Very early research suggests a novel, noninvasive brain stimulation technique guided by ultrasound may improve memory in Alzheimer’s disease (AD).
Investigators found that ultrasound-guided transcranial pulse stimulation (TPS) administered to a small number of patients with probable AD improved memory for up to 3 months and that these improvements correlated with improvements in brain networks observed on functional magnetic resonance imaging (fMRI).
However, although encouraging, Alzheimer’s experts caution the findings are highly preliminary and not near ready for prime time.
“TPS is a promising new brain therapy worthwhile to be further investigated in larger clinical studies on AD and other diseases like Parkinson’s, multiple sclerosis, and stroke,” study investigator Roland Beisteiner, MD, associated professor, Department of Neurology, Laboratory for Functional Brain Diagnostics and Therapy, Medical University of Vienna, Austria, told Medscape Medical News.
“We introduce a new add-on therapy which gives patients an additional chance [and] all established therapies may be continued,” he added.
The study was published online December 23 in Advanced Science.
Precision Medicine
Existing brain stimulation techniques have several disadvantages. In particular, established electrophysiological brain stimulation techniques are “unable to achieve focal brain activation deep in the brain,” said Beisteiner.
Transcranial magnetic stimulation (TMS) lacks precision, while deep brain stimulation (DBS) is an invasive procedure that requires surgical implantation of electrodes.
In contrast, ultrasound-guided TPS can be “spatially distinct, highly focal, and is not restricted to superficial layers of the brain,” thereby enabling a “controlled modulation of a specific brain region without unwanted costimulations of other brain areas,” the authors write.
Beisteiner noted that TPS also differs from other ultrasound-based approaches.
At present, there are three ultrasound therapies. These include tissue ablation, which is “clinically established”; blood-brain barrier opening, which is still in clinical trials; and brain activation.
The efficacy of noninvasive focal ultrasound in modulating brain function has been demonstrated in animal models and in a small clinical study of 10 health subjects who received median nerve sensory evoked potentials to target the primary somatosensory cortex. These were compared with a sham treatment that used verum stimulation.
Results showed that TPS led to increased neuromodulatory effects, which were dose-dependent as pulses increased. Similar effects were not seen in the sham condition.
TPS is delivered via a handheld ultrasound device over the skull. The device emits a stimulation pulse that is between 3 mm and 5 mm wide and roughly 3 cm long. These “ultrashort” ultrasound pulses (3 ηs) are repeated every 200 ms to 300 ms.
“In the spirit of precision medicine, the area of the brain that is to be activated is very precisely targeted [because] these areas can be situated differently in each patient,” Beisteiner said in a release.
“Thanks to a [magnetic resonance] navigation system, the treating neurologist can pinpoint on the screen where the pulse must be delivered and control everything very precisely,” he said.
Network Upregulation
The current study included 35 patients (mean age [SD], 70.37 years [8.57]; over half female) with probable AD being treated at two centers.
All participants were receiving “optimized standardized treatments.”
Subjects were treated with TPS for 2 to 4 weeks and then underwent anatomical MRIs before and after stimulation.
The first center used a “navigated approach to target AD in relevant regions of interest,” and the outcomes were compared with a “non-navigated global brain stimulation approach” at the second center.
The major global outcome parameter for patients’ cognitive state was assessed using the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) neuropsychological battery after 3 months.
In addition, fMRI was used to evaluate changes in the brain memory network related to cognitive performance.
There were no serious adverse events, and the procedure was well tolerated without even minor side effects in 93% of the patients.
The researchers found that the “memory” and “verbal” components of the CERAD score improved significantly after treatment in participants in both centers. However, the “figural” performance declined in patients of Center 1. The researchers assert that this was because the center’s protocol did not include stimulation of the occipitoparietal cortex, which is “an important area for visuospatial processing.” The finding, therefore, “supports a specific treatment effect only found for stimulated networks,” they write.
Data obtained through fMRI in 19 patients from Center 1 showed “specific upregulation of the memory network after TPS therapy,” demonstrating increased functional connectivity for hippocampus, parahippocampal cortex, parietal cortex, and precuneus.”
These increases in functional connectivity were “significantly correlated” with improvements in the CERAD scores, “indicating that upregulation of the memory network is related to cognitive performance,” the authors note.
They also note that the precise mechanism by which ultrasound affects neurons and generates neuroplastic effects is not well understood.
Nevertheless, recent laboratory studies on biological ultrasound effects suggest that TPS may “exert mechanical effects on cell membranes, affecting mechanosensitive ion channels and generating membrane pores,” the authors note. In turn, neurotransmitter and humoral factor concentrations may change.
There may also be an extra-cellular increase in levels of neurotransmitters such as serotonin and dopamine, a reduction in GABA levels, and an increase in brain-derived neurotrophic factor (BDNF) and other neurotrophic factors, which “may support cellular and network changes.”
Promising but Very Preliminary
Commenting on the study for Medscape Medical News, Ralph A. Nixon, MD, PhD, professor of psychiatry and cell biology, New York University School of Medicine, called TPS using single ultrashort ultrasound pulses “a promising novel brain stimulation technique.”
Nixon, who is also the director of the Center for Dementia Research, Nathan Kline Institute, and was not involved with the research, noted that the study was “a small pilot study without control groups,” and the findings are “too preliminary to have immediate applications for practicing clinicians.”
Nevertheless, they are consistent with “encouraging data in the literature using ultrasound-based brain stimulation techniques and justify larger-scale studies of TPS that would more definitely validate useful clinical effects on cognition in an AD population.”
Also commenting on the study for Medscape Medical News, Steven T. DeKosky, MD, deputy director, McKnight Brain Institute, and professor of neurology and neuroscience, University of Florida, called the paper “very interesting,” stating that it “appears [to be] well and carefully investigated by the research group.”
However, he also cautioned that the results in human studies are “very preliminary,” with “more direct biological findings in the animal models.”
On the other hand, “since it is a procedure available for use in humans and is noninvasive, a determination with larger numbers of people whether it really makes an extended difference in cognition over time has to be made,” said DeKosky, who was not involved with the study.
The authors acknowledge that the study was performed with an “uncontrolled design,” which is a limitation. They emphasize that further sham-controlled investigations are necessary to confirm the findings.
This work was supported by a grant from the Medical University of Vienna and University of Vienna research grant from STORZ Medical. Other aspects of funding are listed on the original paper. The authors, Nixon, and DeKosky have disclosed no relevant financial relationships.
Adv Sci. Published online December 23, 2019. Full text
