Transcranial magnetic stimulation

TMS Proves Long-Term Relief for Depression

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Over two thirds of participants responded to the treatment, with a third showing 50% improvement in terms of their symptoms and a fifth managing to move into remission and stay there. Credit: Neuroscience News

Summary: A major clinical trial, BRIGhTMIND, reveals that MRI-guided Transcranial Magnetic Stimulation (TMS) significantly eases symptoms of severe depression for at least six months.

The study, involving five centers across England, marks a substantial advancement over previous TMS treatments, which showed improvements lasting only 1-3 months. The trial demonstrated that precise targeting of brain areas using MRI neuronavigation in TMS treatment leads to sustained improvement in depression, anxiety, and cognitive function.

This research is particularly impactful for patients with treatment-resistant depression (TRD), offering hope for longer-lasting symptom relief with potentially just one or two treatment courses per year.

Key Facts:

  1. MRI-guided TMS significantly improved depression and anxiety symptoms for up to six months.
  2. Over two-thirds of participants responded to treatment, with a third showing a 50% improvement and a fifth achieving sustained remission.
  3. The study’s success has led three NHS Mental Health Trusts to offer TMS services for treatment-resistant depression.

Source: University of Nottingham

A major clinical trial has shown that by using MRI and tracking to guide the delivery of magnetic stimulation to the brains of people with severe depression, patients will see their symptoms ease for at least six months, which could vastly improve their quality of life.

The results of the trial, published in Nature Medicine, found that on average, participants showed substantial improvements in the severity of their depression, anxiety and thinking with better function and quality of life over 26 weeks with MRI neuronavigated Transcranial Magnetic Simulation (TMS). This was a substantial increase on the previous reported improvements lasting only 1-3 months.

The BRIGhTMIND randomised controlled trial was led by experts at the University of Nottingham, hosted by Nottinghamshire Healthcare NHS Foundation Trust, and was funded by a National Institute for Health and Care Research (NIHR) and Medical Research Council (MRC) partnership. It involved five centres across England (Nottingham, Camden and Islington, Newcastle, Northampton and Oldham).

Transcranial Magnetic Simulation (TMS)

TMS is an outpatient treatment where people have powerful magnetic pulses delivered to the left side of their head just in front of the temporal area of the scalp. The person is conscious and has 20 sessions over a four-to-six-week period.

The method has been used since the 1980s to treat people with severe depression, but by targeting the precise area of the brain where stimulation is thought to be helpful, we now have evidence for a more longer lasting benefit of this treatment.

Major depression is the leading cause of disability lost years worldwide (WHO, 2017), and suicide from depression is the biggest killer in people aged between 15-49.

Antidepressants and therapy delivered as first or second-line treatments help two thirds of people with depression, but the remaining third have treatment resistant depression (TRD). This is defined as a lack of response to two courses of antidepressants.

The aim of the trial was to look at whether the effects of using TMS could be extended to at least six months, which would mean that patients with TRD who respond to the treatment might only require one to two courses of treatment each year to remain relatively well and free from symptoms of depression.

Neuronavigation

The trial, which is the first of its size in the world to look at outcomes at six months, suggest this might be achieved using functional MRI with TMS to define the exact area of the brain to hit. MRI is not normally used to deliver this treatment.

The team used neuronavigation, a computerised tracking system using light to deliver the TMS, which is a way of precisely pinpointing the area of stimulation so that the same area is targeted at all 20 treatment sessions.

Richard Morriss, Professor of Psychiatry in the School of Medicine and Lead for the Centre for Mood Disorders at the Institute of Mental Health at the University of Nottingham, said: “Ideally when people come for a TMS session, they would sit in the exact same place, but this is rarely going to happen.

“This method uses light from both ear lobes and the top of the nose to measure the stimulation point from the first time a patient has the treatment. The MRI personalises the site of stimulation and then neuronavigation makes sure the same site is being stimulated at each treatment session.

“This reduces the variability in stimulation at each session. Since the magnetic pulse can be focused, there are usually only minor short-lasting side-effects, and the person can return to their daily activities immediately on return from the hospital.”

A total of 255 participants took part in the trial, all completing 20 TMS sessions. Patients already in specialist mental health services were recruited, and both Primary Care trusts and GPs were approached, with all participants having to be referred by their GP to take part.

Substantial improvement in quality of life

Over two thirds of participants responded to the treatment, with a third showing 50% improvement in terms of their symptoms and a fifth managing to move into remission and stay there.

“Given these patients are people who have not responded to two previous treatment attempts and have been ill for an average of 7 years, to get such a significant response rate and a fifth who have a sustained response is really encouraging,” said Professor Morriss.

He adds: “Patients who responded to the treatment could stay relatively well compared to how they were previously, with as little as one or two treatments a year. The changes we saw were substantial, not only in reducing their depression symptoms, but they were large enough to improve concentration, memory, anxiety and subsequently their quality of life.

“The results have already persuaded three NHS Mental Health Trusts, including Nottinghamshire Healthcare NHS Foundation Trust, to routinely offer new TMS services for treatment resistant depression.”

One of the participants of the trial said: “It has been a privilege to work alongside the research and clinical teams and feel that you are making an important contribution to such a groundbreaking study from a patient perspective. The next challenge is to make transcranial magnetic stimulation a standard and universally available treatment option for difficult to treat depression.”

Professor Danny McAuley, Scientific Director for NIHR Programmes, said: “Once again, high quality research funded by NIHR and MRC is making a step change in improving health and care services. It’s brilliant to see three UK mental health trusts are now routinely offering TMS to patients following robust evidence from this study.

“These are important findings showing this novel technique can hugely benefit patients with severe depression which has not responded to other treatments.”

Abstract

Connectivity-guided intermittent theta burst versus repetitivetranscranial magnetic stimulation for treatment-resistant depression: arandomized controlled trial

Disruption in reciprocal connectivity between the right anterior insula and the left dorsolateral prefrontal cortex is associated with depression and may be a target for neuromodulation.

In a five-center, parallel, double-blind, randomized controlled trial we personalized resting-state functional magnetic resonance imaging neuronavigated connectivity-guided intermittent theta burst stimulation (cgiTBS) at a site based on effective connectivity from the right anterior insula to the left dorsolateral prefrontal cortex.

We tested its efficacy in reducing the primary outcome depression symptoms measured by the GRID Hamilton Depression Rating Scale 17-item over 8, 16 and 26 weeks, compared with structural magnetic resonance imaging (MRI) neuronavigated repetitive transcranial magnetic stimulation (rTMS) delivered at the standard stimulation site (F3) in patients with ‘treatment-resistant depression’. P

articipants were randomly assigned to 20 sessions over 4–6 weeks of either cgiTBS (n = 128) or rTMS (n = 127) with resting-state functional MRI at baseline and 16 weeks. Persistent decreases in depressive symptoms were seen over 26 weeks, with no differences between arms on the primary outcome GRID Hamilton Depression Rating Scale 17-item score (intention-to-treat adjusted mean, −0.31, 95% confidence interval (CI) −1.87, 1.24, P = 0.689).

Two serious adverse events were possibly related to TMS (mania and psychosis). MRI-neuronavigated cgiTBS and rTMS were equally effective in patients with treatment-resistant depression over 26 weeks

Magnets can help ‘reset’ depressed brains, study finds .

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Researchers have shown that non-invasive magnetic pulses can reset unhealthy activity in a region of the brain known to be overactive in patients with depression.

The technique is known as transcranial magnetic stimulation (TMS), and has been shown to treat persistent depression, as well as boost people’s memories, aid Parkinson’s sufferers, and help stroke patients to speak again. But this is the first time researchers have shown exactly how it works on a neurological level, and the results are pretty impressive.

“We found that one session of TMS modifies the connectivity of large-scale brain networks, particularly the right anterior insula, which is a key area in depression,” lead scientist Sarina Iwabuchi, from the University of Nottingham in the UK, told the European College of Neuropsychology at a conference in Amsterdam, where the research was presented.

The right anterior insula is part of the prefrontal cortex, and overactivity in the region is linked to excessive rumination, self-absorption and impaired attention in depressed patients. But after delivering powerful magnetic pulses directly to this area in 16 healthy controls and 16 patients with major depressive disorder, the study showed that TMS could slow the activity in this region down in those with depression.

Even better is the fact that TMS is drug-free and painless – the only known side effect is the occasional headache. The technique simply requires a device to be applied to a patient’s head. But even though TMS was approved for limited use in the treatment of depression by the US Food and Drug Administration (FDA) in 2008, it’s still not widely used.

This is the first study to guide TMS pulses with functional MRI scans, and then measure the changes it produced in the brain, and the results suggest that the treatment may offer a much-needed alternative for the one-third of patients who don’t respond to traditional medications such as Lexapro and Prozac.

Currently these patients are recommended to try electroconvulsive therapy (ECT), or electric shock therapy as it’s sometimes known, which can be effective but requires anaesthesia and has been associated with side effects such as memory loss. A more targeted form of short electric pulses has been shown to be far gentler, but still requires patients to go under general anaesthetic and several treatment sessions. Scientists also still don’t really quite understand how ECT works.

TMS on the other hand doesn’t require any medication and appears to begin working after just one session. Importantly, this new study outlines the neurological changes that appear to be driving the positive results.

Of course, there are some big limits to this research, not least of all its small sample size. It also doesn’t provide evidence on how long-lasting these neurological changes are. But it’s been 30 years since we had a truly new treatment for depression, and so the research provides some much-needed hope for patients and their families.

“These findings are an exciting step in understanding how targeting the brain activity with magnetic stimulation may exert beneficial effects in the treatment of depression,” Catherine Harmer, a neuroscientist from the University of Oxford who wasn’t involved in the study told Amy Ellis Nutt over at TheWashington Post on behalf of the European College of Neuropsychology. “TMS techniques are still evolving … This kind of experimental medicine study is therefore essential for the improved personalisation and treatment of depression in the future.”

FDA Approves Implantable Neurostimulator for Epilepsy.

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The US Food and Drug Administration (FDA) today approved an implantable neurostimulator to reduce the frequency of seizures in patients with epilepsy whose condition is not successfully managed with medication.

The device, called the RNS System (Neuropace, Inc), detects abnormal electrical activity and delivers a remedial dose of electricity before the patient experiences seizures. It contrasts with neurostimulators for other conditions that provide continuous or scheduled stimulation.

The RNS System is implanted inside the skull under the scalp. Its 1 or 2 electrodes are situated near the patient’s seizure focus or foci in the brain.

The FDA based its decision on a clinical trial involving 191 patients with drug-resistant epilepsy who received the implanted device. However, the device was turned on in only half the patients. After 3 months, patients with activated neurostimulators experienced almost a median 34% reduction in the average number of seizures per month. For patients with unactivated devices, the median reduction was 19%. Twenty-nine percent of patients with activated devices had at least a 50% reduction in the overall number of seizures, compared with 27% with turned-off devices.

In February, a 13-member FDA advisory panel recommended approval of the RNS System. The majority of panelists found that the device beneficial, and that the benefits outweighed the risks. There was unanimous agreement that the RNS System was safe.

Implant site infection and premature battery depletion were the most common adverse events reported during the clinical trials.

The FDA cautioned that patients with the RNS System must avoid MRI procedures, diathermy procedures, electroconvulsive therapy, and transcranial magnetic stimulation.

“The energy created from these procedures can be sent through the neurostimulator and cause permanent brain damage, even if the device is turned off,” the agency said in a news release.

Vagus Nerve Stimulation for Children With Epilepsy.

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The Vagus Nerve Stimulator

The first vagus nerve stimulator (VNS) was implanted in 1988.[1]Since then, more than 70,000 have been implanted for epilepsy worldwide.[2]

The VNS consists of a generator, typically implanted in the chest, and an electrode surgically fastened to the left vagus nerve. In addition, an external handheld magnet may be used if the patient senses an aura or to stop a seizure already in progress.

US Food and Drug Administration Approval

In 1997, VNS received US Food and Drug Administration (FDA) approval for the adjunctive treatment of refractory seizures in patients older than 12 years.[3] In 2005, the VNS was approved for the treatment of chronic or recurrent depression in patients older than 18 years.

VNS may also have a beneficial effect on mood in patients with epilepsy in addition to its antiepileptic effect.[1] The mechanism of action of VNS is uncertain, but may be related to metabolic activation of brain stem, limbic, or thalamic structures.[4]

To date, the VNS is the only FDA-approved medical device for the treatment of epilepsy. However, other approaches, such as deep-brain stimulation of the anterior nucleus of the thalamus, responsive neurostimulation, trigeminal nerve stimulation, and transcranial magnetic stimulation, are in development.

Phase 3 Trials for Epilepsy

A randomized, multicenter, clinical trial (Study E03) of 114 patients with partial seizures demonstrated a mean seizure reduction of 31% and a 50% seizure reduction in 39% of patients.[5] A second randomized trial (Study E05) of 254 patients with intractable partial seizures demonstrated an average reduction in seizure frequency of 28% in the high-stimulation group vs a 15% reduction in the low-stimulation (pseudo-placebo) group (P = .04).[4] These results are modest, but similar to those obtained with new antiepileptic drugs in phase 3 trials. Unlike antiepileptic drugs, VNS efficacy appears to improve over time.[3]

Adverse Effects of VNS

Compared with antiepileptic drugs, VNS has a completely different side effect profile. Adverse effects are related to the surgical implantation of the generator, which may result in discomfort and deep or superficial infection. The lead attached to the vagus nerve is subject to breakage. In addition, the electrical stimulation in the neck may be uncomfortable and result in cough, hoarseness, or a feeling of shortness of breath.[4] On the other hand, VNS does not cause sedation or adverse cognitive effects, which are often limiting factors with antiepileptic drug treatment.[6]

Magnet Activation of VNS

Neurostimulation by the VNS occurs at prespecified, continuous intervals (eg, 30 seconds on, 5 minutes off). In addition, the patient may trigger additional stimulation on demand by holding a magnet over the implanted device. Magnet-activated stimulation may abort, diminish, or terminate a seizure.

A retrospective analysis of seizure data collected from the E03 trial demonstrated an increased likelihood of improved seizure control (aborted and decreased) after magnet activation (P = .0479). In the E04 trial, 31% of patients were able to diminish seizures and 22% of patients terminated seizures, but 47% reported no effect with the magnet.[1] The magnet may offer psychological benefits to patients by providing some sense of control over seizures when they occur.[1]

Personal Experience

Years ago, I enrolled 5 of my patients with intractable epilepsy in the open-label E04 VNS safety trial. None of the patients became seizure-free, although as a group they experienced a modest benefit in seizure reduction. One college student did not like the stimulator and insisted that it be removed, even though he had not allowed adequate time for us to assess its therapeutic effects. The other 4 patients continued to use the VNS.

Source: Medscape.com

Heavy smokers cut down or quit after magnetic brain stimulation, study finds.

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Heavy smokers who regularly puffed more than a packet of cigarettes a day cut down or quit for six months after their brains were stimulated with magnets, researchers say.

The apparent success of the simple procedure has led the scientists to organise a large-scale trial which will launch early next year at 15 medical centres worldwide.

Smokers in the pilot study had already tried anti-smoking drugs, nicotine gum and patches or psychotherapy to no avail, raising hopes that magnetic stimulation might offer an effective alternative for those who want to give up but have so far failed.

Nearly half of the smokers in one group, who received high-frequency magnetic pulses, quit after a three-week course of stimulation, with more than a third still abstaining six months on.

“This is a new approach to the problem,” said neuroscientist Abraham Zangen of Ben-Gurion University in Israel. “These are heavy smokers who could not stop smoking before.”

More trials will be needed to prove the value of the procedure, which scientists say should only be offered within a psychotherapy-based programme designed specifically for smokers.

For the pilot study, Zangen recruited 115 people aged 21-70 who smoked at least 20 a day. Only those who had tried to give up before using at least two methods were allowed to take part in the programme.

The smokers were divided into three groups. The first had 15 minutes of high-frequency magnetic stimulation every weekday for two weeks, followed by three sessions in the third week.

The second group had the same number of sessions of low-frequency magnetic stimulation. The third group thought they were having their brains stimulated, but the device was actually turned off to provide a control group.

Before each session, one of Zangen’s PhD students lit a cigarette and took a puff in front of half of the smokers in each group. This was designed to awaken their cravings for a smoke, and hopefully make them more susceptible to the treatment.

Zangen targeted brain regions called the prefrontal cortex and insula with a technique called deep repeated transcranial magnetic stimulation, or rTMS. Throughout the study, he asked the smokers to record how much they smoked up until six months later.

The results showed a placebo effect, or an improvement without any proper intervention, in the control group, and also in the smokers who received low frequency stimulation. In both of these groups, the smokers cut down on average from 26 to 20 cigarettes a day.

But the results were more impressive in the smokers who had high-frequency brain stimulation after witnessing one of the scientists have a drag on a cigarette: 44% quit after the three-week course and six months later, 36% said they were still not smoking.

To check that the smokers were telling the truth, Zangen tested their urine for a breakdown product of nicotine called cotinine. The results were in line with the smokers’ claims.

Though the findings are promising, the study was too small to be convincing. Zangen said a much larger trial, involving medical centres in several countries, was due to start in the next few months to test the stimulation on far more smokers.

More than a third of those treated with high frequency magnetic pulses stopped smoking for at least six months, researchers say.

If the procedure turns out to be effective, smokers might not need to have their brains stimulated regularly to avoid relapsing, he said.

“It’s quite easy to quit for a few days, or even for a few weeks, but if we can help people quit for more than three months, then they are actually quite unlikely to relapse later on,” he said.

A man smoking a cigarette

Peter Eichhammer, who has studied brain stimulation at the University of Regensburg, said that while the procedure might be effective, it was important for smokers to receive treatment in a dedicated psychotherapy-based programme.

“rTMS may help people to reduce smoking, most likely by mimicking nicotine’s actions on the brain reward system,” he said. “But it does not substitute a special psychological therapy. In general, I would be very cautious to promote rTMS as a sole biologically-driven therapeutical strategy.

“rTMS may be helpful but should be embedded in a psychological therapeutical program. Moreover, we need replication from a variety of clinical studies which really treat people with this addiction,” he said.