Posts Tagged tDCS

[ARTICLE] Timing-dependent effects of transcranial direct current stimulation with mirror therapy on daily function and motor control in chronic stroke: a randomized controlled pilot study – Full Text

Abstract

Background

The timing of transcranial direct current stimulation (tDCS) with neurorehabilitation interventions may affect its modulatory effects. Motor function has been reported to be modulated by the timing of tDCS; however, whether the timing of tDCS would also affect restoration of daily function and upper extremity motor control with neurorehabilitation in stroke patients remains largely unexplored. Mirror therapy (MT) is a potentially effective neurorehabilitation approach for improving paretic arm function in stroke patients. This study aimed to determine whether the timing of tDCS with MT would influence treatment effects on daily function, motor function and motor control in individuals with chronic stroke.

Methods

This study was a double-blinded randomized controlled trial. Twenty-eight individuals with chronic stroke received one of the following three interventions: (1) sequentially combined tDCS with MT (SEQ), (2) concurrently combined tDCS with MT (CON), and (3) sham tDCS with MT (SHAM). Participants received interventions for 90 min/day, 5 days/week for 4 weeks. Daily function was assessed using the Nottingham Extended Activities of Daily Living Scale. Upper extremity motor function was assessed using the Fugl-Meyer Assessment Scale. Upper extremity motor control was evaluated using movement kinematic assessments.

Results

There were significant differences in daily function between the three groups. The SEQ group had greater improvement in daily function than the CON and SHAM groups. Kinematic analyses showed that movement time of the paretic hand significantly reduced in the SEQ group after interventions. All three groups had significant improvement in motor function from pre-intervention to post-intervention.

Conclusion

The timing of tDCS with MT may influence restoration of daily function and movement efficiency of the paretic hand in chronic stroke patients. Sequentially applying tDCS prior to MT seems to be advantageous for enhancing daily function and hand movement control, and may be considered as a potentially useful strategy in future clinical application.

Introduction

Stroke remains one of the leading causes of long-term disability [1]. Most stroke patients have difficulties performing every day activities due to paresis of upper limbs, which results in impaired activities of daily living (ADL) and reduced quality of life [23]. Identifying strategies that can facilitate functional recovery is thus an important goal for stroke rehabilitation. In recent years, several neurorehabilitation approaches have been developed to augment functional recovery, for example repetitive, task-oriented training and non-invasive brain stimulation (NIBS) [45]. Repetitive, task-oriented training emphasizes repetitive practice of task-related arm movements to facilitate motor relearning and restore correct movement patterns [6]. On the other hand, non-invasive brain simulation aims to maximize brain plasticity by externally applying electrical stimulation to modulate cortical excitability [7]. Since these two types of approaches individually have been shown to improve stroke recovery, it has been proposed that a synergistic approach that combines both of them may further augment overall treatment effects [89].

Mirror therapy (MT) is one type of repetitive task-oriented training that has been widely used in clinical and research settings [10]. During MT training, a mirror is positioned in between the paretic and non-paretic arm. The paretic arm is behind the mirror and participants can only see the non-paretic arm and its mirror reflection. Participants are required to focus their attention on the mirror reflection and imagine it is the paretic arm while performing bilateral movements as simultaneously as possible. This mirrored visual feedback is hypothesized to restore the efferent-afferent loop that is damaged after stroke and facilitate re-learning of correct movement patterns [11]. MT has been demonstrated to reduce arm impairment and improve sensorimotor function and quality of life in individuals with stroke [10,11,12,13].

Transcranial direct current stimulation (tDCS) is a commonly used NIBS technique in stroke rehabilitation. tDCS applies weak direct current to the scalp to modulate brain excitability [14]. This weak direct current gradually changes neural membrane potentials to facilitate depolarization (excitation) or hyper-polarization (inhibition) of the neurons to enhance plasticity of the brain [15]. tDCS has been demonstrated to modulate neural networks and enhance motor learning in stroke patients [716,17,18]. Although tDCS can be used alone, it is often combined with other rehabilitation approaches to boost responses of the brain to therapies [81920]. A recent meta-analysis further showed that combining tDCS with rehabilitation interventions could produce greater treatment effects on recovery of motor function than tDCS alone in stroke patients [21].

Combining tDCS with MT is a potentially promising approach to not only augment neural responses of the brain but also increase treatment benefits of MT. Nevertheless, one crucial factor that needs to be considered when combining tDCS with MT is the timing of tDCS [22]. tDCS can be applied prior to MT (i.e., offline tDCS) or concurrently with MT (i.e., online tDCS). To our knowledge, only two studies have examined the synergistic effects of combined tDCS with MT in chronic stroke patients [2324]. Cho et al. (2015) applied tDCS prior to MT or motor training without mirror reflection. They found significant improvements in manual dexterity and grip strength in the combined tDCS with MT group, suggesting that sequentially applying tDCS prior to MT could improve motor function. By contrast, Jin et al. (2019) delivered tDCS prior to or concurrently with MT and found advantageous effects on hand function in the concurrent tDCS with MT group. The conflicting results between these two studies indicated further needs to explore the interaction effects of the timing of tDCS with MT to determine the optimal combination strategy.

The important factor to consider when examining the effects of combined tDCS with MT is the treatment outcomes, especially for outcomes that are related to daily activities. ADL such as the basic ADL and complex instrumental ADL (IADL) are essential for independent living and well-being of stroke patients. Therefore, restoring daily function should be one of the priority goals of stroke rehabilitation. However, the previous two studies only examined the effects of combined tDCS with MT on motor function [2324]. No studies to date have examined the timing-dependent effects of tDCS with MT on daily function in chronic stroke patients. Whether the timing of tDCS can affect restoration of daily function with MT remains uncertain.

In addition to daily function, investigating arm movement kinematics changes with respect to the timing of tDCS with MT is also critical for determining the optimal combination strategy. Movement kinematics of the arms can provide information of whether true behavioral changes or compensation strategies occur during training [2526]. However, the two previous studies included only clinical motor function measurements [2324]. While these clinical measurements can inform clinicians/researchers of motor function changes, they may not necessarily capture spatial and temporal characteristics of movement as well as motor control strategies changes after the combined interventions [2627]. Assessing movement kinematics changes with respect to the timing of tDCS with MT would help to unravel the benefits of combined approach on motor control of the paretic arm.

The purpose of this study was to examine the timing-dependent effects of tDCS with MT on daily function, upper extremity motor function and motor control in chronic stroke patients. The tDCS was applied sequentially prior to MT (i.e., sequentially combined tDCS with MT group, SEQ) or concurrently with MT (i.e., concurrently combined tDCS with MT, CON). The sham tDCS with MT was used as the control condition. In addition to motor function outcomes, we further included the ADL/IADL measurement and movement kinematics assessments. We hypothesized that the SEQ and COM groups would demonstrate differential improvements in daily function, motor function and motor control.[…]

Full Text

Source: https://jneuroengrehab.biomedcentral.com/articles/10.1186/s12984-020-00722-1

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[WEB PAGE] Is Brain Stimulation the Next Big Thing?

Over the past decade, athletes, coaches, and researchers have been seduced by the performance-boosting promises of brain stimulation. On a ride-and-zap-your-brain-like-the-pros tour through the Alps, Alex Hutchinson wonders whether it really works—and whether we want it to.

For the first 20 miles of the ride up the Col du Galibier—the storied Alpine climb that debuted in the Tour de France back in 1911, when all but three riders were forced to dismount and walk their chunky pre-carbon-fiber velocipedes to the 8,000-foot summit—I was actually enjoying myself, more or less. The other cyclists on my weeklong tour had decided to bag it and hop in the support van halfway up the climb, as the temperature began to plummet and a cold rain swept down from the surrounding peaks. So had Massimo, our cheerfully inscrutable, Dante-quoting bike guide, who preferred the warmer climes of his native Sardinia. I was alone with the mountain, savoring the subtle gradations of my rising distress.

With a couple miles to go, though, the novelty started to wear off. The rain turned to sleet, and as I switchbacked through canyon-like passageways formed by monstrous ten-foot snowbanks, my hands, in their sodden gloves, became too numb to operate my gears—more of a theoretical problem than an actual one, since I was too spent to get out of my lowest gear anyway. As I neared the summit, the grade seemed to keep getting steeper, the headwind stronger, and my insistence on finishing the climb under my own power more foolish.

Instead of the ghosts of Coppi and Merckx and other bygone stars who’d triumphed here, I found myself chasing the flowing locks of Fabian Cancellara, the flamboyant Swiss rider who was famously (some would say outrageously) accused of hiding a tiny electric motor in his bike in 2010. As a novice cyclist embarking on an ambitious itinerary called Epic Climbs of the Western Alps, I had seriously considered requesting one of the e-bikes offered by my tour company, just to make sure I wouldn’t hold my more experienced trip mates back. Now I contemplated Fabian’s choice: If I had a Go button on my bike, would I press it?

A winding road from the French town of Briançon leads up to Col d’Izoard at 7,743 feet, a pass that frequently features in the Tour de France as a climb rated hors catégorie.
A winding road from the French town of Briançon leads up to Col d’Izoard at 7,743 feet, a pass that frequently features in the Tour de France as a climb rated hors catégorie. (Photo: Edoardo Melchiori)

As I turned yet another corner, with less than half a mile to go, the easterly headwind became a virtual wall. I had to get out of my saddle and lean into a wobbly, slow-motion sprint just to avoid slowing to a complete halt and toppling over sideways. By the time I turned away from the wind a few hundred yards later, my heart rate and breathing were fully maxed out and my legs were jelly. I knew I couldn’t face the gale again. Then I saw that, instead of another hairpin, the road ahead snaked up the rest of the way to the summit without turning back into the wind. I pedaled onward, with a mix of pride and relief—pride that I’d made it, relief that my bike hadn’t, after all, been equipped with a motor that would have tempted me to take an electric shortcut.

A few minutes later, I was thawing in a cozy bistro on the far side of the summit, sipping hot chocolate, with a plush hotel-style bathrobe draped over my shivering shoulders. That’s when an uncomfortable thought struck me: Why should I disparage the boost provided by an electric motor when, that very morning, with precisely the same goal, I’d sat patiently in a hotel lounge while a neuropsychologist trickled electric current through a web of electrodes gelled to my scalp?


Really it was just a matter of time. Back in 2013, when Brazilian scientists first showed that a relatively simple protocol of transcranial direct-current stimulation (tDCS) to the brain seemed to enhance endurance, you could already map out the events that would follow: the flood of copycat studies, the launch of a Silicon Valley startup peddling the technique to early adopters, the murky reports of professional athletes and teams like the Golden State Warriors and the U.S. ski squad experimenting with it, the rising ethical concerns about fairness and safety, and, finally, the press release that showed up in my inbox in January of this year—the field’s “Holy shit, they’re using Crispr on human embryos!” moment.

The pitch was from NeuroFire Cycling, a spin-off of Bahrain Merida Pro Cycling Team’s official sports-medicine clinic, the RIBA Rehabilitation Institute (IRR), based in Turin, Italy. It had enlisted a bike-touring company called Tourissimo, also based in Turin, to run the logistics for a bespoke trip, giving well-heeled amateurs the opportunity to spend a week riding famous Grand Tour passes while eating gourmet meals and receiving “advanced neurostim protocols used by the world’s top riders” for a cool $7,000 plus airfare. Before tackling the Colle delle Finestre, in the Piedmontese Alps of northern Italy, you’d get your prefrontal cortex stimulated to “enhance performance, mood, and the propensity to enter flow states.” After the Col d’Izoard, across the border in France’s Hautes-Alpes region, you’d hit your upper motor cortex “to enhance the central nervous system’s role in natural recovery processes.”

It read like an elaborate piece of satire. But it’s not: the technology is, on at least some level, real, and after six years of speculation and hype, someone was bound to start promoting it to the recreational market. It occurred to me that a tour for weekend warriors run by scientists also working with a top UCI cycling team would offer a unique opportunity to delve into some of the lingering questions about tDCS. Not just the obvious ones—does it work? is it safe?—but also trickier ones about fairness, technological innovation, and the deeper meaning of sport for those of us whose wins and losses are personal and unremunerated. So in early June, I buckled into a red-eye to Turin for a week of hard climbs, fine wines, and credulity-stretching neuroelectrophysiology.

The technology is, on at least some level, real, and after six years of speculation and hype, someone was bound to start promoting it to the recreational market.

The idea that a jolt to your brain might enhance your physical powers isn’t quite as futuristic as it sounds. A history of tDCS published in Psychological Medicine in 2016 traces the technique’s lineage back to Roman times, when an imperial physician named Scribonius Largus prescribed a live torpedo fish to the scalp to relieve headaches. Similar ideas crop up in cultures around the world, but the modern incarnation of tDCS began in the late 1990s and took off a decade or so later. The basic idea is simple: your brain is like a vast interconnected circuit, with neurons that communicate with each other via electric discharges. Applying a very weak current of a few milliamperes tweaks the excitability of the affected neurons, such that they become a little more (or, if you run the current in the opposite direction, less) likely to fire in response to whatever you do in the subsequent hour or two. Exactly what that means depends on which parts of the brain you hook up, but the general upshot is that different brain regions are able to communicate with each other more easily—which, if you believe the hype, can have effects ranging from changing your mood to making you a better sniper. All it takes, as a vibrant and somewhat scary online DIY subculture attests, is a nine-volt battery and a couple of electrodes.

Of course, wiring up your brain still carries some pretty weighty cultural associations. When Massimo, the Tourissimo cycling guide, picked me up at the airport, I found that he was as bemused by the whole thing as I was. As we dodged and weaved through Turin’s Saturday-morning traffic, he outlined the plan: he would take me back to the hotel for lunch and a brief rest, then I’d get fitted for a bike, then he would take me to the IRR clinic for my first—as he described it, air quotes and all—“treatment.” I’d be joined by two other cycling journalists from Britain for NeuroFire’s maiden tour, he said, since no paying customers had actually signed up. Still, “we have another testimonial,” he added cheerfully. “It’s from Jack Nicholson.”

At the clinic, a sleek complex with ultramodern furniture, rows of sophisticated rehab equipment, and the high-wattage brightness of a toothpaste commercial, we met a half dozen members of the tour’s medical and support staff. The plan for the week, they explained, had two main parts. For our first three days of cycling, we would receive 20 minutes of brain stimulation immediately before riding, with the electrodes positioned on our scalp in a configuration designed to enhance our performance, perhaps by kicking us into a flow state for the first hour or two of the ride. For the last two days, as the cumulative fatigue of tens of thousands of feet of climbing mounted, we would switch to 20 minutes of stimulation immediately after riding, this time with an electrode configuration chosen to enhance the recuperative powers of the massage we would receive simultaneously as our synapses sizzled.

But first we needed some baseline testing to figure out where the electrodes should be placed on each of us. A neuropsychologist from the IRR named Elisabetta Geda ushered me down a corridor, past rows of glossy pamphlets and posters displaying before-and-after tummy pics from exotic treatments like “full-body contouring by cryoadypolisis,” to a quiet room where she pulled a neoprene cap studded with electrodes over my scalp. As I visualized cycling up a mountain road, she used electroencephalography (EEG) to monitor the communication between different regions of my brain. “The brain signals are like an orchestra,” she explained. “Every section has a rhythm, and we record these rhythms with EEG. Then we can personalize your electrode montage, because each person may need a different treatment.”

Geda and her colleagues at the rehabilitation clinic have been using tDCS for several years on patients with conditions like chronic pain, addiction, fatigue related to multiple sclerosis, and cognitive deficits after traumatic brain injury. They use it in combination with existing treatments, priming the appropriate neurons to fire more readily in order to amplify the benefits of those therapies. So in 2017, when the IRR signed on as the official sports-medicine provider for the new Bahrain Merida cycling team, Geda began to consider the technique’s athletic potential. She and her collaborators ran a study replicating the 2013 Brazilian results, then floated the idea to Bahrain Merida.

The initial response was lukewarm. “At the beginning, we were a little bit afraid,” Luca Pollastri, one of the cycling team’s medical doctors told me. “We took some time to understand what’s going on, what’s legitimate, what’s the World Anti-Doping Agency’s position, and so on.” Instead of using it to directly enhance performance, Pollastri asked Geda if she could devise a protocol that would help athletes relax and recover after racing, which is a major challenge in Grand Tours, when riders are going to the well day after day for weeks. Geda suggested stimulating the brain during massage, effectively amplifying the massage’s effects on the central nervous system—an unorthodox approach that no one else had tried.

Neuropsychologist Elena Fontana, from the RIBA Rehabilitation Institute, wires up the author for a session of transcranial direct-current stimulation (tDCS) after a long day of riding.
Neuropsychologist Elena Fontana, from the RIBA Rehabilitation Institute, wires up the author for a session of transcranial direct-current stimulation (tDCS) after a long day of riding. (Photo: Edoardo Melchiori)

Among the first riders to try it was Domenico Pozzovivo, an Italian climbing specialist known in the peloton as the Doctor for his cerebral approach—not Bahrain Merida’s star, but someone happy to experiment with new ideas and capable of giving detailed feedback about them. In the 2018 Giro d’Italia, Pozzovivo started using tDCS to boost his recovery a few stages into the race. Night after night, he faithfully donned the electrodes for a massage, and after 17 stages, he found himself in third position in the general classification: on track, at age 35, for his first-ever Grand Tour podium. But the complicated logistics of a grueling mountaintop finish in the resort town of Prato Nevoso meant that he missed his session after the 18th stage, and, for the first time in the race, he slept poorly. The next day, he lost eight minutes to the leader and slipped back to sixth overall, before rallying in the final two stages to finish fifth. To the staff at Bahrain Merida, and to Pozzovivo himself, neither his career-best overall performance nor the timing of his one bad day seemed like a coincidence.

By this time, Pollastri and his colleagues were ready to consider using the technique as a prerace booster. With Gabriele Gallo, a sports scientist at the University of Milan, they brought ten cyclists from Bahrain Merida’s continental team to the lab for a double-blind series of simulated 15-kilometer time trials with real and sham tDCS. For a roughly 20-minute effort, the riders averaged 16 seconds faster with tDCS, right on the margins of a statistically significant improvement. It was suggestive enough that they decided to use it at the opening stage of the 2019 Tour de Romandie, where Slovenian rider Jan Tratnik took the win for Bahrain Merida.


On the morning after our EEG tests, we met Geda in a conference room in the imposingly ornate Grand Hotel Sitea for our first treatment before a test ride up the Colle della Maddalena, one of the hills across the Po River from downtown Turin. When I apologized for encroaching on her Sunday, Geda waved me off: she’d sent her two toddlers to their grandmother’s for the weekend so she could focus on the tour. “This is like a holiday for me,” she laughed. Pulling up a 3-D model of the human brain on her computer, she outlined the results of the previous day’s EEG tests.

Trevor Ward, one of the British journalists, apparently had “a great connection” between his prefrontal and motor cortices—between perception and action, in effect. This is characteristic of elite athletes, Geda explained, so he would receive the same six-electrode tDCS stimulation that the pros got, focusing on the prefrontal cortex (PFC) itself. That’s the region of the brain that integrates information from everywhere else and decides whether and when you can push harder. “Our theory is that the PFC is less active during exercise because other regions are overloaded,” Gallo explained. “So if we stimulate this area, the athlete should have better regulation of pacing.”

The other Brit, John Whitney, and I were not so accomplished, so we’d get a remedial eight-electrode stimulation to help nurture the crucial prefrontal-motor connection in addition to stimulating the PFC. Geda slid the neoprene cap onto my head, and I felt a mild prickling in my scalp as one milliampere of current began to flow. A minute or so later, the sensation faded to nothing, and for the rest of the 20 minutes, I simply sat back and relaxed.

After a short ride through the cobbled maze of Turin’s pedestrian core (and the requisite stop for espresso), we crossed the Po and started climbing. As we pedaled up the incline, I felt a little buzzed and a little jet-lagged, and my bike felt about half as heavy as usual—which it was, since I’d trained for the trip on an aging mountain bike and was now riding a $6,000 carbon-frame Bianchi. Joining us for the ride was Vittoria Bussi, the reigning world-record holder for the one-hour time trial, and I fell in beside her to get her take on the technology.

I felt a little buzzed and a little jet-lagged, and my bike felt about half as heavy as usual—which it was, since I’d trained for the trip on an aging mountain bike and was now riding a $6,000 carbon-frame Bianchi.

Bussi, it turned out, had just returned from a time trial in Slovenia, where she’d been accompanied by Geda to try prerace tDCS. Bussi hadn’t detected any difference in performance or power output, but her heart rate had been lower than usual—a somewhat ambiguous result that she’d also noticed in a previous experiment with the technique. A compulsive tinkerer, with a Ph.D. in math from the University of Oxford, Bussi saw tDCS as just another element of the continual process of experimentation, quantification, and optimization that cycling permits. “I’m curious,” she said. “I like trying to figure out the best possible approach to a problem.” Overall, the race in Slovenia had been a success, with a third-place finish that boded well for her goal of qualifying for the 2020 Olympics. She figured she’d keep using brain stimulation, at least for a while.

As for me—well, I never expected to feel any magical gains from brain stimulation. (Don’t tell my editor.) My pace up the Colle della Maddalena, or any other hill, would be determined by how hard it felt. If the effort that felt sustainable happened to get me to the top a percent or two faster than normal, how would I possibly detect such a subtle difference? At best, the cumulative effects of each day’s brain stimulation would leave me a little fresher as the week (and its 37,000 feet of climbing) proceeded—better able to enjoy the evening feasts, less likely to end up in the sag wagon. But for any given ride, the only useful way to judge something like this is with well-designed research, preferably double-blind and peer-reviewed. Trust the data, not your easily deluded intuition.


Even the data, however, is far from definitive on tDCS. The U.S. National Library of Medicine lists more than 5,000 tDCS studies, the vast majority from the past decade. The technique improves working memory (or maybe it doesn’t), it helps patients with Parkinson’s disease walk better (or maybe it doesn’t), it helps fight depression (or maybe it doesn’t), and on and on for a seemingly limitless variety of conditions. There’s a ton of hype and a corresponding amount of backlash. One researcher described the field as “a sea of bullshit and bad science.”

The sports applications of tDCS face a similarly muddled situation. A review published in Frontiers in Physiology in 2017 identified 12 studies of brain stimulation and exercise performance, eight of which found a performance boost. Conversely, two meta-analyses of 22 and 24 studies published in Brain Stimulation in 2019 concluded that the evidence in favor of an athletic boost is somewhere between slim and nonexistent. Part of the problem is that different studies use different protocols, electrode montages, and exercise tests. Some stimulate the motor cortex, hoping to facilitate a stronger output signal from brain to muscle. That’s the approach that consumer-tech startup Halo Neuroscience uses for its $400 brain-stimulating headphones. Other studies stimulate the regions responsible for evaluating inputs to the brain, hoping to dull the sensation of effort. Geda and Pollastri, by focusing on the prefrontal cortex, take yet another approach.

To skeptics, peering at this hodgepodge of conflicting evidence and concluding that brain stimulation will make you faster sounds a lot like wishful thinking. In July, a postdoctoral researcher at the University of Calgary named James Wrightson posted a preprint (a finished paper that is posted publicly for comment prior to being submitted for peer review) of his latest study, which found no effect of tDCS to the motor cortex on leg endurance. A crucial detail: Wrightson’s study protocol had been preregistered, meaning that he decided in advance how his data would be analyzed, and he committed to sharing the results regardless of whether or not they confirmed his hypothesis. How many of the small, positive reports of tDCS’s athletic effects, he wondered, might be explained by massaged data or counterbalanced by negative studies that no one bothered to publish?

These issues aren’t unique to tDCS research, of course. In fact, they apply to pretty much any sexy and “science-backed” performance aid these days. Wrightson is a passionate advocate of more rigorous methodology in sports science, which lags behind other fields, like neuroscience, in insisting on things like preregistration and large sample sizes that reduce the likelihood of spurious results. His own study, with 22 subjects, isn’t enough to prove that tDCS doesn’t work, he emphasized when I emailed to ask about his research. Many more studies, with far bigger sample sizes, are needed before we can draw any firm conclusions. Until then, his advice to athletes is to skip tDCS—and any other shiny new performance booster—until better evidence is available. “But athletes are always going to be athletes (and coaches, coaches),” he wrote, “so we’ll probably still see Halo devices everywhere at Tokyo 2020 anyway.”

The tDCS protocol used by NeuroFire and the Bahrain Merida cycling team involves electrodes held in place by a neoprene cap, with the current controlled wirelessly from a laptop computer.
The tDCS protocol used by NeuroFire and the Bahrain Merida cycling team involves electrodes held in place by a neoprene cap, with the current controlled wirelessly from a laptop computer. (Photo: Edoardo Melchiori)

From a scientific perspective—the Sisyphean pursuit of knowledge through the eternal evaluation and reevaluation of evidence, let’s say—Wrightson is undeniably correct. We don’t know shit about tDCS, scientifically speaking. But his comment about athletes being athletes, with the implication that anyone who tries an unproven technique like tDCS is a benighted dunce, struck me as unfair. Athletes are not trying to advance human knowledge or settle epistemological questions; they’re trying to win. If you have a technology with minimal cost, no known health risks, and there’s a plausible but unproven chance that it has real performance-boosting effects, isn’t it entirely rational to give it a try? Even ignoring placebo effects—another discussion entirely—there’s a small possibility of life-altering benefits for an elite athlete near the top of their sport, weighed against negligible downsides.

Wrightson, when I put this to him, didn’t buy it. In fact, he felt that even discussing preliminary research in fields like tDCS outside the hallowed halls of academia was highly irresponsible. Writing about tDCS in the “lay press,” as I had done on several occasions (and am doing right now, for that matter), was particularly egregious. “I think you were wrong to publish those articles so early,” he insisted. “It’s a hill I’m willing to die on.”


The first real hill of our tour, on Monday morning, was the Colle delle Finestre—the hero-making climb where, in last year’s Giro, Chris Froome made his winning 50-mile breakaway and where, after a restless night, Pozzovivo’s podium dreams died. We started our day in the Alpine town of Susa, lounging on folding chairs in a public park in the shadow of an imposing 2,000-year-old Roman arch as Geda gelled up the electrodes. But just before she cranked on the current, the ominous clouds above us unleashed a few warning drops. We barely had time to scramble back into the van, where I put in my 20 minutes of stimulation amid the drumbeat of torrential rain on the roof.

An hour later, the rain finally subsided, and we pedaled off, with Massimo setting the pace. We soon settled into a rhythm that would come to feel routine in the days to come, climbing steadily for 10 or 15 or 20 miles at a time, up average grades of 7 or 8 or 9 percent. There was almost no traffic, since other roads and tunnels now provide faster and more direct routes across the mountain passes. We saw nobody other than the occasional shepherd or blueberry picker, though we passed farmhouses and mountain refuges and ancient churches and monuments to cyclists of yore. It’s not like climbing the short, sharp hills that I encounter around my home in Toronto, where you can rely on momentum and a leg-burning sprint to get you to the crest. Instead you have to find a sustainable rhythm, so that the climb becomes not a frantic struggle but a meditative grind.

Just under five miles from the top of Colle delle Finestre, the asphalt ended. The rest of the road was gravel, wet and slippery thanks to the rain that was once again falling. I focused on following Massimo’s rear wheel, weaving between rocks and cutting across stream-washed gullies in the road. I felt surprisingly strong and was almost disappointed when we finally reached the stone monument to cycling star (and thrice-caught doper) Danilo di Luca at the summit. I’d have sworn the brain stimulation had worked, except that the rain-delayed start meant the performance-boosting window—about 90 minutes, Geda had told us—had closed long before we even hit the gravel.

The descent from Colle dell’Agnello, which leads from France back into Italy, passes through quiet, cobbled Piedmontese mountain towns like Chianale.
The descent from Colle dell’Agnello, which leads from France back into Italy, passes through quiet, cobbled Piedmontese mountain towns like Chianale. (Photo: Edoardo Melchiori)

The logistical challenges of combining brain stimulation with cycling, we now realized, weren’t trivial. Geda had brought enough equipment from the clinic to zap two of us at once, but when you added in the time needed to clean electrodes between users and so on, it took about an hour for the three of us. A fully booked tour with eight cyclists would have been even more chaotic, even with extra staff and equipment. Bahrain Merida encountered similar challenges: it had sprung for ten sophisticated clinical-grade tDCS machines, each costing thousands of dollars, but it didn’t have enough trained medical staff to administer the treatment to everyone at once; instead, it only used one or two machines at a time.

Even though we’d come for the explicit purpose of trying out the brain stimulation, Trevor, John, and I couldn’t help grumbling a bit over the next few days. When the morning sun was shining and the mountains beckoned, it felt wrong to spend precious blue-skied hours fiddling with electrodes or to delay our dinner after a long day in the saddle. There were moments, as I waited patiently on van seats and in lobbies and hotel rooms across Piedmont and Savoy, when I began to question the basic premise of the trip. Sometimes I worried that the technology didn’t really work. Other times I worried that it did.


I’m all for e-bikes in the appropriate context. But it’s also obvious that it would be both unfair and meaningless to win a race using a motor, like winning a marathon by wearing roller skates. Even if the only person you’re competing with is yourself, you wouldn’t celebrate a new best time on your favorite training route (or, God forbid, a Strava KOM) if it was battery powered. Despite the Olympic motto, we intuitively understand that simply going faster (or higher or stronger) without any restrictions is not the fundamental goal of sport. Instead, there’s something else that’s harder to articulate—what the World Anti-Doping Agency (WADA) vaguely and unhelpfully refers to as “the spirit of sport.”

For nearly four decades, Thomas Murray, president emeritus of the Hastings Center bioethics research institute, has been trying to pin that elusive spirit down. A research grant from the National Science Foundation in 1979 started him down the path of trying to understand why athletes do or don’t choose to dope, which in turn led to the question of what sport is really about. His conclusion, laid out in academic papers and a 2018 book called Good Sport: Why Our Games Matter and How Doping Undermines Them, is that the highest goal of athletic competition is “the virtuous perfection of natural talents.” “Virtuous is a loaded word,” he acknowledged when I phoned to get his thoughts on brain stimulation. “Absolutely it is. But it’s the right word.”

In some situations, virtue is easy to discern. Training, nutrition, and coaching are all widely sanctioned methods of honing your abilities. Taking a crowbar to your main rival’s kneecap is not. But the distinction is often more nuanced. “There’s a golf ball that flies straighter, but sport bans it,” he points out. “They also bar certain clubs that make it easier to hit accurate shots out of the rough.” The point isn’t that all technology is bad; it’s that slicing into the rough should have a penalty. So the key question, whether you’re talking about drugs or technology, isn’t: Does it make you better? It’s: Does it change the things athletes have to do, and the qualities they have to possess, to win?

As the athletic implications of tDCS have become apparent, academics have started grappling with the ethical questions, variously arguing that it should be allowed, or that it should be banned, or even that athletes should be tested and handicapped to ensure that everyone gets exactly the same net benefit from it. The argument that caught my attention, from a 2013 paper on “neurodoping” by British neuroscientist and psychologist Nick Davis, was that brain stimulation “mediates a person’s ability but does not enhance it in the strictest sense.” You don’t get extra energy or stronger muscles from tDCS; you just find it a little easier to access the energy and strength that’s already present within you. Why would we ban something that simply helps us dig a little deeper?

The key question, whether you’re talking about drugs or technology, isn’t: Does it make you better? It’s: Does it change the things athletes have to do, and the qualities they have to possess, to win?

To me, though, that internal struggle to push a little closer to your limits is an essential part of endurance sport—in a sense, it’s the fundamental, defining characteristic. Change that and you change what it takes to win. After all, if you could just push a button to extract every ounce of power from your quads, what mystery would remain? Why would anyone watch—or participate?

I expected Murray, a long-standing defender of anti-doping orthodoxy, to share my qualms. But when I tried to pin him down about tDCS, he hedged. “The mere fact that something is a biomedical technology and enhances performance is not enough to disqualify it,” he said. “It’s only when it disrupts the connections between natural talents and their perfection.” That’s a judgment that may differ from sport to sport: a barefoot ultrarunner might have a different take on the appropriate role of technology in their sport compared to a gear-happy triathlete. WADA itself, according to spokesman James Fitzgerald, is aware of the controversy and has discussed it with experts in the field but hasn’t yet seen “compelling evidence” that it breaks the rules.

There is, however, one final caveat, Murray acknowledged before hanging up: “Once an effective technology gets adopted in a sport, it becomes tyrannical. You have to use it.” If the pros start brain-zapping, don’t kid yourself that it won’t trickle down to college, high school, and even the weekend warriors.


The queen stage of our tour, with almost 9,000 feet of climbing over two historic passes, started in the crenellated French mountain town of Briançon. In the breakfast room of our hotel, I chatted with Umberto, the tour guide who (to his mild chagrin) had been assigned to drive the support van instead of cycle with us. He comes from a prominent Piedmontese mountaineering family and had trained and worked as a mountain guide before switching to cycling. His affection for the Alpine landscape around us was reverent, almost poetic, and I got the sense that he sees the world much as Reinhold Messner does: where you end up is less important than how you get there. “When I was a kid growing up in the mountains,” he told me when I delicately probed his views on our tech-assisted adventure, “sport was about you. Your quest. But our society pushes everything to extremes.”

Those words echoed in my head as we rolled out under the radiant blue sky to tackle first the 7,400-foot Col d’Izoard and then the 9,000-foot Colle dell’Agnello, which Hannibal and his elephants supposedly crossed en route to Rome more than 2,000 years ago. A few miles from the summit of Agnello, I got confused about my gears. Tailing Massimo, as I had all week, suddenly seemed too slow to stay upright, so with a muttered apology, I moved past him and essentially launched an attack. By the time I realized that I’d accidentally been in my third gear rather than my lowest one, I was too sheepish to admit my mistake, so I decided to simply carry on to the summit and let it all hang out. As on Galibier, I was soon living from switchback to switchback, stretching the elastic thinner and thinner, and not at all sure that it wouldn’t snap before I reached the top.

An hour later, after a long, wobbly descent along endless switchbacks, past startled ibexes licking salt from the recently deiced roads, I coasted into the rustic town of Sampeyre, truly a spent force. There waiting for me in the hotel were Geda and a physical therapist from the IRR. Before I knew it, I was lying facedown on a massage table, having my deltoids kneaded as Geda hooked my brain up to the old familiar juice. It was an extremely pleasant way to end an epic day. I’d made it to the top of Agnello successfully—success being defined by the nebulous but utterly unfakeable sense that I’d pushed as hard as I was capable of and then a little bit more. Now the high-voltage massage would supercharge my recovery and, according to Pozzovivo, deepen my slumbers. “I have to say that, for me, the quality of sleep improved,” he claimed in a post-Giro interview last year.

I’d made it to the top of Agnello successfully—success being defined by the nebulous but utterly unfakeable sense that I’d pushed as hard as I was capable of and then a little bit more.

For the record, the idea that tDCS massage should aid recovery is “highly speculative,” according to Samuele Marcora, a University of Kent expert on the brain’s role in fatigue, who has studied tDCS and cycling. That’s probably being diplomatic. Even Geda acknowledged that the recovery protocol is mostly based on clinical experience rather than research. The pre-ride protocol is more plausible and well supported, Marcora told me. But even then, he added, “caffeine and a session with a good sport psychologist are likely to be much more useful.”

I knew and agreed with all this. Really, I did. But as the week wore on, I’d slowly realized that my ostensible reasons for going on the trip—investigating whether tDCS actually works, reflecting on the role technology should play in sport—were to some extent convenient covers for a more personal obsession. As much as I consider myself a skeptic and Luddite who runs and bikes with nothing but a grimy vintage Timex Ironman, I’ve been drawn in repeatedly by a fascination with brain stimulation. (Much to the annoyance, it turns out, of people like James Wrightson.) I’ve flown to Los Angeles for a zany Red Bull experiment with it, tried Halo Neuroscience’s headphones, written a whole book chapter about it, and now biked across the Alps on a bespoke brain stim tour.

As someone who has spent decades trying to figure out what the edge really feels like, the truth is that I’m as fascinated as I am horrified by the prospect of inching a little closer. If you pin me down, I’d say WADA should at least ban the technique in competition, even if, like stimulants and cannabis, it remains permitted in training. But I absolutely want to know with greater certainty whether it truly boosts endurance. Because if it does, that tells us something profound about the nature of our limits—that they’re in our neurons, not our muscle fibers. Maybe that’s what keeps drawing me back to the topic: the desire to find out if the edge I’ve been skirting all this time is just an illusion.

These are the riddles I was pondering when I finally flicked off my bedside lamp after my Herculean effort on Agnello and the subsequent massage. And for the first time since the trip began, I lay awake in the dark for nearly two hours, tossing and turning while my mind continued to race. Maybe it was because of the brain stimulation, or maybe it was despite it. Maybe it was the long day in the saddle, or the ill-advised third helping of gnocchi in butter, or the imponderable depth of the questions I was wrestling with. I’ll never know for sure—unless, as my history suggests is likely, I wire myself up again sometime.

via Is Brain Stimulation the Next Big Thing? | Outside Online

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[ARTICLE] Feasibility of single and combined with other treatments using transcranial direct current stimulation for chronic stroke: A pilot study – Full Text

This pilot study aimed to investigate the safety and efficacy of transcranial direct current stimulation (tDCS) for chronic stroke in adult and pediatric patients. We also aimed to verify the efficacy of botulinum toxin A and peripheral neuromuscular electrical stimulation combined therapy involving bilateral tDCS in adult patients with chronic stroke.

We conducted a pilot study applying an unblinded, non-randomized design. Eleven patients were recruited, and classified into three groups. Group I-a involved bilateral transcranial direct current stimulation and intensive occupational therapy for chronic stroke in adult patients. Group I-b involved bilateral tDCS and intensive occupational therapy for chronic stroke in pediatric patients. Group II involved bilateral tDCS, peripheral neuromuscular electrical stimulation, and intensive occupational therapy after botulinum toxin A injection for chronic stroke in adult patients. Clinical evaluations to assess motor function and spasticity were performed at baseline as well as in 2-week and 4-month follow-up visits. The questionnaire included questions regarding the presence of tDCS side effects, such as headache, redness, pain, itching, and fever.

There were clinically meaningful changes in total Fugl–Meyer Assessment Upper Extremity (FMA-UE) scores at the 2-week follow-up and in the Action Research Arm Test (ARAT) scores at 4-month follow-up in Group I-b. In addition, Group II showed significant improvement in total FMA-UE scores in the 2-week follow-up (p < 0.05) but not on the ARAT scores (p > 0.05). However, Group II showed improvements in total Motor Activity Log scores at both follow-up visits (p < 0.05). No serious adverse events were reported.

The results of this study indicate that tDCS therapy is a potential treatment in pediatric patients with chronic stroke. Furthermore, our data indicate that botulinum toxin A and peripheral neuromuscular electrical stimulation combined therapy may enhance the efficacy of tDCS on motor function.

Previous longitudinal studies have reported that between 30% and 66% of patients experience upper limb paralysis 6 months after suffering from a stroke.13 Recent studies have demonstrated the efficacy of various treatments for patients with chronic stroke, who experience upper limb paralysis, including botulinum toxin A (BTX-A) treatment, functional electrical stimulation therapy, and robotic therapy for functional motor recovery.46 In addition, repetitive transcranial magnetic stimulation and transcranial direct current stimulation (tDCS), have been reported to induce long-term effects on cortical excitability, lasting for months after the intervention.7,8

tDCS modulates cortical excitability which influences neural plasticity.9 Anodal tDCS (anodal electrode placed over standard scalp coordinates for motor ipsilesional M1, the cathodal electrode over the contralesional supraorbital ridge) also modulates cortical excitability in motor areas within affected hemisphere.9,10 Furthermore, bilateral tDCS, which stimulates both hemispheres simultaneously, could affect excitatory and inhibitory synaptic transmission in the bilateral motor cortex in patients with chronic stroke.9,1113 By modulating cortical excitability, tDCS may alter maladaptive neural plasticity after stroke.9 Moreover, peripheral neuromuscular electrical stimulation (PNMES) enhances the effects of tDCS on cortical excitability, relative to tDCS alone.14,15 Furthermore, rehabilitation therapy using PNMES combined with BTX-A has been shown to be an effective treatment in chronic stroke or spinal cord injury.16

However, no studies have examined the efficacy of the use of bilateral tDCS with PNMES and BTX-A therapy in patients with stroke and upper limb paralysis. Therefore, based on the results of each combination therapy effect from previous studies, we predicted that a new multiple combination of adding BTX-A to existing tDCS and PNMES combination therapy would result in more effective results. In addition, tDCS may help improve upper limb paralysis in pediatric patients with chronic stroke. Since tDCS alone has been rarely used in pediatrics, our pilot study aimed to investigate the safety and efficacy of tDCS in adult and pediatric patients with chronic stroke. We also aimed to verify the efficacy of BTX-A and PNMES combined therapy involving bilateral tDCS in adult patients with chronic stroke.

Study design

We conducted a pilot study applying an unblinded, non-randomized design. This study included patients with chronic stroke (>6 months from stroke onset) experiencing paralysis in an upper limb. Patients between 6 and 85 years old were included. We also excluded patients with epilepsy, complete paralysis, and/or severe pain, as well as those who were unable to follow directions due to cognitive impairment and/or aphasia. All participants provided written informed consent. Our institutional review board approved the study. Patient characteristics are summarized in Table 1.

Table

Table 1. Demographics and clinical characteristics.

We included 11 patients (four males and seven females; mean age 43.5 ± 5.1 years) including 7 cases of hemorrhagic stroke and 4 cases of ischemic stroke. All study participants were right handed. There were six cases of right upper limb paralysis and five cases of left upper limb paralysis. All of four ischemic stroke cases had a lesion in the middle cerebral arterial territtory, and three hemorrhagic stroke patients had a lesion in the putamen, two stroke patients had a lesion in the subcortical, and other two patients had lesions were in the thalamus and pontine. These treatment programs were initiated on 54.9 ± 23.2 days from stroke onset. Of the included cases, data from 1 patient (Case 1) was published previously.13

Five patients, included in Group I, underwent bilateral tDCS therapy alongside intensive occupational therapy (OT) (Group I-a: two adults; Group I-b: three children). Group II included six adult patients in chronic stroke who underwent BTX-A and PNMES combined therapy involving bilateral tDCS.

Each rehabilitation session lasted 60 min. Sessions were performed twice daily for 10 days so that all patients completed 20 sessions for the 2-week intervention period in the hospital. In Group I, tDCS started at the same time as the intensive OT for 25 min; and a 45-min only intensive OT was performed after the tDCS. In Group II, patients were given a BTX-A injection. Following this, patients simultaneously underwent intensive OT for 25 min using tDCS, and PNMES (25 min). Meanwhile, intensive OT was continued as well, and finally alone intensive OT (10 minutes) was performed (Figure 1). Intensive OT involved task-oriented training. The content of the task-oriented training mainly consisted of the task on the desk. The difficulty of the task was adjusted for each patient depending on the extent of their upper limb paralysis and their rehabilitation goals. Examples of activities included gripping or picking up blocks or pegs, varying in size; as well as using a keyboard and playing cards. The activities performed by each patient were recorded. In addition, patients were instructed to increase their use of upper limb paralysis. After the 2-week intervention period, patients presented as outpatients and were given exercises to complete at home. Patients were encouraged to use their paralyzed upper limbs depending on their individual rehabilitation needs. Daily activities involved tasks related to their own rehabilitation goals from the activities of daily living (ADL) and instrumental activities of daily living (IADL) tasks.


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Figure 1. Study protocol in Groups I, bilateral tDCS started at the same time as the intensive occupational therapy for 25 min; and a 45-min-only intensive occupational therapy was performed after bilateral tDCS. Study protocol for combined therapy involving bilateral tDCS. Patients in Group II received BTX-A therapy 25 min prior to bilateral tDCS, which was immediately followed by a 25-min PNMES. Intensive occupational therapy was also provided simultaneously and performed alone for 10 min.

BTX-A: botulinum toxin A; tDCS: transcranial direct current stimulation; PNMES: peripheral neuromuscular electrical stimulation.

Clinical evaluations were performed at baseline and in 2-week and 4-month follow-up visits conducted after the intervention. We used the following clinical outcome measures to evaluate upper limb function, including the Fugl–Meyer Assessment Upper Extremity (FMA-UE; range: 0–66) and the Action Research Arm Test (ARAT; range: 0–57).17,18 Limb functioning used during daily activities were assessed using the Motor Activity Log (MAL; range: 0–5).19 The severity of spasticity symptoms were evaluated using the Disability Assessment Scale (DAS; range: 0–12).20 DAS evaluations were conducted with patients who had received BTX-A injections. The questionnaire included questions regarding the presence of tDCS side effects, such as headache, redness, pain, itching, and fever.

The effective change in this pilot study was defined as the minimal clinically important difference (MCID) for endpoints with established values, and the MCID for FMA-UE, ARAT and MAL were 4.25, 5.7 and 0.5 points, respectively.21,22 Furthermore, the statistically significant difference in the amount of change from the baseline within the group and the presence or absence of serious adverse events were used as reference indicators of feasibility.

Statistical analysis

Within-group comparisons were conducted to investigate changes in clinical symptoms (FMA-UE, ARAT, and MAL) before and after treatment using the Wilcoxon signed-rank test. All analyses were performed using SPSS, version 21.0 (IBM Corp., Armonk, NY, USA). The significance threshold was set to p < 0.05.

tDCS-supported rehabilitation

We used the DC-STIMULATOR PLUS system (neuroConn GmbH, Germany) to perform tDCS. The anodal electrode was placed over standard scalp coordinates for the ipsilesional M1; whereas the cathodal electrode was placed over standard scalp coordinates for the contralesional M1 (C3 or C4 points according to the 10–20 system). Bilateral tDCS using electrodes (size of 5 × 7 cm; 35 cm2) using a constant current intensity of 2.5 mA for 25 min (Figure 2). Our protocol used current densities below 25 mA/cm2 which should not induce damage even when high-frequency stimulation is applied for several hours.23,24 The tDCS protocol that we used has been described previously (Figure 3).13,25

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Figure 2. Bilateral tDCS with intensive occupational therapy: (1) DC-STIMULATOR PLUS system (neuroConn GmbH, Germany) for transcranial direct current stimulation.

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[Abstract] Evaluating the effects of tDCS in stroke patients using functional outcomes: a systematic review

Background and purpose: Transcranial direct current stimulation (tDCS) has been extensively studied over the past 20 years to promote functional motor recovery after stroke. However, tDCS clinical relevance still needs to be determined. The present systematic review aims to determine whether tDCS applied to the primary motor cortex (M1) in stroke patients can have a positive effect on functional motor outcomes.

Materials and methods: Two databases (Medline & Scopus) were searched for randomized, double-blinded, sham-controlled trials pertaining to the use of M1 tDCS on cerebral stroke patients, and its effects on validated functional motor outcomes. When data were provided, effect sizes were calculated. PROSPERO registration number: CRD42018108157

Results: 46 studies (n = 1291 patients) met inclusion criteria. Overall study quality was good (7.69/10 on the PEDro scale). Over half (56.5%) the studies were on chronic stroke patients. There seemed to be a certain pattern of recurring parameters, but tDCS protocols still remain heterogeneous. Overall results were positive (71.7% of studies found that tDCS has positive results on functional motor outcomes). Effect-sizes ranged from 0 to 1.33. No severe adverse events were reported.

Conclusion: Despite heterogeneous stimulation parameters, outcomes and patient demographics, tDCS seems to be complementary to classical and novel rehabilitation approaches. With minimal adverse effects (if screening parameters are respected), none of which were serious, and a high potential to improve recovery when using optimal parameters (i.e.: 20 min of stimulation, at 2 mA with 25 or 35cm2 electrodes that are regularly humidified), tDCS could potentially be ready for clinical applications.

  • Implications for Rehabilitation
  • tDCS could potentially be ready for clinical application.

  • Evidence of very low to very high quality is available on the effectiveness of tDCS to improve motor control following stroke.

  • This should with caution be focused on the primary motor cortex.

via Evaluating the effects of tDCS in stroke patients using functional outcomes: a systematic review: Disability and Rehabilitation: Vol 0, No 0

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[ARTICLE] Transcranial Direct Current Stimulation to Facilitate Lower Limb Recovery Following Stroke: Current Evidence and Future Directions – Full Text HTML

Abstract

Stroke remains a global leading cause of disability. Novel treatment approaches are required to alleviate impairment and promote greater functional recovery. One potential candidate is transcranial direct current stimulation (tDCS), which is thought to non-invasively promote neuroplasticity within the human cortex by transiently altering the resting membrane potential of cortical neurons. To date, much work involving tDCS has focused on upper limb recovery following stroke. However, lower limb rehabilitation is important for regaining mobility, balance, and independence and could equally benefit from tDCS. The purpose of this review is to discuss tDCS as a technique to modulate brain activity and promote recovery of lower limb function following stroke. Preliminary evidence from both healthy adults and stroke survivors indicates that tDCS is a promising intervention to support recovery of lower limb function. Studies provide some indication of both behavioral and physiological changes in brain activity following tDCS. However, much work still remains to be performed to demonstrate the clinical potential of this neuromodulatory intervention. Future studies should consider treatment targets based on individual lesion characteristics, stage of recovery (acute vs. chronic), and residual white matter integrity while accounting for known determinants and biomarkers of tDCS response.

1. Introduction

Stroke is the second leading cause of death and third leading cause of adult disability globally [1]. With advancement in acute medical care, more people now survive stroke, but frequently require extensive rehabilitative therapy to reduce impairment and improve quality of life. For those that survive stroke, the damaging effects not only impact the individual and their family, but there is also increased burden on health unit resources and community services as the person leaves hospital, potentially requiring assistance to live in the community. Novel treatments that can enable restoration and enhance potential for stroke recovery are desperately needed and will have significant value for many aspects of stroke care.
True recovery from stroke impairment is underpinned by neuroplasticity. Neuroplasticity describes the brain’s ability to change in structure or function in order to help restore behavior following neural damage. Mechanisms of neuroplasticity are available throughout life but appear enhanced during critical periods of learning [2]. Across several animal studies, it has been shown that there is a period of heightened neuroplasticity that appears to open within several days following stroke [2,3,4] and correlates with rapid recovery [5]. In humans, the timing and duration of a similar critical period of heightened neuroplasticity are not clear, but it likely emerges early after stroke. Understanding the characteristics of a potential critical period of heightened neuroplasticity in humans is important for optimizing stroke rehabilitation and is the subject of current trials [6]. However, the importance of neuroplasticity for stroke recovery in humans is unequivocal, with imaging and physiological studies providing extensive evidence of brain changes correlating with improved behavior [7,8,9,10,11,12,13].
Transcranial direct current stimulation (tDCS) is a promising, non-invasive, method to induce neuroplasticity within the cerebral cortex and augment stroke recovery. Importantly, tDCS has potential to bidirectionally and selectively alter corticospinal excitability for up to one hour after stimulation [14,15]. Animal models indicate that tDCS modulates resting membrane potential, with anodal stimulation leading to neuronal depolarization and cathodal stimulation leading to neuronal hyperpolarization over large cortical populations [16]. Stimulation-induced changes may be potentiated by changes in intracellular calcium concentrations. For example, anodal tDCS applied to the surface of the rat sensorimotor cortex led to a rise in the intracellular calcium concentrations [17]. Local increases in calcium can result in short- and long-term changes in synaptic function [18]. In humans, pharmacological studies have also provided indirect evidence to suggest that tDCS after effects are mediated by changes in synaptic plasticity through mechanisms that resemble long-term potentiation (LTP) and long-term depression-like effects [19]. Oral administration of the NMDA-receptor antagonist dextromethorphan was found to suppress the post-tDCS effects of both anodal and cathodal stimulation, suggesting that tDCS after effects involve NMDA receptors [19]. Importantly, modulation of cortical activity with tDCS changes human behavior [20]. For example, in randomized sham-controlled trials, anodal stimulation of the motor cortex (M1) in the lesioned hemisphere was found to improve upper limb outcomes in chronic [21,22,23] and subacute stroke survivors [24,25,26], with behavior changes underpinned by increased cortical activity within the M1 [27]. Although much work remains to be performed regarding optimal stimulation doses, cortical targets and electrode montages, these studies provide some indication that tDCS may be beneficial in stroke recovery.
While there is indication that tDCS has potential to improve stroke recovery of the upper limb [28], there are comparatively fewer studies that have investigated tDCS for lower limb recovery after stroke. Lower limb rehabilitation is especially important, as the simple act of regaining the ability to walk has subsequent effects on the ability to engage in activities of daily living [29,30]. Furthermore, those receiving therapy targeting mobility have been shown to have reduced levels of depression and anxiety [31], which are important determinants of stroke recovery [32,33,34]. Therefore, novel interventions capable of enhancing lower limb recovery might improve not only lower limb motor performance but could have added benefit for stroke rehabilitation in general. The purpose of this review is to discuss tDCS as a technique to modulate brain activity and promote recovery of walking following stroke. Within this review, we will outline current studies that have investigated tDCS to improve lower limb motor performance in both healthy adults and people with stroke. Additionally, we propose a best-practice model of experimental design for lower limb tDCS to guide future application for lower limb stroke recovery.

2. Is it Possible to Modify Lower Limb Motor Networks with Transcranial Direct Current Stimulation?

One approach to modify activity of the lower limb motor network with tDCS is to target the M1, similar to studies involving the upper limb. However, targeted application with tDCS is challenging as, compared with upper limb representations, the lower limb M1 representations are more medial and deeper within the interhemispheric fissure (Figure 1). This presents two notable difficulties. First, the ability of targeted stimulation to the lower limb M1 within one hemisphere (e.g., the lesioned hemisphere in stroke) is challenging, as tDCS electrodes can be relatively large compared to the size of cortical representations, resulting in current spread that may inadvertently lead to stimulation within the opposite hemisphere. Second, the depth of the lower limb M1 representations may present a challenge to current penetration and depth with traditional tDCS applications. However, there is evidence to indicate that it is possible to modulate activity of the lower limb M1 with tDCS. Computational modelling has revealed that traditional anodal tDCS electrode montages (anode overlying the lower limb M1 and cathode overlying the contralateral orbit; Figure 1) can lead to the expected cortical excitability enhancement in the target cortex [35]. Indeed, reducing the size of the anode (3.5 cm × 1 cm) was found to improve the specificity of the current delivered to the cortex, while positioning the return electrode (cathode) to a more lateral position (T7/8 on the 10–10 EEG system) further improved current specificity, leading to greater changes in cortical excitability [35]. Experimental evidence also suggests that tDCS targeting the lower limb M1 can modify excitability. Jeffrey and colleagues [36] utilized an anodal-tDCS montage (2 mA, 10 min) over the lower limb M1 and found that motor-evoked potentials (MEPs) of the tibialis anterior muscle increased by as much as 59% compared to sham conditions. Along similar lines, 10 sessions of anodal tDCS (2 mA, 10 min) targeting the lower limb M1 was found to increase the amplitude of MEPs recorded from the paretic tibialis anterior compared to sham stimulation [37]. This empirical evidence provides some support to the computational modelling to suggest that the use of tDCS targeting the lower limb M1 can modify corticospinal excitability.
Although M1 has received attention as a stimulation target to modify excitability of the lower limb M1, there is potential for cerebellar tDCS to induce similar, or possibly more prominent, behavioral and neurophysiological changes. It is noteworthy that a computational modelling study that compared electrode montages targeting M1 and the cerebellum found that cerebellar stimulation produced substantially higher electric field strengths in the target area compared to M1 stimulation, suggesting the cerebellum may indeed be a suitable target for tDCS [38]. Behaviorally, the cerebellum contributes to motor planning, learning, and control; this influence is in part mediated by connections to M1 via the cerebellothalamocortical tracts, previously reported to play a key role in motor skill learning in mice [39]. Although this stimulation technique has received comparatively little attention compared to M1 stimulation, there is some indication that it is possible to modify cerebellar excitability in a focal and polarity specific manner [40]. Whether cerebellar tDCS is required to modify excitability of M1 for behavioral change is unclear. However, if a desired outcome was to modify M1 excitability with cerebellar stimulation, a pertinent challenge would be whether cerebellar tDCS can achieve the specificity required to precisely target the lower limb M1 in one hemisphere. Although speculative, one approach could be to pre-activate M1 through a contralateral lower limb motor task in order to bias the effects of tDCS towards those networks activated to perform the task. In support, there is some evidence in the upper limb that performance of a task during cerebellar tDCS does interact with the change in M1 excitability [41].[…]

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[Review] Immediate and long-term effects of BCIbased rehabilitation of the upper extremity after stroke: a systematic review and metaanalysis – Full Text PDF

Abstract

Background: A substantial number of clinical studies have demonstrated the functional recovery induced by the use of brain-computer interface (BCI) technology in patients after stroke. The objective of this review is to evaluate the effect sizes of clinical studies investigating the use of BCIs in restoring upper extremity function after stroke and
the potentiating effect of transcranial direct current stimulation (tDCS) on BCI training for motor recovery.

Methods: The databases (PubMed, Medline, EMBASE, CINAHL, CENTRAL, PsycINFO, and PEDro) were systematically searched for eligible single-group or clinical controlled studies regarding the effects of BCIs in hemiparetic upper extremity recovery after stroke. Single-group studies were qualitatively described, but only controlled-trial studies were included in the meta-analysis. The PEDro scale was used to assess the methodological quality of the controlled studies. A meta-analysis of upper extremity function was performed by pooling the standardized mean difference (SMD). Subgroup meta-analyses regarding the use of external devices in combination with the application of BCIs were also carried out. We summarized the neural mechanism of the use of BCIs on stroke.

Results: A total of 1015 records were screened. Eighteen single-group studies and 15 controlled studies were included. The studies showed that BCIs seem to be safe for patients with stroke. The single-group studies consistently showed a
trend that suggested BCIs were effective in improving upper extremity function. The meta-analysis (of 12 studies) showed a medium effect size favoring BCIs for improving upper extremity function after intervention (SMD = 0.42; 95% CI = 0.18–0.66; I2 = 48%; P < 0.001; fixed-effects model), while the long-term effect (five studies) was not significant (SMD = 0.12; 95% CI = − 0.28 – 0.52; I2 = 0%; P = 0.540; fixed-effects model). A subgroup meta-analysis indicated that using functional electrical stimulation as the external device in BCI training was more effective than using other devices (P = 0.010). Using movement attempts as the trigger task in BCI training appears to be more effective than using motor
imagery (P = 0.070). The use of tDCS (two studies) could not further facilitate the effects of BCI training to restore upper extremity motor function (SMD = − 0.30; 95% CI = − 0.96 – 0.36; I2 = 0%; P = 0.370; fixed-effects model).

Conclusion: The use of BCIs has significant immediate effects on the improvement of hemiparetic upper extremity function in patients after stroke, but the limited number of studies does not support its long-term effects. BCIs combined with functional electrical stimulation may be a better combination for functional recovery than other kinds
of neural feedback. The mechanism for functional recovery may be attributed to the activation of the ipsilesional premotor and sensorimotor cortical network.

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[ARTICLE] tDCS and Robotics on Upper Limb Stroke Rehabilitation: Effect Modification by Stroke Duration and Type of Stroke – Full Text

Abstract

Objective. The aim of this exploratory pilot study is to test the effects of bilateral tDCS combined with upper extremity robot-assisted therapy (RAT) on stroke survivors. Methods. We enrolled 23 subjects who were allocated to 2 groups: RAT + real tDCS and RAT + sham-tDCS. Each patient underwent 10 sessions (5 sessions/week) over two weeks. Outcome measures were collected before and after treatment: (i) Fugl-Meyer Assessment-Upper Extremity (FMA-UE), (ii) Box and Block Test (BBT), and (iii) Motor Activity Log (MAL). Results. Both groups reported a significant improvement in FMA-UE score after treatment (). No significant between-groups differences were found in motor function. However, when the analysis was adjusted for stroke type and duration, a significant interaction effect () was detected, showing that stroke duration (acute versus chronic) and type (cortical versus subcortical) modify the effect of tDCS and robotics on motor function. Patients with chronic and subcortical stroke benefited more from the treatments than patients with acute and cortical stroke, who presented very small changes. Conclusion. The additional use of bilateral tDCS to RAT seems to have a significant beneficial effect depending on the duration and type of stroke. These results should be verified by additional confirmatory studies.

1. Introduction

Stroke is a common primary cause of motor impairments and disability. Only about 15% of those with initial complete upper limb paralysis after stroke recover a functional use of their affected arm in daily life [12]. Greater intensity of upper extremity training after stroke improves functional recovery [3] as well as repetitive task training [4]. Motor practice, in turn, favors motor cortical reorganization, which is correlated with the degree of functional recovery [5]. Robotic devices for upper extremity rehabilitation after stroke have been shown to improve arm function [69]. They may enhance conventional motor therapy, increasing repetitions of well-defined motor tasks (massed practice) with an improvement of motivation due to the feedback of the device; they can be programmed to perform in different functional modalities according to the subject level of motor impairment. Robotic assistance may increase sensory inputs and reduce muscle tone with an overall improved patients’ confidence in performing movements and tasks that, without assistance, might be frustrating or even impossible to achieve [10]. In the past decade, neuromodulation approaches have been proposed with the aim of optimizing stroke motor rehabilitation. Among these, transcranial direct current stimulation (tDCS) represents a noninvasive tool to modulate motor cortical excitability inducing a brain polarization through the application of weak direct electrical currents on the scalp via sponge electrodes [11]. Transient, bidirectional, polarity-dependent modifications in motor cortical excitability can be elicited: anodal stimulation increases it, whereas cathodal stimulation decreases it [1213]. Moreover, on a behavioral viewpoint, tDCS can promote skilled motor function in chronic stroke survivors [14].

After a stroke, changes in motor cortex excitability occur leading to an unbalanced interhemispheric inhibition [11], because the depression of the contralesional hemisphere on the affected one is not balanced by a similar level of inhibition of the lesional hemisphere onto the unaffected one. It has been hypothesized that this phenomenon represents a potential maladaptive process with detrimental effects on arm motor function [15]. On this basis, to increase paretic arm function, an “interhemispheric competition model” has been adopted in noninvasive brain stimulation stroke research [1116]. Specifically, researchers applied anodal tDCS over the affected primary motor cortex (M1) [14], cathodal stimulation over the unaffected M1 [17], or, more recently, a combination of the two stimulation paradigms through a bilateral tDCS montage [18]. How noninvasive brain stimulation effects are relevant when coupled with a peripheral stimulation as rehabilitative interventions is now well established [19]. So far, tDCS effects on motor learning and arm function in stroke population have been extensively addressed in recent systematic reviews and meta-analysis reporting mixed conclusions [2024]. Indeed, the effectiveness and timing of these new rehabilitative techniques need to be defined by further investigations. We can hypothesize that tDCS primes motor cortex circuits, increasing motor cortex excitability that is sustained after a robot-assisted training [25]. Furthermore, the combination of these techniques enhances synaptic plasticity and motor relearning through long-term potentiation- (LTP-) and long-term depression- (LTD-) like phenomena on M1 [26].

The aims of this exploratory pilot study were twofold. Firstly, we wanted to test the effects of a bilateral tDCS montage combined with upper extremity robot-assisted training (RAT) compared to RAT alone on motor recovery, gross motor function, and arm functional use in a heterogeneous sample of stroke survivors. Secondly, we explored whether additional factors such as stroke duration and type could modify and also be predictors of tDCS and RAT response.[…]

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[ARTICLE] Literature Review on the Effects of tDCS Coupled with Robotic Therapy in Post Stroke Upper Limb Rehabilitation – Full Text

Today neurological diseases such as stroke represent one of the leading cause of long-term disability. Many research efforts have been focused on designing new and effective rehabilitation strategies. In particular, robotic treatment for upper limb stroke rehabilitation has received significant attention due to its ability to provide high-intensity and repetitive movement therapy with less effort than traditional methods. In addition, the development of non-invasive brain stimulation techniques such as transcranial Direct Current Stimulation (tDCS) has also demonstrated the capability of modulating brain excitability thus increasing motor performance. The combination of these two methods is expected to enhance functional and motor recovery after stroke; to this purpose, the current trends in this research field are presented and discussed through an in-depth analysis of the state-of-the-art. The heterogeneity and the restricted number of collected studies make difficult to perform a systematic review. However, the literature analysis of the published data seems to demonstrate that the association of tDCS with robotic training has the same clinical gain derived from robotic therapy alone. Future studies should investigate combined approach tailored to the individual patient’s characteristics, critically evaluating the brain areas to be targeted and the induced functional changes.

Introduction

Stroke is one of the leading factors of morbidity and mortality worldwide (Warlow et al., 2001).

In Italy, stroke annual incidence varies between 175/100.000 and 360/100.000 in men and between 130/100.000 and 273/100.000 in women (Sacco et al., 2011). Further, still in Italy, a total of 196.000 individuals are affected by stroke each year, 80% are new episodes and 20% are relapses (Gensini, 2005).

Activities of daily living (ADLs) and human quality of life strongly depend on upper limb functioning (Franceschini et al., 2010). Therefore, one of the goals of post-stroke upper limb rehabilitation is to recover arm and hand functions, and enable the patients to perform ADLs independently.

It is shown in the literature that intensive as well as task-specific training can be very effective in upper limb rehabilitation treatments after stroke (Feys et al., 2004Lo et al., 2010Klamroth-Marganska et al., 2014); this training should be repetitive, challenging and functional for the patients. To this purpose, robotics represents a key enabling technology for addressing these requirements for a well-stratified group of stroke patients (i.e., moderate-to-severe subjects). Clinical studies, varying in design and methods, have examined the effect of robotic devices on upper-limb and lower-limb rehabilitation in a clinical setting (Prange et al., 2006Brewer et al., 2007Mehrholz et al., 2015). Moreover, in a multicenter randomized controlled trial on moderate-to-severe chronic stroke patients, robotic therapy resulted superior to usual care and not inferior to intensive conventional rehabilitation treatment in terms of recovery of upper limb motor function (Lo et al., 2010). In addition, using robotic devices allows delivering new therapy constraints to maximize the required movement pattern (Kwakkel et al., 2007). Therefore, it is possible to control task learning phase more easily with robots than with traditional therapeutic techniques, since robots allows patients to perform guided movements on predefined pathways and avoid possible uncontrolled movements (Kwakkel et al., 2007).

Despite the interesting advancements in this area, the type of therapy leading to optimal results remains controversial and elusive and patients are often left with considerable disability (Bastani and Jaberzadeh, 2012).

Recently, the application of non-invasive neuro-modulation strategies to counteract inter-hemispheric imbalance has been acquiring a growing interest in post-stroke rehabilitation (Duque et al., 2005Hummel and Cohen, 2006Bolognini et al., 2009Kandel et al., 2012). The adjunct of non-invasive interventions, such as the electrical brain stimulation or magnetic brain stimulation (Di Lazzaro et al., 2016), might be used to speed-up and maximize the potential benefit of rehabilitation treatments. In particular, transcranial Direct Current Stimulation (tDCS) may play an important role in stroke recovery since its capability to modify cortical excitability and neural activity (Lefaucheur, 2016Lefaucheur et al., 2017).

In fact, modulating the excitability of a targeted brain region non-invasively, can favor a normal balance in the interhemispheric interaction and, hence, facilitate the recovery of motor functions of the paretic limb (Kandel et al., 2012).

tDCS consists of applying low-intensity current (1–2 mA) between two or multiple small electrodes on the scalp (Dmochowski et al., 2011). Depending on the electrode polarity, an opposite polarization of brain tissues can be induced with consequent modification of the resting membrane potential. Anodal stimulation will induce depolarization and increased cortical excitability; cathodal stimulation will induce hyperpolarization and decreased cortical excitability (Nitsche and Paulus, 2000Fregni et al., 2005).

In the past, several studies have demonstrated a tDCS effect in terms of increased primary motor cortex activation assessed with fMRI (Hummel et al., 2005Lindenberg et al., 2010).

The inter-hemispheric inhibitory competition model (Duque et al., 2005) implies that, to restore the interhemispheric balance altered after a stroke, one can either increase the excitability of the affected hemisphere with the anodal tDCS, or decrease the activity of the healthy hemisphere with cathodal tDCS (Hummel and Cohen, 2006).

The use of bilateral tDCS (applying simultaneously anodal electrode on the affected hemisphere and cathodal electrode on the unaffected hemisphere, Tazoe et al., 2014) could also be an effective strategy to produce interhemispheric rebalancing effects. Notwithstanding the promising achievements, the debate on tDCS efficacy in neurorehabilitation is still active and not entirely examined (Stagg and Johansen-Berg, 2013).

The application of tDCS might also have an impact on shoulder abduction (SABD) loading effects in individuals with moderate to severe chronic stroke; however, it is insufficient to make significant changes at higher SABD loads (Yao et al., 2015).

Furthermore, several neuromodulatory protocols have been applied together with robotic gait training to induce cortical plasticity and promote motor recovery after stroke. Motor excitability induced by paired associative stimulation, i.e., repetitive transcranial magnetic stimulation (rTMS) and tDCS has shown to be a potential neuromodulatory adjuvant of walking rehabilitation in patients with chronic stroke (Jayaram and Stinear, 2009) although there was no evidence regarding the efficacy of these protocols with respect to the others.

On the other hand, robot-assisted repetition with electromechanical gait trainer (Hesse et al., 1997Hesse and Uhlenbrock, 2000) improved gait performance and maintained functional recovery at follow-up even during the chronic phase of stroke (Peurala et al., 2005Dias et al., 2007). This could be likely due to the gait-like movement that allowed patients to practice a complete gait cycle, achieving better symmetric and physiological walking (Dias et al., 2007).

In this context, the adjunct of tDCS (delivered over the lower extremity motor cortex) to robotic locomotor exercises showed the capability to enhance the effectiveness of robotic gait training in chronic stroke patients (Danzl et al., 2013).

Conversely, while administering tDCS did not produce any reverse effects on chronic stroke patients, on the other hand it seemed to have no additional effect on robot-assisted gait training (Geroin et al., 2011). This could be due to the peculiar neural organization of locomotion, which involves both cortical (motor cortex) and spinal (central pattern generators) control (Dietz, 2002Geroin et al., 2011).

Recently, another study has supported the hypothesis that anodal tDCS combined with cathodal transcutaneous spinal direct current stimulation (tsDCS) may be useful to improve the effects of robotic gait training in chronic stroke (Picelli et al., 2015).

Finally, combination of tDCS and robotic training has shown a promising strategy for improving arm, hand and lower extremity motor functions in persons with incomplete spinal cord injury (Raithatha et al., 2016Yozbatiran et al., 2016).

All these approaches justify the growing interest of the scientific community in the evaluation of the effects of upper limb robot-aided motor training coupled with tDCS in stroke, relying on the adjunct of tDCS to further enhance primary effects of motor recovery (Triccas et al., 2016).

This paper intends to carry out an in-depth study of the literature regarding the effects of the combined use of tDCS and RT on motor and functional recovery in post stroke subjects. Moreover, the expected added value provided by this work is to complete the current knowledge in the neurorehabilitation field, by critically evaluating and comparing (when possible) the available results as well as discussing inconsistencies and possible issues. As a final goal, indications for the development of future and more specific rehabilitation protocols tailored to subject’s needs are provided.

The paper is structured as follows. In Section “Overview of the Main Studies on tDCS Coupled with Upper-Limb Robotic Treatment” an overview of clinical studies that analyze effects of tDCS combined with upper limb robotic therapy (RT) is reported.

Section “Discussion” presents a critical discussion of the presented studies aimed to assess the efficacy of this novel combined approach. Finally, Section “Conclusions and future perspectives” reports final considerations and future suggestions.

Overview of the Main Studies on tDCS Coupled with Upper-Limb Robotic Treatment

The study of the effects deriving from the coupled use of tDCS and RT represents a relatively young field of interest. In fact, the number of studies that have tried to investigate and prove the successful combination of these two techniques is limited.

A wide literature search updated to January 2017 has been conducted resorting to the main databases, such as Pubmed Central (PMC), Cochrane, Scopus, Google Scholar. The following keywords have been employed: tDCS AND stroke* OR ictus OR hemiplegia* AND robot* OR robotic therapy*, upper-limb rehabilitation, brain stimulation techniques, neurorehabilitation, rehabilitation robotics. Studies have been included only when focused on the novel therapeutic approach based on tDCS combined with robotic upper limb therapy.

The following inclusion criteria have been utilized:

1. Be a single session clinical trial (i.e., compare pre-treatment and post-treatment performance) or controlled trial (i.e., clinical trial with a control group, either randomized or not).

2. Involve stroke patients.

3. Concern movement therapy with a robotic device.

4. Include transcranial Direct Current Stimulation (tDCS) as Non-Invasive Brain Stimulation Technique.

5. Focus on upper-limb motor control (and possibly functional abilities).

6. Use relevant motor control and functional ability outcome measures.

7. Be a full-length publication in a peer-reviewed journal.

To enable the most complete overview of the current literature, the search has not been limited by patient subgroups (i.e., acute, subacute, or chronic) or by language.

A flowchart of the search and inclusion process is shown in Figure 1. A total of 830 papers has been gathered by using the aforementioned search method. The abstracts matching the inclusion criteria have been selected. When appropriate, the full paper has been read. Therefore, from the initial 830 papers, 820 have been excluded since they did not meet the inclusion criteria. The remaining 10 papers have been carefully read. Eight studies are journal papers while 2 are conference papers.

Figure 1. Flowchart of the search and inclusion process.

[…]

 

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[Abstract] Timing-dependent interaction effects of tDCS with mirror therapy on upper extremity motor recovery in patients with chronic stroke: A randomized controlled pilot study

Highlights

  • The priming effect of dual tDCS was important to facilitate motor recovery in combination with mirror therapy in stroke.

Abstract

This study was a randomized, controlled pilot trial to investigate the timing-dependent interaction effects of dual transcranial direct current stimulation (tDCS) in mirror therapy (MT) for hemiplegic upper extremity in patients with chronic stroke. Thirty patients with chronic stroke were randomly assigned to three groups: tDCS applied before MT (prior-tDCS group), tDCS applied during MT (concurrent-tDCS group), and sham tDCS applied randomly prior to or concurrent with MT (sham-tDCS group). Dual tDCS at 1 mA was applied bilaterally over the ipsilesional M1 (anodal electrode) and the contralesional M1 (cathodal electrode) for 30 min. The intervention was delivered five days per week for two weeks. Upper extremity motor performance was measured using the Fugl-Meyer Assessment-Upper Extremity (FMA-UE), the Action Research Arm Test (ARAT), and the Box and Block Test (BBT). Assessments were administered at baseline, post-intervention, and two weeks follow-up. The results indicated that concurrent-tDCS group showed significant improvements in the ARAT in relation to the prior-tDCS group and sham-tDCS group at post-intervention. Besides, a trend toward greater improvement was also found in the FMA-UE for the concurrent-tDCS group. However, no statistically significant difference in the FMA-UE and BBT was identified among the three groups at either post-intervention or follow-up. The concurrent-tDCS seems to be more advantageous and time-efficient in the context of clinical trials combining with MT. The timing-dependent interaction factor of tDCS to facilitate motor recovery should be considered in future clinical application.

via Timing-dependent interaction effects of tDCS with mirror therapy on upper extremity motor recovery in patients with chronic stroke: A randomized controlled pilot study – Journal of the Neurological Sciences

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[ARTICLE] A Novel tDCS Sham Approach Based on Model-Driven Controlled Shunting – Full Text

Abstract

Background

Transcranial direct current stimulation (tDCS), a non-invasive brain stimulation technique able to transiently modulate brain activity, is surging as one of the most promising therapeutic solutions in many neurological and psychiatric disorders. However, profound limitations exist in current placebo (sham) protocols that limit single- and double-blinding, especially in non-naïve subjects.

Objective

/hypothesis: To ensure better blinding and strengthen reliability of tDCS studies and trials, we tested a new optimization algorithm aimed at creating an “active” sham tDCS condition (ActiSham hereafter) capable of inducing the same scalp sensations perceived during real stimulation, while preventing currents from reaching the cortex and cause changes in brain excitability.

Methods

A novel model-based multielectrode technique —optimizing the location and currents of a set of small electrodes placed on the scalp— was used to control the relative amount of current delivered transcranially in real and placebo multichannel tDCS conditions. The presence, intensity and localization of scalp sensations during tDCS was evaluated by means of a specifically designed questionnaire administered to the participants. We compared blinding ratings by directly addressing subjects’ ability to discriminate across conditions for both traditional (Bifocal-tDCS and -Sham, using sponge electrodes) and our novel multifocal approach (both real Multifocal-tDCS and ActiSham). Changes in corticospinal excitability were monitored based on Motor Evoked Potentials (MEPs) recorded via concurrent Transcranial Magnetic Stimulation (TMS) and electromyography (EMG).

Results

Subjects perceived Multifocal-tDCS and ActiSham similarly in terms of both scalp sensations and their localization on the scalp, whereas traditional Bifocal stimulation was rated as more painful and annoying compared to its Sham counterpart. Additionally, differences in scalp localization were reported for active/sham Bifocal-tDCS. As for MEPs amplitude, a main effect of stimulation was found when comparing Bifocal-Sham and ActiSham (F(1,13)= 6.67, p=.023), with higher MEPs amplitudes after the application of Bifocal-Sham.

Conclusions

Compared to traditional Bifocal-tDCS, ActiSham offers better participants’ blinding by inducing very similar scalp sensations to those of real Multifocal tDCS both in terms of intensity and localization, while not affecting corticospinal excitability.

Introduction

Non-invasive Brain Stimulation (NIBS) techniques are used to modulate brain activity in a safe and well-tolerated way [1]. In particular, Transcranial direct current stimulation (tDCS), uses low-intensity electrical currents to modulate cortical excitability in a polarity-specific manner [1]. Classical tDCS montages consist of two rectangular sponge electrodes with a contact area of ∼25-35 cm2, where electrical current between 0.5mA and 4mA flows from a positively charged electrode (anode) to a negative one (cathode)[2] passing through various tissue compartments including skin, muscle, bone, cerebrospinal fluid and brain. Due to its safety and relatively low-cost, tDCS experiments have been widely carried out to investigate human neurophysiology and to test its application as a new potential therapeutic solution for neurological and psychiatric conditions. To ensure adequate understanding of the observed effects, however, researchers need to rely on valid and approved control placebo conditions, a fundamental requirement in randomized controlled trials. Traditional standard sham protocols consist on an initial ramp up of the current, followed by a short stimulation period (usually for 5-60 seconds) and a final ramp down [[3][4][5]], (i.e., Fade In of current, brief real Stimulation, Fade-Out; commonly known as “FISSFO” protocol), an approach thought to cause sensory stimulation similar to real tDCS without affecting cortico-spinal excitability [6]. However, both these assumptions (i.e., adequate blinding and absence of effects on the brain) are still under examination. FISSFO sham has been considered effective in providing a proper blinding when compared with real tDCS at 1mA for 20 minutes [6], becoming the standard for sham tDCS [7]. The rationale stems from participants’ reports in which the cutaneous perceptions that generally cue subjects on tDCS being effectively delivered (i.e., tingling or itching sensation), have been mostly reported during the first 30-60 seconds of stimulation to then gradually decrease, possibly due to habituation [4]. However, a recent investigation has revealed that even naïve subjects (N=192) are capable of distinguishing classic sham stimulation (FISSFO) from active tDCS when delivered at 1 mA for 20 minutes over the left dorsolateral prefrontal cortex (DLPFC) [8]. Prior experiments had already suggested blinding inefficacy when real tDCS is applied at 1.5-2 mA, even for only 10 minutes [9,10]. Accordingly, non-naïve subjects seem more capable of distinguishing real from sham tDCS [11] and extreme individual variability has been reported with regard to sensibility to stimulation intensity and duration, with subjects being able to perceive tDCS even at very low intensity (i.e., 400 μA) [11].

On the other hand, additional sham protocols have been developed with modified durations of ramp up/down, or even delivering constant low intensity currents (0.016 or 0.034 mA) [7,12,13]. However, these approaches have not been properly tested on large sample of patients/subjects, with no data on the effects of such alternative sham protocols on the brain, while inconsistent results on many neurophysiological parameters have been documented when adopting such modified approaches [13].

Beyond the single or double blinding efficacy of FISSFO and related approaches [14], an element of interest is the question of whether tDCS effects are due to cortical interaction of the generated electric fields or from peripheral nervous system (PNS) stimulation. Since the ramp-up/ramp-down method for blinding decreases both cortical and peripheral stimulation, they cannot help disentangling cortical and peripheral effects. In addition, cortical effects of the brief period of real stimulation during sham protocols may not completely be excluded [15].

An additional challenge is the fact that the induced tDCS electric field is conditioned by the heterogeneity of cortical and non-cortical tissues, as well as by the complexity of cortical geometry [16]. In recent years, this has been addressed by the use of multichannel tDCS systems in combination with realistic finite element modeling of current propagation in the head derived from subject neuroimaging data (e.g. MRI, fMRI) [17,18]. The rationale for multifocal stimulation resides on both the need for more targeted stimulation of the cortex, as well as the notion that brain regions operate in networks and communicate with each other’s through modulatory interactions [[19][20][21]]. Realistic physical models provide a crucial element for better experimental understanding and control of the electric fields generated by tDCS.

In the present study, we investigate a novel approach to sham stimulation based on controlled shunting of currents via a model-based quantification of transcutaneous and transcranial effects. Specifically, the novel sham tDCS solution benefits from the use of an optimization algorithm allowing tDCS montages to be tailored in such a way that zero or very low magnitude electric fields are delivered on the brain, while medium to high intensity currents are maintained in at least some scalp electrodes, thus eliciting scalp sensations necessary for blinding. Notably, this allows to maintain the stimulation ON for the entire duration of sham tDCS, therefore inducing scalp sensations similar to real tDCS, while avoiding known limitations of the FISSFO protocol. We hypothesize that such montage (Active Sham, ActiSham hereafter) (i) will generate scalp sensations similar to a Multifocal (real) tDCS montage based on the same electrodes’ location and identical stimulation intensity/duration; and that (ii) ActiSham will not induce changes in cortico-spinal excitability (CSE), as assessed through Motor Evoked Potentials (MEPs) induced by Transcranial Magnetic Stimulation (TMS) as an index of corticospinal excitability. If successful, this and similar other approaches for improved sham stimulation could contribute to more efficient design of future tDCS research studies and clinical trials.

Methods

Study design

Fourteen subjects participated in 4 randomized tDCS stimulation visits, spaced 7±3 days to ensure no carryover effects. The tDCS conditions were: real Bifocal-tDCS, Bifocal-Sham, real Multifocal-tDCS and ActiSham. Each session lasted approximately 90 minutes during which participants seated in a comfortable chair with their eyes open. To measure changes in corticospinal excitability, single pulse TMS was applied over the left primary motor cortex (M1) at the beginning and the end of each stimulation session. Somatosensory sensations elicited by tDCS were addressed by means of ad-hoc questionnaires. See dedicated sections below for further details about tools and procedures.

Participants

Fourteen healthy right-handed naïve subjects (25.4 years ± 2.1; 5 males) were recruited at the University Campus of Siena, School of Medicine (Siena, Italy). Possible contraindications to either TMS or tDCS were assessed by means of a screening questionnaire [22]. Exclusion criteria included: history of seizures, head injury, pacemakers or other implanted medical devices, metallic objects in the head, hearing impairments, medications altering cortical excitability or other significant medical concerns. All participants gave written informed consent prior to participating to the study. The research proposal and associated methodologies were approved by the local ethical committee in accordance with the principles of the Declaration of Helsinki.

tDCS

tDCS sessions lasted 15 minutes, with electrode types, scalp montages and stimulation intensities customized for each tDCS protocol (Figure 1). Transcranial stimulation was delivered using a “Starstim 8” brain stimulator controlled via Bluetooth using a laptop computer (Neuroelectrics, Barcelona, Spain). For canonical Bifocal-tDCS (active or sham), stimulation was delivered through traditional 5×7 cm rectangular sponge electrodes, with a contact area of 35 cm2 (SPONSTIM, Neuroelectrics, Barcelona, Spain). Before current delivery, electrodes were soaked with 15 ml of sterile sodium chloride solution (0.9%). For Multichannel stimulation conditions (real and ActiSham), current was instead delivered using circular Ø 20 mm PISTIM electrodes (Neuroelectrics, Barcelona, Spain) with an Ag/AgCl core and a gel/skin contact area of 3.14 cm2. Electrodes were filled with a conductive gel before the tDCS intervention. To further improve current conductivity, the scalp was gently rubbed with an alcohol solution at the beginning of each session. Electrodes were inserted in a neoprene cap with available positions following the 10/20 EEG system.

Figure 1

Figure 1Study design. (A) Active stimulation was delivered for 15 minutes, (30 seconds of ramp up and down). Corticospinal excitability was measured via TMS three times prior to stimulation (Pre-10, Pre-5 and Pre-0) and compared with post measurements collected up to 15 minutes after stimulation (Post-0, Post-5, Post-10, Post-15). Halfway through the protocol (i.e., at minute 7), subjects were asked to rate stimulation-related annoyance and pain levels. tDCS montages for Multifocal-tDCS (B), ActiSham (C), Bifocal-tDCS and Bifocal-Sham (D) are shown.

[…]

Continue —-> A Novel tDCS Sham Approach Based on Model-Driven Controlled Shunting – ScienceDirect

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