Search Results (245)

Background: Tinnitus is a prevalent auditory disorder associated with maladaptive cortical plasticity and aberrant neural synchronization across auditory and non-auditory brain networks. Acoustic desynchronization-based sound therapies, such as coordinated reset neuromodulation, aim to counteract pathological oscillatory patterns but commonly require prolonged daily listening sessions and specialized delivery formats, which may limit their accessibility and practicality in routine clinical settings. To address this limitation, a modified desynchronization protocol embedding therapeutic tones within music was developed to improve tolerability and engagement. This study aimed to evaluate the clinical effects of modified Music-Integrated Desynchronization Sound Therapy (mMIDST) on tinnitus severity in patients with chronic tinnitus. Methods: In this prospective, randomized, controlled, single-blind pilot trial conducted at the Otolaryngology Department of Hospital Clínico Universidad de Chile (Santiago, Chile) between July 2024 and July 2025, adults aged 18–75 years with chronic non-pulsatile tinnitus were assigned to receive either mMIDST or an active control intervention consisting of low-frequency stimulation (LFS) embedded within identical music tracks. Participants listened to personalized sound files for one hour daily, five days per week. Tinnitus severity was assessed using the Tinnitus Handicap Inventory (THI), with audiometric evaluations performed at baseline and after one, two, and three months. Between-group differences were analyzed using the Mann–Whitney U test. Results: Twenty-five participants completed the study (15 mMIDST, 10 LFS). Baseline audiometric thresholds and THI scores were comparable between groups. The mMIDST group showed significantly greater reductions in THI scores than the LFS group at two and three months of treatment (p < 0.05). Conclusions: mMIDST was associated with time-dependent improvements in tinnitus-related distress compared with an active control condition. Embedding desynchronization-based tonal stimulation within music may represent a promising and well-tolerated non-invasive approach for chronic tinnitus management. Full article

Background/Objectives: Low-intensity repetitive transcranial magnetic stimulation (Li-rTMS) is an emerging non-invasive neuromodulation approach for fibromyalgia; however, large-scale data on safety and tolerability in routine clinical settings remain limited. This study aimed to evaluate the safety and tolerability of Li-rTMS in patients with fibromyalgia treated in outpatient practice. Methods: A retrospective multicentre observational cohort study was conducted using routinely collected clinical data from nine outpatient centres (November 2020–March 2026). Safety analyses included all patients initiating Li-rTMS treatment (intention-to-treat cohort, n = 1381). The protocol consisted of eight stimulation sessions delivered using a CE-certified medical device. Patient-reported tolerability and perceived symptom changes in three predefined domains (headache, generalized pain, and sleep) were assessed using a standardized 0–10 scale and analysed descriptively, with stratification by age group. Results: Li-rTMS was generally well tolerated across all age groups, including those >65 years. High-intensity symptom worsening was infrequent (headache 3.8%, generalized pain 6.1%, sleep disturbances 2.1%), predominantly mild and self-limited. No serious adverse events were spontaneously reported or clinically identified during routine clinical follow-up, within the limitations inherent to a real-world passive registry framework. Exploratory observations from patient-initiated recall sessions did not suggest an increased adverse symptom burden with repeated exposure. Conclusions: Li-rTMS demonstrated a favourable patient-reported tolerability profile among patients with available follow-up data, characterized by a low frequency of transient high-intensity symptom worsening and the absence of serious adverse events spontaneously reported or clinically identified during routine, non-systematic follow-up. These findings support the feasibility of repeated Li-rTMS administration in outpatient settings; however, due to the observational design and non-systematic follow-up, no conclusions regarding clinical efficacy can be drawn. Full article

Introduction: Transcranial photobiomodulation (t-PBM) is a non-invasive metabolic neuromodulation technique intended to enhance cerebral bioenergetics by stimulating mitochondrial activity. To characterize both baseline metabolic vulnerability and real-time metabolic engagement during stimulation, this preliminary study integrated phosphorus magnetic resonance spectroscopy (³¹P-MRS) with resting-state fMRI. Methods: Eleven individuals with mild cognitive impairment (MCI) or early Alzheimer’s disease underwent ³¹P-MRS to quantify baseline cerebral metabolism (PCr/Pi, pH), followed by MRI sessions during which t-PBM was applied over bilateral frontal sites. Fractional amplitude of low-frequency fluctuations (fALFF), a resting-state index strongly associated with cerebral glucose metabolism, was used as a real-time proxy of metabolic change during stimulation. Results: Linear regression analyses indicated that lower baseline PCr/Pi and lower pH, markers of impaired oxidative metabolism, predicted greater increases in fALFF during t-PBM, most prominently in the right frontal pole (FP2) and, to a lesser extent, right dorsolateral prefrontal cortex (F4). While greater dementia severity also predicted larger fALFF responses in select regions, our findings suggest that t-PBM can boost metabolism in some brain regions where it is compromised, but that this may be independent of cognitive function in early AD/MCI. These findings suggest that t-PBM may preferentially engage brain regions with reduced metabolic capacity to exhibit stronger acute responses. Discussion: Overall, these hypothesis-generating results support the combined use of ³¹P-MRS and fALFF as complementary biomarkers to quantify baseline metabolic status and real-time target engagement. A single session of t-PBM produced neural activity changes consistent with partial metabolic normalization in vulnerable cortical regions. As these results are preliminary, ongoing longitudinal work with a larger cohort will determine whether baseline metabolic profiles and acute fALFF responses predict clinical outcomes after repeated t-PBM treatment. Full article

Background/Objectives: Alzheimer’s disease (AD) remains a significant global health challenge, characterised by a persistent resistance to traditional pharmacological interventions. While non-invasive brain stimulation (NIBS) techniques like transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) show therapeutic promise, their limited depth of penetration restricts their efficacy in targeting deep-brain AD pathology. Transcranial focused ultrasound stimulation (tFUS) has emerged as a novel, non-invasive neuromodulatory tool capable of precise deep-brain targeting. This scoping review aims to systematically map the current evidence base regarding the neuromodulatory application of tFUS in AD. Methods: Following PRISMA-ScR guidelines, a scoping search was conducted across four major databases (Ovid MEDLINE, Embase, Web of Science, and CENTRAL). Studies were included if they investigated focused ultrasound stimulation (FUS) as a neuromodulatory intervention for AD, excluding applications involving blood–brain-barrier disruption via microbubbles. Two independent reviewers performed screening and data extraction, with inter-rater reliability assessed via Cohen’s kappa. Results: Our analysis indicates that tFUS represents a safe and potent multi-modal intervention for AD that addresses both pathological protein aggregation and electrophysiological network failure. Its ability to modulate neuroplasticity and metabolic recovery suggests a promising therapeutic trajectory. Conclusions: Future research should prioritise the standardisation of acoustic protocols and the pursuit of longitudinal clinical cohorts to establish the long-term efficacy of this non-invasive technology. Full article

Introduction: Multiple Sclerosis (MS) is frequently associated with a range of neurological, cognitive and psychological issues, presenting significant challenges to patients’ Quality of Life (QoL). Among non-invasive neuromodulation techniques, transcutaneous spinal Direct Current Stimulation (tsDCS) is emerging as a potential approach for symptom management in neurological conditions. However, the effects of tsDCS on MS remain poorly explored. Thus, this preliminary study aimed to evaluate the effects of tsDCS on MS symptomatology, focusing on cognitive and psychological variables. Methods: Six patients with MS were recruited for a randomized, sham-controlled, double-blind crossover study, and received anodal tsDCS or sham stimulation in two separate sessions at least one month apart. Assessment outcomes included cognitive and attentional-executive functions, depressive symptoms, and several QoL components. The tests were administered at baseline (T0), immediately after treatment (T1), one week (T2) and one month (T3) post-treatment. Results: Although protocol-by-time interactions did not reach statistical significance across all measures, protocol-independent improvements over time were observed in various QoL subscales, including Physical Functioning, Role Limitations due to Physical Health, Vitality, Health Distress, and Overall QoL. Conclusions: Our findings indicate that tsDCS is a feasible and well-tolerated intervention in patients with MS, with possible implications for QoL. Given the small sample size and the exploratory nature of this study, further research is needed to clarify whether tsDCS may represent a potentially beneficial non-invasive neuromodulation approach for improving well-being in patients with MS across both physical and mental dimensions. Full article

Background/Objectives: The growing aging population is susceptible to cognitive and memory impairment, most commonly due to Alzheimer’s disease, with no cures currently available. Noninvasive brain stimulation (NIBS) techniques may serve to improve cognition and delay catastrophic memory loss. Methods: A systematic review of NIBS research on cognitive impairment was carried out using PubMed, with additional backward citation searching. A total of 81 studies using NIBS were included. Conclusions: The reviewed studies show that NIBS holds promise in improving memory deficits in patients with cognitive impairment. While the longevity of benefits from transcranial electrical stimulation appears limited, its short-term effects may provide benefits when used consistently. Transcranial magnetic stimulation appears to provide longer-lasting benefits. Transcranial focused ultrasound stimulation may also provide further benefits through more precise targeting of deeper brain structures compared to other NIBS techniques. Together, these results suggest that NIBS shows promise for the treatment of symptoms related to cognitive and memory impairment, and may help to alleviate some of the growing issues associated with the increasing level of Alzheimer’s disease in an aging population. Full article

Background and Objectives: Overactive bladder (OAB) is frequently associated with impaired quality of life and sleep disturbances, particularly in women with refractory symptoms. Non-invasive neuromodulation targeting autonomic regulation has emerged as a potential therapeutic approach. The purpose of this pilot trial is to assess the efficacy and safety of NESA non-invasive neuromodulation in the treatment of patients with overactive bladder. Materials and Methods: Triple-blind, randomized, sham-controlled pilot trial. Women ≥ 18 years with refractory OAB were randomized to active NESA or sham using an identical protocol (10 sessions, 60 min, twice weekly). Outcomes were collected at baseline, after session 5, and after session 10. The primary outcome was mean daily micturitions, assessed using a 3-day voiding diary. Secondary outcomes included other diary variables, urinary questionnaires (ICIQ-UI SF, ICIQ-QoL, B-SAQ), and sleep measures (PSQI, ISI). Results: Per-protocol analysis included 43 women (NESA n = 24; sham n = 19). At session 10, mean daily micturitions decreased from 9.19 to 8.07 with NESA and increased from 10.56 to 11.03 with sham (between-group p = 0.043; d = −0.97). Sleep improved with NESA versus sham (PSQI p = 0.001; d = −0.63; ISI p = 0.001; d = −0.59). Between-group differences in urinary symptom questionnaires were not significant. No device-related adverse events occurred. Conclusions: In this pilot trial, NESA neuromodulation was safe and showed preliminary signals of benefit, particularly for mean daily frequency and sleep outcomes. However, given the exploratory design, small sample size, and per-protocol analysis, these findings should be interpreted cautiously and confirmed in larger adequately powered trials before clinical implementation. Full article

Neuropsychiatric disorders are characterized by complex etiologies, widespread involvement of brain regions, and pronounced clinical heterogeneity, with core pathological mechanisms closely associated with abnormal activity in deep brain structures and their functional networks. Although current pharmacological therapies and conventional neuromodulation techniques have shown therapeutic benefits in certain conditions, they are generally limited by insufficient stimulation depth or the risks associated with invasive procedures. Temporal interference (TI) electrical stimulation has recently emerged as a non-invasive deep neuromodulation technique that generates low-frequency difference-envelope fields through high-frequency carrier signals, thereby enabling relatively precise modulation of deep brain regions while maintaining favorable safety and tolerability. This technique provides a novel technical pathway for precision intervention in neuropsychiatric disorders. In this review, we summarize the principles and technical characteristics of TI stimulation and highlight its recent applications in mood and stress-related disorders, cognitive impairment and neurodegenerative diseases, movement disorders, addiction, and disorders associated with dysregulated neural excitability. We integrate its potential mechanisms across multiple levels, including neural oscillations, deep–cortical network synchronization, reward and motivational circuits, synaptic plasticity and structural remodeling, excitatory-inhibitory balance, and gene and epigenetic regulation. Current evidence suggests that TI stimulation can modulate electrophysiological activity and may engage molecular and network-level processes relevant to functional improvement, although durable clinical benefits remain to be established. Although clinical translation remains challenged by parameter optimization, interindividual variability, and long-term safety evaluation, advances in computational modeling, multimodal neuroimaging, and closed-loop stimulation strategies are expected to facilitate its development. Overall, TI stimulation represents a promising non-invasive deep neuromodulation approach for mechanistic investigation and precision treatment of neuropsychiatric disorders. Full article

Spinal cord stimulation (SCS) has expanded beyond pain treatment, becoming a neuromodulatory method capable of recruiting spinal and supraspinal circuits involved in motor recovery. This review summarises mechanistic knowledge, supports engineering developments, and describes the changing clinical translation of SCS in rehabilitation. Mounting scientific data shows that SCS’s effects go beyond dorsal column modulation and may involve segmental networks that promote activity-dependent plasticity and sensorimotor pathway restoration, probably due to a combination of Hebbian and non-Hebbian mechanisms (synaptic potentiation, interneuronal reorganisation, and altered afferent–efferent coupling). More recent advances, such as bursts and the high-frequency paradigm, closed-loop control, and data-driven parameter optimisation methods, improve the precision, stability, and calibration of stimulation for each individual. By combining SCS with non-invasive forms of neuromodulation (TMS, tDCS, and peripheral nerve stimulation), one can potentially further intensify corticospinal plasticity and maintain improvements in functions. Spinal cord stimulation remains an established treatment for chronic neuropathic pain, including failed back surgery syndrome and complex regional pain syndrome. In recent years, however, increasing attention has been directed toward its potential role in motor recovery after spinal cord injury and stroke. Progress in this area is limited by patient heterogeneity, variability in outcome measures, the complexity of multimodal rehabilitation protocols, and regulatory and logistical constraints—particularly when adaptive or closed-loop systems are used. Current evidence suggests that motor-restorative applications of SCS should be interpreted cautiously and integrated within carefully designed rehabilitation programmes, with attention to patient selection and realistic expectations regarding the durability of the benefit. Full article

Laser acupuncture (LA) integrates principles of traditional acupuncture with photobiomodulation (PBM) and has gained increasing attention as a non-invasive modality for pain management. PBM-based integrative LA in medicine refers to the application of low-level laser irradiation to acupuncture points, combining contemporary biomedical mechanisms with holistic, system-oriented therapeutic principles. This narrative review aimed to critically assess the scientific evidence on the efficacy of LA for pain management within the framework of the Principles of Clinical Integration of Photobiomodulation (PCIPBM) in LA, summarizing frequently used laser parameters and clinical indications. LA involves special protocols in standardized acupoints, using defined parameters of wavelength, irradiation, and energy density, consistent with PBM dosing principles. Therapeutic effects are mediated through point-specific neuromodulation and photobiological mechanisms, including modulation of peripheral and central nociceptive processing, reduction in pro-inflammatory mediators, improvement of microcirculation, and mitochondrial activation via cytochrome c oxidase-dependent adenosine triphosphate (ATP) synthesis. Clinical studies report statistically and clinically significant analgesic effects, particularly in chronic musculoskeletal pain, osteoarthritis, low back and neck pain, temporomandibular disorders, neuropathic pain, and selected postoperative pain conditions, when appropriate laser parameters are applied. Reported adverse effects are minimal, and tolerability is high. LA represents a safe, non-invasive therapeutic option and patient-friendly approach with clinically relevant efficacy in pain management. When applied according to PCIPBM, including evidence-based PBM parameters, it may serve as an effective adjunct or alternative to conventional pharmacologic and interventional approaches. Further standardization and high-quality randomized controlled trials are still required. Full article

Objective: The classic excitation/inhibition dichotomy may be insufficient to describe rTMS mechanisms in the aging brain. This study investigated immediate whole-brain resting-state functional connectivity effects of 10 Hz (high-frequency) and 1 Hz (low-frequency) rTMS over the left dorsolateral prefrontal cortex (DLPFC) in healthy older adults. Methods: Thirty healthy older adults (aged 60–75 years) participated in a randomized, single-blind, crossover study, and underwent 20-min 10 Hz and 1 Hz rTMS in separate visits. A 106-channel fNIRS system was used to record resting-state activity before and immediately after each intervention. Functional connectivity was analyzed at the channel, region-of-interest (ROI) and network summary levels, including graph-theoretic metrics and distance-stratified connectivity summaries. Results: At the network summary level, 10 Hz stimulation was associated with relatively more positive changes in global topology and spatially distributed connectivity summaries, whereas 1 Hz stimulation showed the opposite overall trend. In the graph-theoretic analyses, stimulation frequency × time interaction effects were observed for global efficiency, local efficiency, clustering coefficient, and mean node strength. At the edge level, only a small number of effects survived FDR correction, and the broader connection-wise patterns were therefore interpreted as exploratory. Uncorrected analyses suggested widespread enhancement after 10 Hz stimulation and widespread reduction after 1 Hz stimulation, together with localized paradoxical effects, including selective decreases after 10 Hz and selective increases after 1 Hz (e.g., bilateral primary motor cortex connectivity). Conclusions: These findings suggest that 10 Hz and 1 Hz rTMS over the left DLPFC are associated with different patterns of immediate whole-brain network reconfiguration in healthy older adults. The presence of localized paradoxical effects further suggests that rTMS responses in the aging brain may involve more complex forms of reorganization than a simple excitatory/inhibitory dichotomy would predict. Significance: The present study provides preliminary support for a network-level perspective on neuromodulation in older adults and highlights the value of whole-brain fNIRS for characterizing distributed responses to rTMS. Larger, sham-controlled, behavior-linked, and longitudinal studies are needed to determine the robustness and functional significance of these effects. Full article

Selectively modulating specific brain-rhythm bands with physical stimuli helps both to reveal neural mechanisms and to provide non-pharmacological treatment avenues for brain disorders. This study proposes and implements a multi-channel transcranial magneto-acoustic stimulation driving system based on amplitude-modulated (AM) sine waves (AM-TMAS) intended to supply a reliable hardware platform for noninvasive, focal low-frequency rhythmic electrical stimulation of deep-brain structures. The driving system implements a 64-channel AM module based on an FPGA plus high-speed DACs. Multi-channel precision is achieved via a unified high-speed clock and a global UPDATE trigger. To overcome the large separation between envelope and carrier frequencies, we developed a high-fidelity AM waveform generation method based on DDS + LUT + envelope multiplication. The algorithm first centers the carrier samples to preserve waveform symmetry, then applies LUT-based envelope coefficients and fixed-point envelope multiplication, enabling high-precision AM outputs with carrier frequencies from 100 kHz to 2 MHz and envelope frequencies from 0.1 Hz to 100 kHz. We tested the system’s rhythmic multi-channel AM output performance across frequencies and also measured magneto-acoustic-coupled rhythmic electrical signals produced by the AM-TMAS driving setup. Any single channel reliably produced high-fidelity AM waveforms with a 500 kHz carrier and 8 Hz/40 Hz envelopes; the measured carrier was 499.998 kHz with excellent frequency stability. Both envelope and carrier frequencies are flexibly tunable. At the nominal 500 kHz carrier, envelope fidelity was further quantified: the extracted envelopes achieved NRMSEs of 1.0795% (8 Hz) and 1.9212% (40 Hz), confirming high-fidelity AM synthesis. Under a 0.3 T static magnetic field, the AM-TMAS driving system generated rhythmic electrical responses in physiological saline that carried the expected 40 Hz envelope. The proposed AM-TMAS driver achieves high accuracy in AM waveform generation and robust multi-channel performance, and—when combined with an external static magnetic field—can produce rhythmically modulated magneto-acoustic electrical stimulation. This platform provides a practical technical tool for brain-function research and the development of rhythm-targeted neuromodulation therapies. Full article

Motor recovery after stroke, spinal cord injury, or traumatic brain injury reflects relearning rather than simple restitution, as surviving circuits retain plastic potential that can be re-engaged through temporally precise stimulation. This review synthesizes convergent findings demonstrating that Hebbian and spike-timing-dependent mechanisms govern reorganization across cortical, striatal, and spinal levels. Leveraging these timing rules to shape excitability during receptive network states enables durable changes in connectivity and behavior. This effect depends on temporal precision, physiological state, and reinforcement—not stimulus intensity alone—within plasticity windows regulated by metaplastic mechanisms that determine whether Hebbian processes are expressed. Together, these principles define a translational framework for neurorehabilitation, emphasizing biomarker-guided, adaptive, and scalable strategies aligned with intrinsic rules of experience-dependent reorganization. Full article

Background: Individuals with attention deficit hyperactivity disorder (ADHD) can exhibit neurocognitive deficits, psychosocial alterations, and changes in sleep regulation. In this sense, non-invasive techniques such as transcranial magnetic stimulation (TMS) can be used to assess and treat people with neurocognitive disorders. Studies using neuromodulation to estimate the timing and regulation of sleep remain scarce, revealing a gap in its understanding and treatment. Aim: To analyze whether the application of 10 Hz TMS modifies time estimation and sleep quality in people with ADHD for characteristics of inattention and hyperactivity. Material and Methods: Twelve adult male participants with high scores on the assessment of ADHD scale underwent a 10 Hz TMS protocol and a visual stimulus time estimation task. Daily rhythmicity was assessed by actigraphy before and after the repetitive transcranial magnetic stimulation (rTMS) intervention. Sleep quality was evaluated using the Pittsburg Sleep Quality Index and the Morning and Evening Questionnaire. Results: The results showed that rTMS modulated the interpretation of the 9 s long interval (p = 0.028). For the ADHD-AD instrument, no statistically significant differences were observed (p > 0.05). In relation to actigraphic variables—sleep time, bedtime, latency, sleep efficiency, and wakefulness after sleep onset—there were no differences after excitatory neuromodulation (p > 0.05). Conclusions: The findings demonstrate that the application of 10 Hz TMS enhances performance in long intervals during the time estimation task for individuals with ADHD, but does not affect sleep quality. Full article

Background: Lumbosacral plexopathy (LSP) is characterized by severe neuropathic pain, motor weakness, and sensory deficits in the lumbosacral plexus region, often leading to significant functional impairment and reduced quality of life. Post-traumatic LSP is particularly challenging to treat due to its neuropathic nature and limited response to conventional pharmacologic therapies. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulation technique that has shown therapeutic potential for chronic neuropathic pain. Case Report: We report the case of a 16-year-old female who developed LSP following multiple pelvic fractures and subsequently exhibited disabling pain, depressive symptoms, and poor quality of life. High-frequency motor cortex rTMS resulted in meaningful clinical improvement in pain intensity (an NRS reduction from 8 to 2), mood, and daily functioning. Conclusions: This suggests the potential role of rTMS as an adjunctive treatment for refractory neuropathic pain secondary to traumatic LSP. Full article