Summary of a spinal dopaminergic and opioidic hypothesis of Restless Legs Syndrome

This is written for doctors, nurses, neuroscientists and other clinical and research specialists. 
Please don't make treatment decisions concerning drugs or other
medical interventions based
on this material or that on the main page
http://aminotheory.com/rlsd/
This material has not
been peer reviewed, though I have had encouraging feedback
from two neurologists. 

  Robin Whittle    rw@firstpr.com.au    2012-08-22, updated 2015-02-18 and 2016-10-13.


Introduction

I am an independent RLS/PLMD researcher in Daylesford Australia. 
I hope you will be interested to read this summary of my novel
observations and etiological hypotheses and my suggestions for
non-drug treatments:

  http://aminotheory.com/rlsd/

Many researchers believe that the cause of RLS/PLMD is in the
brain.  However, there is no widely accepted etiological theory
for this common condition.  I suggest that the causes involve
dopaminergic and opioidic reflex circuits in the spinal cord,
concerning the regulation of a uniquely human soft-touch
reflex reaction which protects the soft skin of our foot-arch.

I suggest that this is not a "disease", but the result of
recent evolutionary adaptations to bipedalism which do not
work very well.  The condition is best known by the sensory and
movement diagnoses Restless Legs Syndrome and Period Limb
Movement Disorder.  However, I believe the condition, at levels
lower those  required to meet these diagnostic criteria, is
responsible for an even wider incidence of insomnia and sleep
disturbance.



Some novel observations

My wife Tina and I - and some other people - find that RLS
symptoms (including periodic limb movements - PLMs) can be
reduced or eliminated within seconds or minutes, with the
benefits lasting typically for two hours or so, by percussive
massage of the lumbar spinal region.  This reduces or abolishes
symptoms in the legs, whilst not affecting symptoms in the arms. 

In our experience, percussive massage of the upper spinal
region, just below the neck, similarly abolishes or reduces
symptoms in the arms, without affecting the symptoms in the
legs.  Again, the effects begin within seconds or a minute or
so, and last for two or so hours.

General percussive and rubbing massage of the whole body seems
to help as well, with effects which last for several hours -
which suggests a possible endogenous opioid mechanism.

Ingesting sugar also seems to have benefits which last for two
hours or so.  This would not be surprising if it could be shown
that for the particular individual, sugar ingestion boosts
levels of endogenous opioids.  This effect could also be
mediated by raised glucose levels improving many cellular
functions.

From mid-2014 to August 2016 we were taking a potassium
supplement
(potassium gluconate) equivalent to a quarter or
less of the
US RDA of 4.7 grams.  This seems to have reduced
our RLS/PLMD
significantly, and made the symptoms less likely
to appear when
we consume more salt (sodium) than usual. 
(I have not researched potassium nutrition in general, and there are
potential dangers with higher levels.  It will be interesting to see
if symptoms increase now we have stopped this relatively small dose.)
 
We find that a gram or so of oral tyrosine reduces or eliminates
symptoms in the arms and legs within 10 to 15 minutes, with
benefits lasting several hours.  Some other sufferers have
discovered this independently, but I have not heard of doctors
suggesting it as a treatment. 

When RLS/PLMD symptoms are present, we find that the lightest
touch (but not firm rubbing) with a finger or small object such
as a pencil-tip on the foot arch (or palm of the hand) will
elicit an immediate spinal-reflex-like foot (or hand) withdrawal
response which is similar or identical to the PLMs.  The same
actions on other parts of the foot or hand have no such effect.
(See the W. Bara-Jimenez 2000 paper for an electrical equivalent of this
soft-touch experiment.)


Furthermore, we find that local partial anesthetic of the foot
arch is a still more powerful way of reducing or eliminating
symptoms in the feet.  In the past, if oral tyrosine and
percussive massage of the spinal area and the whole body fail
to stop Tina's RLS/PLMD symptoms, we are usually able to stop
them (they are primarily or wholly in her feet and legs) by
applying 70% clove bud oil (active ingredient presumably
eugenol) and 30% coconut oil to the soles of her feet.  Now
she has better iron levels and presumably higher potassium
levels, her symptoms are occasional and never as strong as to
require this.

I am not sure this is without negative consequences, so we only
did it when there is no other way of getting rid of the symptoms.
Pharmaceutical local anesthetics such as EMLA (lidocaine and
prilocaine) work too.  Clove oil works really well and is less
expensive.

Tina almost never gets symptoms in her hands now that she has
improved her iron status and stopped drinking coffee.  We only
discovered the local partial anesthetic approach since her hand
symptoms ceased.  I assume the clove oil is acting only on the
sensory neurons of the foot arch rather than having a systemic
effect.  We haven't tested this by applying it somewhere else.

We and other some people find that coffee of any kind, including
decaf, elicits or worsens RLS/PLMD symptoms.  This is easily
understood in light of the widely recognized protective effects
of opioid agonists and the little-known research, beginning in
1983, which shows that coffee of all kinds, decaf or not,
contains significant quantities of mu opioid receptor
antagonists:

http://www.nature.com/nature/journal/v301/n5897/abs/301246a0.html
http://aminotheory.com/coffee/

As many other sufferers have observed, both unusually heavy
exercise or little movement all day tends to cause or worsen
symptoms.  In the context of the following hypotheses, these
observations could be explained by the lack of exercise leading
to poor replenishment of spinal cord CSF tyrosine, and heavy
exercise leading to lower tyrosine levels there, due to
serum amino acids in general being diverted to unusually high
levels of muscle repair.

SSRIs are widely recognised as contributing to RLS/PLMD
symptoms.  See the serotonin section below for more on this.


Key points of my etiological hypotheses

For brevity I have stated these as if they were facts.

  1 - We have a uniquely human soft-touch activated foot
      withdrawal spinal reflex response which protects the soft
      skin of the foot arch from puncture by withdrawing the
      foot before a spiny objects penetrates or damages the
      skin.  (Only humans have arched feet.)  When this reflex
      circuit is disinhibited, the foot withdrawal can be
      triggered by the slightest touch to the foot arch.  This
      is a typical nociceptive response except that it is
      triggered by a soft touch sensation which would not
      ordinarily be painful.

      While this soft-touch activated foot withdrawal reflex
      has presumably evolved to protect the foot arch, it may
      also have evolved in part to protect the palm of the hand
      when climbing or grasping, or perhaps when walking on all
      fours.  Even assuming that it evolved purely to protect
      the foot arch, the genetic instructions which give rise
      to the requisite neuronal structures would probably also
      produce similar structures in other parts of the spinal
      cord, leading to similar soft-touch, opioidic and
      dopaminergic inhibited, muscle-activating (for limb
      withdrawal) reflex circuits for the palm of the hand, or
      for sensory neurons and muscles in the torso.  In extreme
      cases RLS/PLMD symptoms occur in feet, hands and torso -
      and there are a few reports in the literature of facial
      symptoms too.

  2 - Normally the spinal neurons which mediate this foot-
      arch protective response (or similar neurons for the
      foot and torso) are inhibited by a uniquely human

      set of dopaminergic (dopamine-producing) neurons.  These
      presumably descend from the brain or brainstem. 

      These neurons, like all the other nociceptive and
      withdrawal reflex generating neurons in the spinal cord
      (the same neurons do both functions), are also inhibited
      by opioid receptors and the normal moderate levels of
      endogenous opioids in the CSF of the spinal cord.

  3 - These neurons release dopamine most of the time -
      whenever we are not walking on ground which might contain
      foot-arch puncturing spines, spikes or rocks.  These
      neurons require a nearly continual supply of tyrosine, in
      order to produce
L-DOPA which is then converted into
      dopamine.  While these neurons presumably have their
      nuclei in the brain or brain stem, their output
      terminals are in the lower spinal cord, and the tyrosine
      must be produced in those output terminals.

  4 - The tyrosine supply to these neurons (from the spinal
      cord's CSF) can become depleted at times of lowered
      physical activity, since without vibration and/or high
      rates of blood-flow, the consumption exceeds that
      provided
to the CSF by the immediately adjacent
      capillaries and the
natural degree of diffusion of
     
tyrosine through the CSF in this dense part of the spinal
      cord. 
Following an hour or more of physical inactivity,
      this results in
a localized depletion of tyrosine, such
      as within one or two
millimetres of the output terminals
      of these spinal
dopaminergic neurons, which are
      presumably in the dorsal
horn.  When this causes
      insufficient dopamine release to
properly inhibit the
     
soft-touch-activated foot-arch protective reflex circuit,
      RLS
and/or PLMD symptoms occur.

      This would explain the puzzling characteristic of RLS/
      PLMD
being a movement disorder which is triggered or
      worsened
by lack of movement.

  5 - Robust physical movement, spinal stretch or inversion
      exercises and especially percussive massage shakes up the
      CSF in this area, bringing tyrosine-rich CSF to these
      neurons from a few millimetres away, within seconds or
      minutes.  This restores higher
levels of dopamine
     
production and release, which more effectively inhibits
      this spinal
reflex circuit, leading to a reduction or
      cessation of symptoms.


  6 - With very low levels of inhibition (due to lower levels
      of activation of the opioid and dopamine receptors of the
      nociceptive/reflex neurons) this circuit can be triggered

      by (what I assume is) the low "background noise" level of
      foot-arch soft-touch sensory neuron activation which
      occurs in
the absence of any stimulation, leading to RLS
      sensations and to the PLMD foot (or hand) withdrawal
      actions - or in the torso, to muscle spasms.  I know of
      no
evidence that RLS/PLMD symptoms arise from any
      fundamental problems with the
foot-arch skin soft-touch
     
sensory neurons themselves.  However, see the serotonin
      section below.

  7 - From the above (and assuming that the "noise level" of
      soft-touch sensory neuron activation remains the same -
      which is not necessarily the case, as mentioned below in
      the serotonin section) it follows that the pathological
      state in
which RLS/PLMD symptoms are present is due to
      this extreme
state of disinhibition of the uniquely human
      spinal reflex
circuit.  As far as I know, there are four
      potential
causes of this.  Points 1 and 2 apply to all
      spinal
nociceptive/reflex circuits.  Points 3 and 4 only
      apply to those
circuits which are, or which resemble (for
      the hands and
torso, where similar symptoms may also
      occur), the
recently (last ~3 million years) evolved
      human soft-touch-
activated foot-arch protective reflex
      circuit.

        (The following points assume that the numbers of opioid and
         dopamine inhibitory receptors remain unchanged, which is not
         necessarily the case.)

    

        1 - Any compounds which inhibit the mu opioid receptors
            in this part of the spinal cord.  This includes
            some
drugs and the compounds in coffee such as
            4-Caffeoyl-1, 5-quinide.

        2 - Lower than normal levels of endogenous opioids - or
            levels which are unable to compensate for the
            effects of the mu opioid receptor antagonists.
 
        3 - Similarly, any compounds which antagonise the
            dopamine receptors in these spinal neurons, such as
            promethazine (Phenergan).   

        4 - Similarly, low levels of dopamine receptor agonists
            in the receptors of these foot-arch reflex spinal
            neurons.  Without drug intervention, the only such
            agonists are the dopamine molecules released by the
            descending dopaminergic neurons.  The most
            important
causes of these low levels of dopamine
            release are:


               a - Iron deficiencies in general.  (Iron is
                   essential for the functioning of tyrosine
                   hydroxylase, which converts tyrosine to
                   L-DOPA.)  There may also be problems with
                   the ferritin/serum iron balance, and CSF
                   iron levels.  Low iron levels have long been
                   recognised as a cause of RLS/PLMD.

               b - Iron deficiencies in these spinal
                   dopaminergic neurons.  Perhaps some people
                   have a genetic predisposition to reduced
                   iron
transport across the blood brain
                   barrier and/or from the CSF to the cytoplasm
                   of the
neurons.  This would would have been
                   adaptive in
ancestral times where high-iron
                   diets or water
supplies might otherwise lead
                   to neurotoxicity.


               c - Anything else which reduces the activity of
                   tyrosine hydroxylase in these neurons, such
                   as genetic variations in the gene for this
                   enzyme, enzymes involved in its co-factors
                   or
(perhaps) reduced folate levels.

               d - Low levels of tyrosine in the blood and so
                   in
the CSF.  This could be caused by
                   circadian
rhythms, low protein levels in
                   recent food
intake or high levels of
                   exercise causing
greater than usual amino
                  
acid consumption as muscles are rebuilt.

               e - Potential problems with transporting
                   tyrosine
across the blood-brain barrier (in
                   the spinal
cord) and similarly into the
                   dopaminergic
neurons.  For instance higher
                   serum levels of
the large neutral amino
                   acids other than of
tyrosine, since these
                  
compete with tyrosine in the Large Neutral
                   Amino
Acid transporter system.  (I am keen to
                      find a good description of this this system.)


               f - Localised (within a millimetre or two)
                   depletion of tyrosine due to recent lack of
                   physical activity and vibration as explained
                   above.

               g - Additional localized shortage of tyrosine
                   and
other nutrients in the general area of
                   these
dopaminergic neurons (millimetres and
                   centimetres) due to the effects of spinal
                   injury, including that resulting from spinal
                   surgery.  (Some people who have never had
                   RLS/PLMD develop it on the first night after
                   spinal surgery or injury - and the symptoms
                   remain indefinitely.)
                  
  8 - In this model, it is easy to see why both dopamine
      agonists and opioid agonists are highly effective at
      reducing or eliminating RLS/PLMD symptoms.  However, both
      types of drugs have serious side effects, and I suggest a
      variety of non-drug treatments be tried before resorting 
      to these interventions:

        a - Improve iron intake under medical supervision (as
            is
well known).

        b - Eliminating all coffee, or at least avoiding it in
            the afternoon and evening.  (Caffeine disrupts
            sleep, but I am not convinced it is directly
            involved in RLS/PLMD.  I wrote a letter concerning
            this to the Journal of Caffeine Research, which
            appeared in the March 2015 edition link.)

        c - Reduced salt and improved magnesium and calcium.  I
            don't know the mechanisms but we and some other
            people find that excessive salt causes or
            exacerbates RLS/PLMD.  Some people find that
            improved intake of magnesium or magnesium and
            calcium reduces or eliminates their symptoms.

        d - Improving potassium nutrition.  Medical supervision
            is probably best for this unless the supplements
            are a small fraction of the RDA.

        e - Limiting or avoiding chocolate and cocoa, including
            raw (unroasted) cacao.  We don't know the mechanism,
            but we find, unfortunately, that these drive
            RLS/PLMD symptoms.

        f - Eating high protein meals before bed.  (There may
            be reasons to avoid this, not least the desire to
            boost serotonin in general, or at least at night:
            http://serotoninpowerdiet.com .  Low serotonin
            levels are widely recognised as a cause of mood and
            other problems.  Unfortunately, as noted below in
            the serotonin section boosting serotonin levels may
            worsen RLS to some degree.)

        g - Ensuring that the arms, shoulder and especially
            the back are kept warm when sleeping.  See point
            9 below.

        h - Exercise and/or percussive massage of the spinal
            area (if safe) before or during the times when
            symptoms are present.

        i - Oral tyrosine, such as 2 or 3 500mg tablets or
            capsules.  Tyrosine appears to be safe (see
            the main page for references).  It is  rapidly
            ingested but it is poorly soluble.  Ideally
            there would be slow-release, high availability,
            tyrosine tablets.  Free amino acids such as
            tyrosine are arguably nutrients, rather than drugs.

        j - General massage of the whole body, wherever safe,
            including percussive massage and rubbing, and
            including the soles of the feet.  I am not sure why
            this is so effective, but I suspect it is probably
            due to release of endogenous opioids and/or other
            DNIC (Diffuse Noxious Inhibitory Controls)
            mechanisms which reduce the sensitivity of all
            spinal nociceptive neurons.

            I suspect (I don't know of any research evidence)
            that stretching exercises also boost endogenous
            opioids, so this may help reduce RLS/PLMD symptoms
            to.

        k - Local partial anesthesia of the foot arch and sole,
            and perhaps the palms of the hands.  This is a drug
            approach with potential negative side effects, but
            perhaps it would be preferable to the systemic
            administration of opioid agonists and dopamine
            agonists.
       
  9 - There is an interesting and consistent observation we
      have both made of ourselves, but have not yet compared
      notes with anyone else regarding this: when sleeping or
      trying to  sleep, in a condition where RLS/PLMD symptoms
      are on the edge of occurring, we find that if our arms,
      shoulders or back are cold, such as being uncovered or
      exposed to draft, then the symptoms will occur. 

      Likewise, we find that lying on our back will typically
      cause the symptoms to occur, while lying on our side does
      not.  (I think one correspondent reported the opposite -
      symptoms worsened when lying on their side, and reduced
      when lying on their back.)  At first I thought the back
      pressure and temperature effects might be due to blood or
      perhaps CNS circulation changes, but now I think it is a
      direct sensory stimulus process on the skin, since the
      effect on symptoms seems to occur within seconds.

      I discussed these observations in the PDF file I wrote
      for RLS researchers in 2011.  These are of practical use
      in reducing symptoms, and potentially of interest to
      researchers concerned with CNS development.  I propose
      that cold, or pressure, in these areas is driving the
      same neurons in the lower spinal cord which are primarily
      driven by the soft-touch-based (as well as pinprick-pain-
      based) foot-arch sensory neurons.  I propose that these
      observations reflect the existence of inputs to this
      circuit from other parts of the body which were not
      pruned during early (in utero, I guess) development. 

      Since cold sensations are processed by nociceptive
      circuits in the spinal cord, similarly to the signals
      from pain receptors which report tissue damage and since
      the particular circuit for the foot arch has evolved to
      respond to soft touch as well, such crosstalk from cold
      and soft pressure
sensory neurons in other part of the
      body
would not be surprising - to the degree that the
      axons from these sensory neurons to the foot-arch neurons
      were not completely pruned.

      My primary reference for understanding this crosstalk is:

         Appropriate/Inappropriate Developed Pain Paths
        
Jens Schouenborg     
         Chapter 12, in The Science of Pain (1056 pages)
         Alan Basbaum and M. Bushnell eds
         Elsevier Academic Press Aug 2008 
         ISBN 978-0-12-374625-2
         http://www.worldcat.org/title/science-of-pain/oclc/258351924
      
      I found chapters 23 (Morphological and Neurochemical
      Organization of the Spinal Dorsal Horn), 24(Spinal Cord
      Physiology of Nociception), 25 (What is a Wide-Dynamic-
      Range Cell), 49 (Descending Control Mechanisms) and 50
      (Diffuse Noxious Inhibitory Controls (DNIC)) really
      useful too.

 10 - My proposal of a mechanism involving a localized tyrosine
      deficiency in the spinal cord is unlike any neurological
      condition I have read of.  However, it may have a
      parallel with foot cramps.  I find that these can often
      be resolved, in a few seconds or tens of seconds, much
      more rapidly than by rubbing the foot or calf, by
      percussive massage of the lower spine, exactly as for
      RLS/PLMD.  This doesn't require a mechanical massager -
      I simply stand up and use my fists or the backs of my
      hands on either side of my lower back.

      So perhaps some foot cramps involve either a localized
      deficiency of some precursor(s) and/or a localized build-
      up of reaction byproduct(s) which inhibit a particular
      lower motor neuron process.  Shaking up the cord and its
      CSF seems to fix any such problems.

      There is a well known co-morbidity between foot/leg
      cramps and RLS/PLMD.  Perhaps the common factor is poor
      circulation of the blood and CSF in the spinal cord -
      even if the precursor which is presumably deficient for
      foot cramps is not tyrosine.  I have not yet tried to
      find whatever research literature they may be on foot
      cramps.
        

My hypotheses suggest that multiple systems can contribute to
the disinhibition of the foot-arch protective reflex response,
so it is not surprising that a large number of factors seem to
affect the level of symptoms. 

The central principle of my hypotheses is that RLS/PLMD
symptoms
only arise due to an arguably pathological degree of
disinhibition of what I propose is a uniquely human spinal
reflex circuit, which evolved to protect the soft skin of our
foot arch, and perhaps of the palm of our hands.  This pattern
of neuronal development is evidently present not just for the
foot arch, but for the palm of the hands and for some torso
sensory and motor neurons.  In extreme cases (low iron, high
sodium, high levels of opioid receptor antagonists such as
those in coffee, maybe dopamine receptor antagonists, low
protein levels, poor circulation etc.), all three systems

can be triggered by "background noise" of the sensory neurons,
leading to RLS sensory symptoms and PLMs in all three parts of
the body.  (There have also been reports of RLS/PLMD-like
symptoms in the face.  I haven't researched these but perhaps
the genetic instructions which give rise to the adaptive soft-
touch sensitive foot-arch system also create similar structures
at all levels of the spinal cord.)


As far as I know, there's nothing which could go wrong solely
in
the brain which would cause this disinhibition or the same
pattern of symptoms, which always (as far as I know) respond to
tyrosine, increased blood-flow within and/or vibration of the
spinal cord, increases in opioid and dopamine receptor agonists
and reduction in any level of opioid and dopamine receptor
antagonist activity.  For instance, if the (presumably supra-
spinal) drive for the descending dopaminergic pathway was not
functioning, this would disinhibit the soft-touch foot-arch
protective reflex circuit, giving rise to symptoms.  But in
such a condition, oral tyrosine would have little or no effect.
Nor
would percussive massage of the lower spinal cord area,
unless
it could be shown that this in some way aided opioid
activation
- which I think is possible.

While these processes are pathological, in that they cause
distressing symptoms, they are also very common.  I suggest
this
is due to the recently evolved nature of the proposed
soft-touch
foot-arch protective reflex, and the unusually high
demand for
tyrosine it imposes on certain narrow columns within
the spinal
cord.  The human body plan has not yet evolved a
sufficiently good blood supply to the lower spinal cord, since
the development of bipedalism has greatly increased the size
and complexity of the neuronal circuitry there.

Beyond the widespread symptoms which meet RLS/PLMD diagnostic
criteria, I propose that there is an even more widespread
occurrence of the same processes, to lesser degree, which
manifest as sleep disruption and difficulty getting to sleep. 
If so, then this process contributes enormously to the global
burden of insomnia, sleep disturbance and so to general
ill-health - not least of which are vehicle accidents due to
tiredness.  Also, any sleep disruption leads to people being
more likely to use caffeine, and then to the anxiety and other
ill effects which follow, including the use of alcohol and
other drugs to quell the anxiogenic effects of the caffeine.

In the past I did quite a lot of research on my own mild and
occasional symptoms, and with Tina's.  Now we know how to avoid
the problems, RLS/PLMD is a rare occurrence for us both. 
However there are no-doubt other factors at work beyond those
which we have so far identified, in our own bodies and more
generally with other people. 

It is my impression that those who suffer the most from RLS/
PLMD do so due to spinal injuries and/or due to coffee and
other aspects of nutrition and lifestyle which are generally
amenable to change.  Genetic disposition is no-doubt a factor
but I think the most severe cases often involve spinal injury
- including pressure or changes to blood / CSF circulation
after otherwise successful spinal surgery.

I think there is great scope for reducing or eliminating
symptoms without the use of dopaminergic and opioidic drugs,
all of which have serious negative consequences, not least
with the dopamine agonists, gambling addiction (link) and other
personality changes.  This will require research funding from
somewhere other than drug companies.


Serotonin - new research in 2016
        
SSRIs are well known to cause or exacerbate RLS/PLMD symptoms,
for some people at least.  Haba-Rubio et al. 2014 (Sleep Journal)
report that SSRIs, but not tricyclic antidepressants, worsen
symptoms.

Since I was not aware how serotonin might be involved in
nociception, I wondered whether it might affect the random
"noise" rate of activation, in the absence of stimuli, for the
foot arch soft-touch neurons.

I think this article supports the idea that increased serotonin
levels in the foot-arch itself may contribute to this level of
activation:

    Merkel disc is a serotonergic synapse in the epidermis for
    transmitting tactile signals in mammals
    Weipang Chang, Hirosato Kanda, Ryo Ikeda, Jennifer Ling,
    Jennifer J. DeBerry, and Jianguo G. Gu
    PNAS vol. 113 no. 37 2016-10-11 

This is assuming that Merkel disks or something like them are
found in the foot arch, which is something I have not
established.  The lead author is quoted, in the press release :

   "The serotonergic transmission in the epidermis,
    probably like that in the central nervous system,
    can be regulated by factors affecting serotonin
    uptake and release,"

Assuming that SSRIs affect serotonin reuptake transporters in
soft-touch sensory neurons in the foot arch, and that the
"noise" of their activation in the absence of physical stimulus
is a key component of RLS/PLMS symptoms, then it might be
possible to apply a topical drug there to reduce serotonin
levels, and so make these neurons less likely to fire
sponteneously.  If this could be done in a way which did not
upset serotonin levels elsewhere in the body, then this might
be useful therapeutic technique.  (If I had the money and desire to
invest in patents, I wouldn't be writing this in public.)


This suggests a simple experiment: with a subject prone to
RLS/PLMD (easy to find, there's usually one or a few in every
ten people) apply solution with alcohol of fluoxetine or some
other SSRI topically to one foot arch with the other as a
control (apply a similarly textured liquid there) and see what
happens.  Does RLS/PLMD appear now in the SSRI treated foot?
Is the treated foot arch more sensitive to being touched
lightly with the tip of a pencil?

Conversely, does topical application of a serotonin antagonist
to the foot arch reduce or abolish RLS/PLMD symptoms?  It would
be best to avoid anything which was also a dopamine or opioid
antagonist as well.



The RLS researchers were informed about these observations and hypotheses in 2011
        
I wrote an earlier and much more detailed and well-referenced
version of this material (except for our recent discoveries
about
potassium and the 2016 material on serotonin) in a 32
page PDF document and sent it to the main RLS
researchers in
September 2011.  I haven't received any feedback
from them yet. 

These researchers are busy doctors and academics with a huge
amount to read every week to keep abreast of their fields. 
They
naturally do not wish to be associated with flaky theories
-
and there are plenty of such theories regarding RLS.  They
are
probably not very interested in reading at length what an
electronic technician
from Australia is doing in the field they
have been
researching for decades.  Yet all this professional
RLS/PLMD research has so far failed to provide even a candidate
comprehensive etiological theory - much less one which is
widely accepted.

Electronic technicians get lots of practice debugging systems
which are functioning differently to how they were designed to
work and/or which were never designed properly in the first
place.  Likewise computer programmers, working with complex
not very well documented circumstances in which something is
going wrong, and we need to find out all about it and fix it.

We frequently have to work without circuit diagrams or
adequately documented source code with little or no initial
knowledge of what should be occurring and what actually is
going on.  Many electronic faults involve inadequate power
supply, which is why it was easy for me to think of localised
depletion of tyrosine, the precursor to L-DOPA.  Likewise noise
(random fluctuations) are frequently a problem in electronic
equipment.  So it is easy for me to imagine low levels of
sensory neuron activity becoming a problem if the super-
sensitive neuronal circuit is disinhibited.  I have not read
of any currently recognised neurological conditions involving
such mechanisms. 

The first discovery Tina and I made
- the effectiveness of
percussive massage of the
lumbar spinal area - occurred because
for an electronic technician it is standard procedure to
vibrate, heat, cool, bend etc. various parts of a piece of
equipment which is not functioning, or which is exhibiting
intermittently faulty behaviour.  This will frequently alter
the behaviour and so enable the discovery of a bad solder
joint, an overheated or degraded transistor etc.  (Heating the
lumbar area seems to reduce symptoms too, but not as well as
percussive massage - and I am concerned about overheating any
part of the body, especially the CNS.)  Our most recent
tentative discovery - of the importance of potassium - had
nothing to do with me or our interest in RLS: it was due to
Tina's broad interest in nutrition and health.


RLS/PLMD is extremely common, easy to research and currently
lacks an accepted etiological theory.  In the future I plan to
write a page suggesting the numerous experiments which can be
done, such as with percussive massage, oral tyrosine, the soft-
touch test of the foot arch, local anesthetic on the foot-arch,
exercise techniques etc. 
This research requires no drugs or
special equipment and may involve few safety concerns.  These
would make excellent undergrad,
post-grad and doctoral research
projects - and would be a valuable addition to the drug tests,
genetic research and assumptions about this being a brain
disorder, in which mainstream RLS/PLMD research has been stuck
for decades.


Since late 2011, http://aminotheory.com/rlsd/ has been a
less detailed, publicly accessible and updated
version of the
material I wrote in the PDF for researchers. 
Since then I have
been corresponding and talking with a number
of sufferers and
have have received appreciative responses from
two neurologists
- in Australia and the USA.  Several friends regularly use
percussive massage, with their own fists, if they get a bout
of RLS/PLMD.  One avoids coffee in the evening and uses oral
tyrosine if she has any symptoms.

I suggest that the condition be known not as a disease or
syndrome, but as
Restless Legs Sensorimotor Disorder.  For my
arguments against the name change from "Restless Legs Syndrome"
to "Willis-Ekbom Disease" and my concerns about this condition
being listed in the DSM-5 (it is a movement disorder, not a
psychological disorder), please see:
http://aminotheory.com/rlsd/name-diag/


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