa=
me time=0Acausing TH2 dominance, inappropriately stimulating allergic respo=
nses in the immune=0Asystem. (8,9,10)=0A =0AThere is a=0Apossibility that X=
MRV somehow directly affects TH1 function, and simultaneously=0Adirectly af=
fects the autonomic nervous system, however there is no evidence of=0Athis =
and further research is required.=0A =0AWhat=0Ais most interesting about th=
e XMRV announcement is that the team also found=0Ahigher levels of XMRV in =
people with Autism and atypical Multiple Sclerosis (as=0Ayet unpublished). =
A study by=0ANicholson et al (12) looked at the presence of co-infections i=
n ME/CFS patients=0Aversus patients with Autism Spectrum Disorders. The stu=
dy found that both=0Agroups had higher incidence of multiple, systemic bact=
erial and viral=0Ainfections compared to controls, but interestingly, both =
ME/CFS and Autism=0Apatients had very similar levels of active infections w=
hen compared to one=0Aanother. Autism is a disorder where sustained amygdal=
a hyperarousal is accepted=0Aas a model for partly explaining the disorder =
(13), so once again there is=0Atentative support for the amygdala=E2=80=99s=
role in ME/CFS.=0A =0AThis is a very=0Aimportant finding because of the di=
fferences and commonalities between ME/CFS=0Aand Autism. We would not neces=
sarily expect any commonalities with respect to=0Ainfections as the conditi=
ons seem to have a very different neurobiological=0Abasis. However, the com=
mon factor may be sustained amygdala hyperarousal, but=0Adue to very differ=
ent causes. The sustained amygdala hyperarousal in Autism may=0Adevelop in =
early childhood due to socio-biological reasons, whereas sustained=0Aamygda=
la hyperarousal in ME/CFS may develop as a result of several co-curring=0Aa=
cute factors triggering a conditioned trauma in the amygdala later in life.=
=0ABoth conditions then result in a unique pattern of chronic sympathetic=
=0Astimulation, but for very different reasons, causing similar levels and =
types of=0Aopportunistic viral and bacterial infections. It is likely that =
the level of=0Ahyperarousal in ME/CFS is much more severe and dwarfs that o=
f Autism, but both=0Aconditions exhibit enough of a chronic long term sympa=
thetic response to result=0Ain opportunistic infections. =0A =0ASeveral rec=
ent=0Astudies have reported abnormalities in amygdala volume in Autism. (14=
,15).=0AFurthermore, most studies in Autism show abnormal processing by the=
brain and=0Athe amygdala in response to emotional stimuli, and continual b=
ackground amygdala=0Ahyperarousal is once again suspected (13). Further res=
earch is required to test=0Aany abnormalities in the function of the amygda=
la in patients with ME/CFS,=0Awhich may not show up on standard brain scans=
. It would be interesting to=0Aunderstand the levels of active XMRV virus a=
nd antibodies in Autism.=0A =0AFinally there are=0Aa host of physical chang=
es in the brains and bodies of ME/CFS patients which=0Ahave been well docum=
ented and which are consistent with the concept of chronic=0Aautonomic dysf=
unction. These findings cannot be ignored as a result of the XMRV=0Aannounc=
ement, but need to fit within an integrated hypothesis. =0A =0AThere are ma=
ny=0Apatients who do recover from ME/CFS and Fibromyalgia over time, and ye=
t may not=0Ahave taken any kind of anti-viral medication. This may indicate=
that changes=0Athat a patient themselves initiate, may be enough to streng=
then the immune=0Asystem, bring the body back to homeostasis, and eradicate=
opportunistic=0Ainfections such as the suspected XMRV.=0A =0AHow Controlli=
ng the Amygdala=E2=80=99s Reactions May Reduce=0AXMRV and other Opportunist=
ic Pathogen Levels=0A =0AControlling=0Athe amygdala=E2=80=99s reactions inv=
olves reducing the stimulation of the sympathetic=0Anervous system by creat=
ing a projecting neurone from the prefrontal cortex to=0Athe amygdala to co=
ntrol its over-zealous reactions. This in turn would reduce=0Athe sympathet=
ic overload, allowing TH1/Th2 ratios to gradually return to=0Anormal, allow=
ing the body=E2=80=99s own immune system to fight off opportunistic=0Ainfec=
tions such as the suspected XMRV. Symptoms from amygdala hyperarousal=0A(in=
cluding changes in the brain), and symptoms from opportunistic infections=
=0Awould then subside, as well as any allergic effects of TH2 dominance. =
=0A =0AThe=0Aaim of these types of therapies is to bring homeostasis back t=
o the body after=0Aa period of imbalance, where the balance between the sym=
pathetic and=0Aparasympathetic systems returns to normal, as does the TH1/T=
H2 balance. =0A =0AConclusion=0A =0AThe=0AWPI findings are indeed a step fo=
rward in ME/CFS research, and are significant=0Afindings. However, further =
research is required to validate the idea that XMRV=0Ais a contributing fac=
tor in the pathogenesis of ME/CFS, versus being simply=0Aanother passive co=
-curring infection such as mycoplasma, HHV-6 and EBV. =0A =0ABy=0Acontrolli=
ng the amygdala, the aim is to reduce the levels of opportunistic=0Ainfecti=
ons such as the suspected XMRV virus by strengthening the immune system=0At=
hrough balancing the TH1/TH2 ratio and bringing the body back to homeostasi=
s.=0A =0AFuture Research=0A =0AFurther=0Aresearch is required to answer the=
following questions:=0A- What was the percentage of healthy controls=
that tested positive=0Afor XMRV antibodies? (The 3.7% figure seems to be r=
eferring to the percentage=0Aof healthy controls which tested positive for =
XRMV virus DNA rather than=0Aantibodies in unpublished research)=0A- =
What percentage of people with Autism display evidence of active=0Avirus or=
antibodies?=0A- What percentage of patients with other neurodegenera=
tive disease, fatiguing illnesses and=0Aneurobehavioral disease show eviden=
ce of XMRV?=0A- Can=0Athe studies be replicated effectively across th=
e ME/CFS population?=0A- Can=0Athe studies be replicated in different=
parts of the world?=0A- Why=0Aare controls which have active XMRV no=
t displaying obvious pathology?=0A =0AReferences=0A =0A(1) Mikovits JA et=
al. Detection=0Aof an Infectious Retrovirus, XMRV, in Blood Cells of Patie=
nts with Chronic=0AFatigue Syndrome. Science. 2009 Oct 8=0A(2) Gupta,=0AA=
. Unconscious Amygdalar Fear Conditioning in a Subset of Chronic Fatigue=0A=
Syndrome Patients. Medical Hypotheses Volume 59, Issue 6, 12 November 2002,=
=0APages 727-735=0A(3) Nicolson,=0AG.L. Chronic Infections in Neurodegene=
rative and Neurobehavioral Diseases. Lab=0AMedicine 2008; 39 (5): 291-299=
=0A(4) Nijs Jet al. High prevalence of Mycoplasma infections among Europe=
an chronic fatigue=0Asyndrome patients. Examination of four Mycoplasma spec=
ies in blood of chronic=0Afatigue syndrome patients. FEMS Immunol Med Micro=
biol. 2002 Nov 15;34(3):209-14=0A(5) Nicolson=0AGL et al. Multiple co-inf=
ections (Mycoplasma, Chlamydia, human herpes virus-6)=0Ain blood of chronic=
fatigue syndrome patients: association with signs and=0Asymptoms. APMIS. 2=
003 May;111(5):557-66. =0A(6) Fr=C3=A9mont M et al. Detection=0Aof herpes=
viruses and parvovirus B19 in gastric and intestinal mucosa of chronic=0Afa=
tigue syndrome patients. In Vivo. 2009 Mar-Apr;23(2):209-13=0A(7) Hohn=0A=
0 et al. Lack of evidence for xenotropic murine leukemia virus-related viru=
s=0A(XMRV) in German prostate cancer patients. Retrovirology. 2009 Oct 16;6=
(1):92.=0A[Epub ahead of print]=0A(8) Hashizume=0AH et al. Anxiety accele=
rates T-helper 2-tilted immune responses in patients=0Awith atopic dermatit=
is. Br J Dermatol. 2005 Jun;152(6):1161-4=0A(9) Ermolao A et al. Relation=
ship between stress hormones=0Aand immune response during high altitude exp=
osure in women. J Endocrinol=0AInvest. 2009 May 21. [Epub ahead of print] =
=0A(10)H=C3=B6glund=0ACO et al. Changes in immune regulation in response to=
examination stress in=0Aatopic and healthy individuals. Clin Exp Allergy. =
2006 Aug;36(8):969-71. =0A(11)Fletcher=0AAM et al. Neuropeptide Y (NPY): Co=
rrelates with Symptom Severity in Chronic=0AFatigue Syndrome. Abstract of p=
resentation to IACFS/ME Conference, Mar 2009,=0AReno, Nevada=0A(12)Nicolson=
=0AG. et al. (2009) Similarities of CFS and Autism Spectrum Disorders: Comp=
arison=0Aof Blood Co-Infections. (Source: Abstract of presentation to IACFS=
/ME=0AConference, Mar 2009, Reno, Nevada. By Nicolson GL, Nicolson NL, Haie=
r J. The=0AInstitute for Molecular Medicine, Huntington Beach, California, =
USA; Department=0Aof Surgery, University Hospital, Munster, Germany.=0A(13)=
Kleinhans=0ANM et al. Reduced neural habituation in the amygdala and social=
impairments in=0Aautism spectrum disorders. Am J Psychiatry. 2009 Apr;166(=
4):467-75=0A(14)Schumann=0ACM et al. Amygdala Enlargement in Toddlers with =
Autism Related to Severity of=0ASocial and Communication Impairments. Biol =
Psychiatry. 2009 Sep 1 [Epub ahead=0Aof print]=0A(15) Mosconi MW et al. Lon=
gitudinal study of amygdala=0Avolume and joint attention in 2- to 4-year-ol=
d children with autism. Arch Gen Psychiatry. 2009 May;66(5):509-16. =0A=0A=
=0A
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