27 Apr 2017

In Alzheimer’s disease, synaptic activity goes haywire and brain networks gradually falter. This has made some researchers wonder if externally stimulating brain activity could help people with the disease function better for a while. The answer appears to be a tentative yes. At the 13th International Conference on Alzheimer’s and Parkinson’s Diseases, held March 29 to April 2 in Vienna, Babak Tousi of the Cleveland Clinic Lou Ruvo Center for Brain Health in Lakewood, Ohio, reported positive results from a short Phase 3 trial of neuroAD, a therapy system developed by the Israeli medical technology company Neuronix. Classed as a medical device, neuroAD combines repetitive transcranial magnetic stimulation (rTMS) of several brain areas with cognitive training tailored to strengthen those same regions. Participants with mild AD who received the intervention for six weeks maintained stable cognitive abilities six weeks later, whereas cognition continued to decline in those who received sham stimulation, Tousi said. Though the effects were small, they met prespecified outcomes and were consistent with previous reports of efficacy from smaller studies. The system is already approved for use with AD in Europe, and Neuronix is now applying for marketing clearance from the U.S. Food and Drug Administration.

Marwan Sabbagh at Barrow Neurological Institute in Phoenix ran the trial along with Alvaro Pascual-Leone of Beth Israel Deaconess Medical Center in Boston. “The [beneficial] effect appears to be symptomatic, but very well tolerated. What needs to be determined from future studies is the duration and sustainability,” Sabbagh wrote to Alzforum

Other groups are investigating similar approaches. Lorenzo Pini works at the health care organization IRCCS Centro San Giovanni di Dio–Fatebenefratelli, Brescia, Italy. In Vienna, Pini presented preliminary results from a small ongoing trial of transcranial direct current stimulation (tDCS), which he said sharpened verbal abilities in participants. tDCS is similar to rTMS, but is delivered in a way that may be less bothersome to people with dementia. In addition, researchers are investigating whether brain stimulation may help other neurodegenerative disorders. Two poster presentations at AD/PD touted better motor control in Parkinson’s patients after TMS. This area of research has received far less attention in the neurodegenerative disease field than pharmacological approaches.

In other disorders, rTMS, which has been around since 1984, has a history of success. rTMS has been FDA-approved since 2008 for the treatment of depression and since 2014 for migraine headaches. Many local clinics offer it, and consensus guidelines have been issued for its therapeutic use in various indications (e.g., Lefaucheur et al, 2014). 

On the research front, scientists are investigating the benefits of the technology for neuropathic pain, schizophrenia, and AD. One recent review of 11 studies concluded that, in general, noninvasive brain stimulation improves cognition in AD patients (see Hsu et al., 2015). Some studies have found that rTMS of AD patients coordinates firing in the brain’s default mode network, and this correlates with better associative memory (see Dec 2011 news; Aug 2014 news). 

To apply TMS, clinicians place a magnetic coil over particular spots on the head. The magnetic field induces electrical currents in the brain region below it, triggering neurons to fire. Patients may feel a slight knocking sensation on their heads as the magnetic pulses fire, and occasionally experience tingling, muscle twitches, or mild headaches or dizziness. Most applications use rTMS, rather than single-pulse, as it has more sustained effects.

Mixing Stimulation With Cognitive Training Boosts Efficacy
Neuronix combined rTMS with cognitive training based on pilot studies that found this combo worked better than either approach alone. In each treatment session, participants first take part in computerized training for language, memory, executive function, and spatial attention skills. The computer adjusts the level of difficulty to each participant’s ability based on his or her previous answers. Then participants undergo rTMS that targets six brain regions corresponding to these skills: Broca’s area, Wernicke’s area, the bilateral dorsolateral prefrontal cortex, and the bilateral parietal somatosensory cortex. These regions control, respectively, the production and understanding of speech, executive functions, and the integration of sensory inputs. They are all cortical regions that lie just under the skull. Three of the regions are stimulated in a single session, and the other three in the next. 

In small pilot studies of AD patients, short-term use of the neuroAD system for five or six weeks reportedly improved scores on the ADAS-Cog by 3-4 points (see Bentwich et al., 2011; Rabey et al., 2012). Since then, small studies of the device in Korea and France likewise reported modest benefits to memory, language skills, and mood of AD patients undergoing the treatment (see Lee et al., 2016; Nguyen et al., 2017). 

In Vienna, Tousi reported results of the pivotal Phase 3 study, which took place at nine U.S. sites and one in Israel. The trial enrolled 130 people between 60 and 90 years old who had mild to moderate AD according to NIA-AA criteria. About 85 percent of the cohort was classified as mild AD, based on having an ADAS-Cog equal to or less than 30. Participants taking acetylcholinesterase or memantine were allowed to continue on those drugs.

The cohort was randomized to either the active group or a sham condition. In the latter, participants interacted with a computer program and sat under a machine that made the same sounds as rTMS, but did not generate magnetic fields. Because some people feel sensations of TMS on the head, the research field has debated how well blinding works, and whether placebo effects might predominate in short studies. Sabbagh told Alzforum that participants were not told about the sensations they might experience from rTMS, and noted that all study staff except the TMS technician were blinded. He believes the sham condition was convincing. Supporting this, at the end of the trial participants were asked whether they thought they had received active or sham treatment, and people in both conditions were equally likely to guess sham.

Participants underwent rTMS or sham treatment for one hour five days per week for six weeks, or a total of 30 sessions. This trial length was pre-cleared with the FDA as sufficient to obtain marketing clearance, Tousi noted. Requirements for medical devices are much less stringent than for pharmaceuticals. 

Adherence to this regimen was excellent, Tousi told the audience. More than 90 percent of participants did at least 90 percent of the sessions. Six people dropped out, most because they missed more than the allowed number of sessions. Overall, patients reported enjoying the treatment and asked to continue at the end of the study, Tousi noted. About 10 percent of participants had adverse effects related to rTMS, most commonly headache or skin irritation. Occasionally, participants experienced muscle twitches, which were alleviated by adjusting the settings on the device. All these effects went away within minutes to hours, and there were no serious adverse events, Tousi said.

Curiously, the cognitive benefits of treatment showed up only after the sessions stopped. At the end of the six weeks, the treatment and placebo groups looked similar on both the ADAS-Cog and the clinical global impression of change (CGIC), but six weeks later, the placebo group had worsened slightly on both measures, while the treatment group improved. Improvement occurred mainly in the 110 people with mild AD. In this group, ADAS-Cog scores at week 12 were 1.8 points better in the treatment group than in placebo, a statistically significant difference. For the CGIC, the difference was 0.45 in favor of treatment, missing significance (p=0.07). 

It remains unclear how long the treatment benefit might last. No follow-up studies with the Phase 3 cohort are planned, but in some of the early pilot studies, researchers reported improved scores for as long as 4.5 months after treatment, Tousi told Alzforum. A Neuronix poster shown at AD/PD claims there can be long-lasting benefits. Jose Rabey of Tel Aviv University, Israel, and Evgenia Dobronevsky at Neuronix Medical Center in Ramat Gan treated a separate cohort of 30 AD patients with 30 sessions on the neuroAD system, following the protocol outlined above. In the treatment group, they saw improvement of 2.4 points on the ADAS-Cog and 1.7 points on the MMSE compared to control. This improvement lasted for at least nine months, the researchers reported (see Rabey and Dobronevsky, 2016). 

How might rTMS be used in clinical practice? Tousi sees it as an adjunct to the standard of care and to potential future pharmacological interventions. He believes it may provide a symptomatic benefit that helps AD patients maintain their cognitive abilities and function better day-to-day. However, future studies are needed to determine how often a person might need to repeat the 30-session treatment for maximum benefit. Given that it worked better for people with mild AD, it is possible that those in prodromal stages might benefit more. That, too, remains to be investigated.

Direct Current Stimulation—Does Gentler Approach Hold Potential?
One drawback to rTMS is that the noise of the machinery and the sensations can be upsetting, particularly for dementia patients, making it less likely that patients will sit still through a session. A potential alternative might be transcranial direct current stimulation of the brain, which delivers electricity through electrodes placed on the scalp. Compared with rTMS systems, tDCS devices are portable, cheaper, and quieter, and sessions are shorter. However, tDCS effects are milder than those of rTMS, and tend to affect broader swaths of the brain, making it harder to target specific functions. 

tDCS comes in two flavors, anodal (or positive) stimulation, and cathodal (or negative) stimulation. The former heightens the likelihood of neuron firing, while the latter dampens it. There has been relatively little research on the potential therapeutic effects of tDCS, although at least two small studies reported a cognitive benefit from anodal tDCS in AD patients (see Ferrucci et al., 2008; Boggio et al., 2011). 

To gather data, researchers led by Michela Pievani at IRCCS started a small pilot study of both anodal and cathodal tDCS in AD patients. The researchers hope to enroll 20 participants; in Vienna, Pini reported on the first 16. They were between 55 and 85 years old and had mild AD, as judged by an MMSE of 18 or higher. Eight participants received 10 daily 25-minute sessions of anodal tDCS, eight cathodal. There was no placebo group. The treatment was targeted to the default mode network (DMN) by stimulating the right angular gyrus, and to the salience network by stimulating right dorsolateral prefrontal cortex (see Pievani et al., 2017). The researchers chose these networks based on evidence that, early in AD, connectivity wanes in the former while increasing in the latter (see Jul 2012 news; Aug 2014 news). They speculated that stimulation might normalize these networks and thus improve cognition. Participants underwent a battery of language, memory, and neuropsychological tests, as well as fMRI to measure changes in functional brain connectivity.

Anodal and cathodal stimulation had distinct effects, the researchers found. The cathodal tDCS group did not improve on any cognitive measure, but their global Neuropsychiatric Inventory (NPI) score dropped, suggesting behavioral improvement. Their functional connectivity showed no change.

The anodal group notched improvements on the Rey auditory verbal test, semantic fluency, clock drawing, and a language comprehension test, but not the other 11 tests in the battery. This group displayed fMRI changes, though surprisingly, connectivity in their DMN dropped, rather than increasing as might be expected given the cognitive improvement. The connectivity change did not correlate with test scores in this small sample, leaving it unclear whether it was related.

“We are still trying to understand this result,” Pievani told Alzforum. She noted that in healthy volunteers, high-frequency anodal stimulation has been reported to lower DMN connectivity, while low-frequency stimulation enhanced it (see Eldaief et al., 2011). In her study, as in most previous AD studies, the participants received high-frequency stimulation. “Future studies assessing different paradigms and collecting surrogate measures of network activity might help to identify the most appropriate intervention for AD,” she suggested.

So far, anodal tDCS appears to be more effective than cathodal for cognitive disorders, Pini said in Vienna. He noted that the treatment appeared safe, with few side effects, though two participants complained of headaches, and some noted burning sensations or itching skin.

The researchers are now looking for changes in structural connectivity using MPRAGE, a type of three-dimensional MRI, and diffusion tensor imaging. In addition, Pini will assess participants six months after treatment to see if the benefit persists. He believes these pilot results support running larger, placebo-controlled studies in AD and other diagnostic groups. Pievani stressed that future trials should collect biomarker data on amyloid and tau pathology as well as brain activity and connectivity. Animal studies hint that stimulating brain activity could increase amyloid deposition, though more recent work on inducing gamma waves in mouse brain by way of external stimulation had the opposite effect (see Dec 2005 news; Iaccarino et al., 2016). 

Can rTMS help Parkinson’s patients?
Among other neurodegenerative diseases, Parkinson’s seems ripe for noninvasive brain stimulation, given that deep brain stimulation (DBS) is effective for many patients. Alas, most studies to date have found only mild benefits from rTMS (for review, see Benninger and Hallett, 2015), though a recent study of 50 PD patients by Pascual-Leone and colleagues did report motor improvement after targeting rTMS to the primary motor cortex (see Brys et al., 2016). Deep TMS, which uses several magnetic coils placed in a helmet worn by the patient to access deeper brain regions, may boost efficacy further (see Torres et al., 2015). 

In Vienna, researchers from Japan and Korea added to this data. Tomoo Mano of Osaka University reported on a placebo-controlled crossover study of rTMS in 19 PD patients. Over the course of three days, participants received stimulation to their primary motor cortices, supplementary motor area (SMA), or dorsolateral prefrontal cortex. Stimulation of either the primary motor cortex or SMA correlated with better motor function on the UPDRS-III scale, Mano found. Targeting the dorsolateral prefrontal cortex, on the other hand, slightly improved mood but not motor abilities.

Similarly, Suk Yun Kang of Hallym University College of Medicine in Hwaseong-Si, Gyeonggi-do, Republic of Korea, described a study in 12 PD patients whose episodes of “freezing” during walking rendered them suddenly unable to move. After four brief rTMS sessions per day for two days, participants who received stimulation to their SMA had significantly fewer freezing episodes. The SMA helps plan and coordinate movements. Curiously, stimulation of motor cortex did not affect gait freezing.

Data from this and other studies of noninvasive brain stimulation emphasize that effects vary depending on which brain areas are stimulated, and how. Before conducting multicenter trials for neurodegenerative disorders, researchers will have to agree on the best regions to stimulate, as well as for how long, how often, and at what frequency or intensity, Pievani said.—Madolyn Bowman Rogers

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References

News Citations

1. Shifting Default Modes—Magnetic Stimulation Resets Brain Connectivity 19 Dec 2011
2. Boosting Memory Through Stimulation of a Brain Network 29 Aug 2014
3. Communication Breakdown: Multiple Networks Decline in AD Brains 11 Jul 2012
4. Neural Circuitry Goes Haywire in Both Sporadic and Familial AD 15 Aug 2014
5. Paper Alert: Synaptic Activity Increases Aβ Release 22 Dec 2005

Therapeutics Citations

1. Memantine

Paper Citations

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11. Eldaief MC, Halko MA, Buckner RL, Pascual-Leone A. Transcranial magnetic stimulation modulates the brain's intrinsic activity in a frequency-dependent manner. Proc Natl Acad Sci U S A. 2011 Dec 27;108(52):21229-34. Epub 2011 Dec 12 PubMed.
12. Iaccarino HF, Singer AC, Martorell AJ, Rudenko A, Gao F, Gillingham TZ, Mathys H, Seo J, Kritskiy O, Abdurrob F, Adaikkan C, Canter RG, Rueda R, Brown EN, Boyden ES, Tsai LH. Gamma frequency entrainment attenuates amyloid load and modifies microglia. Nature. 2016 Dec 7;540(7632):230-235. PubMed.
13. Benninger DH, Hallett M. Non-invasive brain stimulation for Parkinson's disease: Current concepts and outlook 2015. NeuroRehabilitation. 2015;37(1):11-24. PubMed.
14. Brys M, Fox MD, Agarwal S, Biagioni M, Dacpano G, Kumar P, Pirraglia E, Chen R, Wu A, Fernandez H, Shukla AW, Lou JS, Gray Z, Simon DK, Di Rocco A, Pascual-Leone A. Multifocal repetitive TMS for motor and mood symptoms of Parkinson disease: A randomized trial. Neurology. 2016 Nov 1;87(18):1907-1915. Epub 2016 Oct 5 PubMed.
15. Torres F, Villalon E, Poblete P, Moraga-Amaro R, Linsambarth S, Riquelme R, Zangen A, Stehberg J. Retrospective Evaluation of Deep Transcranial Magnetic Stimulation as Add-On Treatment for Parkinson's Disease. Front Neurol. 2015;6:210. Epub 2015 Oct 26 PubMed.

External Citations

1. Phase 3 trial

Further Reading

News

1. Magnet Test Finds Cortex Overexcitable in All ALS 15 Sep 2015
2. A Cortical Neuron Circuit Overloads in ALS Model Mice 24 Feb 2016