A NEW QUALITY CONTROL PATHWAY IN THE CELL

Proteins are important building blocks in our cells and each cell contains millions of different protein molecules. They are involved in everything from structural to regulatory aspects in the cell. Proteins are constructed as linear molecules but they only become functional once they are folded into specific three-dimensional structures. Several factors, like mutations, stress and age, can interfere with this folding process and induce protein misfolding. Accumulated misfolded proteins are toxic and to prevent this, cells have developed quality control systems just like any other production chain or manufacturing process

A team of researchers at the Centre for Genomic Regulation in Barcelona has just published a paper inScience describing a new quality control system in our cells. It is specific to the inner nuclear membrane, a specialised part of the endoplasmic reticulum (ER), a network of membranes that spreads throughout the cell and which also forms the nuclear envelope that wraps the chromosomes.

Other quality control systems have been described but exactly how misfolded proteins in the inner nuclear membrane were degraded was not known. Ombretta Foresti, Victoria Rodríguez-Vaello and Pedro Carvalho, from the Organelle Biogenesis and Homeostasis laboratory at the CRG have just described the new system. "We have found that this quality control system has two key functions. It gets rid of misfolded proteins and, surprisingly, it also helps prevent the nucleus accumulating proteins that should not be there," explains Pedro Carvalho, principal investigator of this paper.

The studies have been conducted using a unicellular model organism (Baker's yeast) but they may also apply to human physiology. The newly identified quality control system protects the nucleus by targeting foreign proteins that could enter the nucleus by mistake. This could be particularly significant in non-dividing cells where the inner nuclear membrane is isolated from the rest of the ER for long periods of time

These findings have been made possible thanks to funding from the Howard Hughes Medical Institute (HHMI) and MCCIN at the CRG in Barcelona.

Oxytocin Not Oxycontin! Vital For Control Of Nerve Pain

Today's fascinating post from sciencedaily.com (see link below) talks about another element of our nervous system essential for reducing pain responses naturally and that is Oxytocin. Oxytocin is a peptide that is synthesised in the hypothalamus (The hypothalamus is in the brain and is responsible for certain metabolic processes and other activities of the autonomic nervous system.) What it does when it's released into the blood and spinal cord, is reduce the severity of pain signals to a bearable degree, otherwise they would be too extreme and traumatic and possibly cause a shut-down of all systems (during childbirth for instance). Oxytocin release is controlled by 30 neurons that are situated in the hypothalamus and are essential messengers in the neurological system. Having discovered this nerve control centre (so to speak) scientists will be able to target it to release more oxytocin and diminish the negative effects of certain treatments. It is true, the more this sort of information is released, the more confused we could become (through sheer information overload) but on the other hand, you get the feeling that we are only at the beginning of astounding new discoveries as to how our nervous system works and as long as we can get the gist of what's being discovered as we go along, we can trust the scientists to take their discoveries to logical and beneficial conclusions and eventually relieve nerve pain much easier. Oxytocin is also known as the 'love hormone' but you'll need to Google why!

30 small neurons join forces against pain 
Date: March 3, 2016 Source: CNRS

Oxytocin plays a crucial role in modulating the response to pain, but until now the process leading to its release was unknown. An international team[1], coordinated by Alexandre Charlet, at the CNRS Institut des Neurosciences Cellulaires et Intégratives in Strasbourg (France) and Valery Grinevich from the DKFZ[2] in Germany, has just identified a new pain control center situated in the hypothalamus. It comprises some thirty neurons that are wholly responsible for coordinating the release of oxytocin into the blood and spinal cord, thus reducing painful sensations. These findings, which open new perspectives in the treatment of pathological pain, are detailed in an article published on 3 March 2016 in Neuron.

That hammer blow on the fingers of the weekend DIY enthusiast must have hurt. But it would have been worse if oxytocin, a peptide synthesized by a region in the brain called the hypothalamus, had not intervened very rapidly in the cerebral processes modulating the pain response. From contractions of the uterus during delivery to the release of breast milk after birth, and not forgetting its involvement in regulating social interactions, anxiety or pain, oxytocin is an essential, but currently somewhat mysterious, messenger. Indeed, the mechanisms which lead to its dissemination had never previously been deciphered.

An international team of scientists coordinated by Alexandre Charlet at the CNRS Institut des Neurosciences Cellulaires et Intégratives (France) and Valery Grinevich at DKFZ (Germany) focused on the process underlying oxytocin release when pain is perceived. It discovered that the control center in the brain that coordinates the release of oxytocin only comprises some thirty neurons in the hypothalamus.

During acute pain or inflammatory sensitization (burns, pinching, cuts, etc.), information is transmitted via the peripheral nerves[3] to neurons in the spinal cord. These interpret the intensity of the message and encode it accordingly. The information is then sent to other neurons, which include the small population of 30 small cells in the hypothalamic paraventricular nucleus that has been identified by Alexandre Charlet's team. These in return activate a family of large, magnocellular neurons in another region of the hypothalamus, which release oxytocin into the bloodstream. The target is the peripheral neurons that continue to send the message responsible for pain to the brain. Oxytocin has "anesthetized" them and thus reduced the pain.

However, the thirty controlling neurons do not stop there. In parallel, projections from these cells, or axons, which are up to a meter long in humans, reach the deepest of the ten layers of the spinal cord (where the intensity of the sensory message is encoded) and release oxytocin. Thus via two simultaneous pathways, they diminish retransmission of the pain signal to the brain.

Work by the team has thus explained how different populations of oxytocin neurons are coordinated in order to control interpretation of the "pain" message by the nervous system. Discovery of this analgesic control center is promising in the context of treating pathological pain. Targeting this handful of neurons could indeed diminish the adverse effects of potential therapies. At present, the team is continuing to study them, this time in order to discover their involvement in oxytocin release that enables lactation and certain sexual behaviors.

[1] The team included scientists from the CNRS, Inserm, Université de Strasbourg, DKFZ and other institutions in Germany, Switzerland, China, Italy and the US.

[2] Deutsches Krebsforschungszentrum (German Cancer Research Center).

[3] The peripheral nerves link different organs to the central nervous system, made up of the brain and spinal cord.

Story Source:

The above post is reprinted from materials provided by CNRS. Note: Materials may be edited for content and length.

Journal Reference:
Marina Eliava, Meggane Melchior, H. Sophie Knobloch-Bollmann, Jérôme Wahis, Miriam da Silva Gouveia, Yan Tang, Alexandru Cristian Ciobanu, Rodrigo Triana del Rio, Lena C. Roth, Ferdinand Althammer, Virginie Chavant, Yannick Goumon, Tim Gruber, Nathalie Petit-Demoulière, Marta Busnelli, Bice Chini, Linette L. Tan, Mariela Mitre, Robert C. Froemke, Moses V. Chao, Günter Giese, Rolf Sprengel, Rohini Kuner, Pierrick Poisbeau, Peter H. Seeburg, Ron Stoop, Alexandre Charlet, Valery Grinevich. A New Population of Parvocellular Oxytocin Neurons Controlling Magnocellular Neuron Activity and Inflammatory Pain Processing. Neuron, 2016; DOI: 10.1016/j.neuron.2016.01.041

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https://www.sciencedaily.com/releases/2016/03/160303133628.htm

PROGRAM PREDICTS PLACEMENT OF CHEMICAL TAGS THAT CONTROL GENE ACTIVITY

Biochemists working at the University of California, San Diego, have developed a program that predicts the placement of chemical marks that control the activity of genes based on sequences of DNA. They describe their analysis and report results from its application to human embryonic cells in a paper published in Nature Methods online September 21

"All of our cells have the same blueprint, the same DNA, although they serve separate functions," said John Whitaker, lead author of the report. "Skin cells protect, nerve cells send signals, and these differences emerge because different subsets of genes are active or silent within particular kinds of cells."

These patterns of activity are controlled by modifications of the DNA that do not alter its sequence -- chemical tags that influence which genes are read and which are skipped within a particular cell.

By comparing sequences with and without epigenomic modification, the researchers identified DNA patterns associated with the changes. They call this novel analysis pipeline Epigram and have made both the program and the DNA motifs they identified openly available to other scientists.

"The interplay between genetic and epigenomic regulation has only begun to be deciphered," said Wei Wang, professor of chemistry and biochemistry who directed the work. "This study revealed that there are specific DNA sequences that are recognized by DNA-binding proteins," which specify exactly where other enzymes place epigenomic marks.

The epigenome guides the development of complex organisms from single fertilized eggs. The researchers analyzed epigenomic patterns in human embryonic stem cells and four cell lineages derived from them to catalogue genetic elements that shape the epigenome during development.

Damage to the epigenome not only disrupts development, but can happen at any point in our lives and sometimes leads to illness. Identification of the DNA sequences that guide the placement of epigenomic could guide experimental analysis, the authors say. By editing DNA sequences that control epigenomic modifications, scientists could probe their functions and perhaps in the future mend epigenomic mistakes that cause harm.

BIOLOGISTS DELAY THE AGING PROCESS BY REMOTE CONTROL

U CLA biologists have identified a gene that can slow the aging process throughout the entire body when activated remotely in key organ systems

Working with fruit flies, the life scientists activated a gene called AMPK that is a key energy sensor in cells; it gets activated when cellular energy levels are low.

Increasing the amount of AMPK in fruit flies' intestines increased their lifespans by about 30 percent -- to roughly eight weeks from the typical six -- and the flies stayed healthier longer as well.

The research, published Sept. 4 in the open-source journal Cell Reports, could have important implications for delaying aging and disease in humans, said David Walker, an associate professor of integrative biology and physiology at UCLA and senior author of the research.

"We have shown that when we activate the gene in the intestine or the nervous system, we see the aging process is slowed beyond the organ system in which the gene is activated," Walker said.

Walker said that the findings are important because extending the healthy life of humans would presumably require protecting many of the body's organ systems from the ravages of aging -- but delivering anti-aging treatments to the brain or other key organs could prove technically difficult. The study suggests that activating AMPK in a more accessible organ such as the intestine, for example, could ultimately slow the aging process throughout the entire body, including the brain.

Humans have AMPK, but it is usually not activated at a high level, Walker said.

"Instead of studying the diseases of aging -- Parkinson's disease, Alzheimer's disease, cancer, stroke, cardiovascular disease, diabetes -- one by one, we believe it may be possible to intervene in the aging process and delay the onset of many of these diseases," said Walker, a member of UCLA's Molecular Biology Institute. "We are not there yet, and it could, of course, take many years, but that is our goal and we think it is realistic.

"The ultimate aim of our research is to promote healthy aging in people."

The fruit fly, Drosophila melanogaster, is a good model for studying aging in humans because scientists have identified all of the fruit fly's genes and know how to switch individual genes on and off. The biologists studied approximately 100,000 of them over the course of the study.

Lead author Matthew Ulgherait, who conducted the research in Walker's laboratory as a doctoral student, focused on a cellular process called autophagy, which enables cells to degrade and discard old, damaged cellular components. By getting rid of that "cellular garbage" before it damages cells, autophagy protects against aging, and AMPK has been shown previously to activate this process.

Ulgherait studied whether activating AMPK in the flies led to autophagy occurring at a greater rate than usual.

"A really interesting finding was when Matt activated AMPK in the nervous system, he saw evidence of increased levels of autophagy in not only the brain, but also in the intestine," said Walker, a faculty member in the UCLA College. "And vice versa: Activating AMPK in the intestine produced increased levels of autophagy in the brain -- and perhaps elsewhere, too."

Many neurodegenerative diseases, including both Alzheimer's and Parkinson's, are associated with the accumulation of protein aggregates, a type of cellular garbage, in the brain, Walker noted.

"Matt moved beyond correlation and established causality," he said. "He showed that the activation of autophagy was both necessary to see the anti-aging effects and sufficient; that he could bypass AMPK and directly target autophagy."

Walker said that AMPK is thought to be a key target of metformin, a drug used to treat Type 2 diabetes, and that metformin activates AMPK.

The research was funded by the National Institutes of Health's National Institute on Aging (grants R01 AG037514 and R01 AG040288). Ulgherait received funding support from a Ruth L. Kirschstein National Research Service Award (GM07185) and Eureka and Hyde fellowships from the UCLA department of integrative biology and physiology.

Co-authors of the research were Anil Rana, a postdoctoral scholar in Walker's lab; Michael Rera, a former UCLA postdoctoral scholar in Walker's lab; and Jacqueline Graniel, who participated in the research as a UCLA undergraduate.

Mind Control For Pain

Today's article from psychologytoday.com (see link below) looks at the potential for a 'mind-over-matter' solution for chronic pain. It's sensibly and realistically written and once again, some people may gain significant relief by following up some of the suggestions. Others may react with a hollow laugh because their pain is so much bigger than any of the mind tools shown here. Sometimes, it's a question of 'matter-over-mind'.

Mind Control: Coping with Chronic Pain

I can see for miles.

Published on April 30, 2011 by Dr. Mark Borigini, M.D. in Overcoming Pain

We are told this: The mind is able to control the body. For the chronic pain patient who may have seemingly exhausted treatment options, this notion of mind over matter takes on a hopeful urgency.
When there is some sort of injury or insult causing pain, the signal conveying pain travels to the brain via a sensory pathway and an emotional pathway. This emotional aspect of the experience of pain travels to the parts of the brain known as the amygdale and the anterior cingulated cortex. The mind-body treatments that involve such activities as meditation and relaxation likely affect these emotional networks.

Researchers have used functional magnetic resonance imaging to allow chronic pain patients to "visualize" pain. These images allow a patient to actively participate in manipulating what has heretofore been an amorphous concept. The chronic pain patient becomes empowered, whether it be through yoga, biofeedback, or meditation.

Any such coping technique for chronic pain should begin with controlled deep breathing:

1. It is best to be in a relaxed position in a dark room, with eyes closed or focused on a point.

2. Breathe deeply, while continuing to focus.

3. Continue with controlled breathing for a few minutes.

4. If you sense this control of respirations is allowing for a slowing down of breathing, then try a particular imagery technique.

Examples of imagery and chronic pain control techniques include:

1. Focus on a non-painful body part, and see whether this diverts the mind away from focusing on, say, chronic back pain.

2. Mentally separate the painful body part from the remainder of the body; use dissociation to keep the pain away.

3. Divide different sensations of pain into separate parts: If a patient feels burning associated with pain, he or she might find it helpful to focus solely on the burning sensation, and not on the pain by using such sensory splitting.

4. Imagine a numbing injection of some miraculous medicine.

5. "Travel" back in time, when the patient was pain free.

6. Imagine a symbol for one's chronic pain, for example, a loud noise; turn the volume down, and reduce the pain.

7. Use positive imagery to focus on something pleasant.

8. Count silently to divert the mind from the chronic pain.

These tasks seem silly to some; or at best, self-evident. But for some chronic pain patients, they do help. A professional may be needed during the learning process; and it may take practice before these techniques have an impact on the chronic pain patient. Such a patient should work on these pain coping mental exercises at least 30 minutes three times a week.

You know you are good when you can reduce pain and increase relaxation with a few deep breaths. The sense of control that accompanies such mastery in and of itself can be responsible for a significant reduction in chronic pain.

http://www.psychologytoday.com/blog/overcoming-pain/201104/mind-control-coping-chronic-pain

Brain Implants To Control Pain The Way Forward

Today's post from painresearchforum.org (see link below) is one of those that gives hope for the future but makes us wish that the future was a little bit closer by. It talks about transcranial magnetic stimulation, which means that drugs can be avoided by means of an implant in the brain which alters circuit activity in the brain itself. This means that pain signals can be interrupted, or controlled. It's a complex, scientific article but simply enough explained to give you a good idea of what is meant. The article does warn that this procedure is not without its doubters and maybe risks and needs to be refined so that its results prove beyond doubt that it's an effective treatment. However, such warnings are reassuring to the reader that it's being taken seriously and it's clearly a promising development for future pain control without having to resort to drugs and medications. Another case of 'watch this space'.


Transcranial Magnetic Stimulation: The Next Wave in Pain Treatment?
Non-invasive technique shows promise but needs more study
by Stephani Sutherland on 3 Oct 2013 
 
Electrical stimulation of the motor cortex was established as an effective treatment for pain 20 years ago, but the risks and drawbacks of surgically implanting electrodes in the brain keep many patients from pursuing this invasive treatment (Tsubokawa et al., 1991; Kurata, 1993; Nguyen et al., 2011). What if there was a safer, non-invasive way to deliver analgesic neurostimulation? Transcranial magnetic stimulation (TMS) holds out promise as just such a next-generation pain treatment. In TMS, a magnetic field generated outside the head alters circuit activity inside the brain. TMS was approved in 2008 by the U.S. Food and Drug Administration for treatment of major depression, and researchers are investigating TMS for a number of other neurological conditions, including chronic, intractable pain.

Anne Louise Oaklander, a neurologist and pain researcher at Massachusetts General Hospital, Boston, US, said there is much work to be done, but the potential payoff of TMS for pain makes it well worth pursuing. “It has a huge potential advantage over pain medications,” she said. Drugs move indiscriminately throughout the body, often causing side effects at non-target tissues that limit their use or even prevent them from getting into the clinic. TMS, by contrast, delivers its therapeutic effects directly to the brain, with only minor, local side effects. “That is the trump card of TMS over drugs,” Oaklander said.

The evidence

Because TMS can modulate brain circuits safely and painlessly, the technique has had tremendous utility for studying pain processing, said Jean-Pascal Lefaucheur, a pioneer in the field of neurostimulation for pain at the Université Paris-Est, Créteil, France. Lefaucheur and his colleagues recently reviewed some of the hundreds of small studies that have examined the effects of TMS on evoked pain in experimental settings (Mylius et al., 2012). (In a separate review, Lefaucheur and colleagues recently discussed the mechanisms of action and the clinical indications of TMS for non-invasive stimulation therapy of pain disorders; see Nizard et al., 2012.)

Clinically, TMS is routinely used as a screening technique to predict a patient’s reaction to cortical stimulation before surgical implantation of electrodes, said Lefaucheur. A person who responds to TMS will almost always benefit from brain stimulation with implanted electrodes, he said. If a patient could receive the same benefit without implantation surgery, all the better.

But few studies have addressed the technique’s clinical efficacy. A 2010 Cochrane Review of non-invasive brain stimulation aimed at chronic pain looked at the accumulated data and concluded that high-frequency TMS showed a small but consistent reduction in patient-reported pain scores compared to sham treatment (O’Connell et al., 2010). Most of the studies’ participants had chronic, intractable neuropathic pain, and TMS produced a small and transient decrease in pain scores by about 15 percent for up to a week. However, inadequate sham controls and blinding may have exaggerated this effect, said lead author Neil O’Connell, Brunel University, Uxbridge, UK.

Although the pooled data involving just 368 subjects in 19 trials did not provide Neil O’Connell evidence of a clinically meaningful, long-term analgesic effect of TMS, O’Connell said one could yet emerge with further study. It is difficult to synthesize the results of small, heterogeneous studies, he told PRF. While it would be premature to roll out TMS clinically for pain, “I absolutely encourage scientists to study it more,” O’Connell said. “I am not saying it will not be useful [in the clinic], just that substantial uncertainty remains.” An updated review now in preparation will include more studies, but the conclusions for TMS will not change drastically, O’Connell said.

The rationale

All brain stimulation techniques work by activating neural circuitry. With TMS, a figure eight-shaped plastic paddle containing a coiled wire is placed over the head and briefly charged with high-intensity current, inducing a magnetic field that passes into the brain. Just as a wire placed in a magnetic field will carry current, so do axons. Neurostimulation therapy, Lefaucheur explained, prompts axons to fire action potentials and thereby influences circuits. “It is not [just] a local stimulation. You can stimulate local, short circuits or circuits with distant projections,” he said. Accordingly, TMS of the richly connected cortex can modulate the activity of structures deep within the brain.

Perhaps because its effects go beyond the cortex, David Yeomans TMS seems to affect different aspects of the experience of pain. “Pain is not a monolithic entity,” said David Yeomans, a pain researcher at Stanford University, California, US. Just as pain can arise from a variety of sources, so does it vary in its qualities and characteristics—for example, our discriminative sense feels the bodily sensation of pain, but the emotional aspects of pain cause our suffering.

Cortical stimulation seems to affect both these components, said Lefaucheur. Improvement of the sensory discrimination of pain might arise from modulation of descending inhibition circuits, which pass through the thalamus en route to brainstem structures and the spinal cord. In contrast, changes in the emotional aspects of pain likely arise from effects on the brain’s limbic circuitry, he explained.

Like any treatment, people do not respond uniformly to TMS; patients may see improvement in one aspect of the pain experience but not the other.

In practice

Further complicating the clinical understanding of TMS are the endless variations in its delivery. In clinical studies, the motor cortex has emerged as the clear winner in terms of where to target TMS for pain; the few studies that were aimed at dorsolateral prefrontal cortex—the bullseye for treating depression—were ineffective for pain (O’Connell et al., 2010). But the clarity ends there when it comes to the details of effective stimulation. Where, for example, within the motor cortex should one stimulate? One might aim intuitively at the cortical real estate representative of the painful area, but experts agree that the analgesic effects do not correspond to the somatotopic map.

Repetitive TMS (rTMS), in which a series of pulses is delivered in rapid succession within a single session, has emerged as the preferred method, but the protocol can be highly variable in details such as pulse frequency, stimulation intensity, and timing and duration of the treatments—for how long and how often should rTMS be delivered? The exact best technique is likely to vary for different people with different types of pain. Most clinical studies have used a pulse frequency somewhere between 1 and 10 hertz, with high-frequency stimulation consistently producing better effects than low-frequency (O’Connell et al., 2010).

It now seems clear that any long-lasting effects on pain will require multiple sessions of rTMS. In addition to the clinical evidence for the treatment’s transient nature, one current theory of how rTMS works also fits with the need for ongoing sessions. Multiple sessions of rTMS might affect the brain’s connectivity much like learning does. When you learn to play the piano or speak a new language, Oaklander said, “you create new synapses and you lose others; you change your brain.” If TMS engages the same types of synaptic plasticity, many treatments might be required to reshape signaling in circuits molded by chronic pain. As for how many, Oaklander said, “Nobody knows how often it needs to be repeated.” Treatments might be required daily at first and then as often as weekly for months or even years.

The updated Cochrane Review will include several studies of multiple sessions, O’Connell said, which were absent from the 2010 review. In one recent small study, a course of 14 rTMS sessions over 21 weeks for fibromyalgia resulted in long-term improvements in pain and quality-of-life scores (Mhalla et al., 2011). But even repeated treatments might not change the brain enough to provide lasting relief for some. The first randomized, multicenter, sham-controlled trial of repeated rTMS for neuropathic pain showed that 10 daily 5 Hz sessions provided only short-lived benefits with no cumulative effects (Hosomi et al., 2013).

Youichi Saitoh, a neurosurgeon at Osaka University in Japan and lead author of that study, believes that relief from neuropathic pain will require indefinite treatment with rTMS. Even in patients with implanted electrodes who have used neurostimulation for 10 years, analgesia does not last beyond about a day, Saitoh told PRF in an email. That leads him to think that rTMS does not lead to permanent neuroplastic changes in the pain processing system, he said.

Some researchers are investigating whether multiple sessions of rTMS cause structural remodeling in the brain. Neuropathic pain leads to well-documented structural changes in the brain, for example in the cingulate cortex (May, 2008). Yeomans and his colleagues plan to use brain imaging to investigate whether those changes might be reversed following a course of treatment with rTMS.

In practice, the delivery of TMS over multiple sessions remains a challenge because of the need to reproducibly target a specific brain area from outside of the head. Newly developed magnetic resonance imaging (MRI)-guided neuro-navigation can help the technician to hit the intended mark, but it remains to be seen whether the exceedingly expensive technique will be worth the price tag.

The cutting edge

One property—some would say limitation—of TMS is that it can only reach regions that lie within centimeters of the brain’s surface. Could pain pathways be better

In MRI-guided TMS, the operator holds the figure-eight coil to the patient’s scalp while monitoring the brain stimulation site on the three-dimensional MRI. Stereotactic spheres mounted on the coil identify its position relative to the spheres on the goggles that localize the patient’s head. Credit: Roi Treister, Massachusetts General Hospital, Boston, UStargeted at deeper structures? Several groups are asking that question. Brainsway, a company in Israel, has developed an “H-coil” to deliver what they call deep TMS. In a recent study, researchers used the H-coil to target the area of the motor cortex representing the leg, deep in the central sulcus, in subjects with diabetic neuropathy and saw pain relief that lasted up to three weeks (Onesti et al., 2013). In other work, Yeomans and his collaborators used four coils and what he described as “high-level math” to model how the combined coils might “shape” magnetic fields to direct currents deep into the brain (Tzabazis et al., 2013). They aimed at the dorsal anterior cingulate cortex (dACC), an area Yeomans says is activated by any experience of pain, according to neuroimaging studies. In their study, both acute pain in healthy subjects and chronic pain in subjects with fibromyalgia were attenuated by rTMS.

Although leading researchers in the field were supportive of these exploratory forays into the deeper reaches of TMS, they overwhelmingly agreed that what is most needed is a better fundamental understanding of the technique. Who might benefit most from TMS—people with neuropathic pain or other forms of pain? What is the optimal stimulation site, at what device settings, when and for how long? And what will benefits look like? How might TMS treatment interact with analgesic drugs? All of these basic questions remain unanswered. “It is a very complicated problem,” said Lefaucheur. “We need a large series of patients to clearly determine the correlations” among all these factors, he said.

O’Connell agreed and in a 2011 editorial (O’Connell and Wand, 2011) argued that rather than develop new coil configurations, researchers should prioritize robust Anne Louise Oaklander but basic studies of TMS. “Large, well-controlled studies are needed to test whether that early promise is real,” he said. Oaklander and her team recently wrote a review of TMS (Treister et al., 2013, in press in Rambam Maimonides Medical Journal) and have applied for funding for the planning stage of a large-scale clinical trial of TMS for neuropathic pain. This October, the Radcliffe Institute of Harvard University will host a gathering of scientists, clinicians, and regulatory agents to set out a path to designing such a trial. (Click here for more information; interested researchers are invited to a poster session and reception associated with the workshop.)

Other non-invasive stimulation techniques are being investigated, too, including transcranial direct current stimulation (tDCS) and cranial electrotherapy stimulation (CES), in which electrodes applied to the scalp deliver low-intensity current directly. Much fewer data are available for these modalities compared to TMS: The Cochrane review of six small studies suggested tDCS might provide a slight benefit for pain, but the updated review of data suggests no significant effect over sham stimulation, O’Connell said. CES appeared to provide no benefit in four studies reviewed.

The bottom line

Even if the promise of TMS for pain holds up, the technique surely will not be a panacea. “The main limitation for TMS is the short duration of its [analgesic] effect,” said Lefaucheur. “It may not be feasible for some refractory, chronic neuropathic pain,” he said, considering the ongoing need for treatment that is costly, time-consuming, and requires technical expertise for delivery. Lefaucheur has had several patients with neuropathic pain who initially shunned electrode implantation for rTMS, but after a year of the toil of monthly treatments, they eventually opted for surgery.

In Japan, Saitoh and his colleagues are working to make daily rTMS treatment more accessible by developing a cheap, user-friendly rTMS machine for everyday home use. He hopes such a device will eliminate the need for electrode implantation.

Overall, TMS may be more useful to treat acute forms of pain and pain that is not so refractory to other treatments, Lefaucheur concluded. In treating depression, TMS is often used for a few days during an acute depressive episode, and “there can be a synergy between stimulation and [antidepressant] drugs,” Lefaucheur said. But with refractory, chronic pain, “the pain is constant, and the drugs do not work well.” Such conditions may require ongoing treatment in repeated sessions.

Despite the caveats and the need for more study, researchers were hopeful that rTMS could turn out to be useful in the pain clinic. David Brock, Medical Director at Neuronetics, Malvern, Pennsylvania, US, a company that makes the TMS machines widely used in clinics for depression, likens TMS to a Swiss Army knife. “We have figured out how to use one blade—for depression—but it has so many other potential tools. We just have to figure out how to use them,” he said. If TMS can change the disease state of chronic pain without drugs, as it has for depression, Brock said, “that would be a real boon to patients and society.”

Stephani Sutherland, PhD, is a neuroscientist, yogi, and freelance writer in Southern California.

http://www.painresearchforum.org/news/32343-transcranial-magnetic-stimulation-next-wave-pain-treatment