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Jarred Younger has been waiting for 20 years for the new technology he talks about in his “Reaching Deep Into the Brain” video from his Pain and Fatigue Lab at the University of Alabama at Birmingham.

Some of us have been waiting a lot longer than that (lol), but Younger’s long wait underscores something important. For most of us, the answer probably lies in the development of better technologies, and those technologies simply haven’t been available.

THE GIST

  • tFUS device (From study)

    The tFUS device. An at-home device is being developed.

    Jarred Younger’s research suggests that neuroinflammation in the brain plays a significant role in ME/CFS, fibromyalgia, and long COVID.

  • He’s been waiting for 20 years for a brain stimulation device that can reach deep enough in the brain to impact the areas that play a role in ME/CFS, fibromyalgia, and long COVID.
  • In a “Reaching Deep Into the Brain” video from his Pain and Fatigue Lab at the University of Alabama at Birmingham, Younger described how transcranial focused ultrasound (tFUS) devices use sound waves to precisely reach deep into the brain.
  • These devices can, among other things, switch the microglia from an inflammatory to an anti-inflammatory state.
  • In a second video, “Focused ultrasound reduces chronic pain,” Younger reviewed the results of a recent study which found that tFUS dramatically reduced pain levels in 60% of the participants. The effects were especially noteworthy given the wide variety of pain conditions found in the study, the focus on one specific area of the brain, and the lack of clarity regarding the best dose and duration of the treatment.
  • The study targeted a part of the brain – the subgenual region of the anterior cingulate cortex (ACC) – that has repeatedly been linked to fatigue and pain problems in ME/CFS, fibromyalgia, and long COVID studies.
  • Called the “brain’s alarm center”, the ACC appears to be wired for threat detection. A core component of the descending pain inhibitory pathways, damage to the ACC could result in increased pain sensitivity. By the same token, the ACC’s connection to the salience network could result in increased fatigue.
  • Because the ACC regulates the autonomic nervous system via its connections to the brainstem and the hypothalamus, dysautonomia is a likely result as well.
  • Interestingly, the ACC may be more quickly and intensely impacted by peripheral inflammation (inflammation in the body) than any other organ in the brain. (Peripheral inflammation appears to be particularly effective in producing neuroinflammation in several areas of the brain implicated in these diseases.)
  • Whether the tFUS can be used to directly impact the brainstem – an area of great interest in these diseases – is unclear, but it can impact brainstem activity by targeting areas above it.
  • Once Younger decides on which device to use, he will test it as quickly as possible. If he obtains good early results, expect a clinical trial to conclusively determine how effective it is in these diseases.
  • These devices are already in the process of getting FDA approval, and Younger expected “multiple devices to be available quite soon.” Younger ended by saying, “It’s really exciting to see the rapidly advancing technologies”.
  • It goes without saying how lucky we are to have Younger in our corner. With Younger, we don’t have to wait for advances in brain stimulation like tFUS to filter down over a decade or two to diseases like ME/CFS and fibromyalgia (FM).
  • Time will tell how the tFUS saga goes, but it’s yet another reminder that the technology is moving very quickly and we can’t predict what the future will bring.

 

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Neuroinflammation Buster?

As many people are aware, Jarred Younger is a neuroscientist whose research suggests that microglial and astrocyte-produced neuroinflammation in the brain plays a significant role in ME/CFS, fibromyalgia, and long COVID. We know these diseases are “brain diseases”. We don’t know if the brain is where they start or if the brain is the smoking gun, but we do know that the brain and the central nervous system are significantly affected.

There’s also no doubt that the microglia/astrocytes in the brain that Younger has been so focused on for the past ten years are involved in chronic pain, and probably fatigue. In 2023 ,Younger stated that he was surer than ever that neuroinflammation plays a major role in these diseases.

The Younger Interview: Neuroinflammation, a Brain Invasion?, Psilocybin Trial,and More…

Getting at these microglia, though, has been hard. Many drugs and supplements can’t cross the blood-brain barrier. Non-invasive neuromodulatory techniques are a possibility, and several (transcranial direct current stimulation (tDCS), repetitive Transcranial Magnetic Stimulation (rTMS), Transcranial Alternating Current Stimulation (tACS)) have been tried in ME/CFS/FM. The results have generally been moderate.

One problem has been their inability to penetrate deeply and precisely enough to reach some the structures of the brain that studies show us are involved in these diseases. While these techniques are getting more precise and effective, Jarred Younger is not abuzz about them. He is abuzz, though, about something called transcranial focused ultrasound (tFUS).

Transcranial Focused Ultrasound (tFUS)

tFUS device (From study)

The tFUS device. An at-home device is being developed.

Instead of using magnets, tFUS uses high-frequency sound waves to reach – and this is the key point – any part of the brain…The small wavelengths of the sound waves allow for greater precision than can be achieved with magnets.

By sending sound waves from multiple directions, Younger said that tFUS can precisely modulate neuronal activity. How precise? This technique can open a specific part of the blood-brain barrier, allowing a drug to pass through at that precise part of the brain. The clincher for Younger, though, is tFUS’s ability to switch the microglia from an inflammatory to an anti-inflammatory state.

Since lower intensity soundwaves inhibit neurons while higher intensity soundwaves have an excitatory effect, tFUS has the capability to turn on or off neurons across the brain. In effect, tFUS has the potential to reset malfunctioning brain circuits.

The University of Utah Study

“Targeted noninvasive modulation of deep brain circuits has long been a dream of neural sciences.” the authors

In a second video, Younger went over the main points of a recent study, “Noninvasive targeted modulation of pain circuits with focused ultrasonic waves” from the University of Utah in Salt Lake City.

The study involved a wide variety of chronic pain patients, many of whom had multiple pain conditions. Note that many of these are associated with each other. They included fibromyalgia (10), myofascial pain syndrome (4), generalized pain syndrome (4), migraines (3), back pain (3), neuropathy (3), arthritis (3), chronic fatigue syndrome (2), complex pain syndrome, piriformis syndrome, atypical trigeminal neuralgia, cervical myelopathy, shoulder pain, foot pain, joint pain, endometriosis, scleroderma, dysautonomia, common variable immunodeficiency, temporomandibular joint dysfunction, Guillain–Barré syndrome, Crohn’s disease, and post-cancer pain (!).

tFUS Utah study

Note how precise tFUS is (brain image lower right).

Given the wide variety of conditions, this might not seem like the best group to test a treatment. The researchers clearly thought, though, that fTUS could tackle a wide variety of pain conditions.

First, they did an MRI to determine their target. (The authors believe that, at some point, MRIs will not be required.) In this crossover study, each of the participants, for 40 minutes, received tFUS and a sham procedure twice over a week. During each procedure (real/sham), they were followed for a week.

Results

“The results demonstrate that it is possible to modulate deep brain structures in humans precisely, non-invasively, and in a controlled manner.” The authors

Sixty percent of subjects experienced a clinically meaningful reduction of pain on day 1 and on day 7 following the active stimulation, while sham stimulation provided such benefits only to 15% and 20% of subjects, respectively. On average, the ultrasound reduced pain by 60% immediately, which dropped to 30% by the end of the week.

Younger considered the results impressive given how early we are in this process. Despite the study’s wide variety of conditions, its focus on a specific area, the potential for other areas to work better, and the unknown optimum dose or timing of stimulation, the study still managed to produce significant reductions in pain very quickly. Younger was clear that this is only the beginning and that fTUS will only get more effective over time.

Anterior Cingulate Cortex – Neurological Ground Zero for Post-Infectious Diseases?

Corticolimbic System

(Image from Benes 2010 corticolimbic system Wikimedia Commons)

The Utah researchers targeted the same region of the brain – the subgenual region of the anterior cingulate cortex (ACC) – that Younger said would have been his first choice.

It’s no wonder. The ACC appears to be perfectly positioned to influence key brain regions in these diseases. The ACC is like a hub around which the prefrontal cortex – the seat of executive functioning – and the limbic system (fight/flight) revolve.

Called the “brain’s alarm center”, the ACC appears to be wired for threat detection. If the connection between the prefrontal cortex and the ACC breaks down, as it appears to have in these diseases, and the prefrontal cortex can’t talk to the ACC, the limbic system, with its fight/flight tendencies, is given full rein. A core component of the descending pain inhibitory pathways, damage to the ACC could result in increased pain sensitivity.

By the same token, the ACC’s connection to the salience network could result in increased fatigue. Because the ACC regulates the autonomic nervous system via its connections to the brainstem and the hypothalamus, dysautonomia is a likely result as well.

Interestingly, the ACC may be more quickly and intensely impacted by peripheral inflammation (inflammation in the body) than any other organ in the brain. (Peripheral inflammation appears to be particularly effective in producing neuroinflammation in several areas of the brain implicated in these diseases (hippocampus, ACC, cerebellum, amygdala and substantia nigra (basal ganglia).)

A hyperactive ACC produces pro-inflammatory cytokines that create a feedback loop which triggers more neuroinflammation. Levels of excitotoxic brain chemicals, such as glutamate, increase, while levels of calming brain chemicals, like GABA, decrease.

The ACC in ME/CFS, Fibromyalgia and Long COVID

In FM, the ACC appears to be disturbed in every which way. Decreased gray matter and connectivity in the ACC, decreased connectivity to the prefrontal regions outside the ACC, and elevated markers of neuroinflammation in the ACC have been found in FM.

Altered metabolite levels, reduced cerebral blood flows, and reduced acetylcarnitine uptake have been linked to fatigue, as well as problems with motor planning (movement) in ME/CFS.

Note that a small study found that six weeks of creatine supplementation increased creatine levels in the ACC and decreased fatigue in ME/CFS.

Creatine – An Alternative Mitochondrial Energy Source for ME/CFS, Fibromyalgia, Long COVID?

Similar abnormalities have been found in long COVID (reduced glucose metabolism, neuroinflammation, decreased connectivity).

All in all, ACC issues have been associated with pain, fatigue, and cognitive deficits in these diseases. Indeed, an AI Perplexity analysis suggested that the ACC could be the neurological ground zero for post-infectious illnesses.

Going Even Deeper?

Could tFUS go even deeper and modulate activity and reduce inflammation in that most intriguing part of the brain – the brainstem? Animal studies suggest it can hit the brainstem, but human studies are apparently a ways off. Still, targeting areas upstream of the brainstem, such as the amygdala, has allow tFUS to affect brainstem activity.

The Future

Multiple devices are being produced, and Younger is currently deciding which one he wants to test in these diseases. Once he gets it, he will test it as quickly as possible. If he gets good early results, expect a clinical trial to conclusively determine efficacy in these diseases.

These devices are already in the process of getting FDA approval, and Younger expected “multiple devices to be available quite soon”, and at some point, we can expect devices to be used at home. Younger ended by saying, “it’s really exciting to see the rapidly advancing technologies”.

Jarred Younger 2022

Jarred Younger – we are lucky to have him.

It goes without saying how lucky we are to have Younger in our corner. Younger’s record of innovation – the low-dose naltrexone studies, the dextronaltrexone work underway, the new thermal mapping technique, the immune invasion of the brain work (unpublished as of yet), the Good Day/Bad Day studies, the psilocybin trial, etc. – has been remarkable.

With Younger, we don’t have to wait for advances in brain stimulation like tFUS to filter down over a decade or two to diseases like ME/CFS and fibromyalgia (FM). Take the small fiber neuropathy saga. Given its presence in FM, it made sense for it to be present in ME/CFS, but it took the ME/CFS field six years after SFN had been found in fibromyalgia to start to look for it. Compare that to Younger’s outreach to industry BEFORE the devices have received FDA approval.

Time will tell how the tFUS saga goes, but it’s yet another reminder that the technology is moving very quickly and we can’t predict what the future will bring.

 

Please Support Health Rising and Keep the Information Flowing

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