Low-frequency Stimulation Research Articles

Top-down control of vestibular inputs by the dorsolateral prefrontal cortex.

The vestibular apparatus provides spatial information on the position of the head in space and with respect to gravity. Low-frequency sinusoidal galvanic vestibular stimulation (sGVS), a means of selectively changing the firing of vestibular afferents, induces a frequency-dependent perception of sway and, in some individuals, induces nausea. Given that vestibular afferents project to the insular cortex-which forms part of the vestibular cortex-and that the insula receives inputs from the dorsolateral prefrontal cortex (dlPFC), we tested the hypothesis that electrical stimulation of the dlPFC can modulate vestibular inputs. Sinusoidal electrical stimulation (± 2mA, 0.08Hz, 100 cycles) was delivered via surface electrodes over (1) the mastoid processes alone (sGVS), (2) electroencephalogram (EEG) site F4 (right dlPFC) and the nasion or (3) to each site concurrently (sGVS + dlPFC) in 23 participants. The same stimulation protocol was used in a separate study to investigate EEG site F3 (left dlPFC) instead of F4 in 13 participants. During sGVS, all participants reported perceptions of sway and 13 participants also reported nausea, neither sensation of which occurred as a result of dlPFC stimulation. Interestingly, when sGVS and dlPFC stimulations were delivered concurrently, vestibular perceptions and sensations of nausea were almost completely abolished. We conclude that the dlPFC provides top-down control of vestibular inputs and further suggests that dlPFC stimulation may provide a novel means of controlling nausea.

Observation on the efficacy of different targets low-frequency repetitive transcranial magnetic stimulation for the treatment of tremor-dominant subtypes of Parkinson's disease

Objective: To analyze the efficacy of different targets low-frequency repetitive transcranial magnetic stimulation (rTMS) for the treatment of tremor Parkinson's disease(PD). Method: A total of 82 patients with primary PD who were admitted to the Department of Neurology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from April 1, 2020 to March 31, 2021 were prospectively collected. According to the clinical characteristics of major movement disorders, 82 patients with tremor type (TD) were selected to enroll.The patients were randomly divided into 3 groups at a 1∶1∶1 ratio according to the randomized coding sequence of the trial: the primary motor cortex (M1) group with 26 cases, the cerebellum group with 26 cases and the dual-site (M1, cerebellum) group with 30 cases. All patients were treated with 1 Hz low-frequency stimulation of the corresponding target once a day for 5 days a week for 2 weeks, a total of 10 times; The dosage remained unchanged during the treatment for all groups. Before and after 2 weeks' treatment, the patients were assessed with the Unified PD Rating Scale (UPDRS) and PD Quality of Life Questionnaire-39 (PDQ-39) without medication. Cortical excitability, namely transcranial magnetic stimulation motor evoked potential (TMS-MEP), [including resting motor threshold (rMT) and active motor threshold (aMT) examinations], timed up and go (TUG) and electromyographic tremor were conducted. Result: There were 82 patients, 39 males and 43 females, with an average age of (67±8) years. Before the treatment, there was no statistically significant difference in the evaluation indicators among the three groups (all P>0.05). After the treatment, the differences of the UPDRS-Ⅲ score [(38.9±2.5) vs (29.2±3.6) ], UPDRS tremor score [(23.7±2.1) vs (14.6±3.1) ], TUG time [(44.8±3.1) s vs (33.7±4.1) s], tremor amplitude [(480±126) μV vs (276±94) μV], PDQ-39 score [(51±13) vs (45±13) ], rMT [(36±17)% vs (43±13)%], and aMT [(26±16)% vs (31±12)%] were statistically significant (all P<0.01) from those before the treatment. There was no statistical difference in the above factors between the M1 group and cerebellum group (all P>0.05). There was no statistically significant difference in tremor peak frequency among the three groups before and after the treatment (all P>0.05). Conclusions: Dual-site low-frequency rTMS can improve PD tremor, while M1 or cerebellar low-frequency rTMS does not significantly improve PD tremor. Its mechanism may be to improve PD tremor symptoms by regulating cortical excitability.

The potent analgesia of intrathecal 2R, 6R-HNK via TRPA1 inhibition in LF-PENS-induced chronic primary pain model

BackgroundChronic primary pain (CPP) is an intractable pain of unknown cause with significant emotional distress and/or dysfunction that is a leading factor of disability globally. The lack of a suitable animal model that mimic CPP in humans has frustrated efforts to curb disease progression. 2R, 6R-hydroxynorketamine (2R, 6R-HNK) is the major antidepressant metabolite of ketamine and also exerts antinociceptive action. However, the analgesic mechanism and whether it is effective for CPP are still unknown.MethodsBased on nociplastic pain is evoked by long-term potentiation (LTP)-inducible high- or low-frequency electrical stimulation (HFS/LFS), we wanted to develop a novel CPP mouse model with mood and cognitive comorbidities by noninvasive low-frequency percutaneous electrical nerve stimulation (LF-PENS). Single/repeated 2R, 6R-HNK or other drug was intraperitoneally (i.p.) or intrathecally (i.t.) injected into naïve or CPP mice to investigate their analgesic effect in CPP model. A variety of behavioral tests were used to detect the changes in pain, mood and memory. Immunofluorescent staining, western blot, reverse transcription-quantitative real-time polymerase chain reaction (RT-qPCR) and calcium imaging of in cultured dorsal root ganglia (DRG) neurons by Fluo-8-AM were used to elucidate the role and mechanisms of 2R, 6R-HNK in vivo or in vitro.ResultsIntrathecal 2R, 6R-HNK, rather than intraperitoneal 2R, 6R-HNK or intrathecal S-Ketamine, successfully mitigated HFS-induced pain. Importantly, intrathecal 2R, 6R-HNK displayed effective relief of bilateral pain hypersensitivity and depressive and cognitive comorbidities in a dose-dependent manner in LF-PENS-induced CPP model. Mechanically, 2R, 6R-HNK markedly attenuated neuronal hyperexcitability and the upregulation of calcitonin gene-related peptide (CGRP), transient receptor potential ankyrin 1 (TRPA1) or vanilloid-1 (TRPV1), and vesicular glutamate transporter-2 (VGLUT2) in peripheral nociceptive pathway. In addition, 2R, 6R-HNK suppressed calcium responses and CGRP overexpression in cultured DRG neurons elicited by the agonists of TRPA1 or/and TRPV1. Strikingly, the inhibitory effects of 2R, 6R-HNK on these pain-related molecules and mechanical allodynia were substantially occluded by TRPA1 antagonist menthol.ConclusionsIn the newly designed CPP model, our findings highlighted the potential utility of intrathecal 2R, 6R-HNK for preventing and therapeutic modality of CPP. TRPA1-mediated uprgulation of CGRP and neuronal hyperexcitability in nociceptive pathways may undertake both unique characteristics and solving process of CPP.

Maximal Fusion Capacity and Efficient Replenishment of the Dense Core Vesicle Pool in Hippocampal Neurons.

Neuropeptides and neurotrophins, stored in dense core vesicles (DCVs), are together the largest currently known group of chemical signals in the brain. Exocytosis of DCVs requires high-frequency or patterned stimulation, but the determinants to reach maximal fusion capacity and for efficient replenishment of released DCVs are unknown. Here, we systematically studied fusion of DCV with single vesicle resolution on different stimulation patterns in mammalian CNS neurons. We show that tetanic stimulation trains of 50-Hz action potential (AP) bursts maximized DCV fusion, with significantly fewer fusion event during later bursts of the train. This difference was omitted by introduction of interburst intervals but did not increase total DCV fusion. Interburst intervals as short as 5 s were sufficient to restore the fusion capacity. Theta burst stimulation (TBS) triggered less DCV fusion than tetanic stimulation, but a similar fusion efficiency per AP. Prepulse stimulation did not alter this. However, low-frequency stimulation (4 Hz) intermitted with fast ripple stimulation (200 APs at 200 Hz) produced substantial DCV fusion, albeit not as much as tetanic stimulation. Finally, individual fusion events had longer durations with more intense stimulation. These data indicate that trains of 50-Hz AP stimulation patterns triggered DCV exocytosis most efficiently and more intense stimulation promotes longer DCV fusion pore openings.SIGNIFICANCE STATEMENT Neuropeptides and neurotrophins modulate multiple regulatory functions of human body like reproduction, food intake or mood. They are packed into dense core vesicles (DCVs) that undergo calcium and action potential (AP) fusion with the plasma membrane. In order to study the fusion of DCVs in vitro, techniques like perfusion with buffer containing high concentration of potassium or electric field stimulation are needed to trigger the exocytosis of DCVs. Here, we studied the relationship between DCVs fusion properties and different electric field stimulation patterns. We used six different stimulation patterns and showed that trains of 50-Hz action potential bursts triggered DCV exocytosis most efficiently and more intense stimulation promotes longer DCV fusion pore openings.

Modulation of the spinal N13 SEP component by high- and low-frequency electrical stimulation. Experimental pain models matter

ObjectiveThe N13 component of somatosensory evoked potential (N13 SEP) represents the segmental response of cervical dorsal horn neurons. Neurophysiological studies in healthy participants showed that capsaicin-induced central sensitization causes an increase of the N13 SEP amplitude. Consequently, in human research, this spinal component may serve as a valuable readout of central sensitization.In this study, we wanted to verify if the sensitivity of the N13 SEP for detecting central sensitization is consistent across different experimental pain models inducing central sensitization and secondary hyperalgesia, namely high and low-frequency electrical stimulation (HFS and LFS). MethodsIn 18 healthy participants, we recorded SEP after bilateral ulnar nerve stimulation before and after secondary hyperalgesia was induced through HFS and LFS applied on the ulnar nerve territory of the hand of one side. The area of secondary hyperalgesia was mapped with a calibrated 128-mN pinprick probe, and the mechanical pain sensitivity with three calibrated 16–64-256-mN pinprick probes. ResultsAlthough both HFS and LFS successfully induced secondary hyperalgesia only LFS increased the amplitude of the N13 SEP. ConclusionsThese findings suggest that the sensitivity of the N13 SEP for detecting dorsal horn excitability changes may critically depend on the different experimental pain models. SignificanceOur results indicate that LFS and HFS could trigger central sensitization at the dorsal horn level through distinct mechanisms, however this still needs confirmation by replication studies.

Measurement of distortion-product otoacoustic emissions at low frequency and effect of contralateral acoustic stimulation on its level

Measurement of distortion-product otoacoustic emissions (DPOAEs) is one of the functional tests for the outer hear cells in the cochlea. Since the sound levels of the DPOAEs are quite low, it is easy to be buried in noise especially in the low frequency range, and frequency analysis and time averaging are required to detect them. In this study, focusing on the frequency stability of two stimulus sounds and a most prominent DPOAE-component, we tried to reduce noise floor and shorten the measurement time by choosing an adequate time window length for averaging the sound pressure waveform in the ear canal and the number of the averaging. As a result, it has become possible to measure DPOAEs at the low frequencies around 300 Hz in a relatively short time. Using this method, the changes in the DPOAE level induced by contralateral acoustic stimulation, which are caused by medial olivocochlear reflex, were measured. Although some exceptions were observed, the DPOAE was suppressed with increasing the sound pressure of the contralateral stimulus, and the degree of suppression was greater for the lower-frequency DPOAEs.

Optoα1AR activation in astrocytes modulates basal hippocampal synaptic excitation and inhibition in a stimulation-specific manner.

Astrocytes play active roles at synapses and can monitor, respond, and adapt to local synaptic activity. While there is abundant evidence that astrocytes modulate excitatory transmission in the hippocampus, evidence for astrocytic modulation of hippocampal synaptic inhibition remains more limited. Furthermore, to better investigate roles for astrocytes in modulating synaptic transmission, more tools that can selectively activate native G protein signaling pathways in astrocytes with both spatial and temporal precision are needed. Here, we utilized AAV8-GFAP-Optoα1AR-eYFP (Optoα1AR), a viral vector that enables activation of Gq signaling in astrocytes via light-sensitive α1-adrenergic receptors. To determine if stimulating astrocytic Optoα1AR modulates hippocampal synaptic transmission, recordings were made in CA1 pyramidal cells with surrounding astrocytes expressing Optoα1AR, channelrhodopsin (ChR2), or GFP. Both high-frequency (20 Hz, 45-ms light pulses, 5 mW, 5 min) and low-frequency (0.5 Hz, 1-s pulses at increasing 1, 5, and 10 mW intensities, 90 s per intensity) blue light stimulation were tested. 20 Hz Optoα1AR stimulation increased both inhibitory and excitatory postsynaptic current (IPSC and EPSC) frequency, and the effect on miniature IPSCs (mIPSCs) was largely reversible within 20 min. However, low-frequency stimulation of Optoα1AR did not modulate either IPSCs or EPSCs, suggesting that astrocytic Gq -dependent modulation of basal synaptic transmission in the hippocampus is stimulation-dependent. By contrast, low-frequency stimulation of astrocytic ChR2 was effective in increasing both synaptic excitation and inhibition. Together, these data demonstrate that Optoα1AR activation in astrocytes changes basal GABAergic and glutamatergic transmission, but only following high-frequency stimulation, highlighting the importance of temporal dynamics when using optical tools to manipulate astrocyte function.

Low-frequency deep brain stimulation reveals resonant beta-band evoked oscillations in the pallidum of Parkinson's Disease patients.

Evidence suggests that spontaneous beta band (11-35 Hz) oscillations in the basal ganglia thalamocortical (BGTC) circuit are linked to Parkinson's disease (PD) pathophysiology. Previous studies on neural responses in the motor cortex evoked by electrical stimulation in the subthalamic nucleus have suggested that circuit resonance may underlie the generation of spontaneous and stimulation-evoked beta oscillations in PD. Whether these stimulation-evoked, resonant oscillations are present across PD patients in the internal segment of the globus pallidus (GPi), a primary output nucleus in the BGTC circuit, is yet to be determined. We characterized spontaneous and stimulation-evoked local field potentials (LFPs) in the GPi of four PD patients (five hemispheres) using deep brain stimulation (DBS) leads externalized after DBS implantation surgery. Our analyses show that low-frequency (2-4 Hz) stimulation in the GPi evoked long-latency (>50 ms) beta-band neural responses in the GPi in 4/5 hemispheres. We demonstrated that neural sources generating both stimulation-evoked and spontaneous beta oscillations were correlated in their frequency content and spatial localization. Our results support the hypothesis that the same neuronal population and resonance phenomenon in the BGTC circuit generates both spontaneous and evoked pallidal beta oscillations. These data also support the development of closed-loop control systems that modulate the GPi spontaneous oscillations across PD patients using beta band stimulation-evoked responses.

Machine Learning Integrated Workflow for Predicting Schwann Cell Viability on Conductive MXene Biointerfaces.

Severe injuries to the peripheral nervous system (PNS) require Schwann cells to aid in neuronal regeneration. Low-frequency electrical stimulation is known to induce the cogrowth of neurons and Schwann cells in an injured PNS. However, the correlations between electrical stimulation and Schwann cell viability are complex and not well understood. In this work, we develop a machine learning (ML)-integrated workflow that uses conductive hydrogel biointerfaces to evaluate the impacts of fabrication parameters and electrical stimulation on the Schwann cell viability. First, a hydrogel array with varying MXene and peptide loadings is fabricated, which serves as conductive biointerfaces to incubate Schwann cells and introduce various electrical stimulation (at different voltages and frequencies). Upon specific fabrication parameters and stimulation, the cell viability is evaluated and input into an artificial neural network model to train the model. Additionally, a data augmentation method is applied to synthesize 1000-fold virtual data points, enabling the construction of a high-accuracy prediction model (with a testing mean absolute error ≤11%). By harnessing the model's predictive power, we can accurately predict Schwann cell viability based on a given set of fabrication/stimulation parameters. Finally, the SHapley Additive exPlanations model interpretation provides several data-scientific insights that are validated by microscopic cellular observations. Our hybrid approach, involving conductive biointerface fabrication, ML algorithms, and data analysis, offers an unconventional platform to construct a preclinical prediction model at the cellular level.

Early magnetic stimulation combined with low-frequency electrical stimulation to prevent urinary retention on patients with cervical cancer after radical surgery: A historical control study in China

Early magnetic stimulation combined with low-frequency electrical stimulation to prevent urinary retention on patients with cervical cancer after radical surgery: A historical control study in China

An amygdala-to-cingulate cortex circuit for conflicting choices in chronic pain

Chronic pain is a complex experience with multifaceted behavioral manifestations, often leading to pain avoidance at the expense of reward approach. How pain facilitates avoidance insituations with mixed outcomes is unknown. The anterior cingulate cortex (ACC) plays a key role in pain processing and in value-based decision-making. Distinct ACC inputs inform about the sensory and emotional quality of pain. However, whether specific ACC circuits underlie pathological conflict assessment in pain remains underexplored. Here, we demonstrate that mice with chronic pain favor cold avoidance rather than reward approach in a conflicting task. This occurs along with selective strengthening of basolateral amygdala inputs onto ACC layer 2/3 pyramidal neurons. The amygdala-cingulate projection is necessary and sufficient for the conflicting cold avoidance. Further, low-frequency stimulation of this pathway restores AMPA receptor function and reduces avoidance in pain mice. Our findings provide insights into the circuits and mechanisms underlying cognitive aspects of pain and offer potential targets for treatment.

Brain Response to Interferential Current Compared with Alternating Current Stimulation.

Temporal interference (TI) stimulation, which utilizes multiple external electric fields with amplitude modulation for neural modulation, has emerged as a potential noninvasive brain stimulation methodology. However, the clinical application of TI stimulation is inhibited by its uncertain fundamental mechanisms, and research has previously been restricted to numerical simulations and immunohistology without considering the acute in vivo response of the neural circuit. To address the characterization and understanding of the mechanisms underlying the approach, we investigated instantaneous brainwide activation patterns in response to invasive interferential current (IFC) stimulation compared with low-frequency alternative current stimulation (ACS). Results demonstrated that IFC stimulation is capable of inducing regional neural responses and modulating brain networks; however, the activation threshold for significantly recruiting a neural response using IFC was higher (at least twofold) than stimulation via alternating current, and the spatial distribution of the activation signal was restricted. A distinct blood oxygenation level-dependent (BOLD) response pattern was observed, which could be accounted for by the activation of distinct types of cells, such as inhibitory cells, by IFC. These results suggest that IFC stimulation might not be as efficient as conventional brain modulation methods, especially when considering TI stimulation as a potential alternative for stimulating subcortical brain areas. Therefore, we argue that a future transcranial application of TI on human subjects should take these implications into account and consider other stimulation effects using this technique.

Acupuncture for lumbar myofascial pain syndrome: systematic review and Meta-analysis.

This study systematically reviewed the clinical efficacy of acupuncture for lumbar myofascial pain syndrome. The randomized controlled trials (RCTs) regarding acupuncture for lumbar myofascial pain syndrome were searched in PubMed, Cochrane Library, Web of Science, EMbase, Scopus, China national knowledge infrastructure (CNKI), Wanfang database, VIP database, and China biomedical literature service system (SinoMed) from database inception until August 1st, 2022. The Cochrane's risk of bias assessment tool was used to assess the risk of bias in all included studies, and Review Manager 5.3 software was used for statistical analysis of the extracted data. As a result, 12 RCTs, involving 1 087 patients with lumbar myofascial pain syndrome, were ultimately included. The Meta-analysis results showed that the visual analog scale (VAS) score of pain in the observation group was lower than those in the oral non-steroidal anti-inflammatory medication control [SMD=-1.67, 95%CI (-2.44, -0.90), Z=4.26, P<0.000 1] and other treatment control [low-frequency electrical stimulation, tuina, electromagnetic wave irradiation combined with piroxicam gel, SMD=-1.98, 95%CI (-2.48, -1.48), Z=7.74, P<0.000 01]. The pain rating index (PRI) score in the observation group was lower than those in the lidocaine injection control [MD=-2.17, 95%CI (-3.41, -0.93), Z=3.44, P=0.000 6] and other treatment control [low-frequency electrical stimulation, tuina, MD=-5.75, 95%CI (-9.97, -1.53), Z=2.67, P=0.008]. The present pain intensity (PPI) score in the observation group was lower than that in other treatment control [low-frequency electrical stimulation, tuina, MD=-1.04, 95%CI (-1.55, -0.53), Z=4.01, P<0.000 1]. In conclusion, compared with oral non-steroidal anti-inflammatory medication, low-frequency electrical stimulation, tuina, and electromagnetic wave irradiation combined with piroxicam gel, acupuncture is more effective in reducing pain in patients with lumbar myofascial pain syndrome; acupuncture also exhibites advantage over lidocaine injection in improving PRI score and showed better outcomes over tuina and low-frequency electrical stimulation in improving PRI and PPI scores.

On-demand low-frequency stimulation for seizure control: efficacy and behavioural implications.

Mesial temporal lobe epilepsy (MTLE), the most common form of focal epilepsy in adults, is often refractory to medication and associated with hippocampal sclerosis. Deep brain stimulation represents an alternative treatment option for drug-resistant patients who are ineligible for resective brain surgery. In clinical practice, closed-loop stimulation at high frequencies is applied to interrupt ongoing seizures, yet has (i) a high incidence of false detections; (ii) the drawback of delayed seizure-suppressive intervention; and (iii) limited success in sclerotic tissue. As an alternative, low-frequency stimulation (LFS) has been explored recently in patients with focal epilepsies. In preclinical epilepsy models, hippocampal LFS successfully prevented seizures when applied continuously. Since it would be advantageous to reduce the stimulation load, we developed a protocol for on-demand LFS. Given the importance of the hippocampus for navigation and memory, we investigated potential consequences of LFS on hippocampal function. To this end, we used the intrahippocampal kainate mouse model, which recapitulates the key features of MTLE, including spontaneous seizure activity and hippocampal sclerosis. Specifically, our online detection algorithm monitored epileptiform activity in hippocampal local field potential recordings and identified short epileptiform bursts preceding focal seizure clusters, triggering hippocampal LFS to stabilize the network state. To probe behavioural performance, we tested the acute influence of LFS on anxiety-like behaviour in the light-dark box test, spatial and non-spatial memory in the object location memory and novel object recognition test, as well as spatial navigation and long-term memory in the Barnes maze. On-demand LFS was almost as effective as continuous LFS in preventing focal seizure clusters but with a significantly lower stimulation load. When we compared the behavioural performance of chronically epileptic mice to healthy controls, we found that both groups were equally mobile, but epileptic mice displayed an increased anxiety level, altered spatial learning strategy and impaired memory performance. Most importantly, with the application of hippocampal LFS before behavioural training and test sessions, we could rule out deleterious effects on cognition and even show an alleviation of deficits in long-term memory recall in chronically epileptic mice. Taken together, our findings may provide a promising alternative to current therapies, overcoming some of their major limitations, and inspire further investigation of LFS for seizure control in focal epilepsy syndromes.

Effects of eccentric contraction on force enhancement in rat fast-twitch muscle.

The aim of this study was to elucidate the effects of eccentric contraction (ECC) on force enhancement in rat fast-twitch skeletal muscle. Gastrocnemius (GAS) muscles were subjected to 200 ECCs in situ by electrical stimulation. Immediately before and after the stimulation, isometric torque produced by ankle flexion was measured at an ankle angle of 90°. After the second torque measurement, the superficial regions of the muscles were dissected and subjected to biochemical and skinned fiber analysis. ECC did not induce changes in the amount of degraded titin. After ECC, isometric torques in the GAS muscles were markedly reduced, especially at low stimulation frequency. ECC increased passive torque in whole muscle and passive force in skinned fibers. Passive force enhancement and the ratio of passive force to the maximal Ca2+ -activated force, but not residual force enhancement, were augmented in the skinned fibers subjected to ECC. An ECC-induced increase in titin-based stiffness may contribute to the increased PFE. These results suggest that skeletal muscle is endowed with a force potentiation system that can attenuate ECC-induced force reductions.

Alterations in brain connectivity patterns in schizophrenia patients with auditory verbal hallucinations during low frequency repetitive transcranial magnetic stimulation

ObjectiveAuditory verbal hallucinations (AVH) are a characteristic symptom of schizophrenia. Although low-frequency repetitive transcranial magnetic stimulation (rTMS) has been demonstrated to alleviate the severity of AVH, its exact neurophysiological mechanisms remain unclear. This study aimed to elucidate the alterations in brain connectivity patterns in schizophrenia patients with AVH after low frequency rTMS. Furthermore, the relationship between these alterations and clinical outcomes was examined, thereby identifying potential biomarkers for rTMS treatment efficacy. MethodsA total of 30 schizophrenia patients with AVH and 33 healthy controls were recruited. The patients received 1 Hz rTMS applied to the left temporoparietal junction region over 15 days. Resting-state functional magnetic resonance imaging scans were conducted for all participants. Subsequently, degree centrality (DC) and seed-based functional connectivity (FC) analyses were employed to identify specific alterations in brain connectivity patterns after rTMS treatment. ResultsAt baseline, patients exhibited divergent DC patterns in the frontal, occipital, and limbic lobes compared to healthy controls. In addition, prior to treatment, patients demonstrated altered FC from the superior frontal gyrus seeds that linked to the frontal, temporal, and somatosensory regions. Following rTMS treatment, these abnormalities were notably reversed, correlating with improved clinical outcomes. ConclusionsThese findings demonstrate that schizophrenia patients with AVH exhibited atypical interactions within the frontal and temporal lobes. These alterations might be crucial biomarkers for predicting the efficacy of low frequency rTMS.

Unlocking potential: low frequency subthalamic nucleus stimulation enhances executive function in Parkinson's disease patients with postural instability/gait disturbance.

Postural instability/gait disturbance (PIGD) is very common in advanced Parkinson's disease, and associated with cognitive dysfunction. Research suggests that low frequency (5-12 Hz) subthalamic nucleus-deep brain stimulation (STN-DBS) could improve cognition in patients with Parkinson's disease (PD). However, the clinical effectiveness of low frequency stimulation in PIGD patients has not been explored. This study was designed in a double-blinded randomized cross-over manner, aimed to verify the effect of low frequency STN-DBS on cognition of PIGD patients. Twenty-nine PIGD patients with STN-DBS were tested for cognitive at off (no stimulation), low frequency (5 Hz), and high frequency (130 Hz) stimulation. Neuropsychological tests included the Stroop Color-Word Test (SCWT), Verbal fluency test, Symbol Digital Switch Test, Digital Span Test, and Benton Judgment of Line Orientation test. For conflict resolution of executive function, low frequency stimulation significantly decreased the completion time of SCWT-C (p = 0.001) and Stroop interference effect (p < 0.001) compared to high frequency stimulation. However, no significant differences among stimulation states were found for other cognitive tests. Here we show, low frequency STN-DBS improved conflict resolution of executive function compared to high frequency. Our results demonstrated the possibility of expanding the treatment coverage of DBS to cognitive function in PIGD, which will facilitate integration of low frequency stimulation into future DBS programming.

A microfabricated lab-on-chip with three-dimensional electrodes for microscopic observation of bioelectromagnetic effects of cells

Electromagnetic (EM) signals are widely used in electronic instruments and biomedical systems and might have affected the human bodies surrounded by them. However, the interaction mechanism of EM signals with biological structures is poorly understood. We propose a micro-fabricated low-frequency EM stimulation lab-on-chip with three-dimensional interdigital electrodes for observation of cell lines with microscope. The field strength between the electrodes at various frequencies is estimated through simulation. An electric field strength of 4.45Vrms/m is reached in the culture medium with a 10Vpp, 10 kHz input signal. According to the simulation results, the high end of the applicable frequency range of the testbench is 3 MHz. A prototype is fabricated using full-wafer microfabrication techniques. The impedance of the prototype between 20 Hz and 30 MHz is characterized. Moreover, human cell line HEK293T is cultured in the testbench for 24 h and observed using microscope to check the biocompatibility of the electrodes. The prototype is thus applicable to long-term microscopic observation of cell lines for study of EM effect on biological structures. The 24-h cell culturing experiment with and without EM stimulation with the proposed prototype shows that the cell growth is obviously affected by a 10 kHz EM signal.

Investigation of the efficacy of low-frequency repetitive transcranial magnetic stimulation on upper-limb motor recovery in subacute ischemic stroke without cortical involvement: a protocol paper for a multi-center, double-blind randomized controlled trial.

The incidence of stroke is increasing steadily due to factors such as population aging. Approximately 80% of stroke survivors have motor disorders affecting their daily lives. Repetitive transcranial magnetic stimulation (rTMS) has been reported to maximize functional recovery after stroke along with exercise intervention in upper limb rehabilitation treatment. However, whether rTMS affects the recovery of upper limb function in patients with stroke remains unclear. Therefore, in this trial, we will investigate the efficacy of low-frequency rTMS in patients with subcortical and brainstem ischemic stroke. This study has been designed as a multi-center, double-blind, randomized controlled trial to compare the efficacy of low-frequency rTMS over the contralesional M1 with sham stimulation. Overall, 88 participants will be allocated to the intervention or control group in a 1:1 ratio, with stratification according to their initial upper extremity Fugl-Meyer assessment (UE-FMA) score. The participants will receive either 30 min of real rTMS (intervention group) or sham rTMS (control group), followed by 30 min of occupational therapy for 10 consecutive workdays. All the participants will receive the same amount of rehabilitation therapy throughout the intervention period. Evaluations will be performed at baseline (T0), at the end of treatment (T1), and 4 weeks after the end of treatment (T2), including the box and block test (BBT), UE-FMA, Korean version of the Modified Barthel Index, and NIH Stroke Scale scores, Finger tapping test, Brunnstrom stage, modified Ashworth scale, and grip strength. The primary outcome will be the change in the BBT score between T0 and T2. This study will provide evidence on the efficacy of low-frequency rTMS in motor function recovery of the upper limb in patients with subacute, subcortical, and brainstem ischemic stroke. ClinicalTrials.gov, identifier [NCT05535504].

Unilateral optogenetic stimulation of Lhx6 neurons in the zona incerta increases REM sleep.

To determine how a waking brain falls asleep researchers have monitored and manipulated activity of neurons and glia in various brain regions. While imaging Gamma-Aminobutyric Acid (GABA) neurons in the zona incerta (ZI) we found a subgroup that anticipates onset of NREM sleep (Blanco-Centurion C, Luo S, Vidal-Ortiz A, Swank C, Shiromani PJ. Activity of a subset of vesicular GABA-transporter neurons in the ventral ZI anticipates sleep onset. Sleep. 2021;44(6):zsaa268. doi:10.1093/sleep/zsaa268.). To differentiate the GABA subtype we now image and optogenetically manipulate the ZI neurons containing the transcription factor, Lhx6. In the first study, Lhx6-cre mice (n = 5; female = 4) were given rAAV-DJ-EF1a-DIO-GCaMP6M into the ZI (isofluorane anesthesia), a GRIN lens implanted, and 21days later sleep and fluorescence in individual Lhx6 neurons were recorded for 4 hours. Calcium fluorescence was detected in 132 neurons. 45.5% of the Lhx6 neurons were REM-max; 30.3% were wake-max; 11.4% were wake + REM max; 9% were NREM-max; and 3.8% had no change. The NREM-max group of neurons fluoresced 30 seconds ahead of sleep onset. The second study tested the effects of unilateral optogenetic stimulation of the ZI Lhx6 neurons (n = 14 mice) (AAV5-Syn-FLEX-rc[ChrimsonR-tdTomato]. Stimulation at 1 and 5 Hz (1 minute on- 4 minutes off) significantly increased percent REM sleep during the 4 hours stimulation period (last half of day cycle). The typical experimental approach is to stimulate neurons in both hemispheres, but here we found that low-frequency stimulation of ZI Lhx6 neurons in one hemisphere is sufficient to shift states of consciousness. Detailed mapping combined with mechanistic testing is necessary to identify local nodes that can shift the brain between wake-sleep states.