Long Term Transcranial Pulse Stimulation (TPS) on Older Adults With Mild Neurocognitive Disorder (NCD)

Background: Dementia, now known as major neurocognitive disorder (NCD), is a great health burden in Hong Kong and worldwide. Interventions that aim to ameliorate cognitive decline or prevent dementia offer a compelling alternative paradigm for reducing the impact of the disease. In principle, to achieve its optimal benefits, intervention for dementia should begin at the earliest preclinical stage, which is defined as mild cognitive impairment (MCI) or mild NCD defined by the 5th Edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). However, no evidence has been found to support a pharmacological approach to the prevention or postponement of cognitive decline during the stage of mild NCD or MCI (1, 2). Non-invasive brain stimulation (NIBS) is increasingly recognized as a potential alternative to tackle this problem. The introduction of TPS: The typical examples of NIBS are transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS). Besides these, there is a new NIBS named transcranial pulse stimulation (TPS), which recently obtained CE marking in 2018 for the treatment of the central nervous system (CNS) in patients with mild to moderate Alzheimer's disease (AD). TPS is using repetitive single ultrashort pulses in the ultrasound frequency range to stimulate the brain. With a neuro-navigation device, TPS can achieve this in a highly focal and precisely targeted manner (3). TPS differs from tDCS and TMS using direct or induced electric current. Using electric current to stimulate the brain may be limited by the problem of conductivity (4) and failure to reach deep brain regions (5). Instead, TPS provides good spatial precision and resolution to noninvasively modulate subcortical areas, despite the problem of skull attenuation (6). Using lower ultrasound frequencies TPS can successfully improve skull penetration in humans (3). Biological mechanism of TPS: The basic mechanism of TPS is mechanotransduction. It is a biological pathway through which the cells convert the mechanical TPS stimulus into biochemical responses, thus influencing some fundamental cell functions such as migration, proliferation, differentiation, and apoptosis (7, 8). The ultrashort ultrasound pulse could enhance cell proliferation and differentiation in cultured neural stem cells, which plays an important role in the repair of brain function in CNS diseases (9). The TPS probably affects neurons and induces neuroplastic effects through several pathways including increasing cell permeability (9), stimulation of mechanosensitive ion channels (7), the release of nitric oxide resulting in vasodilation, increased metabolic activity and angiogenesis (10), stimulation of vascular growth factors (VEGF) (11) and stimulation of brain-derived neurotrophic factor (BDNF) (12). Another animal study showed that ultrasound stimulation immediately after ischemic brain injury is neuroprotective through the increase of cerebral blood flow and activation of the synthesis of nitric oxide (13). Previous clinical experience of TPS and its safety issue: TPS demonstrated neuromodulation effects in the human brain. There are a few advantages of TPS techniques. First, the ultrashort TPS pulses avoid brain heating and secondary stimulation maxima. Second, TPS can modulate the amplitude of somatosensory evoked potentials (SEPs) at both the cortical regions (3) and even the deep structure such as the thalamus (6). Third, TPS may alter human brain morphology (14). For clinical use, long-term TPS was shown to bring significant improvement in patients with unresponsive wakefulness syndrome. (15). In another clinical study, TPS was applied to elderly with AD. Significant improvement in cognition was demonstrated (immediately as well as 1 and 3 months after stimulation. fMRI also showed significantly increased connectivity within the memory network (3). During the subsequent follow-up in the same study, TPS has been shown reduced cortical atrophy within the default mode network, which is associated with neuropsychological improvement (14). Another TPS study done on the human brain found that the active TPS increased the functional and structural coupling within the stimulated area and adjacent areas up to one week after the last stimulation compared with the sham TPS control. It suggested that TPS could induce neuroplastic changes with long-term effects in humans (16). In summary, TPS has shown its neuroprotective effects by inducing long-term neuroplastic changes, supported by neuropsychological tests and neuroimaging investigations both in animal and human studies. Concerning the safety issue, in vivo animal TPS study did not cause any tissue damage despite using 6-7-fold higher energy levels compared with those in human studies. Furthermore, the intervention did not cause any serious adverse effects such as intracranial bleeding, oedema or other intracranial pathology in human, as confirmed with MRI in a previous AD study. No serious adverse effects except headache (4%), pain or pressure (1%) and mood deterioration (3%) was reported (3). The CE marked TPS system has proven to be safe in \>1500 treatments. Knowledge gap and results from our pilot study: Mild NCD is a golden period for intervention to avoid further progression to dementia. Although TPS has great potential as a new treatment option due to its neuroprotective effects, there is no TPS study done on mild NCD subjects according to our knowledge. To determine the effectiveness of TPS in mild NCD, an open-label pilot study was conducted by our team from Dec 2020 to Dec 2021. (Appendix 1) The preliminary result was presented at 2021 Brain Stimulation Conference and published in abstract format (17). We recruited 16 older adults who had mild NCD. They received 6 sessions of TPS over 2 weeks. Assessments were done at the 3 time points. No subjects dropped out during the study. Statistically significant improvement was found in the primary outcome, HK-MoCA, from 18.06 to 20.25. The improvement was maintained till 12 weeks after the TPS intervention. No adverse effect was observed. The result suggested that TPS is likely to have an immediate effect on global cognition in mild NCD, and the improvements were sustainable. However, a 2-week treatment duration may not be long enough to induce a significant change in neurodegenerative disease in long term. Previous research showed that long-term deep brain stimulation may reverse hippocampal atrophy and influence the natural course of brain atrophy in Alzheimer's disease (AD) (18). Up to date, there is no long-term NIBS treatment done on NCD. Therefore, we plan to conduct a pilot case-controlled trial to evaluate the efficacy of long-term TPS on cognition and brain structure in patients with mild NCD based on the results of our pilot study.