Mark H Myers ^1* Gahangir Hossain ²

• ¹ University of Tennessee Health Science Center (UTHSC), Memphis, United States
• ² University of North Texas, Denton, Texas, United States

Kawasaki, Y., & Fudaba, H. (2023). Monophasic-quadri-burst stimulation robustly activates bilateral swallowing motor cortices. Frontiers in Neuroscience, 17, 1163779).Clinical and animal studies have confirmed that TMS is also suitable for investigating the excitability and plasticity of ascending corticospinal respiratory pathways. In addition, although rTMS and tDCS differ in their respective mechanisms, both can regulate respiratory networks in healthy individuals and in diseased states. Supplementary motor area (SMA) and the phrenic motor neuron (PMN) may be key regulatory areas. After an injury, diaphragmatic motor evoked potentials (DiMEPs) decreased on the non-injured side, but not the injured side, indicating increased excitability of PMNs on the ipsilateral side. In a recent clinical case report, the authors selected tDCS on SMA combined with peripheral electrical stimulation (PES) based on the results of high-frequency TMS research. Corticospinal excitability may also be affected by PES, depending on the parameters used. Sensory PES is often inhibitory, while motor PES is usually excitatory. The authors reported two cases of spinal cord injury (P1 and P2) with long-term tracheotomy (>40 days) and hospitalization (>50 days). P1 received the combined application of sensory PES on the pectoral and abdominal muscles and anode tDCS on the SMA, while P2 received isolated excitatory PES on the abdominal muscles. Both patients were extubated 15 times after stimulation and presented clinical effects such as cough effectiveness. This suggests that the SMA, under both TMS and tDCS, may be a key area for respiratory regulation (Lv, L., Cheng, X., Yang, J., Chen, X., & Ni, J. (2023). Novel role for non-invasive neuromodulation techniques in central respiratory dysfunction. Frontiers in Neuroscience, 17, 1226660).Repetitive transcranial magnetic stimulation (rTMS) has emerged as an effective intervention for post-stroke cognitive impairment (PSCI). After a stroke has occurred, increased neural excitability of the unaffected hemisphere and heightened inhibition of the damaged hemisphere is likely to occur. This is due to the reduced inhibition from the damaged hemisphere of the skull. By applying high frequency (HF)-rTMS to stimulate the affected side of bilateral dorsolateral prefrontal cortex (DLPFC) DLPEF and reduce cortical excitability by employing low frequency (LF)-rTMS on the healthy side of DLPEF, cortical homeostasis can be restored. In terms of treatment, a total intervention duration of 4 weeks was commonly employed, with a minimum duration of 10 days and a maximum duration of 8 weeks , with a treatment session lasting 20 to 30 minutes (Wang, Y., Wang, L., Ni, X., Jiang, M., & Zhao, L. (2024). Efficacy of repetitive transcranial magnetic stimulation with different application parameters for post-stroke cognitive impairment: a systematic review. Frontiers in Neuroscience, 18, 1309736).Another study considers intermittent theta-burst stimulation on upper limb motor recovery and improve the quality of life after a stroke. Intermittent theta burst stimulation significantly improved motor impairment, functional activities, and reduced muscle tone of upper limbs, thereby increasing the ability to perform activities of daily living in stroke patients, while there were no significant differences in motor evoked potentials (Chen, S., Zhang, S., Yang, W., Chen, Y., Wang, B., Chen, J., ... & Li, H. (2023). The effectiveness of intermittent theta burst stimulation for upper limb motor recovery after stroke: a systematic review and meta-analysis of randomized controlled trials. Frontiers in Neuroscience, 17, 1272003).Repetitive transcranial magnetic stimulation triggers the modulation of cortical connectivity. High frequency rTMS with 2 s train duration and 25 s inter-train interval increased cortex excitability and the power spectral density of bilateral central regions in the alpha frequency band and enhanced the functional connectivity between central regions and other brain regions. When the train duration was prolonged to 5 s, the effects from high frequency rTMS disappeared. When rTMS with 5 s train duration and 100 s inter-train interval were applied, the same effect appeared as those of rTMS with 2 s train duration and 25 s inter-train interval (Jin, J., Wang, X., Wang, H., Li, Y., Liu, Z., & Yin, T. (2023). Train duration and inter-train interval determine the direction and intensity of high frequency rTMS after-effects. Frontiers in Neuroscience, 17, 1157080).Transcranial magneto-acoustic stimulation (TMAS), a technique based on focused ultrasound stimulation within a static magnetic field, in the APP/PS1 mouse model of Alzheimer's disease (AD) was utilized to explore the feasibility on improving AD related spatial memory deficits and abnormal neural oscillation. TMAS were applied to mice over a 21-day treatment and were evaluated through recordings of local field potential signals in the hippocampal CA1 region in-vivo electrophysiology, analyzing sharp-wave ripple (SWR), gamma oscillations during SWRs, and phase-amplitude coupling (PAC). Spatial memory of the mice was examined by the Morris water maze (MWM) task. TMAS improved the performance of MWM related spatial cognitive functions with the mouse model of Alzheimer's disease through the modulation of brain oscillations (Zhang, S., Guo, Z., Xu, Y., Mi, J., Liu, J., Li, Z., ... & Xu, G. (2024). Transcranial magneto-acoustic stimulation improves spatial memory and modulates hippocampal neural oscillations in a mouse model of Alzheimer's disease. Frontiers in Neuroscience, 18, 1313639).Using the radius positioning (RP) method after identifying the intracranial target regions from brain CT images, a method for focused ultrasound treatment of brain tumors is introduced. Transcranial focused ultrasound (tFUS) offers higher spatial precision and regulation depth. This framework used a new transducer localization method to offer a reliable basis for further research and offered new methods for the use of tFUS in brain tumor-related research (Gao, P., Sun, Y., Zhang, G., Li, C., & Wang, L. (2023). A transducer positioning method for transcranial focused ultrasound treatment of brain tumors. Frontiers in Neuroscience, 17, 1277906).Several approaches have been considered for treatment fibromyalgia. Transcranial alternating current stimulation (tACS) modulates neural activity by applying sinusoidal alternating current to the scalp, thus generating an electric field within the brain. Much like direct current stimulation (tDCS), tACS effectively modulates cortical excitability. It has the unique capability to mimic the natural alternation of brain oscillations and induce long-term synaptic plasticity, thereby effectively regulating brain function. It has struggled with the precise localization of specific brain regions. Electrodes attached to the patient's scalp generate a specific current frequency, allowing the current to penetrate deeper into the cortex by reducing the impedance of the skin and potentially leading to improved stimulation effects. Transcranial focused ultrasound (tFUS) boasts remarkable spatial precision, capable of targeting and stimulating deep brain regions with millimeter accuracy. This technique employs piezoelectric-element transducers that emit ultrasound pulses, effectively reaching and stimulating deep brain areas. (Zhang, J. H., Liang, J., & Yang, Z. W. ( 2023). Non-invasive brain stimulation for fibromyalgia: current trends and future perspectives. Frontiers in Neuroscience, 17, 1288765).Invasive cervical vagus nerve stimulation (VNS) is a technique that involves implanting a device under the skin of the chest that delivers electrical impulses to the vagus nerve (VN) in the neck. transcutaneous auricular vagus nerve stimulation (taVNS) was introduced as a non-invasive, more affordable, and easily implemented alternative. TaVNS is a non-invasive brain stimulation technique that involves the delivery of electrical stimulation to the auricular branch of the vagus nerve (ABVN), accessible through the skin of the outer ear. Compared to VNS intervention, taVNS may be considered as a therapeutic intervention for various neurological and psychiatric conditions, such as epilepsy, depression, and migraine. Regarding disorders of consciousness (DOC), taVNS has the potential to modulate thalamo-cortical connectivity and neurotransmitter systems. In a study comprisng of 10 participants, seven in vegetative state and three in conscious state, the study revealed favorable outcomes following 4 weeks of taVNS treatment in response to auditory stimuli (RtAS) DOC patients. The influence of taVNS was further elucidated by elevated cerebral blood flow in diverse brain regions among RtAS DOC patients, with a notably restricted impact in non-RtAS individuals. Remarkably, the presence of preserved auditory function emerged as a pivotal determinant of taVNS responsiveness in DOC patients (Wang, L., Gao, F., Wang, Z., Liang, F., Dai, Y., Wang, M., ... & Wang, L. ( 2023). Transcutaneous auricular vagus nerve stimulation in the treatment of disorders of consciousness: mechanisms and applications. Frontiers in Neuroscience, 17, 1286267).Transcranial alternating current stimulation (tACS) is an emerging tool for improving cognitive functions such as Electronic Sports (eSports) Multiplayer Online Battle Arena (MOBA) and First/Third Person Shooting Games (FPS/TPS). By modulating regional oscillatory cortical networks, tACS can alter regional and larger network connectivity, decreasing reaction time in the visual spatial attention and improving quick classification tasks, such as exact aiming. High definition HD-tACS improved visual spatial attention distraction task performance during stimulation, which might be due to enhanced alpha activity coherence between the frontal and parietal lobes. This approach may be carried onto rehabilitation training in patients with cognitive deficits (Jiao, F., Zhuang, J., Nitsche, M. A., Lin, Z., Ma, Y., & Liu, Y. (2024). Application of transcranial alternating current stimulation to improve eSports-related cognitive performance. Frontiers in Neuroscience, 18, 1308370).Transcranial alternating current stimulation is a non-invasive neuromodulation technique that is being tested clinically for treatment of a variety of neural disorders. The spiking activity of cerebellar nuclear (CN) cells was transsynaptically entrained to the frequency of AC stimulation in an intensity and frequency-dependent manner. These results show that subthreshold AC stimulation can induce such PC spike synchrony without resorting to supra-threshold pulse stimulation for precise timing. Transsynaptic entrainment of deep CN cells via cortical stimulation could help keep stimulation currents within safety limits in tACS applications, allowing development of tACS as an alternative treatment to deep cerebellar stimulation. This treatment maybe useful for those patients with cerebellar damage who often suffer from comorbid cognitive impairments, including impaired timing, attention, memory, and language. This treatment can also be considered for those who suffer from tremor type conditions (Kang, Q., Lang, E. J., & Sahin, M. (2023). Transsynaptic entrainment of cerebellar nuclear cells by alternating currents in a frequency dependent manner. Frontiers in Neuroscience, 17, 1282322).The next set of experimental stimulation are discussed, such as, cortico-cortical paired associative stimulation (ccPAS), Low-intensity pulsed ultrasound (LIPUS), and transcranial Photobiomodulation (tPBM), Transcranial Burst Electrical Stimulation (tBES) and Rapid X-ray based genetically targeted (X-genetic) manipulation. This work highlights remote intervention, low power systems to reduce patient risk, generalized pain reduction, merged interventions such as tBES, and genetic modulation. This work is still in the early stages but show the next advancement in neurological intervention and cognition research.Cortico-cortical paired associative stimulation (ccPAS) differs from the PAS, which uses a dual-coil TMS approach to apply repetitive paired-pulse stimulations over two cortical regions. ccPAS is believed to induce spike-timing dependent plasticity over a cortico-cortical connection, such as primary motor cortex to primary motor cortex (M1), ventral premotor cortex to primary motor cortex, supplementary motor area to primary motor cortex, and posterior parietal cortex (PPC)-M1. ccPAS over the ventral premotor cortex (PMv) and M1 tapped into motor tasks could increase the motor-evoked potential in healthy adults. ccPAS over the PMv and M1 could decrease the motor-evoked potential in healthy adults. These effects may be due to the PMv-M1 glutamatergic projections which activates the local inhibitory circuits more than the excitatory circuits within the M1. ccPAS may be a therapeutic solution for a host of various neurological issues such as stroke, Parkinson's disease, and major depressive disorders that involve brain connectivity and networks (Zhang, J. J. ( 2024). Cortico-cortical paired associative stimulation: a novel neurostimulation solution for modulating brain connectivity and networks. Frontiers in Neuroscience, 17, 1336134).Low-intensity pulsed ultrasound (LIPUS) has been used to promote nerve regeneration and repair. LIPUS treatments led to increased neurite length which has been associated with higher BDNF expression and increased phosphorylation of extracellular signal-regulated kinase (ERK)1/2, protein kinase B (Akt), and mammalian target of rapamycin (mTOR) signaling pathways. mTOR has been recognized as a vital regulator in neuronal development and plasticity by participating in multiple signaling pathways, whereby aberrant mTOR signaling correlates with abnormal neuronal function and failure of many cellular processes. Therefore, these findings underscore the considerable promise of LIPUS as a potential therapeutic strategy for neural regeneration and repair. The capacity of LIPUS to stimulate neuroblastoma cells to facilitate neurite outgrowth could be utilized for neurodegenerative diseases such as Alzheimer's, Parkinson's, and possibly for the application in recovery after neurotrauma (Ye, X., Wang, Z., van Bruggen, R., Li, X. M., Zhang, Y., & Chen, J. ( 2023). Low-intensity pulsed ultrasound enhances neurite growth in serum-starved human neuroblastoma cells. Frontiers in Neuroscience, 17, 1269267).Photobiomodulation (PBM) is a method for treating a variety of pain and/or infections using low-dose red to near-infrared (630-1,100 nm) light. Transcranial PBM (tPBM), which refers to PBM administered to the cerebral cortex, has also been proven to boost human cognition, including attentional performance, treatment for traumatic brain injury, Alzheimer's disease and and Parkinson's disease. In the experiment described by the authors, using a 1,064-nm continuouswave (CW) laser with a 13.6 cm2 irradiation area, and its power set at 3.4 W, the light was delivered over the right frontopolar region close to the Fp2 site without physical contact. Using this laser's output, a total energy dose of 1,632 J was delivered throughout an 8-min tPBM session (3.4 W × 60 s/min × 8 min = 1,632 J), resulting in a laser power density of 0.25 W/cm2. In the alpha band, significant increase of power was seen during the active tPBM session compared to the sham session. This increase in power in the alpha band, observed in the central to the leftparietal region and in the mid-frontal to the left-parietal region during the tPBM session. Photobiomodulation continues to be non-evasive method that can be effectively applied to a host of neurological applications (Truong, N. C. D., Wang, X., & Liu, H. ( 2023). Temporal and spectral analyses of EEG microstate reveal neural effects of transcranial photobiomodulation on the resting brain. Frontiers in Neuroscience, 17, 1247290).Deep brain stimulation is a therapeutic technique that involves implanting electrodes into subcortical areas of brain regions in order to administer electrical currents. It is considered minimally invasive, considering other surgical techniques. A study focusing on deep brain stimulation (DBS) for the treatment chronic pain considered two major areas, chronic pain treatment (DBS-P), and DBS for other indications (DBS-O), such as Parkinson's disease or dystonia. The analysis included 966 patients in 43 original research studies with chronic pain who underwent DBS (340 for DBS-P and 625 for DBS-O). An average pain reduction of 47.67 ± 20.01% for the DBS-P group and 59.59 ± 23.81% [51.01 ± 21.4% for both groups]. The DBS-P exhibited a significant effect on chronic pain relief, with a standardized mean difference (SMD) of 1.65 and a 95% confidence interval (CI) of [1.31; 2.00]. These findings contribute valuable insights into DBS's utility for chronic pain, emphasizing the need for further research to optimize outcomes (Shaheen, N., Shaheen, A., Elgendy, A., Bezchlibnyk, Y. B., Zesiewicz, T., Dalm, B., ... & Flouty, O. (2023). Deep brain stimulation for chronic pain: a systematic review and metaanalysis. Frontiers in Human Neuroscience, 17, 1297894).A closed-loop neurostimulation simulation has been developed based on pre-defined stimulation sets through observations that fulfil pre-defined criteria. This closed-loop controller can then estimate in real-time the required closed-loop neurostimulation signal necessary to reach the desired output. Through this simulator, researchers may find tDCS therapy may be administered for a duration of 60 minutes and a maximum current of 4 mA without yielding health risks. This work presents a brain stimulation simulator to provide several techniques to apply to a range of clinical issues, such as Parkinson's disease (PD) or obsessive-compulsive disorders (Wahl, T., Riedinger, J., Duprez, M., & Hutt, A. (2023). Delayed closed-loop neurostimulation for the treatment of pathological brain rhythms in mental disorders: a computational study. Frontiers in Neuroscience, 17, 1183670).Transcranial Burst Electrical Stimulation (tBES) is an innovative non-invasive brain stimulation technique that combines direct current (DC) and theta burst stimulation (TBS) for brain neuromodulation. In a study by Nguyen et al. 2023, tBES (-) stimulation caused an elevation in GAD-65 expression, which has been used as a marker for excitatory and inhibitory neuronal activity in the brains of rodents. tBES (-) led to a notable decrease in MEPs relative to baseline (p = 0.04) and sham condition. Although tBES showed a more favorable neuromodulatory effect than tDCS, statistical analysis revealed no significant differences between these two groups. tBES has shown to modulate motor cortical excitability and has the potential for treating neurological disorders (Nguyen, T. X. D., Kuo, C. W., Peng, C. W., Liu, H. L., Chang, M. Y., & Hsieh, T. H. (2023). Transcranial burst electrical stimulation contributes to neuromodulatory effects in the rat motor cortex. Frontiers in Neuroscience, 17, 1303014). Rapid X-ray based genetically targeted (X-genetic) manipulation of cellular electrical activity in intact behaving animals has been demonstrated in Caenorhabditis elegans. Transgenic expression of LITE-1 in C. elegans muscle cells resulted in paralysis and egg ejection responses to stimulation, demonstrating that ectopic expression of LITE-1 confers X-ray sensitivity to otherwise insensitive cells. LITE-1 mediates an avoidance response to X-rays, and there is strong evidence that LITE-1 can function as an X-ray sensitive receptor in C. elegans. This study identifies an X-ray receptor protein that can be trans-genetically expressed in different cell types to acutely control the activity of those cells using X-rays, and demonstrates X-genetic control of cellular electrical activity. These findings suggest a minimally invasive approach to neuromodulation using transcranial X-ray signals for manipulation of neural activity in mammals (Cannon, K. E., Ranasinghe, M., Millhouse, P. W., Roychowdhury, A., Dobrunz, L. E., Foulger, S. H., ... & Bolding, M. (2023). LITE-1 mediates behavioral responses to X-rays in Caenorhabditis elegans. Frontiers in Neuroscience, 17, 1210138).Altogether, neurological pathologies and the approach to non-invasive intervention is a multi-pronged, multi-layered approach. Electrical intervention (direct/alternating), magnetic, acoustic, ultrasound, paired-pulsed, electrical bursts, photobiomodulation, rapid x-ray based and deep brain stimulation has their merits to solving their respective neurological disease. Parkinson's and stroke intervention present the initial beachhead to provide the early results through this intervention and prove its efficacy. There are specialized techniques that focus on a specific condition such as respiratory rehabilitation for spinal injury patients, directed treatments for dysphagia, and further bolstering the cognitive capabilities for those who have Alzheimer's disease. Non-invasive techniques are now considered an approach to higher spatial precision and regulation depth to brain tumors. What was considered improbable in terms of rapid memory and learning enhancement is now in practice for improving cognitive functions such as Electronic Sports. High definition HD-tACS has shown to reduce visual spatial attention distraction and improve task performance during stimulation for eSports participants. Furthermore, it is now being considered as a rehabilitation approach. Even remote intervention is possible while maintaining low power incidence to the patient. The next set of research highlights generalized pain reduction, merged interventions, and genetic modulation. This work represents research that may find itself very quickly in clinical environments. This field of neurological intervention and rehabilitation is moving rapidly. The most interesting non-invasive measures are just around the corner!