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Stress-related disorders constitute a fast-progressing worldwide societal problem that needs urgent attention and new solutions. Recent neuroscientific research has shown that stress-related disorders are characterized by maladaptive dynamic changes in large-scale brain networks in response to stressors, raising the possibility of modulating these networks as a promising target for intervention. Neurofeedback can be used to train individuals to endogenously modulate brain network dynamics. Once learned, this skill is transferrable to ecologically relevant scenarios outside of a laboratory or treatment facility, and individuals can be trained to explicitly apply it at the right moments as part of a just-in-time adaptive intervention in response to actual stressors in daily life. We argue that these characteristics position neurofeedback as a prime candidate for a personalized preventive neuroscience-based intervention strategy. Stress-related disorders are among the biggest global health challenges. Despite significant progress in understanding their neurocognitive basis, the promise of applying insights from fundamental research to prevention and treatment remains largely unfulfilled. We argue that neurofeedback – a method for training voluntary control over brain activity – has the potential to fill this translational gap. We provide a contemporary perspective on neurofeedback as endogenous neuromodulation that can target complex brain network dynamics, is transferable to real-world scenarios outside a laboratory or treatment facility, can be trained prospectively, and is individually adaptable. This makes neurofeedback a prime candidate for a personalized preventive neuroscience-based intervention strategy that focuses on the ecological momentary neuromodulation of stress-related brain networks in response to actual stressors in real life. [ABSTRACT FROM AUTHOR]

There is a significant unmet need for safe and effective nonpharmacological therapies for restless legs syndrome (RLS). The objective was to evaluate the efficacy and safety of tonic motor activation (TOMAC) in patients with RLS. A multicenter, randomized, participant-blinded, sham-controlled trial enrolled 45 adults with primary moderate-to-severe RLS who were either medication-naïve (n = 20) or medication-refractory (n = 25). Participants were 1:1 randomized to TOMAC (n = 22) or sham (n = 23) for two weeks and instructed to self-administer 30-min TOMAC sessions when they experienced RLS symptoms. The primary outcome was mean change in International RLS Study Group Rating Scale (IRLS) total score. A subsequent meta-analysis included the present trial and a previous randomized clinical trial that enrolled medication-naïve RLS patients. IRLS reduction was significantly greater for TOMAC than sham (TOMAC -6.59 vs. sham −2.17; mean difference (MD) = −4.42; 95 % confidence interval [CI] −1.57 to −7.26; p = 0.0040). Subgroup analysis showed similar IRLS mean difference for medication-refractory (MD = −4.50; p = 0.02) and medication-naïve (MD = −4.40; p = 0.08) cohorts, which was significantly different from sham only for the medication-refractory cohort. Meta-analysis of combined data from 33 medication-naïve RLS patients showed a significant reduction in mean IRLS score after two weeks for TOMAC compared to sham (MD = −4.30; 95 % CI -1.36 to −7.24; p = 0.004). The present trial confirmed previous reports documenting efficacy and safety of TOMAC in refractory RLS and indicated similar effect sizes in refractory versus naïve subgroups. The meta-analysis demonstrated that TOMAC significantly improves RLS symptoms in naïve participants. • Tonic motor activation (TOMAC) reduces restless legs syndrome (RLS) symptoms. • TOMAC is efficacious for both medication-refractory and -naïve RLS patients. • TOMAC is safe and well tolerated. [ABSTRACT FROM AUTHOR]

To evaluate if acute intermittent hypoxia (AIH) coupled with transcutaneous spinal cord stimulation (tSCS) enhances task-specific training and leads to superior and more sustained gait improvements as compared with each of these strategies used in isolation in persons with chronic, incomplete spinal cord injury. Proof of concept, randomized crossover trial. Outpatient, rehabilitation hospital. Ten participants completed 3 intervention arms: (1) AIH, tSCS, and gait training (AIH + tSCS); (2) tSCS plus gait training (SHAM AIH + tSCS); and (3) gait training alone (SHAM + SHAM). Each arm consisted of 5 consecutive days of intervention with a minimum of a 4-week washout between arms. The order of arms was randomized. The study took place from December 3, 2020, to January 4, 2023. 10-meter walk test at self-selected velocity (SSV) and fast velocity, 6-minute walk test, timed Up and Go (TUG) and secondary outcome measures included isometric ankle plantarflexion and dorsiflexion torque TUG improvements were 3.44 seconds (95% CI: 1.24-5.65) significantly greater in the AIH + tSCS arm than the SHAM AIH + tSCS arm at post-intervention (POST), and 3.31 seconds (95% CI: 1.03-5.58) greater than the SHAM + SHAM arm at 1-week follow up (1WK). SSV was 0.08 m/s (95% CI: 0.02-0.14) significantly greater following the AIH + tSCS arm than the SHAM AIH + tSCS at POST. Although not significant, the AIH + tSCS arm also demonstrated the greatest average improvements compared with the other 2 arms at POST and 1WK for the 6-minute walk test, fast velocity, and ankle plantarflexion torque. This pilot study is the first to demonstrate that combining these 3 neuromodulation strategies leads to superior improvements in the TUG and SSV for individuals with chronic incomplete spinal cord injury and warrants further investigation. [ABSTRACT FROM AUTHOR]

The zona incerta (ZI) is a subcortical structure primarily investigated in rodents that is implicated in various behaviors, ranging from motor control to survival-associated activities, partly due to its integration in multiple neural circuits. In the current study, we used diffusion magnetic resonance imaging tractography to segment the ZI and gain insight into its connectivity in various circuits in humans. We performed probabilistic tractography in 7T diffusion MRI on 178 participants from the Human Connectome Project to validate the ZI's anatomical subdivisions and their respective tracts. K-means clustering segmented the ZI based on each voxel's connectivity profile. We further characterized the connections of each ZI subregion using probabilistic tractography with each subregion as a seed. We identified 2 dominant clusters that delineated the whole ZI into rostral and caudal subregions. The caudal ZI primarily connected with motor regions, while the rostral ZI received a topographic distribution of projections from prefrontal areas, notably the anterior cingulate and medial prefrontal cortices. We generated a probabilistic ZI atlas that was registered to a patient-participant's magnetic resonance imaging scan for placement of stereoencephalographic leads for electrophysiology-guided deep brain stimulation to treat their obsessive-compulsive disorder. Rostral ZI stimulation improved the patient's core symptoms (mean improvement 21%). We present a tractography-based atlas of the rostral and caudal ZI subregions constructed using high-resolution diffusion magnetic resonance imaging from 178 healthy participants. Our work provides an anatomical foundation to explore the rostral ZI as a novel target for deep brain stimulation to treat refractory obsessive-compulsive disorder and other disorders associated with dysfunctional reward circuitry. [ABSTRACT FROM AUTHOR]

One of the most common applications of transcranial electrical stimulation (tES) at low current intensity is to induce a relaxed state or reduce anxiety. With technical advancement, different waveforms, montages, and parameters can be incorporated into the treatment regimen. We developed a novel protocol to treat individuals with anxiety disorders by transcranial alternating current stimulation (tACS). A total of 27 individuals with anxiety disorders underwent tACS treatment for 12 sessions, with each session lasting 25 min. tACS at 5 Hz was applied to F4 (1.0 mA), P4 (1.0 mA), and T8 (2.0 mA) EEG lead positions (tripod), with sinewave oscillation between T8 and F4/P4. We evaluated the primary and secondary outcomes using the Beck Anxiety Inventory (BAI) and neuropsychological assessments. Of the 27 patients, 19 (70.4 %) experienced a reduction in symptom severity >50 %, with an average reduction of BAI 58.5 %. All reported side effects were mild, with itching or tingling being the most common complaint. No significant differences were noted in attention, linguistic working memory, visuospatial working memory, or long-term memory in neuropsychological assessments. The results suggest the potential of this novel tripod tACS design as a rapid anxiety alleviator and the importance of a clinical trial to verify its efficacy. • Transcranial alternating current stimulation (tACS) was applied to treat anxiety disorders. • tACS at 5 Hz was applied to F4 (1 mA), P4 (1 mA), and T8 (2 mA) EEG lead positions (tripod), with the sinewave oscillation between T8 and F4/P4. • Following 12 treatment sessions, the reduction of symptoms amounted to 58.5%, and 70.4% of participants responded positively. • The tripod tACS design could be a rapid anxiety alleviator. [ABSTRACT FROM AUTHOR]

Magnetic stimulation, represented by transcranial magnetic stimulation (TMS), is used to treat neurological diseases. Various strategies have been explored to improve the spatial resolution of magnetic stimulation. While reducing the coil size is the most impactful approach for increasing the spatial resolution, it decreases the stimulation intensity and increases heat generation. We aim to demonstrate the feasibility of magnetic stimulation using an epidurally implanted millimeter-sized coil and that it does not damage the cortical tissue via heating even when a repetitive stimulation protocol is used. A coil with dimensions of 3.5 × 3.5 × 2.6 mm3 was epidurally implanted on the left motor cortex of rat, corresponding to the right hindlimb. Before and after epidural magnetic stimulation using a quadripulse stimulation (QPS) protocol, changes in the amplitude of motor evoked potentials (MEPs) elicited by a TMS coil were compared. The experimental group showed an average increase of 88 % in MEP amplitude in the right hindlimb after QPS, whereas the MEP amplitude in the left hindlimb increased by 18 % on average. The control group showed no significant change in MEP amplitude after QPS in either hindlimb. The temperature changes at the coil surface remained <2 °C during repetitive stimulation, meeting the thermal safety limit for implantable medical devices. These results demonstrate the feasibility of epidural magnetic stimulation using an implantable coil to induce neuromodulation effects. This novel method is expected to be a promising alternative for focal magnetic stimulation with an improved spatial resolution and lowered stimulus current than previous magnetic stimulation methods. • Focal magnetic stimulation of the brain was achieved by implanting a mm-sized coil epidurally. • Epidural magnetic stimulation modulated the amplitude of motor evoked potentials (MEPs), though not directly evoking MEPs. • Heat generation during epidural magnetic stimulation was managed to remain within the thermal safety limit. [ABSTRACT FROM AUTHOR]

Non-invasive deep brain modulation (DBM) stands as a promising therapeutic avenue to treat brain diseases. Acoustic DBM represents an innovative and targeted approach to modulate the deep brain, employing techniques such as focused ultrasound and shock waves. Despite its potential, the optimal mechanistic parameters, the effect in the brain and behavioral outcomes of acoustic DBM remains poorly understood. To establish a robust protocol for the shock wave DBM by optimizing its mechanistic profile of external stimulation, and to assess its efficacy in preclinical settings. We used shockwaves due to their capacity to leverage a broader spectrum of peak intensity (10–127 W/mm2) in contrast to ultrasound (0.1–5.0 W/mm2), thereby enabling a more extensive range of neuromodulation effects. We established various types of shockwave pressure profiles of DBM and compared neural and behavioral responses. To ascertain the anticipated cause of the heightened neural activity response, numerical analysis was employed to examine the mechanical dynamics within the brain. An optimized profile led to an enhancement in neuronal activity within the hypothalamus of mouse models. The optimized profile in the hippocampus elicited a marked increase in neurogenesis without neuronal damage. Behavioral analyses uncovered a noteworthy reduction in locomotion without significant effects on spatial memory function. The present study provides an optimized shock wave stimulation protocol for non-invasive DBM. Our optimized stimulation profile selectively triggers neural functions in the deep brain. Our protocol paves the way for new non-invasive DBM devices to treat brain diseases. • Neural activity depended on the mechanistic profile of external stimulation. • c-Fos density and pressure gradient were both highly concentrated in hypothalamus. • Optimal stimuli increased neuronal activation and its concentration in the thalamus. • Optimal stimuli elicited a marked increase in neurogenesis without neuronal damage. [ABSTRACT FROM AUTHOR]

Cardiac control is mediated via nested-feedback reflex control networks involving the intrinsic cardiac ganglia, intra-thoracic extra-cardiac ganglia, spinal cord, brainstem, and higher centers. This control system is optimized to respond to normal physiologic stressors; however, it can be catastrophically disrupted by pathologic events such as myocardial ischemia. In fact, it is now recognized that cardiac disease progression reflects the dynamic interplay between adverse remodeling of the cardiac substrate coupled with autonomic dysregulation. With advances in understanding of this network dynamic in normal and pathologic states, neuroscience-based neuromodulation therapies can be devised for the management of acute and chronic cardiac pathologies. [ABSTRACT FROM AUTHOR]

The contemporary history of the cardiac autonomic nervous system includes early descriptions of neuroanatomy in the 19th century, followed by an understanding of the physiologic determinants of neurocardiology in the 20th century. Neurology and cardiology preceded the arrival of clinical cardiac electrophysiology, a specialized field in medicine devoted to the diagnosis and treatment of cardiac arrhythmias. The rapid growth in pharmacology, ablation, pacing and defibrillation, associated with significant technological breakthroughs, have resulted in new opportunities for neuromodulation in the 21st century. Small changes in autonomic tone can potentially provide important therapeutic benefits for patients with cardiac and arrhythmia disorders. [ABSTRACT FROM AUTHOR]

The cardiac autonomic nervous system plays a key role in maintaining normal cardiac physiology, and once disrupted, it worsens the cardiac disease states. Neuromodulation therapies have been emerging as new treatment options, and various techniques have been introduced to mitigate autonomic nervous imbalances to help cardiac patients with their disease conditions and symptoms. In this review article, we discuss various neuromodulation techniques used in clinical settings to treat cardiac diseases. [ABSTRACT FROM AUTHOR]

Transcranial direct current stimulation (tDCS) is a safe, accessible, and promising therapeutic approach for obsessive-compulsive disorder (OCD). This study aimed to evaluate the effect of tDCS on electroencephalography (EEG) microstates and identify potential biomarkers to predict efficacy. A total of 24 individuals diagnosed with OCD underwent ten sessions of tDCS targeting the orbitofrontal cortex, while 27 healthy individuals were included as controls. Microstates A, B, C, and D were extracted before and after tDCS. A comparative analysis of microstate metrics was performed between the OCD and the healthy control groups, as well as within the OCD group before and after tDCS. Multiple linear regression analysis was performed to identify potential biomarkers of tDCS. Comparison to healthy controls, the OCD group exhibited a significantly reduced duration of microstate A and increased occurrence of microstate D. The transition between microstates A and C was significantly different between patients with OCD and healthy controls and was no longer observed following tDCS. Multiple linear regression analysis revealed that the duration of microstate C was associated with an improvement OCD symptom after tDCS. The results revealed an aberrant large-scale EEG brain network that could be modulated by tDCS. In particular, the duration of EEG microstate C may be a neurophysiological characteristic associated with the therapeutic effects of tDCS on OCD. • Patients with OCD showed a decrease in the duration of microstate A and an increase in the occurrence of microstate D. • tDCS could modulate large-scale EEG brain network in OCD. • The duration of EEG microstate C may be a neurophysiological characteristic associated with the therapeutic effects of tDCS on OCD. [ABSTRACT FROM AUTHOR]

Functional neurosurgery involves the surgical management of a wide range of neurological diseases with the aim of treating conditions such as movement disorders, spasticity, epilepsy and intractable pain. Functional neurosurgery began with ablative surgical techniques involving destruction of neural structures responsible for the aberrant neural pathways/networks causing pathology. In more recent years there has been a move away from the creation of permanent destructive lesions towards modulation of the neural networks utilizing neuro-modulation. Neuromodulation therapies include invasive (e.g. deep brain stimulators, cortical stimulators, vagal nerve stimulators and spinal cord stimulators) and non-invasive (e.g. transcranial magnetic stimulation) approaches that involve the application of electrical stimulation to drive or inhibit neural function within a circuit. Most implantable neuromodulation systems include three primary components: stimulating electrode(s) with contacts at the tip through which electricity is delivered, an implantable pulse generator (IPG) that serves as a signal generator/battery pack, and the extension cable(s) to subcutaneously connect the electrode(s) to the IPG. In this article we primarily focus on the current role of neuromodulation in treating movement disorders, epilepsy and pain, and also consider emerging and evolving applications. [ABSTRACT FROM AUTHOR]

• Meticulous presurgical evaluation and the selection of appropriate surgical procedure can effectively control seizure to a certain extent. • Pooled outcomes of resective surgery showed that 74 % of patients achieved Engel I at the last follow-up. • Pooled outcomes of neurostimulation showed that 9 % patients achieved seizure free and 61 % of patientsachieved 50 % reduction in seizure frequency at the last follow-up. • Univariate analysis indicated that being female, having somatic mutations, and presenting with focal seizure symptoms were associated with a better prognosis. To summarize the surgical outcomes of genetically refractory epilepsy and identify prognostic factors for these outcomes. A literature search of the PubMed, Web of Science, and Embase databases for relevant studies, published between January 1, 2002 and December 31, 2023, was performed using specific search terms. All studies addressing surgical outcomes and follow-up of genetically refractory epilepsy were included. All statistical analyses were performed using STATA software (StataCorp LLC, College Station, TX, USA). This review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, 2020 (i.e., "PRISMA") reporting guidelines. Of the 3833 studies retrieved, 55 fulfilled the inclusion criteria. Eight studies were eligible for meta-analysis at the study level. Pooled outcomes revealed that 74 % of patients who underwent resective surgery (95 % confidence interval [CI] 0.55–0.89; z = 9.47, p < 0.05) achieved Engel I status at the last follow-up. In the study level analysis, pooled outcomes revealed that 9 % of patients who underwent vagus nerve stimulation achieved seizure-free status (95 % CI 0.00–0.31; z = 1.74, p < 0.05), and 61 % (95 % CI 0.55–0.89; z = 11.96, p < 0.05) achieved a 50 % reduction in seizure frequency at the last follow-up. Fifty-three studies comprising 249 patients were included in an individual-level analysis. Among patients who underwent lesion resection or lobectomy/multilobar resection, 65 % (100/153) achieved Engel I status at the last follow-up. Univariate analysis indicated that female sex, somatic mutations, and presenting with focal seizure symptoms were associated with better prognosis (p < 0.05). Additionally, 75 % (21/28) of patients who underwent hemispherectomy/hemispherotomy achieved Engel I status at the last follow-up. In the individual-level analysis, among patients treated with vagus nerve stimulation, 21 % (10/47) were seizure-free and 64 % (30/47) experienced >50 % reduction in seizure frequency compared with baseline. Meticulous presurgical evaluation and selection of appropriate surgical procedures can, to a certain extent, effectively control seizures. Therefore, various surgical procedures should be considered when treating patients with genetically refractory epilepsy. [ABSTRACT FROM AUTHOR]

Neuromodulatory interventions are relatively novel and approaches to studying harms and tolerability have varied. Using a checklist based on guidelines from Good Clinical Practice and the Harms Extension of the CONSORT (Consolidated Standards of Reporting Trials) Statement, we identified how adverse events are measured, assessed, and reported in studies evaluating neuromodulation for the treatment of mental and neurodevelopmental disorders among children and adolescents. A systematic literature review identified 56 experimental and quasi-experimental studies evaluating transcranial magnetic stimulation (TMS), transcranial alternating (tACS) or direct (tDCS) current stimulation, transcranial pulse stimulation (TPS), and vagus or trigeminal nerve stimulation (VNS or TNS). For 22 studies (39%), the types of adverse events to be monitored were identified, and for 31 studies (55%), methods for collecting adverse event data were described. Methods for assessing adverse events were less commonly described with 23 studies (41%) having details on assessing event severity, and 11 studies (20%) having details on assessing event causality. Among 31 studies with reported results, headache, skin irritation, and general pain or discomfort were the most reported across studies. Seizure, untoward medical occurrences, and intracranial bleeding, edema, or other intracranial pathology were considered serious events, but these events were not reported as occurring in any results-based papers. Taken together, the findings from this review indicate that most studies of pediatric neuromodulatory interventions did not include descriptions of adverse event monitoring and evaluation. Comprehensive event monitoring and reporting across studies can significantly augment the current knowledge base. [ABSTRACT FROM AUTHOR]

Deep brain stimulation (DBS) holds promise for neuropsychiatric conditions where imbalance in network activity contributes to symptoms. Treatment-resistant Combat post-traumatic stress disorder (TR-PTSD) is a highly morbid condition and 50% of PTSD sufferers fail to recover despite psychotherapy or pharmacotherapy. Reminder-triggered symptoms may arise from inadequate top-down ventromedial prefrontal cortex (vmPFC) control of amygdala reactivity. Here, we report long-term data on two TR-PTSD participants from an investigation utilizing high-frequency amygdala DBS. The two combat veterans were implanted bilaterally with quadripolar electrodes targeting the basolateral amygdala. Following a randomized staggered onset, patients received stimulation with adjustments based on PTSD symptom severity for four years while psychiatric and neuropsychiatric symptoms, neuropsychological performance, and electroencephalography were systematically monitored. Evaluation of vmPFC-Amygdala network engagement was assessed with 18FDG positron emission tomography (PET). CAPS-IV scores varied over time, but improved 55% from 119 at baseline to 53 at 4-year study endpoint in participant 1; and 44%, from 68 to 38 in participant 2. Thereafter, during 5 and 1.5 years of subsequent clinical care respectively, long-term bilateral amygdala DBS was associated with additional, clinically significant symptomatic and functional improvement. There were no serious stimulation-related adverse psychiatric, neuropsychiatric, neuropsychological, neurological, or neurosurgical effects. In one subject, symptomatic improvement was associated with an intensity-dependent reduction in amygdala theta frequency power. In our two participants, FDG-PET findings were inconclusive regarding the hypothesized mechanism of suppression of amygdala hyperactivity. Our findings encourage further research to confirm and extend our preliminary observations. • There are limited treatment options for treatment-resistant combat PTSD (TR-PTSD) • Functional neuroimaging implicates amygdala hyperactivity • Two veterans with severe combat TR-PTSD received amygdala DBS for 9 and 5.5 years • Stimulation resulted in no seizures, neuropsychological or psychiatric impairments • Significant clinical and functional improvements were observed [ABSTRACT FROM AUTHOR]

Many neurodegenerative disease treatments, such as deep brain stimulation for Parkinson's Disease, can alleviate symptoms by primarily compensating for circuit dysfunctions. However, the stimulation's effect on the underlying disease progression remains relatively unknown. Here, we report that neuromodulation can not only modulate circuit function but also modulate the in vivo spreading dynamics of α-synuclein pathology, the primary pathological hallmark observed in Parkinson's Disease. In a mouse model, pre-formed fibrils were injected into the striatum to induce widespread α-synuclein pathology. Two days after fibril injection, mice were treated for two weeks with daily optogenetic stimulation of the Secondary Motor Area, Layer V. Whole brains were then extracted, immunolabeled, cleared, and imaged with light-sheet fluorescent microscopy. Repeated optogenetic stimulation led to a decrease in pathology at the site of stimulation and at various cortical and subcortical regions, while the contralateral cortex saw a consistent increase. Aligning the pathology changes with optogenetic-fMRI measured brain activity, we found that the changes in pathology and brain function had similar spatial locations but opposite polarity. These results demonstrate the ability to modulate and predict whole brain pathology changes using neuromodulation, opening a new horizon for investigating optimized neuromodulation therapies. • We report that neuromodulation can alter in vivo dynamics of α-synuclein pathology. • In a mouse model, optogenetic stimulation modified pathology at the stimulation site and cortical and subcortical regions. • Changes in pathology had similar spatial locations but opposite polarity compared to brain function measured through ofMRI. • Neuromodulation alters brain pathology and ofMRI predicts the changes, opening a new horizon for brain disorder treatments. [ABSTRACT FROM AUTHOR]

Transcranial focused ultrasound (tFUS) neuromodulation has shown promise in animals but is challenging to translate to humans because of the thicker skull that heavily scatters ultrasound waves. We develop and disseminate a model-based navigation (MBN) tool for acoustic dose delivery in the presence of skull aberrations that is easy to use by non-specialists. We pre-compute acoustic beams for thousands of virtual transducer locations on the scalp of the subject under study. We use the hybrid angular spectrum solver mSOUND, which runs in ∼4 s per solve per CPU yielding pre-computation times under 1 h for scalp meshes with up to 4000 faces and a parallelization factor of 5. We combine this pre-computed set of beam solutions with optical tracking, thus allowing real-time display of the tFUS beam as the operator freely navigates the transducer around the subject' scalp. We assess the impact of MBN versus line-of-sight targeting (LOST) positioning in simulations of 13 subjects. Our navigation tool has a display refresh rate of ∼10 Hz. In our simulations, MBN increased the acoustic dose in the thalamus and amygdala by 8–67 % compared to LOST and avoided complete target misses that affected 10–20 % of LOST cases. MBN also yielded a lower variability of the deposited dose across subjects than LOST. MBN may yield greater and more consistent (less variable) ultrasound dose deposition than transducer placement with line-of-sight targeting, and thus could become a helpful tool to improve the efficacy of tFUS neuromodulation. • Model-based navigation (MBN) precomputes thousands of transcranial focused ultrasound beams in individualized skull models. • MBN's graphical user interfaces are easy to use and connect to Localite and Brainsight optical tracking systems. • This allows visualization of the 3D ultrasound beam while freely navigating the transducer around the subject' scalp. • MBN precomputation is fast enough (<60 min.) to perform the MRI and navigated ultrasound sessions in a single visit. • Acoustic dose scalp maps are highly heterogeneous across subjects and brain targets. • MBN increases the acoustic dose in the thalamus and amygdala by up to 67% compared to line-of-sight targeting. • MBN significantly reduces the variability of the dose across subjects compared to line-of-sight targeting. [ABSTRACT FROM AUTHOR]

Acute cerebral ischemia triggers a number of cellular mechanisms not only leading to excitotoxic cell death but also to enhanced neuroplasticity, facilitating neuronal reorganization and functional recovery. Transferring these cellular mechanisms to neurophysiological correlates adaptable to patients is crucial to promote recovery post-stroke. The combination of TMS and EEG constitutes a promising readout of neuronal network activity in stroke patients. We used the combination of TMS and EEG to investigate the development of local signal processing and global network alterations in 40 stroke patients with motor deficits alongside neural reorganization from the acute to the chronic phase. We show that the TMS-EEG response reflects information about reorganization and signal alterations associated with persistent motor deficits throughout the entire post-stroke period. In the early post-stroke phase and in a subgroup of patients with severe motor deficits, TMS applied to the lesioned motor cortex evoked a sleep-like slow wave response associated with a cortical off-period, a manifestation of cortical bistability, as well as a rapid disruption of the TMS-induced formation of causal network effects. Mechanistically, these phenomena were linked to lesions affecting ascending activating brainstem fibers. Of note, slow waves invariably vanished in the chronic phase, but were highly indicative of a poor functional outcome. In summary, we found evidence that transient effects of sleep-like slow waves and cortical bistability within ipsilesional M1 resulting in excessive inhibition may interfere with functional reorganization, leading to a less favorable functional outcome post-stroke, pointing to a new therapeutic target to improve recovery of function. • TMS-EEG responses portray both reorganization and persistent signal alterations. • Impaired signal processing is linked to function from the acute to chronic phase. • Motor recovery is accompanied with recovery of global brain complexity. • Mechanisms of cortical bistability early after stroke contribute to motor recovery. • Lesion data link sleep-like waves to ascending activating brainstem fibers. [ABSTRACT FROM AUTHOR]

Low-intensity transcranial ultrasound has surged forward as a non-invasive and disruptive tool for neuromodulation with applications in basic neuroscience research and the treatment of neurological and psychiatric conditions. To provide a comprehensive overview and update of preclinical and clinical transcranial low intensity ultrasound for neuromodulation and emphasize the emerging role of functional brain mapping to guide, better understand, and predict responses. A systematic review was conducted by searching the Web of Science and Scopus databases for studies on transcranial ultrasound neuromodulation, both in humans and animals. 187 relevant studies were identified and reviewed, including 116 preclinical and 71 clinical reports with subjects belonging to diverse cohorts. Milestones of ultrasound neuromodulation are described within an overview of the broader landscape. General neural readouts and outcome measures are discussed, potential confounds are noted, and the emerging use of functional magnetic resonance imaging is highlighted. Ultrasound neuromodulation has emerged as a powerful tool to study and treat a range of conditions and its combination with various neural readouts has significantly advanced this platform. In particular, the use of functional magnetic resonance imaging has yielded exciting inferences into ultrasound neuromodulation and has the potential to advance our understanding of brain function, neuromodulatory mechanisms, and ultimately clinical outcomes. It is anticipated that these preclinical and clinical trials are the first of many; that transcranial low intensity focused ultrasound, particularly in combination with functional magnetic resonance imaging, has the potential to enhance treatment for a spectrum of neurological conditions. • Low-intensity ultrasound is a non-invasive, disruptive tool for neuromodulation. • Comprehensive review of preclinical and clinical ultrasound neuromodulation. • Functional brain mapping brings exciting inferences into ultrasound neuromodulation. [ABSTRACT FROM AUTHOR]

Spinal cord stimulators (SCSs) are commonly implanted via a laminotomy or laminectomy. Revision surgery may be necessary in instances of hardware failure or loss of efficacy. It is uncommon for leads to have been initially misplaced in a suboptimal position and revision in these cases necessitates additional dissection for appropriate repositioning. Accordingly, there is concern with a more extensive revision for a potentially higher risk of associated complications. This study aims to describe a series of patients with failed paddle SCS electrodes due to misplacement who underwent revision and replacement. Patients who underwent SCS paddle replacement for misplaced paddles between 2021 and 2023 were identified. Medical charts were reviewed for demographic data, operative details, and incidence of complications. Sixteen patients underwent thoracic SCS paddle revision and replacement. The mean age was 59.6 ± 12.6 years, with 11 females and 5 males. Misplaced paddles were too lateral (n = 12), too high (n = 2), or incompletely within the epidural space (n = 2). The mean duration from initial implantation to revision surgery was 44.8 ± 47.5 months. The mean operative duration was 126.1 ± 26.9 minutes and all patients required a "skip" laminectomy or laminotomy. No complications were encountered. The mean length of follow-up was 18.4 ± 7.3 months. Mean preoperative pain intensity was 7.9 ± 1.5 and at last follow-up was 3.6 ± 1.7 (P < 0.001). All but 1 patient continued to use their device in follow-up. The revision and replacement of misplaced paddle SCS electrodes is a feasible and durable revision strategy, even in long-term implants with extensive scarring. [ABSTRACT FROM AUTHOR]

To evaluate the efficacy and safety of sacral neuromodulation (SNM) in patients with underlying neurologic conditions and compare outcomes to non-neurogenic patients. Between 2017-2022 patients undergoing 2-staged implantation of InterStim II were included in a single-center retrospective study. Patients were allocated into two groups: underlying neurologic conditions (group 1) or non-neurogenic (group 2). Efficacy and safety were evaluated by comparing patients' bladder/bowel logs pre- and post-operative. Patients' demographics, indications, preimplantation urodynamic study variables, surgery duration, number of postop visits, and time to revision/removal procedures were compared and included in the data analysis. Sixty-seven patients (64.2% female) with a mean age of 63.23 ± 14.15 years were included in the study – 16/67(23.9%) patients assigned to group 1. There is no statistically significant difference between the groups regarding the indication for the treatment. The most common indication was nonobstructing urinary retention (NOUR) in both study groups. The common neurologic pathologies were multiple sclerosis, disc disease, and spinal stenosis. Overall and subgroup (based on an indication for SNM implantation) analyses showed no significant difference in patients' demographics, the surgery duration, or the chances for clinical success with a similar follow-up period. During the follow-up, the device was removed in 4 (25.0%) and 10 (19.6%) of the patients in group 1 and group 2, respectively (P =.912). There was no significant difference between the groups in the time till InterStim II removal (P =.905). All NOUR patients with clinical success in group 1 had an improvement of at least 75% from the baseline compared to 69% of patients in group 2 (P =.42). Univariate analysis in NOUR patients demonstrated that maximal cystometric capacity below 430 mL and the presence of detrusor contraction at voiding were statistically significant predictors of successful SNM. Overall, at the end of the follow-up period, 8 (50.0%) and 29 (56.9%) patients in groups 1 and 2, respectively, were defined as clinical success (P =.775). [ABSTRACT FROM AUTHOR]

Transcranial magnetic stimulation (TMS) is an intervention for treatment-resistant depression (TRD) that modulates neural activity. Deep TMS (dTMS) can target not only cortical but also deeper limbic structures implicated in depression. Although TMS has demonstrated safety in adolescents, dTMS has yet to be applied to adolescent TRD. This pilot study evaluated the safety, tolerability, and clinical effects of dTMS in adolescents with TRD. We hypothesized dTMS would be safe, tolerable, and efficacious for adolescent TRD. 15 adolescents with TRD (Age, years: M = 16.4, SD = 1.42) completed a six-week daily dTMS protocol targeting the left dorsolateral prefrontal cortex (BrainsWay H1 coil, 30 sessions, 10 Hz, 3.6 s train duration, 20s inter-train interval, 55 trains; 1980 total pulses per session, 80 % to 120 % of motor threshold). Participants completed clinical, safety, and neurocognitive assessments before and after treatment. The primary outcome was depression symptom severity measured by the Children's Depression Rating Scale-Revised (CDRS-R). 14 out of 15 participants completed the dTMS treatments. One participant experienced a convulsive syncope; the other participants only experienced mild side effects (e.g., headaches). There were no serious adverse events and minimal to no change in cognitive performance. Depression symptom severity significantly improved pre- to post-treatment and decreased to a clinically significant degree after 10 treatment sessions. Six participants met criteria for treatment response. Main limitations include a small sample size and open-label design. These findings provide preliminary evidence that dTMS may be tolerable and associated with clinical improvement in adolescent TRD. • dTMS may be helpful for some adolescents with treatment resistant depression (TRD). • dTMS was tolerable for most adolescents with TRD in this sample. • Clinical improvements were observable within two weeks of treatment. • Additional research to test efficacy and to inform parameter selection is needed. [ABSTRACT FROM AUTHOR]

To examine if the use of an antibacterial envelope (TYRX) decreases the rate of postoperative infection in chronic pain patients undergoing treatment with spinal cord stimulation (SCS) involving device implantation. Single-center retrospective cohort study comparing postoperative infections rates in non-TYRX recipients from 2018 to 2020 with recipients of a TYRX antibacterial envelope from 2020 to 2021. Infection was registered if a patient received any form of antibiotic treatment after hospital discharge within a follow-up period of 100 days. A total of 198 patients were included: 100 in the TYRX group and 98 in the non-TYRX group. There were no significant differences between the 2 groups regarding age, body mass index (BMI), smoking, diabetes, and use of immunosuppression. The overall infection rate was 5.6%. The infection rate was 4% in the TYRX group and 7.1% in the non-TYRX group (P = 0.6). However, the 4 cases of postoperative infection in the TYRX group could be effectively managed with oral antibiotics alone, whereas 6 out of the 7 patients in the non-TYRX group required intravenous antibiotics. Moreover, device explantation was necessary in 3 of these patients suggesting the event of more severe infections in the non-TYRX group (P = 0.014). The TYRX antibacterial envelope displayed infection rates reducing capabilities, along with a clear tendency to reduce revision surgeries and system removals due to infections. [ABSTRACT FROM AUTHOR]

[Display omitted] • First trial using tDCS for Parkinsońs disease-related pain has been performed. • tDCS alleviates perceived pain and increases descending inhibitory systems in Parkinsońs disease patients. • Conditioned Pain Modulation could mediate pain relief in Parkinsońs disease. To evaluate the effects of transcranial direct current stimulation (tDCS) on Parkinson's disease (PD)-related pain. This triple-blind randomized controlled trial included twenty-two patients (age range 38–85, 10 male) with PD-related pain. Eleven subjects received ten sessions of 20 minutes tDCS over the primary motor cortex contralateral to pain at 2 mA intensity. Eleven subjects received sham stimulation. Outcome measures included changes in the Kinǵs Parkinsońs Pain Scale (KPPS), Brief Pain Inventory (BPI), widespread mechanical hyperalgesia (WMH), temporal summation of pain (TS), and conditioned pain modulation (CPM). Significant differences were found in KPPS between groups favoring the active-tDCS group compared to the sham-tDCS group at 15-days follow-up (p = 0.014) but not at 2 days post-intervention (p = 0.059). The active-group showed significant improvements over the sham-group after 15 days (p = 0.017). Significant changes were found in CPM between groups in favor of active-tDCS group at 2 days post-intervention (p = 0.002) and at 15 days (p = 0.017). No meaningful differences were observed in BPI or TS. tDCS of the primary motor cortex alleviates perceived PD-related pain, reduces pain sensitization, and enhances descending pain inhibition. This is the first study to test and demonstrate the use of tDCS for improving PD-related pain. [ABSTRACT FROM AUTHOR]

Many areas of science and medicine would benefit from selective release of drugs in specific regions. Nanoparticle drug carriers activated by focused ultrasound—remotely applied, depth-penetrating energy—may provide such selective interventions. Here, we developed stable, ultrasound-responsive nanoparticles that can be used to release drugs effectively and safely in non-human primates. The nanoparticles were used to release propofol in deep brain visual regions. The release reversibly modulated the subjects' visual choice behavior and was specific to the targeted region and to the released drug. Gadolinium-enhanced MR imaging suggested an intact blood-brain barrier. Blood draws showed normal clinical chemistry and hematology. In summary, this study provides a safe and effective approach to release drugs on demand in selected deep brain regions at levels sufficient to modulate behavior. [Display omitted] [ABSTRACT FROM AUTHOR]

Cilia are critical for detecting chemo-, photo-, and mechanosensory stimuli in the sensory systems. Most neurons in the central nervous system harbor cilia enriched in neuromodulatory receptors. Neuronal cilia are structurally and molecularly diverse, and play various roles in the central nervous system. The functionality of cilia is determined by their structure, the presence of receptors and ion channels, and their specific context. Neuronal cilia are found adjacent to chemical synapses and axonal segments, and can form axociliary synapses. Cilia are fascinating organelles that act as cellular antennae, sensing the cellular environment. Cilia gained significant attention in the late 1990s after their dysfunction was linked to genetic diseases known as ciliopathies. Since then, several breakthrough discoveries have uncovered the mechanisms underlying cilia biogenesis and function. Like most cells in the animal kingdom, neurons also harbor cilia, which are enriched in neuromodulatory receptors. Yet, how neuronal cilia modulate neuronal physiology and animal behavior remains poorly understood. By comparing ciliary biology between the sensory and central nervous systems (CNS), we provide new perspectives on the functions of cilia in brain physiology. [ABSTRACT FROM AUTHOR]

Treatment-resistant depression (TRD) occurs more commonly in women. Deep brain stimulation (DBS) is an emerging treatment for TRD, and its efficacy continues to be explored. However, differences in treatment outcomes between males and females have yet to be explored in formal analysis. A PRISMA-compliant systematic review of DBS for TRD studies was conducted. Patient-level data were independently extracted by two authors. Treatment response was defined as a 50 % or greater reduction in depression score. Percent change in depression scores by gender were evaluated using random-effects analyses. Of 737 records, 19 studies (129 patients) met inclusion criteria. The mean reduction in depression score for females was 57.7 % (95 % CI, 64.33 %–51.13 %), whereas for males it was 35.2 % (95 % CI, 45.12 %–25.23 %) (p < 0.0001). Females were more likely to respond to DBS for TRD when compared to males (OR = 2.44, 95 % CI 1.06, 1.95). These differences varied in significance when stratified by DBS anatomical target, age, and timeframe for responder classification. Studies included were open-label trials with small sample sizes. Our findings suggest that females with TRD respond at higher rates to DBS treatment than males. Further research is needed to elucidate the implications of these results, which may include connectomic sexual dimorphism, depression phenotype variations, or unrecognized symptom reporting differences. Methodological standardization of outcome scales, granular demographic data, and individual subject outcomes would allow for more robust comparisons between trials. • Our findings suggest females are more likely to respond to deep brain stimulation for treatment-resistant depression. • Females had a greater mean reduction in depression score compared to males. • Outcomes varied when stratified by anatomical target, age, and follow-up time. [ABSTRACT FROM AUTHOR]

Current eating disorder treatments include a range of psychological interventions, such as cognitive behavioural therapy, family therapy, or more structured specialised treatments such as Maudsley model of anorexia treatment for adults (MANTRA), and some off-label pharmacological interventions. Even with best available treatments, remission rates remain suboptimal and many patients go on to develop long-term treatment-refractory disorders. It is, therefore, crucial that novel treatments are developed, in attempts to significantly speed up and improve remission rates. Neuromodulation, virtual reality therapy, psychedelics, and leptin analogues are among emerging treatments that may help improve patient outcomes. Eating disorders (EDs) are common mental health conditions that carry exceedingly high morbidity and mortality rates. Evidence-based treatment options include a range of psychotherapies and some, mainly adjunctive, pharmacological interventions. However, around 20–30% of people fail to respond to the best available treatments and develop a persistent treatment-refractory illness. Novel treatments for these disorders are emerging, but their efficacy and clinical relevance need further investigation. In this review article, we first outline the evidence-base for the established treatments of the three 'classical' EDs [anorexia nervosa (AN), bulimia nervosa (BN), and binge eating disorder (BED)]. We then review research on some of the most promising emerging treatment modalities, discussing the questions and challenges that remain. [ABSTRACT FROM AUTHOR]

The mechanisms for spinal cord stimulation (SCS) to alleviate chronic pain are only partially known. We aimed to elucidate the roles of adenosine A1 and A3 receptors (A1R, A3R) in the inhibition of spinal nociceptive transmission by SCS, and further explored whether 2′-deoxycoformycin (dCF), an inhibitor of adenosine deaminase, can potentiate SCS-induced analgesia. We used RNAscope and immunoblotting to examine the distributions of adora1 and adora3 expression, and levels of A1R and A3R proteins in the spinal cord of rats after tibial-spared nerve injury (SNI-t). Electrophysiology recording was conducted to examine how adenosine receptor antagonists, virus-mediated adora3 knockdown, and dCF affect SCS-induced inhibition of C-fibre-evoked spinal local field potential (C-LFP). Adora1 was predominantly expressed in neurones, whereas adora3 is highly expressed in microglial cells in the rat spinal cord. Spinal application of antagonists (100 μl) of A1R (8-cyclopentyl-1,3-dipropylxanthine [DPCPX], 50 μM) and A3R (MRS1523, 200 nM) augmented C-LFP in SNI-t rats (DPCPX: 1.39 [0.18] vs vehicle: 0.98 [0.05], P =0.046; MRS1523: 1.21 [0.07] vs vehicle: 0.91 [0.03], P =0.002). Both drugs also blocked inhibition of C-LFP by SCS. Conversely, dCF (0.1 mM) enhanced SCS-induced C-LFP inhibition (dCF: 0.60 [0.04] vs vehicle: 0.85 [0.02], P <0.001). In the behaviour study, dCF (100 nmol 15 μl−1, intrathecal) also enhanced inhibition of mechanical hypersensitivity by SCS in SNI-t rats. Spinal A1R and A3R signalling can exert tonic suppression and also contribute to SCS-induced inhibition of spinal nociceptive transmission after nerve injury. Inhibition of adenosine deaminase may represent a novel adjuvant pharmacotherapy to enhance SCS-induced analgesia. [ABSTRACT FROM AUTHOR]

Increasing evidence suggests that the clinical effects of transcranial magnetic stimulation are target dependent. Within any given symptom, precise targeting of specific brain circuits may improve clinical outcomes. This principle can also be extended across symptoms—stimulation of different circuits may lead to different symptom-level outcomes. This may include targeting different symptoms within the same disorder (such as dysphoria vs. anxiety in patients with major depression) or targeting the same symptom across different disorders (such as primary major depression and depression secondary to stroke, traumatic brain injury, epilepsy, multiple sclerosis, or Parkinson's disease). Some of these symptom-specific changes may be desirable, while others may be undesirable. This review focuses on the conceptual framework through which symptom-specific target circuits may be identified, tested, and implemented. [ABSTRACT FROM AUTHOR]

Several types of neuromodulation have been investigated for the treatment of fibromyalgia, but they show varied efficacy on pain, functioning, comorbid depression and comorbid anxiety. Whether some types of neuromodulation or some factors are associated with a better response also awaits clarification. We conducted a systematic review and network meta-analysis of randomized controlled trials to evaluate the efficacy of neuromodulation in patients with fibromyalgia. We searched PubMed, EMBASE, the Cochrane Central Register of Controlled Trials and PsycINFO before March 2022. We employed a frequentist random-effects network meta-analysis. Forty trials involving 1541 participants were included. Compared with sham control interventions, several types of transcranial direct current stimulation (tDCS), transcranial random noise stimulation (tRNS), and high-frequency repetitive transcranial magnetic stimulation (rTMS) were associated with significant reduction of pain, depression, anxiety, and improvement in functioning. Many significantly effective treatment options involve stimulation of the primary motor cortex or dorsolateral prefrontal cortex. We concluded that several types of rTMS, tDCS and tRNS may have the potential to be applied for clinical purposes. • Several options of tDCS, tRNS and rTMS revealed beneficial effects on fibromyalgia. • aFP2-cEC-tDCS, aEC-cFP2-tDCS, aF3-cF4-tDCS and HFrTMS-M1 had effects on pain. • aC3-cEC-tDCS, aF3-cF4 + aONS-cONS-tDCS, aF3-cF4-tDCS had effects on depression. • aC3-cFP2-tRNS and aC3-cEC-tDCS had significant effects on anxiety. • aC3-cFP2-tRNS, aF3-cF4-tDCS and HFrTMS-M1 had effects on functioning. [ABSTRACT FROM AUTHOR]

New focused ultrasound spinal cord applications have emerged, particularly those improving therapeutic agent delivery to the spinal cord via blood–spinal cord barrier opening and the neuromodulation of spinal cord tracts. One hurdle in the development of these applications is safety. It may be possible to use safety trends from seminal and subsequent works in focused ultrasound to guide the development of safety guidelines for spinal cord applications. We collated data from decades of pre-clinical studies and illustrate a clear relationship between damage, time-averaged spatial peak intensity and exposure duration. This relationship suggests a thermal mechanism underlies ultrasound-induced spinal cord damage. We developed minimum and mean thresholds for damage from these pre-clinical studies. When these thresholds were plotted against the parameters used in recent pre-clinical ultrasonic spinal cord neuromodulation studies, the majority of the neuromodulation studies were near or above the minimum threshold. This suggests that a thermal neuromodulatory effect may exist for ultrasonic spinal cord neuromodulation, and that the thermal dose must be carefully controlled to avoid damage to the spinal cord. By contrast, the intensity–exposure duration threshold had no predictive value when applied to blood–spinal cord barrier opening studies that employed injected contrast agents. Most blood–spinal cord barrier opening studies observed slight to severe damage, except for small animal studies that employed an active feedback control method to limit pressures based on measured bubble oscillation behavior. The development of new focused ultrasound spinal cord applications perhaps reflects the recent success in the development of focused ultrasound brain applications, and recent work has begun on the translation of these technologies from brain to spinal cord. However, a great deal of work remains to be done, particularly with respect to developing and accepting safety standards for these applications. [ABSTRACT FROM AUTHOR]

Objective : The objective of this study was to investigate the effect of FUS on autonomic nervous system activity, including heart and respiratory rates, and to separate the thermal modulation from combined thermal and mechanical FUS effects. Methods : The thalamus and hypothalamus of wild-type mice were sonicated with a continuous-wave, 2 MHz FUS transducer at pressures of 425 and 850 kPa for 60 seconds. Cardiac and respiratory rates were monitored as signs of autonomic nervous activity. FUS-induced changes in autonomic activity were compared to FUS targeted to a spatially-distant motor region and to laser-induced heating. Results : FUS delivered to the primary target over the thalamus and hypothalamus at 850 kPa reversibly increased the respiratory rate by 6.5 ± 3.2 breaths per minute and decreased the heart rate by 3.2 ± 1.8 beats per minute. No significant changes occurred in this region at 425 kPa or when targeting the motor regions at 850 kPa. Laser heating with the same temperature rise profile produced by 850 kPa sonication resulted in cardiorespiratory modulation similar to that of FUS. Conclusions : FUS is capable of reversibly and non-invasively modulating cardiorespiratory activity in mice. Localized changes in temperature may constitute the main cause for this activity, though further investigation is warranted into the distinct and complementary mechanisms of mechanically- and thermally-induced FUS neuromodulation. Close monitoring of vital signs during FUS neuromodulation may be warranted to monitor systemic responses to stimulation. [ABSTRACT FROM AUTHOR]

Ultrasound is being researched as a method to modulate the brain. Studies of the interaction of sound with neurons support the hypothesis that mechanosensitive ion channels play an important role in ultrasound neuromodulation. The response of cells other than neurons (e.g., astrocytes, pericytes and endothelial cells) have not been fully characterized, despite playing an important role in brain function. To address this gap in knowledge, we examined cultured murine primary cortical neurons, astrocytes, endothelial cells and pericytes in an in vitro widefield microscopy setup during application of a 500 ms burst of 250 kHz focused ultrasound over a pressure range known to elicit neuromodulation. We examined cell membrane health in response to a range of pulses and used optical calcium indicators in conjunction with pharmacological antagonists to selectively block different groups of thermo- and mechanosensitive ion channels known to be responsive to ultrasound. All cell types experienced an increase in calcium fluorescence in response to ultrasound. Gadolinium (Gad), 2-aminoethoxydiphenyl borate (2-APB) and ruthenium red (RR) reduced the percentage of responding neurons and magnitude of response. The percentage of astrocytes responding was significantly lowered only by Gad, whereas both 2-APB and Gad decreased the amplitude of the fluorescence response. 2-APB decreased the percentage of responding endothelial cells, whereas only Gad reduced the magnitude of responses. Pericytes exposed to RR or Gad were less likely to respond to stimulation. RR had no detectable effect on the magnitude of the pericyte responses while 2-APB and Gad significantly decreased the fluorescence intensity, despite not affecting the percentage responding. Our study highlights the role of non-neuronal cells during FUS neuromodulation. All of the investigated cell types are sensitive to mechanical ultrasound stimulation and rely on mechanosensitive ion channels to undergo ultrasound neuromodulation. [ABSTRACT FROM AUTHOR]

Ascorbate is a small antioxidant molecule essential for the proper development and function of the brain. Ascorbate is transported into the brain and between brain cells via the Sodium vitamin C co-transporter 2 (SVCT2). This review provides an in-depth analysis of ascorbate's physiology, including how ascorbate is absorbed from food into the CNS, emphasizing cellular mechanisms of ascorbate recycling and release in different CNS compartments. Additionally, the review delves into the various functions of ascorbate in the CNS, including its impact on epigenetic modulation, synaptic plasticity, and neurotransmission. It also emphasizes ascorbate's role on neuromodulation and its involvement in neurodevelopmental processes and disorders. Furthermore, it analyzes the relationship between the duo ascorbate/SVCT2 in neuroinflammation, particularly its effects on microglial activation, cytokine release, and oxidative stress responses, highlighting its association with neurodegenerative diseases, such as Alzheimer's disease (AD). Overall, this review emphasizes the crucial role of the dynamic duo ascorbate/SVCT2 in CNS physiology and pathology and the need for further research to fully comprehend its significance in a neurobiological context and its potential therapeutic applications. [Display omitted] • The Sodium Vitamin C co-transporter 2 (SVCT2) is the key molecule to regulate ascorbate bioavailability in the central nervous system (CNS). SVCT2 is responsible for ascorbate entrance into the CNS and its distribution among CNS cells. Neurons, microglia, and oligodendrocytes express SVCT2. • Ascorbate is released during neurotransmission. The SVCT2 transporter can release ascorbate from neurons. • Ascorbate is a crucial neuromodulator that regulates neuronal excitability, neurotransmitter synthesis, release, and the functioning of its receptors. • Ascorbate/SVCT2 are crucial for CNS development by regulating essential functions such as morphogenesis, neurogenesis, neuronal differentiation, synaptogenesis, and myelination. • Ascorbate modulates neuroinflammation by inhibiting the transcription factor NF-kB activation and the synthesis of Prostaglandin E2 (PGE2). Additionally, neuroinflammatory stimuli decrease SVCT2 expression in neurons and microglia. [ABSTRACT FROM AUTHOR]

Spinal cord stimulators (SCSs) can be implanted via a percutaneous or paddle approach, the latter technique requiring a laminotomy or laminectomy. Revision surgery may be necessary in instances of migrated, misplaced, or failed stimulators. When revision of a percutaneous system is necessary, it is common to replace the electrodes with a paddle SCS. This study aims to describe a case series of patients with failed paddle SCS electrodes who underwent revision with percutaneous SCS hardware. A series of 5 patients were retrospectively analyzed. Medical records were reviewed for demographic data, operative technique, postoperative follow-up, and complications. Five patients were included in this series. The median age was 63 (range 51–84), and the median duration from initial implantation to revision surgery was 19 months (range 5–60). The median operative duration was 92 minutes (mean 99 ± 19.6 minutes). The median length of follow-up after surgery was 24 months (mean 21.8 ± 6.0 months). All patients had improved pain relief and therapeutic coverage with no complications. Paddle-to-percutaneous SCS surgery is a feasible and durable revision option in appropriately selected patients. [ABSTRACT FROM AUTHOR]

• Non-invasive brain and spinal stimulation techniques have been investigated as a potential treatment in motoneuron disease. • Stimulation methods aim at counteracting glutamate-mediated excitotoxicity leading to motoneuron degeneration. • Targeted, individualized and home-deliverable treatments are critical challenges for future advancements. Non-invasive brain stimulation techniques have been exploited in motor neuron disease (MND) with multifold objectives: to support the diagnosis, to get insights in the pathophysiology of these disorders and, more recently, to slow down disease progression. In this review, we consider how neuromodulation can now be employed to treat MND, with specific attention to amyotrophic lateral sclerosis (ALS), the most common form with upper motoneuron (UMN) involvement, taking into account electrophysiological abnormalities revealed by human and animal studies that can be targeted by neuromodulation techniques. This review article encompasses repetitive transcranial magnetic stimulation methods (including low-frequency, high-frequency, and pattern stimulation paradigms), transcranial direct current stimulation as well as experimental findings with the newer approach of trans-spinal direct current stimulation. We also survey and discuss the trials that have been performed, and future perspectives. [ABSTRACT FROM AUTHOR]

• The pathological features of inflammatory pain are briefly described. • Optogenetics is an emerging tool for studying pain. • The fundamentals of optogenetics are considered. • The application s of optogenetic neuromodulation in inflammatory pain is summarized. Inflammatory pain is one of the most prevalent forms of pain and negatively influences the quality of life. Neuromodulation has been an expanding field of pain medicine and is accepted by patients who have failed to respond to several conservative treatments. Despite its effectiveness, neuromodulation still lacks clinically robust evidence on inflammatory pain management. Optogenetics, which controls particular neurons or brain circuits with high spatiotemporal accuracy, has recently been an emerging area for inflammatory pain management and studying its mechanism. This review considers the fundamentals of optogenetics, including using opsins, targeting gene expression, and wavelength-specific light delivery techniques. The recent evidence on application and development of optogenetic neuromodulation in inflammatory pain is also summarised. The current limitations and challenges restricting the progression and clinical transformation of optogenetics in pain are addressed. Optogenetic neuromodulation in inflammatory pain has many potential targets, and developing strategies enabling clinical application is a desirable therapeutic approach and outcome. [ABSTRACT FROM AUTHOR]

The objective of this study was to analyze the trends in publications on intrathecal baclofen (ITB) therapy. We searched Elsevier's Scopus database in February 2022 to find articles focused on ITB therapy. Data extracted included citation count, publication year, author's country and income category, journal and its 5-year impact factor, research type, disease requiring ITB, and target population. The analysis covered 615 articles from 1985 to 2022. The average citation count per article was 27.47 (95% confidence interval 23.75–31.18) and the mean impact factor was 4.54 (95% confidence interval 3.84–5.24). The majority (76.42%) were primary research, with 8.1% being interventional and 91.9% observational. Even so, one half of the top ten most cited were interventional. Secondary research and case reports made up 12.68% and 10.73% respectively, with narrative reviews making up most of the secondary research (79.48%). Only 1 study conducted a meta-analysis. The United States was the most prolific country. High-income countries published 96.42% of articles. The rising number of ITB articles and citations indicates growing interest and expanding knowledge in this field. However, there's a notable scarcity of research from low- and middle-income countries, particularly those with high prevalence of ITB-treatable diseases. The need for more evidence to overcome potential barriers to ITB implementation is emphasized. Despite an increasing number of publications, a large proportion presented low levels of evidence, such as case reports and narrative reviews, highlighting the need for more rigorous research methods to solidify the evidence base for ITB therapy. [ABSTRACT FROM AUTHOR]

To evaluate the effectiveness and safety of a novel wearable neuromodulation system incorporating embedded electromyographic evaluation, representing the first closed-loop wearable therapy for bladder control. This 12-week, multicenter, open-label, single-arm study of subjects with overactive bladder assessed response of bladder diary parameters and quality of life (QOL) metrics. Subjects used the transcutaneous tibial neuromodulation system, either once or three times weekly, with evaluations at weeks 1, 4, 8, and 12. Enrolled subjects (N = 96) were assessed for changes in urinary frequency, urgency, and urgency urinary incontinence episodes, and QOL changes using various questionnaires. In the intent-to-treat population (N = 96, mean age 60.8 ± 13.0 years, 88.5% female), significant reductions in 3-day diary parameters were observed for daily voids, incontinence, and urgency episodes at 12 weeks. QOL improvements exceeded the minimal clinically important difference for all QOL questionnaires. Long-term results remained robust at 12 months. Device-related adverse events were mild and there were no device-related serious adverse events. Mean therapy compliance at 12 weeks was 88.5%. High satisfaction rates were reported for the device overall. The Avation device demonstrates promising efficacy in treating adults with overactive bladder and urge urinary incontinence. At 12 weeks, both diary parameters and QOL indicators showed significant improvement and remained robust at 12 months. The device had a favorable safety profile with high compliance and patient satisfaction. This novel, closed-loop wearable tibial neuromodulation system represents a significant advancement in bladder control therapy, offering a noninvasive, patient-centered alternative with improved accessibility and ease of use. [ABSTRACT FROM AUTHOR]

This study explores Transcranial Pulse Stimulation (TPS) as a potential non-invasive treatment for Alzheimer's disease (AD), focusing on its impact on cognitive functions and behavioral symptoms. In a prospective, one-arm open-label trial, ten patients with mild to moderate dementia due to AD were assessed using the Alzheimer's Disease Assessment Scale (ADAS-Cog), Neuropsychiatric Inventory (NPI), Pfeffer Functional Activities Questionnaire, and Zarit Caregiver Burden Interview. Assessments occurred at 30- and 90-days post-treatment. The TPS protocol consisted of 10 sessions over five weeks, using the Neurolith® device to deliver 6000 focused shockwave pulses at 0.25 mJ/mm2 and a frequency of 4 Hz. TPS significantly reduced neuropsychiatric symptoms, with NPI scores decreasing by 23.9 points (95% CI: −39.19 to −8.61, p = 0.0042) after 30 days, and by 18.9 points (95% CI: −33.49 to −2.91, p = 0.022) after 90 days. These changes had large effect sizes (Cohen's dz = 1.43 and dz = 0.94, respectively). A decreasing trend was observed in the ADAS-Cog score (−3.6, 95% CI: −7.18 to 0.00, p = 0.05) after 90 days, indicating a potential reduction in cognitive impairment, though not statistically significant. The preliminary results indicate that TPS treatment leads to significant improvement in neuropsychiatric symptoms in AD patients, showing promise as a therapeutic approach for AD. Further research is needed to fully establish its effectiveness, especially concerning cognitive functions. [ABSTRACT FROM AUTHOR]

• Multi-electrode tDCS might help steering the electric field, also at deep level. • Bilateral motor tDCS with extracephalic reference might induce significant electric fields at deep brain level. • Bilateral motor anodal tDCS with cathode over right hemisphere might selectively affect brainstem reflexes. To assess whether monopolar multi-electrode transcranial direct current stimulation (tDCS) montages might selectively affect deep brain structures through computational predictions and neurophysiological assessment. Electric field distribution in deep brain structures (i.e., thalamus and midbrain) were estimated through computational models simulating tDCS with two monopolar and two monopolar multi-electrode montages. Monopolar multi-electrode tDCS was then applied to healthy subject, and effects on pontine and medullary circuitries was evaluated studying changes in blink reflex (BR) and masseter inhibitory reflex (MIR). Computational results suggest that tDCS with monopolar multi-electrode montages might induce electric field intensities in deep brain structure comparable to those in grey matter, while neurophysiological results disclosed that BR and MIR were selectively modulated by tDCS only when cathode was placed over the right deltoid. Multi-electrode tDCS (anodes over motor cortices, cathode over right deltoid) could induce significant electric fields in the thalamus and midbrain, and selectively affect brainstem neural circuits. Multi-electrode tDCS (anodes over motor cortices, cathode over right deltoid) might be further explored to affect brainstem activity, also in the context of non-invasive deep brain stimulation. [ABSTRACT FROM AUTHOR]

Transcranial ultrasound neuromodulation is a promising potential therapeutic tool for the noninvasive treatment of neuropsychiatric disorders. However, the expansive parameter space and difficulties in controlling for peripheral auditory effects make it challenging to identify ultrasound sequences and brain targets that may provide therapeutic efficacy. Careful preclinical investigations in clinically relevant behavioral models are critically needed to identify suitable brain targets and acoustic parameters. However, there is a lack of ultrasound devices allowing for multi-target experimental investigations in awake and unrestrained rodents. We developed a miniaturized 64-element ultrasound array that enables neurointerventional investigations with within-trial active control targets in freely behaving rats. We first characterized the acoustic field with measurements in free water and with transcranial propagation. We then confirmed in vivo that the array can target multiple brain regions via electronic steering, and verified that wearing the device does not cause significant impairments to animal motility. Finally, we demonstrated the performance of our system in a high-throughput neuromodulation experiment, where we found that ultrasound stimulation of the rat central medial thalamus, but not an active control target, promotes arousal and increases locomotor activity. • We developed a miniaturized ultrasound array to enable neurointerventional investigations in freely behaving rats. • The array can target any brain region to implement within-trial active controls with no impairment to animal motility. • Using this device, we show that ultrasound stimulation of the central medial thalamus promotes arousal. • Our programmable device facilitates carefully controlled ultrasound neuromodulation experiments in rat behavioral models. [ABSTRACT FROM AUTHOR]

Deep brain stimulation (DBS) and other neuromodulatory techniques are being increasingly utilized to treat refractory neurologic and psychiatric disorders. /Hypothesis: To better understand the circuit-level pathophysiology of treatment-resistant depression (TRD) and treat the network-level dysfunction inherent to this challenging disorder, we adopted an approach of inpatient intracranial monitoring borrowed from the epilepsy surgery field. We implanted 3 patients with 4 DBS leads (bilateral pair in both the ventral capsule/ventral striatum and subcallosal cingulate) and 10 stereo-electroencephalography (sEEG) electrodes targeting depression-relevant network regions. For surgical planning, we used an interactive, holographic visualization platform to appreciate the 3D anatomy and connectivity. In the initial surgery, we placed the DBS leads and sEEG electrodes using robotic stereotaxy. Subjects were then admitted to an inpatient monitoring unit for depression-specific neurophysiological assessments. Following these investigations, subjects returned to the OR to remove the sEEG electrodes and internalize the DBS leads to implanted pulse generators. Intraoperative testing revealed positive valence responses in all 3 subjects that helped verify targeting. Given the importance of the network-based hypotheses we were testing, we required accurate adherence to the surgical plan (to engage DBS and sEEG targets) and stability of DBS lead rotational position (to ensure that stimulation field estimates of the directional leads used during inpatient monitoring were relevant chronically), both of which we confirmed (mean radial error 1.2±0.9 mm; mean rotation 3.6±2.6°). This novel hybrid sEEG-DBS approach allows detailed study of the neurophysiological substrates of complex neuropsychiatric disorders. • Used inpatient intracranial monitoring to study pathophysiology in depression. • Implanted DBS and sEEG electrodes targeting depression-relevant network regions. • Utilized interactive, holographic visualization platform to plan lead placement. • Performed neurophysiological assessments during patients' hospital admission. • Hybrid sEEG-DBS approach can be used to develop novel DBS therapeutic applications. [ABSTRACT FROM AUTHOR]

A neurobiological feature of Fetal Alcohol Spectrum Disorder (FASD) is a global decrease in neuronal connectivity, which leads to significant impairments in everyday functionality. Non-invasive repetitive transcranial magnetic stimulation (rTMS) could potentially positively influence neuronal plasticity but has not yet been studied in FASD. The present trial addresses this gap, making it the first-ever study of rTMS in FASD. The prospective clinical trial was conducted at the LMU University Hospital Munich and enrolled eight FASD participants aged 6–16. Six sessions of 1 Hz-rTMS over the left dorsolateral prefrontal cortex were administered two times a week for three weeks consisting of 1500 pulses at 90 % of resting motor threshold in four trains of 375s. Outcome measures investigated feasibility and treatment response of rTMS on executive functions, attention/impulsivity, social-emotional regulation and quality of life (QoL) via standardized tests and the FASD parents' app. Adherence and retention rate were 100 %. Adverse events (AEs) were mild and self-limiting, resulting in a per-session risk of 53.3 %, with local paraesthesia accounting for 54.2 % of the AEs. There were individual relevant but no significant group-level improvements in the investigated functional cerebral domains or participants' QoL. The FASD parents' app showed no significant change in participants' daily functioning or caregivers' QoL. Caregivers' parental stress decreased significantly. FASD is a very complex disorder that is difficult to treat. In addition, comorbidities as atypical responses to pharmacotherapies are frequent. For this reason, non-invasive, innovative therapies for children with FASD have to be developed. For the first time, rTMS was shown to be safe, tolerable, and acceptable and thus well feasible in paediatric patients with FASD. Further clinical studies with larger samples are needed to identify effective stimulation protocols and to evaluate treatment response. • First published study of rTMS in children and adolescents with FASD. • 1-Hz rTMS has shown to be feasible with only mild, self-limiting adverse events. • rTMS resulted in individual but no group-level improvements in executive functions, attention and emotional regulation. • A significant reduction in caregivers' parental stress could be shown. • Further research is needed for the identification of effective stimulation protocols. [ABSTRACT FROM AUTHOR]

The delivery of electrical pulses to the brain via penetrating electrodes, known as brain stimulation, has been recognized as an effective clinical approach for treating neurological disorders. Resident brain neural precursor cells (NPCs) are electrosensitive cells that respond to electrical stimulation by expanding in number, migrating and differentiating which are important characteristics that support neural repair. Here, we report the design of a conductive cryogel brain stimulation electrode specifically developed for NPC activation. The cryogel electrode has a modulus switching mechanism permitting facile penetration and reducing the mechanical mismatch between brain tissue and the penetrating electrode. The cryogel demonstrated good in vivo biocompatibility and reduced the interfacial impedance to deliver the stimulating electric field with lower voltage under charge-balanced current controlled stimulation. An ex vivo assay reveals that electrical stimulation using the cryogel electrodes results in significant expansion in the size of NPC pool. Hence, the cryogel electrodes have the potential to be used for NPC activation to support endogenous neural repair. The objective of this study is to develop a cryogel-based stimulation electrode as an alternative to traditional electrode materials to be used in regenerative medicine applications for enhancing neural regeneration in brain. The electrode offers benefits such as adaptive modulus for implantation, high charge storage and injection capacities, and modulus matching with brain tissue, allowing for stable delivery of electric field for long-term neuromodulation. The electrochemical properties of cryogel electrodes were characterized in living tissue with an ex vivo set-up, providing a deeper understanding of stimulation capacity in brain environments. The cryogel electrode is biocompatible and enables low voltage, current-controlled stimulation for effective activation of endogenous neural precursor cells, revealing their potential utility in neural stem cell-mediated brain repair. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] The persistence of pathological memory is the basis of several psychiatric disorders. Memory retrieval induces "reconsolidation", a time interval during which the original memory becomes labile and destabilized. Time- and retrieval-dependent processes and memory reconsolidation are critical periods for memory interference. Modulating memory reconsolidation has received considerable research attention as a treatment protocol for several psychiatric conditions such as posttraumatic stress disorder, addiction, anxiety, and trauma-related disorders. This specific time window provides an opportunity for intervention regarding mental diseases. This article reviews the effect of modulating memory reconsolidation using behavioral-, brain stimulation-, and pharmacological-based interventions, which may help bridge the gap between intervention in laboratories and application in clinical practice. The potential advantages, limitations, challenges, and opportunities for memory reconsolidation manipulations were discussed. [ABSTRACT FROM AUTHOR]