Proteins on the Brain: Spinal Tapping for ME/CFS (March, 2010)
by Cort Johnson
In 2008 I participated in Dr. Baraniuk’s spinal tap study at
Georgetown University in Washington, D.C. Some readers may
remember how exciting Dr. Baraniuk’s first proteome study was; it was the easy
winner of the 2006 Phoenix Rising Paper of the Year. The study suggested that
chronic fatigue syndrome (ME/CFS) patients had unusual proteins in their
cerebral spinal fluid.
These results suggested that clumps of abnormally folded proteins could be
causing small punctures in the blood vessels of ME/CFS patients brains. These
punctures, in turn, could cause blood to leak out into the brain causing the
symptoms of ME/CFS. This, the first attempt at finding a protein (as opposed to
gene) signature, was stunningly successful in its ability to clearly elucidate a
possible cause of chronic fatigue syndrome.
Unique Protein Signature? - These proteins consisted of the following:
-
two proteins suggesting a protease – antiprotease imbalance is
present. This implicates increased production of elastase, an enzyme Dr. De
Meirleir believes plays a role.
-
several proteins suggesting small amounts of bleeding in the brain
could be caused by the aggregation of proteins (amyloids) in the blood vessesl.
-
Another protein suggests increased free radical production is present
-
Another suggests that problems with the vasoconstriction of the blood
vessels and damage to the cells lining the blood vessels (the endothelial
cells).
-
Another protein is associated with inflammation
-
One protein suggesting altered rates of cell suicide (apoptosis) are
present
I was excited to meet Dr. Baraniuk and was even happier to find
out that both he and his assistant Dr. Murugam Ravindran were quite willing to
sit down and discuss what they believed chronic fatigue syndrome (ME/CFS)
was all about.
Yes – It’s All in Your Head.
Dr. Ravindran, Dr. Baraniuk’s young assistant, took great delight in telling me
again and again that yes, ME/CFS
was indeed all in my head. He didn’t mean it was psychological, though. Dr.
Baraniuk’s proteome paper stated that their "proteomic model provides initial
objective evidence for the legitimacy of CFS as a distinct neurological disease’
Indeed, in an interview Dr. Baraniuk stated that he believed his study "ushers in
a whole new era for identifying [and] recognizing the legitimacy of these
disorders.” (!).
Dr. Baraniuk is clearly enthusiastic about the potential of his study to
uncover key elements of this disease. It's take a closer look at some of the
specific proteins he’s most interested in.
Amyloid Proteins: The amyloidic
proteins appear to be the key elements of the protein signature; the
inflammation, hemorrhagic elements, increased cell death and free radical
production could all derive from the body’s attempt to recover from damage done
by
amyloidic proteins bunching up, impeding blood flow and finally puncturing
the blood vessel walls in the brain.
Amyloid proteins are proteins that generally get folded improperly as they are
being made. Since shape in a protein is everything - proteins
trigger cellular activity by locking into each other like 3-dimensional keys -
improper folding can turn a protein useless or even dangerous.
The types of amyloid proteins Dr. Baraniuk found in chronic fatigue syndrome
(ME/CFS) patients are unique to the
brain. These same general types of proteins are also found in
neurodegenerative diseases such as Alzheimer’s and Down’s syndrome.
Improperly folded proteins can cause two major problems; (a) because the
proteins are not doing the job they’re supposed to do they
can cause vital processes to be neglected and (b) if they’re not removed quickly
enough they can build up and cause damage.
Possible Causes? -
What could cause amyloid proteins to build up present in ME/CFS patients? There are at least three possibilities.
(1) ME/CFS patients could be producing more of these proteins than
normal; that is their ability to produce normal proteins could be impaired. This
would suggest a deficit exists in very basic cellular processes in the brain.
(2) The processes
designed to remove damaged proteins (some always inevitably occur) may be
underperforming - allowing excessive accumulations of damaged
proteins to build up.
(3) It’s also possible
but less likely, in Dr. Baraniuk’s opinion, that high levels of oxidative stress
are damaging correctly built proteins.
How do these
proteins affect ME/CFS patients? First of all Dr. Baraniuk believes they’ve made
it difficult for ME/CFS patient’s brains to interpret and respond correctly to
the signals coming from the body. He believes that the part of the brain that
controls our breathing, heart rate, blood flows, immune system etc., namely, the
autonomic nervous system, appears not to be functio
ning normally.
Focus on the Brainstem -
In particular he’s focused on the gating mechanisms in the lower part of the
brain that filter the amount of information that the upper part of the brain
receives. He believes that the neural circuits running from the spinal cord to
the brainstem are not working properly and that the system that should close and
latch those gates is dysfunctional. These gates filter out unnecessary
information and protect the brain from being flooded with too much information.
He believes they’ve been left wide open in chronic fatigue syndrome (ME/CFS).
The most critical neural circuit appears to be the Papez Circuit which ties
together the anterior cingulate, amygdala and hippocampus. It’s associated with
heightened awareness and anxiety and effects autonomic nervous system
functioning.
Interestingly studies have shown that the gating mechanisms involving pain are
wide open in fibromyalgia patients. (FM patients display over activation of the
pain producing and under activation of the pain inhibiting circuits in the
brain. Dr. Baraniuk believes ME/CFS, FM, GWS, etc. are all subsets of each other.) Which
problem is accentuated in each person may depend on where small ruptures in the
blood vessels occur.
'Arousal' and CFS. My experiences with feeling
wired/tired, muscle tension, rushing thoughts, an inability to settle down and
the positive results some people have seen from mindfulness programs like
Ashok Gupta’s Amygdala Retraining program – which are intended to tamp down the stress response -
lead me to ask him straight out what he thought about 'system arousal' in
ME/CFS.
Dr. Baraniuk repeatedly stated that he does not believe
CFS is a ‘psychiatric condition’; he believes it is a
neurological condition possibly caused by the damage reflected in the proteome
signature. He strongly believes, though, that the brain
confusion just described creates anxiety-like components in this disease and
that the medical profession took a 20 year tramp down the wrong rabbit hole when
they focused on depression. The heightened sensory awareness seen most
prominently in fibromyalgia but also to some extent in ME/CFS is associated with increased not depressed brain
activity. (The only disease the Isreali researchers Naschitz was unable to
differentiate from chronic fatigue syndrome (ME/CFS) using measures of autonomic
nervous system functioning was anxiety.)
The inherent plasticity of the brain allows people, however, as he put it to
“purposefully introduce conscious actions to block that abnormal circuit’ by
doing behavioral therapies such as meditation, Amygdala Retraining program,
cognitive behavioral therapy, etc. and he’s all for them. Another way to slow
down the overactivity of the brain is to use Klonopin – which numerous
physicians have described as the most helpful drug for ME/CFS patients.Focus on Klonopin – Klonopin (Clonzepam) is a
benzodiazepine that calms down the brain by reducing the ‘set point’ at which
it’s neurons are activated. It does this by increasing the production of GABA, a
chemical that reduces neuronal activity. Klonopin has primarily been used to
treat panic and seizure disorders. For more on
Klonopin
A Key Gene? Dr. Baraniuk is focusing
on a particular gene – CNDP1 - that has a long and short form. His evidence
suggests that GWS (and ME/CFS) patients tend to have the longer version. This
form of the gene, interestingly enough, given all the evidence of increased
oxidative stress in this disease, appears to impair the ability of the brain to
protect itself from free radical attack.
A Key Protein -
Since genes produce proteins linking a
poorly functioning gene with a ‘bad’ protein would be a considerable step
forward; something other researchers have not done. The second part of the
study is to attack the problem with treatment. He doesn’t expect miracles but if
successful he hopes it could lead to a 10-50% improvement.
CNDP1 (carnosine dipeptidase)
degrades
carnosine, an amino acid that’s highly concentrated in brain and muscle tissues.
Carnosine has a number of different functions; it’s a free radical scavenger and
increases corticosterone levels and reduces glycolysis. Corticosterone is an
intermediate in the steroid pathway from pregnenalone to aldosterone – an
interesting finding given the hormonal questions regarding ME/CFS.
Presumably the version of the gene Dr. Baraniuk has found is more active than
usual at degrading carnosine and thus could lead to reduced carnosine
levels. Low carnosine levels could, then, conceivably
contribute in increased oxidative stress and hormonal problems seen in ME/CFS. This, of course, is just a theory and is
very preliminary at this point.
Too Much Stress in ME/CFS or Too Much
Pressure? – Besides examining proteins in the spinal fluid a second
component of the spinal tap involved determining spinal fluid pressure. Dr.
Ravindran explained that Dr. Frazier Henders
on – a neurosurgeon that Dr.
Baraniuk works with - believes excessive spinal fluid pressure could be
disrupting nervous system signals to the brain in chronic fatigue syndrome (ME/CFS).
(Dr. Mavrindran informed me that since the spinal tap relieves spinal fluid
pressure that I might experience some relief after the spinal tap. My
pressure was a bit higher than normal (10-14; mine-18) but not quite in the
accepted high range (20). While my spinal tap was decidedly not a
pleasant experience I did experience substantial relief afterwards; cognitively
I felt much clearer and physically I felt light and relaxed for some hours. It
was if some overlying tension (anxiety) had been removed.
Dig Deeper: For more on my spinal tap.
The Autonomic Nervous System (ANS)
Connection - Dr. Baraniuk measured ANS functioning using handgrip and nasal
tests. As the handgrip tests stresses the ANS and he measures it’s functioning
using what looks like a horn that he places into your nose. Suffice it to say
it's a bizarre (but painless) Test. When we contract the muscles our diastolic
blood pressure should increase. The diastolic blood pressure is the low reading
in the blood pressure test. It's increase reflects a general ‘tightening’ in the
blood vessels that allows us to push more blood to the small capillaries in the
muscles as we exercise.
Dr. Baraniuk has found that ME/CFS patient’s diastolic blood pressure didn’t
increase as much as in healthy controls. This suggests that ME/CFS patients may
have more difficulty driving blood to the muscles during exercise. It wasn't
just the diastolic blood pressure, though, that was abnormal; both the expected
increase in systolic blood pressure and the heart rate kicked in later in ME/CFS
patients than expected. The fact that their nasal passages didn't open up as
much during the handgrip tests suggested they were getting less oxygen delivery
to the tissues. In fact, some (probably very ill) ME/CFS patients display
exactly the opposite response to muscle contraction than they should; at a time
when their nasal passages should be opening to drive oxygen delivery to
their muscles their nasal passages closed. At the very time their body needed
more oxygen it was reducing oxygen delivery.
Dr. Baraniuk believes the ANS problems in ME/CFS are due not to abnormalities in
the brain but to problems in the brain stem.
Multiple Chemical Sensitivity (MCS) –
Dr. Baraniuk lamented the bad reputation MCS has in the medical establishment. His approach is
focused on the nose. It turns out that different subpopulations of nerves
respond to different types of sensory inputs. There’s always a wide range of
sensory sensitivity in the population; some people for instance can smell from a
fire from miles away while others are largely oblivious to it.
Just as with pain and FM he believes that the nervous system gating or filtering
problems are involved in MCS. They
could cause overstimulated nerves and a heightened perception of and
hypersensitivity to odors. He noted (correctly) that odors are not a necessary
component of MCS; it’s the effect
that chemicals have on the brain. He’d love to measure odor
hypersensitivity with EEG’s but there’s no money. He noted again that Klonopin,
CBT and other therapies work to the extent that they do
because they tend to dampen down the speed and strength of the aberrant brain
signals (i.e. help to close the gate).
A Nasal/Stress Connection? – Dr.
Baraniuk is an allergist and focused on the nose in chronic fatigue syndrome
(ME/CFS) in the past. He found – in a pattern that repeats itself again and
again in ME/CFS – that baseline
nasal measurements were normal but when he stimulated the nasal passages the
mucousal secretions plateaued at a much lower level that the normal controls.
We see this kind of pattern – relatively normal levels at rest – but
quite abnormal levels under stress – all over the body in ME/CFS patients; in
the HPA axis, NK cells, the heart, during the repeat exercise tests, and the
brain.
Dr. Baraniuk believes the substance the Fletcher/Klimas team is studying in
connection with natural killer cell dysfunction, neuropeptide Y, will be a very
important stress marker in this disease.
Low Blood Flows - I asked Dr.
Baraniuk if the low blood flows in chronic fatigue syndrome (ME/CFS) patients could simply allow more proteins to build up
and get stuck in the blood vessels of their brain – if this was purely a
low-flow problem. He thought low blood flows might contribute but clearly didn’t
think they played a central role. (Studies
with blood volume inducing drugs indicate that increasing blood volume in this
disease does not in itself relieve the condition in many patients).
The Migraine Connection – At the last CFSAC meeting Dr. Baraniuk talked
about a possible connecti
on between and chronic fatigue syndrome. He noted that
not only do many ME/CFS patients have migraines but that most of his migraine
patients meet the criteria for ME/CFS. Furthermore both migraine and ME/CFS
appear to involve abnormalities in blood flows in the brain. Both sets of
patients have problems with stimuli such as noise, light, smell, etc. and both
have a kind of relapsing/recurring nature.
Behan and Chaudhuri noted several similarities between
CFS and migraine about 7 years ago.
Many migraine and ME/CFS patients are sensitive to light and I asked
Dr. Mavrindrin about this. He noted
that the vasoconstrictor Imitrex is used to treat migraine – another
hypersensitivity reaction. My notes suggest that Dr. Baraniuk has used Imitrex
successfully to treat light sensitivity reactions in ME/CFS.
(In a CFSAC meeting Dr. Row from Australia stated that the only thing
that helped ME/CFS adolescents headaches was migraine medication. She said “it's very uncommon for the headaches not
to be managed by one of the migraine medications’. She was also focused on
treating dizziness, and (neutrally mediated) cardiac symptoms -both of which
imply autonomic nervous system dysfunction. She noted that the nausea she
frequently encountered appeared to be a function of blood pressure problems -
another possible ANS complication.)
Pathogens? - Dr. Baraniuk has not found any pathogens in his cerebral
spinal fluid samples thus far.
GWS and ME/CFS - Dr. Baraniuk
believes GWS/chronic fatigue syndrome (ME/CFS) are two facets of the same
diamond; by looking through one side he hopes to illuminate the other. He’ll be
looking for the same form of that gene he found in GWS in his present ME/CFS
study (and in fact said it was present). In a year – when he has enough
preliminary data – he hopes to apply for a similar study in ME/CFS.
I laughed when he said he expected it to get rejected first and then hopefully
get approved the next time around but he didn’t find that fact humorous at all.
The March of Technology: improvements
in technology in the last few years are allowing Dr. Baraniuk and his team get a
much more detailed look at patients cerebral spinal fluid than they could
before. This suggests, of course, that as exciting as the last study was that
the results of this study could be even more so, particularly given how
comprehensive it is regards to the ANS functioning, etc. This study also
indicates the kind of work at the National Institutes of Health funds when it’s
on the ball. Even our biggest support group doesn't have the funds to pay for a
study like this. This kind of study is why we need to continue to pressure the
National Institutes of Health and Centers for Disease Control to fund ME/CFS
research.
The Study
- CFS patients have been forthcoming but the study has been having a
great deal of trouble finding healthy controls.
Thanks very much to Dr. Baraniuk and Dr. Mavrindrin for being willing to sit
down and talk about these issues basically until I ran out of questions.
Throughout the day and a half I spent there they were very accommodating.