Thermoregulation

 

Warning: technical jargon ahead

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From a physics perspective, the back to normal event switches from an abnormal state to homeostasis in zero-time. Because zero-time feels weird, we call it 2 seconds.

Could the weird feeling stem from the conventional notion that pain won’t end any time soon? Or, that the need for another dose determines whether a pain-masking intervention is “working”?

But what is weird about the body returning back to normal?

Thermal imaging

Thermal imaging provides a ring-side seat for watching previously unexpected events. For example, after 30-years of coldness discomfort, would you expect your hands to return back-to-normal function? Within minutes of the first therapy?

Thermal imaging of warming responses suggests a few questions. Could the events provide a few answers?

You may be wondering, could the magnitude of the warming be associated with the therapy parameters?

Could physics account for the apparent disconnect between warming hands and information about the treatment parameters that prompted the response? What if the body doesn’t respond to therapy in a nice one-to-one relationship?


Could the event be like taking your hand out of cold water? Would your hands warm back-to-normal irrespective of the water temperature or how long your hand remained cold (within reason)? Wouldn’t you be surprised if your hands remained cold for years?

Could you feel precisely when warming resumed? Thermal imaging only shows changes in temperature AFTER the back-to-normal event? Would you feel the cold leaving before you felt warming arriving?

Where should you look to find the earliest indication of a warming response?

You might want to start/stop the clip in Figure 1 before reading on. Hint: darker is colder.

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+ Machine-learning methods uncover possible relationships

Measurements taken at the finger tips seems intuitive because that's where warming first appears with the gray becoming lighter. The graph is Figure 1 charts the temperatures of the man's thumbs.

Machine-learning methods uncovered other places to look. For example, the darkening of veins across the back of the hands provides an earlier indication of increased circulation in his other finger tips.

After enough time, the lightening of the veins in the fingers and across the hand show warming according to the temperature-brightness scale.

The Instant Verification System captured stories about the volunteer's reports that their coldness was leaving before they perceived the arrival of warming arrived.

Without knowing the “before” state, PhotoMed's advisors and team couldn't distinguish between normal warming responses upon removing the hand from cold water and the responses to the therapy.

Insights from the examination of hundreds of warming responses led to the concept of back-to-normal function.


+ Could the warming responses really be special?

Later, the team learned that chemically or surgically induced warming are easy to distinguishable from normal warming responses. For example: the warmer state from Botox™ or a sympathetic block does NOT go back to normal when the intervention fades.

Curiously, the perception of coldness sometimes appears to be disconnected from the actual skin temperature. Link to sympathectomy below.

Additionally, normal isn’t expected to wear off. Of course, the normal state might end for biomechanical reasons.

PhotoMed's advisors and team couldn’t find explanations in texts on pain and neuroscience for the crazy-fast responses.

Could quantum biology provide possible mechanism? The Instant Verification System™ provides an efficient method for testing speculative models for how the therapy might work. Your guess?


 

Abnormal skin temperatures

Abnormal skin temperatures may provide diagnostic signs for complex regional pain syndrome (CRPS or RSD), Raynaud’s syndrome, or diabetic neuropathy. However, discomforting coldness may be present for decades with no known reason.

 
 
 
 
 
 
 

PhotoMed’s advisor’s “best guess” was that the therapy “worked” like a stellate ganglion block (external links open in a new window) (1).

  • The endpoints are similar with hands warmer than before

  • And, volunteers reported less pain.

The nerdy engineers tried to fit their model to the data. It later turned out that the model seemed okay only if you looked at the endpoints. Machine-learning methods uncovered problems in between. They wondered about fundamental differences between invasive interventions and non-invasive therapies suggested by the preliminary findings.

The differences appear to be central to debates among practitioners of invasive vs. non-invasive modalities.

Link to the discussion of the failure.


Following are some cases that led to the model’s collapse.

Complex regional pain syndrome (CRPS or RSD)

CRPS makes the news because of its pain level and intractability. The cause of the pain may be from a small injury or even from an unknown cause.

Painfully cold hands and vascular abnormalities provide diagnostic signs of complex regional pain syndrome (CRPS or RSD). This disorder was previously called “reflex sympathetic dystrophy” for its apparent link to the sympathetic nervous system.

The volunteers had pain that had not responded adequately to:

  • Pain-masking medications

  • Surgical interventions

  • Spinal-cord stimulators

Examination of many cases suggested that the previous failures increased the likelihood that PhotoMed’s therapy might prompt a back-to-normal response.

The team wondered, could the success of a previous intervention “rule-out” the people who had an acute reason for their pain? An acute problem might not be solved so quickly and completely. Could PhotoMed’s therapy work most effectively for injuries that had completed the healing process except for the last step?


The Triple 2 Algorithm and machine learning uncover innate principles

Thermal imaging lets the operator “see” changes in temperature, in real time, that may be useful for running the Triple 2 Algorithm. For example in Figure 2, the lack of a noticed response suggested to try different settings (Tx 1, Tx 2, and Tx 3). Observation of the warming response suggested that enough therapy had been delivered during that visit.

People with bilateral or whole-body abnormal temperatures contributed real-time recordings whether or not the therapy worked for them. For years, the team missed the observation that responses to PhotoMed’s therapy are typically bilateral when both sides are affected.

The team was a bit embarrassed when someone pointed out that both of their hands got better when only one side received therapy.

They quickly confirmed the observation through real-time recordings. The recordings provided an economical way to confirm the insight without additional studies. One value of machine learning methods is that new questions may be asked of the same events, recordings, or data.

The finding of bilateral responses was simplified because:

  • The data were collected without the bias of a hypothesis

  • The mechanism wasn’t known (and still isn’t) that might limit the questions asked

  • The recordings included responses by people unexpected to improve

  • The data includes a variety of disorders of the sensory, motor, and skin temperature systems.

Upon detecting bilateral warming, bilateral responses appeared in the other innate functions. Link to the neuroscience page.


Figure 2, demonstrates three applications of different settings (Tx1 – Tx 3). Tx3 appears to prompt the back-to-normal response followed by comfortable hand temperatues. Both hands warmed until an overwarm condition may have prompted the return to a maintained (from later data) comfortable temperature. The therapy was applied at the neck and not to the cold hands.

 

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+ What others say about CRPS pathophysiology

CRPS makes the news because of its pain level and intractability. The pain is frequently precipitated by a small injury or even an unknown cause.

  1. For an overview of the disorder, see this **external link to NINDS description of CRPS (2)**
  2. See Table 1 and Figure 1 for the grim details in An Update on the Pathophysiology of Complex Regional Pain Syndrome by Stephen Bruehl, PhD. external link to the article.(3) Could all those factors resolve after a response to a few photons?

For many with this disorder, the blood circulation in affected limbs might drop low enough to cause changes in the bone and skin. However, circulation doesn’t appear to go out of control as may occur with Raynaud’s syndrome. Wasner (4) examined different cases of initial hand temperatures. His studies cycled the patient’s body temperatures to study their vascular responses. None of the patients improved function or reported pain relief.

For an overview of vascular abnormalities, see this external link to a paper(4) by Gunner Wasner, et al in 2001.

PhotoMed’s team hasn’t found predictions or proposed mechanisms for the observed warming responses in textbooks on pain or neuroscience. Even a complete return to normal function does not solve all of the person’s problems, such as the loss of job, friends, and community.


+ Key observations for Figure 2

The constant offset (parallel lines) in left/right hand temperature trend lines suggests that the sensing and control functions are working correctly. Except for the initial temperature and unremitting pain?

The bilateral warming responses suggest that the controlling command occurs deep in the brain before signals make their left-right split. This characteristic warming should help brain imaging researchers get started.

From thermal imagining recordings in Figure 2:

• The temperatures during the first 10 minutes remain stable without either hand becoming colder.

• The temperatures appear to be synchronized throughout low and high rates of blood circulation.

• The single overshoot suggests a systematic means to achieve a new state in the minimum time. Isn’t that cool?

• Without knowing the “before” state, could the warming response look “normal”?

Could the magnitude of the warming response be a function of the therapy or the body? Could the starting temperature affect the apparent magnitude of the response?


+ PhotoMed's therapy wasn't the first to prompt warming and relief

Infrared therapy began to help a few people in the 1990s. The IR therapy was too inefficient for commercial success for its required knowledge, treating skills, and clinic time.

PhotoMed’s team and its pain-specialist advisors set out to solve the efficiency problem for addressing CRPS and diabetic neuropathy. Development of the Triple 2 Algorithm began by recording data when it took 5 visits to detect the probable failure of the therapy. That’s a lot of visits for someone with horrible pain. We especially thank the volunteers who left with their pain unabated for their contribution of failure data.

Today, photon-based therapies are called photobiomodulation therapies.


Raynaud’s syndrome

Raynaud’s syndrome reduces blood circulation in affected fingers or limbs. The loss can be so severe that the fingers turn white, blue, or red and may lead to gangrene. The blood circulation does not appear to be regulated to maintain a low temperature, as with typical CRPS. Link to External Information (Opens in a new window) (5)

PhotoMed’s Triple 2 Algorithm suggests that therapy be applied to points about the neck. Our neurologist advisors look for a pupillary response to tell when the patient begins to respond. The low initial temperatures of the affected extremities and low blood circulation delays the observation of a warming response.

Figure 3 - Thermal imaging of finger temperatures lets the operator monitor for possible warming in response to the therapy. Four 2-minutes procedures applied variable wavelengths to the woman’s neck and later to her finger. Lighter gray is warmer. 29 seconds.

 
 
 

“Sarah’s” middle finger occasionally went cold and turned white. She reported that the problem usually occurred after using gardening clippers.

In Figure 3, Sarah received four 2-minute applications of variable wavelength light. Her affected finger continued to cool and then began to slowly warm. The cold finger’s temperature dropped below 18 deg C which is represented by the blue color. At about 20 seconds into the video, you can observe lightening gray on the sides of her cold finger which indicates warming from increasing blood circulation.

Sarah’s fingers normalized after about 30 minutes. She later reported that she had had no incidents for 3 years.


Sympathectomy

Years before this visit, “Katherine” underwent a sympathectomy to force her cold left hand to warm aimed to relieve her CRPS pain. Over several years, her hand turned cold and painful again. She experienced periods of abnormal blood circulation, sometimes in half of her face. Link to External Page (6)

Then Katherine’s whole body became painful. Nothing helped. Katherine decided to take the risk for being placed in an experimental coma for a week in Germany. The coma provided a few months of relief that began to fade.

Katherine volunteered in a PhotoMed study to learn if the therapy might provide relief. The therapy provided relief from her painful coldness feeling in both of her hands despite that her left hand did not warm.

“Katherine’s abnormal sympathetic modulation of blood circulation in her face. Photo by permission.

“Katherine’s abnormal sympathetic modulation of blood circulation in her face. Photo by permission.

“Katherine” in an experimentally induced coma aimed to “reset” her nervous system to relieve her CRPS. Photo by Permission

“Katherine” in an experimentally induced coma aimed to “reset” her nervous system to relieve her CRPS. Photo by Permission

 

Years before her coma intervention, she had a procedure, called a sympathectomy, that killed the nerve that controls thermoregulation in her left hand. The aim was to force that hand to warm such that she might experience less pain. After a few years, her hand reverted to cold and the pain returned.

Trying PhotoMed’s therapy for her first time

Katherine arrived with pain “like holding ice” in both of her hands. Her hands responded to PhotoMed’s therapy during her first visit. At her second visit, she reported that her pain and unrelenting feeling of piercing coldness disappeared. She slept great without her usual pile of blankets.

Thermal imaging told an interesting story. Her right hand appeared to respond by warming after her second application of PhotoMed’s therapy.

Katherine’s relief from the feeling of coldness didn’t match what happened. Her left hand had continued to cool during the therapy and visit. Her feeling of coldness or warmth appeared to be disconnected from the actual temperature. What happens to your perception of temperature after your hand has been in cold or hot water for a few minutes?

 
 

Figure 4 - Thermal imaging of the response to five 2-minute procedures using varying wavelengths of visible light. Her left hand was unresponsive due to a sympathectomy. She reported that the painful coldness experience was gone in both hands. 11 seconds.

 
 

Katherine’s pain remained low for more than 3 years after her first PhotoMed’s therapy with the help of annual “boosters”. Katherine, if you are reading this, please let us know what happened later.

Stellate ganglion block vs. PhotoMed’s therapy

The stellate ganglion block (SGB) is aimed to provide temporary relief from certain types of pain, such as CRPS, that affect thermoregulation in a single limb. The block shuts off thermoregulation in one hand by anesthetizing the nerve that controls thermoregulation in the limb. The block is used diagnostically to test whether forced warming might relieve pain. If the procedure works, then the pain specialist may consider performing a sympathectomy to kill the nerve. 

 
 

PhotoMed’s “best” model blows up

For nearly 10 years, PhotoMed’s advisors and team used the SGB as a model for how its therapy might work. This was based upon the comparison of effects of the intervention and PhotoMed’s therapy. Both aimed to achieve a warming response and pain relief.

Machine-learning methods uncover key differences:

  • The benefits of the SGB typically wears off after a week or two.

  • The benefits from PhotoMed’s therapy could continue without an expectation of ending.

It was a bit embarrassing for the team when they realized that the long-lasting effects from PhotoMed’s therapy might be the default way the body works. Was it really just homeostasis in action? We’re engineers without an academic stake in this guess. Please let us know if you have another explanation.

Figure 5  - Comparison of the thermal effects of a stellate ganglion block (SGB) vs. PhotoMed’s therapy. For illustration purposes, the starting times and temperatures are aligned.

Figure 5 - Comparison of the thermal effects of a stellate ganglion block (SGB) vs. PhotoMed’s therapy. For illustration purposes, the starting times and temperatures are aligned.

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+ A few more details from Figure 5 that belw up the model

A key observation is that the SGB forces warming by stopping thermoregulation (E), whereas PhotoMed’s non-invasive therapy prompts thermoregulation to return with a shift to a comfortable temperature (C).

The mechanisms for the warming are distinctly different:

  • The non-invasive therapy prompts the bilateral return of normal thermoregulatory controls. (A-B-C)
  • The invasive intervention forces a unilateral loss of normal thermoregulatory controls (D-E) to abnormally increase blood circulation and warming of the hand.
  • The magnitude of some responses appeared astoundingly large at 10 degrees C. We later realized that the magnitude is limited by the initial and maximum available temperatures. In this example, the hands were already warm at nearly their maximum temperatures.

It was the recognition of the difference between prompting and forcing increased circulation that led to the collapse of the comparative model.


 A caution for a diagnostic stellate ganglion block (SGB)

Both the SGB and PhotoMed’s therapy aim for a warming response. People with a variant of CRPS called “hot CRPS” may be adversely affected by a diagnostic SGB.

Thermal imaging, see Figure 6, helps the practitioner distinguish hot vs. cold variants of CRPS:

  • “Cold” typically shows a cooling trend toward the finger tips

  • “Hot” typically shows a warming trend toward the finger tips.

Red and lighter gray represent warmer temperatures.

 
 
Figure 6  - Thermal imaging of variants of CRPS. PhotoMed’s therapy aims to prompt a warming response similar to the stellate ganglion block. Both are thought to reduce vasoconstrictive outflow. Patients with the “hot” variant do not benefit from additional warming.

Figure 6 - Thermal imaging of variants of CRPS. PhotoMed’s therapy aims to prompt a warming response similar to the stellate ganglion block. Both are thought to reduce vasoconstrictive outflow. Patients with the “hot” variant do not benefit from additional warming.

Detection of the “hot” variant CRPS is an important aspect of PhotoMed’s Triple 2 Algorithm. If hot is suspected, the algorithm suggests that the operator apply a “mini” (about 5 seconds) procedure and wait about 1 minute for the patient to notice if their hand(s) are getting even warmer.

Repetitions of the “mini” therapy during different visits has been found to prompt the CRPS to switch from the “hot” to the “cold” variant. Then, the “cold” steps in the algorithm may prompt the return to normal function.

See research by Stephen Bruehl, PhD for details about the warm and cold variants of the disorder. (7)

 
 

Citations

(1) https://my.clevelandclinic.org/health/treatments/17507-stellate-ganglion-block

(2) https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Complex-Regional-Pain-Syndrome-Fact-Sheet

(3) https://anesthesiology.pubs.asahq.org/article.aspx?articleid=1933227 Stephen Bruehl; An Update on the Pathophysiology of Complex Regional Pain Syndrome. Anesthesiology 2010;113(3):713-725. doi: 10.1097/ALN.0b013e3181e3db38.

(4) https://academic.oup.com/brain/article/124/3/587/334375 Gunnar Wasner, Jörn Schattschneider, Klaus Heckmann, Christoph Maier, Ralf Baron, Vascular abnormalities in reflex sympathetic dystrophy (CRPS I): mechanisms and diagnostic value, Brain, Volume 124, Issue 3, March 2001, Pages 587–599, https://doi.org/10.1093/brain/124.3.587

(5) https://www.nhlbi.nih.gov/health-topics/raynauds

(6) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2758836/ Groeneweg G, Huygen FJ, Coderre TJ, Zijlstra FJ. Regulation of peripheral blood flow in complex regional pain syndrome: clinical implication for symptomatic relief and pain management. BMC Musculoskelet Disord. 2009;10:116. Published 2009 Sep 23. doi:10.1186/1471-2474-10-116

(7) https://journals.lww.com/pain/Abstract/2016/08000/Complex_regional_pain_syndrome__evidence_for_warm.16.aspx Complex regional pain syndrome: evidence of warm and cold subtypes in a large prospective clinical sample, Bruehl S, et al. DOI: 10.1097/j.pain.0000000000000569