BACKGROUND: Temporal interference stimulation (TIS) is a novel noninvasive electrical stimulation technique to focally modulate deep brain regions; a minimum of two high-frequency signals (f1 and f2 > 1 kHz) interfere to create an envelope-modulated signal at a deep brain target with the frequency of modulation equal to the difference frequency: Δf = |f2 - f1|. OBJECTIVE: The goals of this study were to verify the capability of TIS to modulate the subthalamic nucleus (STN) with Δf and to compare the effect of TIS and conventional deep brain stimulation (DBS) on the STN beta oscillations in patients with Parkinson's disease (PD). METHODS: DBS leads remained externalized after implantation, allowing local field potentials (LFPs) recordings in eight patients with PD. TIS was performed initially by two pairs (f1 = 9.00 kHz; f2 = 9.13 kHz, 4 mA peak-peak per pair maximum) of scalp electrodes placed in temporoparietal regions to focus the envelope signal maximum (Δf = 130 Hz) at the motor part of the STN target. RESULTS: The comparison between the baseline LFPs and recordings after TIS and conventional DBS sessions showed substantial suppression of high beta power peak after both types of stimulation in all patients. CONCLUSIONS: TIS has the potential to effectively modulate the STN and reduce the beta oscillatory activity in a completely noninvasive manner, as is traditionally possible only with intracranial DBS. Future studies should confirm the clinical effectiveness of TIS and determine whether TIS could be used to identify optimal DBS candidates and individualize DBS targets. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
- MeSH
- Beta Rhythm * physiology MeSH
- Deep Brain Stimulation * methods MeSH
- Middle Aged MeSH
- Humans MeSH
- Subthalamic Nucleus * physiopathology MeSH
- Parkinson Disease * therapy physiopathology MeSH
- Aged MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
Temporal interference (TI) is a method of non-invasive brain stimulation using transcutaneous electrodes which allows the targeting and modulation of deeper brain structures, not normally associated with non-invasive simulation, while avoiding unwanted stimulation of shallower cortical structures. The properties of TI have been previously demonstrated, however, the problem of decoupling stimulation focality from stimulation intensity has not yet been well addressed. In this paper, we provide a possible novel solution, multipolar TI (mTI), which allows increased independent control over both the size of the stimulated region and the stimulation intensity. The mTI method uses multiple carrier frequencies to create multiple overlapping amplitude-modulated envelopes, rather than using one envelope as in standard TI. The study presents an explanation of the concept of mTI along with experimental data gathered from Rhesus macaques and mice. We improved the focality at depth in anesthetized mice and monkeys, and using the new focality in awake monkeys, evoked targeted activity at depth in the superior colliculus. The mTI method could be an interesting and potentially useful new tool alongside other forms of non-invasive brain stimulation. Teaser Multipolar Temporal Interference Stimulation can produce a more focal brain stimulation at depth compared to Temporal Interference.
- Publication type
- Journal Article MeSH
Statínová intolerancia predstavuje významnú výzvu v liečbe dyslipidémie, najmä u pacientov s vysokým kardiovaskulárnym rizikom. Tento problém, definovaný ako neschopnosť pacienta tolerovať dávku statínu potrebnú na efektívne zníženie hladín LDL-cholesterolu (LDL-C), môže byť asociovaný so svalovými symptómami, zvýšením pečeňových enzýmov alebo inými nežiaducimi účinkami. Prevalencia statínovej intolerancie sa pohybuje od 7 % do 29 % v klinickej praxi, pričom úplná intolerancia sa vyskytuje iba u 3–6 % pacientov. Mierne formy svalových symptómov, ako sú myalgie, sú najčastejšie, zatiaľ čo závažné komplikácie, ako je rabdomyolýza, sú veľmi zriedkavé. Diagnóza statínovej intolerancie zahŕňa hodnotenie časovej súvislosti medzi začiatkom liečby a symptómami, vylúčenie alternatívnych príčin a potvrdenie kauzality pomocou opätovného nasadenia lieku. Zaujímavým fenoménom je nocebo efekt, ktorý môže zodpovedať za väčšinu subjektívnych sťažností na svalové symptómy bez priameho súvisu so statínmi. Manažment pacientov so statínovou intoleranciou zahŕňa nefarmakologické prístupy, ako je zmena životného štýlu, a farmakologické alternatívy, vrátane podávania ezetimibu, kyseliny bempedoovej a inhibítorov PCSK9. Väčšina pacientov aj napriek určitému stupňu statínovej intolerancie toleruje malú dávku statínu a ezetimibu, prípadne novú inovatívnu terapiu (ak je indikovaná) a u týchto pacientov vieme efektívne dosiahnuť cieľové hladiny LDL-C. Jedinou limitáciou pri využití alternatívnych liekov na dosiahnutie cieľového zníženia hladiny LDL-C je hradenie týchto postupov zo zdrojov verejného zdravotného poistenia.
Statin intolerance represents a significant challenge in the treatment of dyslipidemia, particularly in patients with high cardiovascular risk. This condition, defined as the inability of a patient to tolerate a statin dose required for effective LDL cholesterol reduction, can result from muscle symptoms, elevated liver enzymes, or other adverse effects. The prevalence of statin intolerance ranges from 7 % to 29 % in clinical practice, with complete intolerance observed in only 3–6 % of patients. Mild forms of muscle symptoms, such as myalgia, are the most common, while severe complications like rhabdomyolysis are very rare. The diagnosis of statin intolerance involves evaluating the temporal relationship between the onset of therapy and symptoms, excluding alternative causes, and confirming causality through rechallenge with the drug. An interesting phenomenon is the nocebo effect, which may account for the majority of subjective complaints of muscle symptoms without a direct link to statins. The management of patients with statin intolerance includes non-pharmacological approaches, such as lifestyle modifications, and pharmacological alternatives, including ezetimibe, PCSK9 inhibitors, and novel drugs like inklisiran. Inklisiran, an RNA interference-based drug, offers a significant reduction in LDL cholesterol of over 50 % with only biannual dosing and minimal side effects.
- MeSH
- Dyslipidemias drug therapy therapy MeSH
- Hypolipidemic Agents pharmacology classification therapeutic use MeSH
- Cholesterol, LDL blood drug effects MeSH
- Humans MeSH
- Muscular Diseases chemically induced diagnosis physiopathology pathology MeSH
- Drug-Related Side Effects and Adverse Reactions diagnosis epidemiology pathology MeSH
- Hydroxymethylglutaryl-CoA Reductase Inhibitors * adverse effects MeSH
- Drug Tolerance * MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review MeSH
BACKGROUND: Electrical stimulation involving temporal interference of two different kHz frequency sinusoidal electric fields (temporal interference (TI)) enables non-invasive deep brain stimulation, by creating an electric field that is amplitude modulated at the slow difference frequency (within the neural range), at the target brain region. OBJECTIVE: Here, we investigate temporal interference neural stimulation using square, rather than sinusoidal, electric fields that create an electric field that is pulse-width, but not amplitude, modulated at the difference frequency (pulse-width modulated temporal interference, (PWM-TI)). METHODS/RESULTS: We show, using ex-vivo single-cell recordings and in-vivo calcium imaging, that PWM-TI effectively stimulates neural activity at the difference frequency at a similar efficiency to traditional TI. We then demonstrate, using computational modelling, that the PWM stimulation waveform induces amplitude-modulated membrane potential depolarization due to the membrane's intrinsic low-pass filtering property. CONCLUSIONS: PWM-TI can effectively drive neural activity at the difference frequency. The PWM-TI mechanism involves converting an envelope amplitude-fixed PWM field to an amplitude-modulated membrane potential via the low-pass filtering of the passive neural membrane. Unveiling the biophysics underpinning the neural response to complex electric fields may facilitate the development of new brain stimulation strategies with improved precision and efficiency.
- MeSH
- Electric Stimulation MeSH
- Brain * MeSH
- Computer Simulation MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Behavioral variant frontotemporal dementia (bvFTD) is characterized by profound and early deficits in social cognition (SC) and executive functions (EF). To date it remains unclear whether deficits of the respective cognitive domains are based on the degeneration of distinct brain regions. In 103 patients with a diagnosis of bvFTD (possible/probable/definite: N = 40/58/5) from the frontotemporal lobar degeneration (FTLD) consortium Germany cohort (age 62.5±9.4 years, gender 38 female/65 male) we applied multimodal structural imaging, i.e. voxel-based morphometry, cortical thickness (CTH) and networks of structural covariance via source based morphometry. We cross-sectionally investigated associations with performance in a modified Reading the Mind in the Eyes Test (RMET; reflective of theory of mind - ToM) and five different tests reflective of EF (i.e. Hamasch-Five-Point Test, semantic and phonemic Fluency, Trail Making Test, Stroop interference). Finally, we investigated the conjunction of RMET correlates with functional networks commonly associated with SC respectively ToM and EF as extracted meta-analytically within the Neurosynth database. RMET performance was mainly associated with gray matter volume (GMV) and CTH within temporal and insular cortical regions and less within the prefrontal cortex (PFC), whereas EF performance was mainly associated with prefrontal regions (GMV and CTH). Overlap of RMET and EF associations was primarily located within the insula, adjacent subcortical structures (i.e. putamen) and the dorsolateral PFC (dlPFC). These patterns were more pronounced after adjustment for the respective other cognitive domain. Corroborative results were obtained in analyses of structural covariance networks. Overlap of RMET with meta-analytically extracted functional networks commonly associated with SC, ToM and EF was again primarily located within the temporal and insular region and the dlPFC. In addition, on a meta-analytical level, strong associations were found for temporal cortical RMET correlates with SC and ToM in particular. These data indicate a temporo-frontal dissociation of bvFTD related disturbances of ToM and EF, with atrophy of the anterior temporal lobe being critically involved in ToM deficits. The consistent overlap within the insular cortex may be attributable to the multimodal and integrative role of this region in socioemotional and cognitive processing.
- MeSH
- Executive Function * physiology MeSH
- Frontotemporal Dementia * pathology diagnostic imaging physiopathology psychology MeSH
- Middle Aged MeSH
- Humans MeSH
- Magnetic Resonance Imaging * MeSH
- Brain diagnostic imaging pathology MeSH
- Neuropsychological Tests * MeSH
- Cross-Sectional Studies MeSH
- Aged MeSH
- Social Cognition MeSH
- Theory of Mind * physiology MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
In mammals, RNA interference (RNAi) was historically studied as a cytoplasmic event; however, in the last decade, a growing number of reports convincingly show the nuclear localization of the Argonaute (AGO) proteins. Nevertheless, the extent of nuclear RNAi and its implication in biological mechanisms remain to be elucidated. We found that reduced Lamin A levels significantly induce nuclear influx of AGO2 in SHSY5Y neuroblastoma and A375 melanoma cancer cell lines, which normally have no nuclear AGO2. Lamin A KO manifested a more pronounced effect in SHSY5Y cells compared to A375 cells, evident by changes in cell morphology, increased cell proliferation, and oncogenic miRNA expression. Moreover, AGO fPAR-CLIP in Lamin A KO SHSY5Y cells revealed significantly reduced RNAi activity. Further exploration of the nuclear AGO interactome by mass spectrometry identified FAM120A, an RNA-binding protein and known interactor of AGO2. Subsequent FAM120A fPAR-CLIP, revealed that FAM120A co-binds AGO targets and that this competition reduces the RNAi activity. Therefore, loss of Lamin A triggers nuclear AGO2 translocation, FAM120A mediated RNAi impairment, and upregulation of oncogenic miRNAs, facilitating cancer cell proliferation.
- MeSH
- Active Transport, Cell Nucleus MeSH
- Argonaute Proteins * metabolism genetics MeSH
- Cell Nucleus * metabolism MeSH
- Lamin Type A * metabolism genetics MeSH
- Humans MeSH
- Melanoma genetics metabolism pathology MeSH
- MicroRNAs * metabolism genetics MeSH
- Cell Line, Tumor MeSH
- Cell Proliferation * genetics MeSH
- RNA-Binding Proteins metabolism genetics MeSH
- RNA Interference * MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
PURPOSE: The time structures of proton spot delivery in proton pencil beam scanning (PBS) radiation therapy are essential in many clinical applications. This study aims to characterize the time structures of proton PBS delivered by both synchrotron and synchrocyclotron accelerators using a non-invasive technique based on scattered particle tracking. METHODS: A pixelated semiconductor detector, AdvaPIX-Timepix3, with a temporal resolution of 1.56 ns, was employed to measure time of arrival of secondary particles generated by a proton beam. The detector was placed laterally to the high-flux area of the beam in order to allow for single particle detection and not interfere with the treatment. The detector recorded counts of radiation events, their deposited energy and the timestamp associated with the single events. Individual recorded events and their temporal characteristics were used to analyze beam time structures, including energy layer switch time, magnet switch time, spot switch time, and the scanning speeds in the x and y directions. All the measurements were repeated 30 times on three dates, reducing statistical uncertainty. RESULTS: The uncertainty of the measured energy layer switch times, magnet switch time, and the spot switch time were all within 1% of average values. The scanning speeds uncertainties were within 1.5% and are more precise than previously reported results. The measurements also revealed continuous sub-milliseconds proton spills at a low dose rate for the synchrotron accelerator and radiofrequency pulses at 7 μs and 1 ms repetition time for the synchrocyclotron accelerator. CONCLUSION: The AdvaPIX-Timepix3 detector can be used to directly measure and monitor time structures on microseconds scale of the PBS proton beam delivery. This method yielded results with high precision and is completely independent of the machine log files.
- MeSH
- Time Factors MeSH
- Particle Accelerators * instrumentation MeSH
- Radiotherapy Dosage * MeSH
- Humans MeSH
- Neoplasms radiotherapy MeSH
- Radiotherapy Planning, Computer-Assisted * methods MeSH
- Semiconductors * MeSH
- Proton Therapy * instrumentation MeSH
- Protons MeSH
- Synchrotrons instrumentation MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
Canonical RNA interference (RNAi) is sequence-specific mRNA degradation guided by small interfering RNAs (siRNAs) made by RNase III Dicer from long double-stranded RNA (dsRNA). RNAi roles include gene regulation, antiviral immunity or defense against transposable elements. In mammals, RNAi is constrained by Dicer's adaptation to produce another small RNA class-microRNAs. However, a truncated Dicer isoform (ΔHEL1) supporting RNAi exists in mouse oocytes. A homozygous mutation to express only the truncated ΔHEL1 variant causes dysregulation of microRNAs and perinatal lethality in mice. Here, we report the phenotype and canonical RNAi activity in DicerΔHEL1/wt mice, which are viable, show minimal miRNome changes, but their endogenous siRNA levels are an order of magnitude higher. We show that siRNA production in vivo is limited by available dsRNA, but not by Protein kinase R, a dsRNA sensor of innate immunity. dsRNA expression from a transgene yields sufficient siRNA levels to induce efficient RNAi in heart and muscle. DicerΔHEL1/wt mice with enhanced canonical RNAi offer a platform for examining potential and limits of mammalian RNAi in vivo.
- MeSH
- DEAD-box RNA Helicases genetics metabolism MeSH
- RNA, Double-Stranded * metabolism genetics MeSH
- RNA, Small Interfering * genetics metabolism MeSH
- MicroRNAs genetics metabolism MeSH
- Mice MeSH
- Protein Isoforms genetics metabolism MeSH
- Ribonuclease III * genetics metabolism MeSH
- RNA Interference * MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Deep brain stimulation (DBS) via implanted electrodes is used worldwide to treat patients with severe neurological and psychiatric disorders. However, its invasiveness precludes widespread clinical use and deployment in research. Temporal interference (TI) is a strategy for non-invasive steerable DBS using multiple kHz-range electric fields with a difference frequency within the range of neural activity. Here we report the validation of the non-invasive DBS concept in humans. We used electric field modeling and measurements in a human cadaver to verify that the locus of the transcranial TI stimulation can be steerably focused in the hippocampus with minimal exposure to the overlying cortex. We then used functional magnetic resonance imaging and behavioral experiments to show that TI stimulation can focally modulate hippocampal activity and enhance the accuracy of episodic memories in healthy humans. Our results demonstrate targeted, non-invasive electrical stimulation of deep structures in the human brain.
- MeSH
- Electric Stimulation MeSH
- Hippocampus physiology MeSH
- Deep Brain Stimulation * methods MeSH
- Electrodes, Implanted MeSH
- Humans MeSH
- Brain * physiology MeSH
- Cerebral Cortex MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
BACKGROUND: Sensory deficits can result in limitations regarding how well neuropsychological test findings can be interpreted. Only a few studies have investigated the influence of vision alteration on neuropsychological tests. In 2012 the Czech Republic experienced mass methanol poisoning. Methanol metabolites cause histotoxic hypoxia to the optic nerve. OBJECTIVE: In the current study, the effect of the toxic damage on the parts of the visual pathway on visual and non-visual neuropsychological measures was investigated using electrophysiological methods (visual evoked potential (VEP) and optical coherence tomography (OCT) with retinal nerve fibre layer (RNFL) thickness measurement. METHODS: 53 individuals who experienced methanol poisoning participated in this research (76% men; ages 24 to 74 years, mean = 43.8±14.6 years; education 11.9±1.4 years). Each participant underwent comprehensive neurological, ophthalmological, and neuropsychological examinations. RESULTS: The results of mixed-effect models revealed significant small to a medium association between the Stroop test weak interference and Grooved Pegboard with the left eye global, nasal and temporal RNFL thickness. Also, medium associations between the Finger Tapping test and the Stroop test weak interference and left eye temporal RNFL, right eye temporal RNFL, and the latency P1 of VEP in the left eye were significant. CONCLUSION: The results of this study found a small to medium association (r = .15- .33; p = .010- .046) between RNFL thickness and cognitive visual test performance. Careful interpretation is suggested regarding results obtained from visual tests of the executive or motor functioning with participants with RNFL decrease or other types of early visual processing damage.
- MeSH
- Cognition MeSH
- Humans MeSH
- Methanol * MeSH
- Neuropsychological Tests MeSH
- Survivors MeSH
- Evoked Potentials, Visual * MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
