The RECOVER trial randomized 493 patients with markedly treatment-resistant major depressive disorder to treatment-as-usual with or without active vagus nerve stimulation (VNS Therapy). While the primary outcome measure did not statistically separate the treatment conditions, the field may lack optimal metrics for quantifying symptom improvement in markedly treatment-resistant patients.

This study examined the impact of three factors on sensitivity to clinical improvement across the total RECOVER sample and to differences in the effectiveness of the randomized conditions, systematically varying outcome classification (remission, response, and partial response), observation period (3-12 months, 6-12 months, 10-12 months and last observation), and depression rating scale.

Effect sizes for detecting therapeutic change across the total sample and the difference in effectiveness between the randomized groups were markedly higher for partial response than response or remission classifications. Longer observation periods produced larger therapeutic effects across the sample, but the effect sizes for the randomized treatment differences were substantially higher in the final 10-12 month period. The MADRS showed the least sensitivity to change across the sample and between the treatment groups. Using the partial response classification and the 10-12 month observation period, a significant difference between the groups was obtained for 3 of 4 depression scales.

The findings derive from a retrospective assessment of alternative outcome metrics.

In a large randomized controlled trial of VNS for markedly treatment-resistant depression, the magnitude of therapeutic effects and separation of treatment groups differed as a function of outcome classification, measurement period, and rating scale.

Epilepsy, a prevalent neurological disorder characterized by recurrent seizures, affects millions worldwide, with a significant proportion resistant to pharmacological treatments. Surgical interventions have emerged as pivotal in managing drug-resistant epilepsy (DRE), aiming to reduce seizure frequency or achieve seizure freedom. Traditional resective surgeries have evolved with technological advances, enhancing precision and safety. Neurostimulation techniques, such as responsive neurostimulation (RNS) and deep brain stimulation (DBS), now provide personalized, real-time seizure management, offering alternatives to traditional surgery. Minimally invasive ablative methods, such as laser interstitial thermal therapy (LITT) and Magnetic Resonance-guided Focused Ultrasound (MRgFUS), allow for targeted destruction of epileptogenic tissue with reduced risks and faster recovery times. The use of stereo-electroencephalography (SEEG) and robotic assistance has further refined surgical precision, enhancing outcomes. These advancements mark a paradigm shift towards precision medicine in epilepsy care, promising improved seizure management and quality of life for patients globally. This review outlines the latest innovations in epilepsy surgery, emphasizing their mechanisms and clinical implications to improve outcomes for patients with DRE.

Treatment-resistant depression (TRD) remains a vital challenge in psychiatry, affecting a significant number of patients with major depressive disorder. Current pharmacological approaches often do not provide sufficient therapeutic results, prompting the need for innovative treatments. This review summarizes recent advances in TRD management, including non-pharmacological therapies such as transcranial magnetic stimulation, deep brain stimulation, electroconvulsive therapy, and vagus nerve stimulation, and describes their mechanisms of action. Novel pharmacotherapies, particularly glutamatergic modulators like ketamine and esketamine, have shown promising results with esketamine being available to eligible patients in Poland since 2023 within a drug program. Electroconvulsive therapy remains an effective treatment for TRD, usually with small side effects mainly including transient memory impairment, headache, or cardiovascular changes. Transcranial magnetic stimulation is a non-invasive procedure with proven efficacy; therefore several psychiatric organizations recommend it as a treatment option for major depressive disorder in their clinical guidelines. Deep brain stimulation is a relatively new treatment modality for TRD, with its primary risk being associated with the required neurosurgical procedure. Vagus nerve stimulation seems to be a promising adjunctive treatment for TRD, showing significant improvements in depressive symptoms, especially at higher electrical doses but with no side effects. While these treatments appear to have potential, personalized approaches are crucial for optimizing outcomes. Future research should focus on refining the techniques, improving safety profiles, and validating the long-term efficacy.

This systematic review aims to comprehensively analyze the efficacy and underlying mechanisms of vagus nerve stimulation (VNS) in enhancing cognitive functions and its therapeutic potential for various cognitive impairments. The review focuses on the impact of VNS on emotional processing, executive functions, learning, memory, and its clinical applications in conditions such as epilepsy, depression, Alzheimer's disease, and other neurological disorders.

A systematic search of electronic databases (PubMed, Scopus, Web of Science) was conducted using the keywords "vagus nerve stimulation," "cognitive enhancement," "emotional processing," "executive function," "learning and memory," "epilepsy," "depression," "Alzheimer's disease," "neurological disorders," "attention-deficit/hyperactivity disorder," "sleep disorders," and "long COVID." The inclusion criteria encompassed controlled trials, longitudinal studies, and meta-analyses published in English between 2000 and July 2024.

A comprehensive review of 100 articles highlighted the cognitive effects of Vagus Nerve Stimulation (VNS). Studies show that VNS, especially through transcutaneous auricular VNS (taVNS), enhances emotional recognition, particularly for facial expressions, and improves selective attention under high cognitive demands. Additionally, VNS enhances learning and memory, including associative memory and spatial working memory tasks. In clinical applications, VNS exhibits promising benefits for improving cognitive functions in treatment-resistant epilepsy, depression, and Alzheimer's disease.

VNS represents a promising therapeutic approach for enhancing cognitive function across diverse patient populations. The reviewed evidence highlights its efficacy in modulating cognitive domains in healthy individuals and improving cognition in neurological conditions. However, the comparative effectiveness of different VNS modalities and the differential effects of online versus offline VNS on cognitive psychology require further investigation. Future research should focus on optimizing VNS protocols and elucidating specific cognitive domains that benefit most from VNS interventions. This ongoing exploration is essential for maximizing the therapeutic potential of VNS in clinical practice.

Neuropsychiatric symptoms (NPS) and mood disorders are common in individuals with mild cognitive impairment (MCI) and increase the risk of progression to dementia. Wearable devices collecting physiological and behavioral data can help in remote, passive, and continuous monitoring of moods and NPS, overcoming limitations and inconveniences of current assessment methods. In this longitudinal study, we examined the predictive ability of digital biomarkers based on sensor data from a wrist-worn wearable to determine the severity of NPS and mood disorders on a daily basis in older adults with predominant MCI. In addition to conventional physiological biomarkers, such as heart rate variability and skin conductance levels, we leveraged deep-learning features derived from physiological data using a self-supervised convolutional autoencoder. Models combining common digital biomarkers and deep features predicted depression severity scores with a correlation of r = 0.73 on average, total severity of mood disorder symptoms with r = 0.67, and mild behavioral impairment scores with r = 0.69 in the study population. Our findings demonstrated the potential of physiological biomarkers collected from wearables and deep learning methods to be used for the continuous and unobtrusive assessments of mental health symptoms in older adults, including those with MCI. TRIAL REGISTRATION: This trial was registered with ClinicalTrials.gov (NCT05059353) on September 28, 2021, titled "Effectiveness and Safety of a Digitally Based Multidomain Intervention for Mild Cognitive Impairment".

Implantable bioelectronic devices, designed for both monitoring and modulating living organisms, require functional and biological adaptability. Pure silk is innovatively employed, which is known for its excellent biocompatibility, to engineer water-triggered, geometrically reconfigurable membranes, on which functions can be integrated by Micro Electro Mechanical System (MEMS) techniques and specially functionalized silk. These devices can undergo programmed shape deformations within 10 min once triggered by water, and thus establishing stable bioelectronic interfaces with natively fitted geometries. As a testament to the applicability of this approach, a twining peripheral nerve electrode is designed, fabricated, and rigorously tested, demonstrating its efficacy in nerve modulation while ensuring biocompatibility for successful implantation.

Mental illnesses are among the leading causes of morbidity and disability worldwide, and the burden associated with these disorders has increased steadily over the past three decades [...].

Objective.Electrical stimulation of peripheral nerves has long been a treatment option to restore impaired neural functions that cannot be restored by conventional pharmacological therapies. Endovascular neurostimulation with stent-mounted electrode arrays is a promising and less invasive alternative to traditional implanted electrodes, which typically require invasive implantation surgery. In this study, we investigated the feasibility of endovascular stimulation of the femoral nerve using a stent-mounted electrode array and compared its performance to that of a commercially available pacing catheter.Approach.In acute animal experiments, a pacing catheter was implanted unilaterally in the femoral artery to stimulate the femoral nerve in a bipolar configuration. Electromyogram of the quadriceps and electroneurogram of a distal branch of the femoral nerve were recorded. After retrieval of the pacing catheter, a bipolar stent-mounted electrode array was implanted in the same artery and the recording sessions were repeated.Main Results.Stimulation of the femoral nerve was feasible with the stent-electrode array. Although the threshold stimulus intensities required with the stent-mounted electrode array (at 100-500µs increasing pulse width, 2.17 ± 0.87 mA-1.00 ± 0.11 mA) were more than two times higher than the pacing catheter electrodes (1.05 ± 0.48 mA-0.57 ± 0.28 mA), we demonstrated that, by reducing the stimulus pulse width to 100µs, the threshold charge per phase and charge density can be reduced to 0.22 ± 0.09µC and 24.62 ± 9.81µC cm-2, which were below the tissue-damaging limit, as defined by the Shannon criteria.Significance.The present study is the first to reportin vivofeasibility and efficiency of peripheral nerve stimulation using an endovascular stent-mounted electrode array.

Little research exists on extending ex-vivo systems to large animal nerves, and to the best of our knowledge, there has yet to be a study comparing these against in-vivo data. This paper details the first ex-vivo system for large animal peripheral nerves to be compared with in-vivo results.

Detailed ex-vivo and in-vivo closed-loop neuromodulation experiments were conducted on pig ulnar nerves. Temperatures from 20 °C to 37 °C were evaluated for the ex-vivo system. The data were analysed in the time and velocity domains, and a regression analysis established how evoked compound action potential amplitude and modal conduction velocity (CV) varied with temperature and time after explantation.

Pig ulnar nerves were sustained ex-vivo up to 5 h post-explantation. CV distributions of ex-vivo and in-vivo data were compared, showing closer correspondence at 37 °C. Regression analysis results also demonstrated that modal CV and time since explantation were negatively correlated, whereas modal CV and temperature were positively correlated.

Previous ex-vivo systems were primarily aimed at small animal nerves, and we are not aware of an ex-vivo system to be directly compared with in-vivo data. This new approach provides a route to understand how ex-vivo systems for large animal nerves can be developed and compared with in-vivo data.

The proposed ex-vivo system results were compared with those seen in-vivo, providing new insights into large animal nerve activity post-explantation. Such a system is crucial for complementing in-vivo experiments, maximising collected experimental data, and accelerating neural interface development.

Depression, a common mental illness, seriously affects the health of individuals and has deleterious effects on society. The prevention and treatment of depression has drawn the attention of many researchers and has become an important social issue. The treatment strategies for depression include drugs, psychotherapy, and physiotherapy. Drug therapy is ineffective in some patients and psychotherapy has treatment limitations. As a reliable adjuvant therapy, physiotherapy compensates for the shortcomings of drug and psychotherapy and effectively reduces the disease recurrence rate. Physiotherapy is more scientific and rigorous, its methods are diverse, and to a certain extent, provides more choices for the treatment of depression. Physiotherapy can relieve symptoms in many ways, such as by improving the levels of neurobiochemical molecules, inhibiting the inflammatory response, regulating the neuroendocrine system, and increasing neuroplasticity. Physiotherapy has biological effects similar to those of antidepressants and may produce a superimposed impact when combined with other treatments. This article summarizes the findings on the use of physiotherapy to treat patients with depression over the past five years. It also discusses several methods of physiotherapy for treating depression from the aspects of clinical effect, mechanism of action, and disadvantages, thereby serving as a reference for the in-depth development of physiotherapy research.

An electroceutical is a medical device that uses electrical signals to control biological functions. It can be inserted into the human body as an implant and has several crucial advantages over conventional medicines for certain diseases. This research develops a new vagus nerve simulation (VNS) electroceutical through an innovative approach to overcome the communication limitations of existing devices. A phased array antenna with a better communication performance was developed and applied to the electroceutical prototype. In order to effectively respond to changes in communication signals, we developed the steering algorithm and firmware, and designed the smart communication protocol that operates at a low power that is safe for the patients. This protocol is intended to improve a communication sensitivity related to the transmission and reception distance. Based on this technical approach, the heightened effectiveness and safety of the prototype have been ascertained, with the actual clinical tests using live animals. We confirmed the signal attenuation performance to be excellent, and a smooth communication was achieved even at a distance of 7 m. The prototype showed a much wider communication range than any other existing products. Through this, it is conceivable that various problems due to space constraints can be resolved, hence presenting many benefits to the patients whose last resort to the disease is the VNS electroceutical.

Heart rate variability (HRV),a measure of the fluctuations in the intervals between consecutive heartbeats, is an indicator of changes in the autonomic nervous system. A chronic reduction in HRV has been repeatedly linked to clinical depression. However, the chronological and mechanistic aspects of this relationship, between the neural, physiological, and psychopathological levels, remain unclear. In this review we present evidence by which changes in HRV might precede the onset of depression. We describe several pathways that can facilitate this relationship. First, we examine a theoretical model of the impact of autonomic imbalance on HRV and its role in contributing to mood dysregulation and depression. We then highlight brain regions that are regulating both HRV and emotion, suggesting these neural regions, and the Insula in particular, as potential mediators of this relationship. We also present additional possible mediating mechanisms involving the immune system and inflammation processes. Lastly, we support this model by showing evidence that modification of HRV with biofeedback leads to an improvement in some symptoms of depression. The possibility that changes in HRV precede the onset of depression is critical to put to the test, not only because it could provide insights into the mechanisms of the illness but also because it may offer a predictive anddiagnosticphysiological marker for depression. Importantly, it could also help to develop new effective clinical interventions for treating depression.

The global prevalence of depression has risen over the past three decades across all socioeconomic groups and geographic regions, with a particularly rapid increase in prevalence among adolescents (aged 12-17 years) in the United States. Depression imposes large health, economic, and societal costs, including reduced life span and quality of life, medical costs, and reduced educational attainment and workplace productivity. A wide range of treatment modalities for depression are available, but socioeconomic disparities in treatment access are driven by treatment costs, lack of culturally tailored options, stigma, and provider shortages, among other barriers. This review highlights the need for comparative research to better understand treatments' relative efficacy, cost-effectiveness, scalability, and potential heterogeneity in efficacy across socioeconomic groups and country and cultural contexts. To address the growing burden of depression, mental health policy could consider reducing restrictions on the supply of providers, implementing digital interventions, reducing stigma, and promoting healthy lifestyles.

To treat diseases associated with vagal nerve control of peripheral organs, it is necessary to selectively activate efferent and afferent fibers in the vagus. As a result of the nerve's complex anatomy, fiber-specific activation proves challenging. Spatially selective neuromodulation using micromagnetic stimulation(μMS) is showing incredible promise. This neuromodulation technique uses microcoils(μcoils) to generate magnetic fields by powering them with a time-varying current. Following the principles of Faraday's law of induction, a highly directional electric field is induced in the nerve from the magnetic field. In this study on rodent cervical vagus, a solenoidalμcoil was oriented at an angle to left and right branches of the nerve. The aim of this study was to measure changes in the mean arterial pressure (MAP) and heart rate (HR) followingμMS of the vagus. Theμcoils were powered by a single-cycle sinusoidal current varying in pulse widths(PW = 100, 500, and 1000μsec) at a frequency of 20 Hz. Under the influence of isoflurane,μMS of the left vagus at 1000μsec PW led to an average drop in MAP of 16.75 mmHg(n = 7). In contrast,μMS of the right vagus under isoflurane resulted in an average drop of 11.93 mmHg in the MAP(n = 7). Surprisingly, there were no changes in HR to either right or left vagalμMS suggesting the drop in MAP associated with vagusμMS was the result of stimulation of afferent, but not efferent fibers. In urethane anesthetized rats, no changes in either MAP or HR were observed uponμMS of the right or left vagus(n = 3). These findings suggest the choice of anesthesia plays a key role in determining the efficacy ofμMS on the vagal nerve. Absence of HR modulation uponμMS could offer alternative treatment options using VNS with fewer heart-related side-effects.

Deep brain stimulation (DBS) has emerged as a promising treatment for select patients with refractory major depressive disorder (MDD). The clinical effectiveness of DBS for MDD has been demonstrated in meta-analyses, open-label studies, and a few controlled studies. However, randomized controlled trials have yielded mixed outcomes, highlighting challenges that must be addressed prior to widespread adoption of DBS for MDD. These challenges include tracking MDD symptoms objectively to evaluate the clinical effectiveness of DBS with sensitivity and specificity, identifying the patient population that is most likely to benefit from DBS, selecting the optimal patient-specific surgical target and stimulation parameters, and understanding the mechanisms underpinning the therapeutic benefits of DBS in the context of MDD pathophysiology. In this review, we provide an overview of the latest clinical evidence of MDD DBS effectiveness and the recent technological advancements that could transform our understanding of MDD pathophysiology, improve the clinical outcomes for MDD DBS, and establish a path forward to develop more effective neuromodulation therapies to alleviate depressive symptoms.

Laryngopharyngeal reflux disease (LPRD) is primarily characterized by discomfort in the pharynx and has limited treatment options. This research aimed to assess the efficacy of transcutaneous auricular vagus nerve stimulation (tVNS) in patients with LPRD and delve into the potential underlying mechanisms.

A total of 44 participants, diagnosed with LPRD were divided into two groups randomly. Twice-daily stimulation was delivered for 2 weeks for patients in experimental group, with stimulation ranging from 1.0 mA to 1.5 mA (n = 22), while the control group underwent sham tVNS (n = 22) with the same stimulation parameters and different anatomical location. The severity of symptoms and levels of anxiety and depression were monitored using questionnaires. High-resolution esophageal manometry data were collected, and the patients' autonomic function was assessed through heart rate variability analysis.

There was a positive correlation between reflux symptom index (RSI) scores and low frequency/high frequency (LF/HF) ratio (r = 0.619; p < 0.001), Hamilton anxiety scale (HAMA) scores (r = 0.623; p < 0.001), and Hamilton depression scale (HAMD) scores (r = 0.593; p < 0.001). Compared to the pre-tVNS phase, RSI (p < 0.001), HAMA (p < 0.001), and HAMD (p < 0.001) scores were significantly reduced after 2 weeks of treatment. Additionally, the resting pressure of the upper esophageal sphincter (UESP; p < 0.05) and lower esophageal sphincter (LESP; p < 0.05) showed significant enhancement. Notably, tVNS led to an increase in root mean square of successive differences (RMSSD; p < 0.05) and high frequency (HF; p < 0.05) within heart rate variability compared to the pre-treatment baseline. Compared to the control group, RSI (p < 0.001), HAMA (p < 0.001), and HAMD (p < 0.001) scores in tVNS group were significantly lower at the end of treatment. Similarly, the resting pressure of UESP (p < 0.05) and LESP (p < 0.05) in tVNS group were significantly higher than that of control group. Notably, RMSSD (p < 0.05) and HF (p < 0.05) in tVNS group were significantly higher than that of control group.

This study demonstrated that tVNS as a therapeutic approach is effective in alleviating LPRD symptoms. Furthermore, it suggests that improvements in esophageal motility could be associated with vagus nerve-dependent mechanisms.

Vagus nerve stimulation (VNS) has been approved as an adjunctive treatment for epilepsy and depression. As the progress of VNS treatment for these neuropsychiatric disorders continues, its applications have expanded to a wide range of conditions, including inflammatory diseases to cognitive dysfunctions. The branches of the vagal nerves directly or indirectly innervate the anatomical structures implicated in these neuropsychiatric conditions, which has led to promising results regarding the effectiveness of VNS. Previous studies investigating the effectiveness of VNS have mostly utilized invasive forms of stimulation. However, current preclinical and clinical research indicates that non-invasive forms of VNS, such as transcutaneous vagus nerve stimulation, hold the promise for treating various neuropsychiatric conditions. This review aims to delve into relevant clinical studies of VNS in various illness states, different methods of VNS, and the potential mechanisms underlying the therapeutic effects in these neuropsychiatric conditions.

Major depressive disorder (MDD) is characterized by persistent depressed mood, loss of interest or pleasure in previously enjoyable activities, recurrent thoughts of death, and physical and cognitive symptoms. People with MDD can have reduced quality of life owing to the disorder itself as well as related medical comorbidities, social factors, and impaired functional outcomes. MDD is a complex disorder that cannot be fully explained by any one single established biological or environmental pathway. Instead, MDD seems to be caused by a combination of genetic, environmental, psychological and biological factors. Treatment for MDD commonly involves pharmacological therapy with antidepressant medications, psychotherapy or a combination of both. In people with severe and/or treatment-resistant MDD, other biological therapies, such as electroconvulsive therapy, may also be offered.

Lyme disease, the most common tick-borne disease in the United States, is caused by infection with the spirochete Borrelia burgdorferi. While most patients with acute Lyme disease recover completely if treated with antibiotics shortly after the onset of infection, approximately 10-30% experience post-treatment symptoms and 5-10% have residual symptoms with functional impairment (post-treatment Lyme disease syndrome or PTLDS). These patients typically experience pain, cognitive problems, and/or fatigue. This narrative review provides a broad overview of Lyme disease, focusing on neuropsychiatric manifestations and persistent symptoms. While the etiology of persistent symptoms remains incompletely understood, potential explanations include persistent infection, altered neural activation, and immune dysregulation. Widely recognized is that new treatment options are needed for people who have symptoms that persist despite prior antibiotic therapy. After a brief discussion of treatment approaches, the article focuses on vagus nerve stimulation (VNS), a neuromodulation approach that is FDA-approved for depression, epilepsy, and headache syndromes and has been reported to be helpful for other diseases characterized by inflammation and neural dysregulation. Transcutaneous VNS stimulates the external branch of the vagus nerve, is minimally invasive, and is well-tolerated in other conditions with few side effects. If well-controlled double-blinded studies demonstrate that transcutaneous auricular VNS helps patients with chronic syndromes such as persistent symptoms after Lyme disease, taVNS will be a welcome addition to the treatment options for these patients.

Peripheral nerve interfacing (PNI) has a high clinical potential for treating various diseases, such as obesity or diabetes. However, currently existing electrodes present challenges to the interfacing procedure, which limit their clinical application, in particular, when targeting small peripheral nerves (<200 µm). To improve the electrode handling and implantation, a nerve interface that can fold itself to a cuff around a small nerve, triggered by the body moisture during insertion, is fabricated. This folding is achieved by printing a bilayer of a flexible polyurethane printing resin and a highly swelling sodium acrylate hydrogel using photopolymerization. When immersed in an aqueous liquid, the hydrogel swells and folds the electrode softly around the nerve. Furthermore, the electrodes are robust, can be stretched (>20%), and bent to facilitate the implantation due to the use of soft and stretchable printing resins as substrates and a microcracked gold film as conductive layer. The straightforward implantation and extraction of the electrode as well as stimulation and recording capabilities on a small peripheral nerve in vivo are demonstrated. It is believed that such simple and robust to use self-folding electrodes will pave the way for bringing PNI to a broader clinical application.

Evidence has shown the roles of taVNS and TECS in improving depression but few studies have explored their synergistic effects on MDD. Therefore, the treatment responsivity and neurological effects of TECAS were investigated and compared to escitalopram, a commonly used medication for depression. Fifty patients with mild-to-moderate MDD (29 in the TECAS group and 21 in another) and 49 demographically matched healthy controls were recruited. After an eight-week treatment, the outcomes of TECAS and escitalopram were evaluated by the effective rate and reduction rate based on the Montgomery-Asberg Depression Rating Scale, Hamilton Depression Rating Scale, and Hamilton Anxiety Rating Scale. Altered brain networks were analyzed between pre- and post-treatment using independent component analysis. There was no significant difference in clinical scales between TECAS and escitalopram but these were significantly decreased after each treatment. Both treatments modulated connectivity of the default mode network (DMN), dorsal attention network (DAN), right frontoparietal network (RFPN), and primary visual network (PVN), and the decreased PVN-RFPN connectivity might be the common brain mechanism. However, there was increased DMN-RFPN and DMN-DAN connectivity after TECAS, while it decreased in escitalopram. In conclusion, TECAS could relieve symptoms of depression similarly to escitalopram but induces different changes in brain networks.

Postoperative cognitive dysfunction (POCD) is a common complication of central nervous system after anesthesia or surgery. Sevoflurane, an inhalation anesthetic, may inhibit cholinergic pathway that induce neuronal death and neuroinflammation, ultimately leading to POCD. Transauricular vagus nerve stimulation (taVNS) has neuroprotective effects in POCD rats, but the mechanisms related to cholinergic system have not been revealed. Sprague-Dawley rats were anesthetized with sevoflurane to construct the POCD model. The immunotoxin 192-IgG-saporin (192-sap) selectively lesioned cholinergic neurons in the basal forebrain, which is the major source of cholinergic projections to hippocampus. After lesion, rats received 5 days of taVNS treatment (30 min per day) starting 24 h before anesthesia. Open field test and Morris water maze were used to test the cognitive function. In this study, rats exposed to sevoflurane exhibited cognitive impairment that was attenuated by taVNS. In addition, taVNS treatment activated cholinergic system in the basal forebrain and hippocampus, and downregulated the expression of apoptosis- and necroptosis-related proteins, such as cleaved Caspase-3 and p-MLKL, in the hippocampus. Meanwhile, the activation of Iba1⁺ microglial by sevoflurane was reduced by taVNS. 192-sap blocked the cholinergic system activation in the basal forebrain and hippocampus and inhibited taVNS-mediated neuroprotection and anti-inflammation effects in the hippocampus. Generally, our study indicated that taVNS might alleviate sevoflurane-induced hippocampal neuronal apoptosis, necroptosis and microglial activation though activating cholinergic system in the basal forebrain.

Epilepsy and autism spectrum disorder (ASD) are highly mutually comorbid, suggesting potential overlaps in genetic etiology, pathophysiology, and neurodevelopmental abnormalities. Adenosine, an endogenous anticonvulsant and neuroprotective neuromodulator of the brain, has been proved to affect the process of epilepsy and ASD. On the one hand, adenosine plays a crucial role in preventing the progression and development of epilepsy through adenosine receptordependent and -independent ways. On the other hand, adenosine signaling can not only regulate core symptoms but also improve comorbid disorders in ASD. Given the important role of adenosine in epilepsy and ASD, therapeutic strategies related to adenosine, including the ketogenic diet, neuromodulation therapy, and adenosine augmentation therapy, have been suggested for the arrangement of epilepsy and ASD. There are several proposals in this review. Firstly, it is necessary to further discuss the relationship between both diseases based on the comorbid symptoms and mechanisms of epilepsy and ASD. Secondly, it is important to explore the role of adenosine involved in epilepsy and ASD. Lastly, potential therapeutic value and clinical approaches of adenosine-related therapies in treating epilepsy and ASD need to be emphasized.

In 2021, the U.S. Food and Drug Administration (FDA) approved paired vagus nerve stimulation (VNS) for patients with moderate-to-severe upper extremity motor impairments following chronic ischemic stroke.

Previous meta-analyses have shown that VNS may impact stroke rehabilitation, but each has some limitations.

PubMed, Ovid, Cochrane Library, ScienceDirect, Web of Science and WHO ICTRP databases were searched until July 14, 2022 for randomized controlled trials (RCTs). We defined primary outcomes as Fugl-Meyer Assessment for Upper Extremity (FMA-UE) and Wolf Motor Function Test (WMFT). Subgroup analyses included types of VNS, time since onset and long-term effects. Secondary outcomes included adverse events of VNS.

Eight RCTs involving 266 patients were analyzed, of which five used direct VNS and three transcutaneous auricular VNS. The results revealed that VNS enhanced upper extremity function via FMA-UE (SMD = 0.73; 95% CI: 0.48 to 0.99; P < 0.00001) and WMFT (SMD = 0.82; 95% CI:0.52 to 1.13; P < 0.00001) in comparison to the control group, but showed no significant change on long-term effects of FMA-UE (SMD = 0.69; 95% CI: - 0.06 to 1.44; P = 0.07). There was no difference in adverse events between the VNS and control groups (RR = 1.16; 95% CI: 0.46 to 2.92; P = 0.74).

For stroke victims with upper limb disabilities, VNS paired with rehabilitation was significantly safe and effective. More high-quality multicentric RCTs are needed to validate this conclusion.

Post-stroke depression (PSD) is a biopsychosocial disorder that affects individuals who have suffered a stroke at any point. PSD has a 20 to 60 percent reported prevalence among stroke survivors. Its effects are usually adverse, can lead to disability, and may increase mortality if not managed or treated early. PSD is linked to several other medical conditions, including anxiety, hyper-locomotor activity, and poor functional recovery. Despite significant awareness of its adverse impacts, understanding the pathogenesis of PSD has proved challenging. The exact pathophysiology of PSD is unknown, yet its complexity has been definitively shown, involving mechanisms such as dysfunction of monoamine, the glutamatergic systems, the gut-brain axis, and neuroinflammation. The current effectiveness of PSD treatment is about 30-40 percent of all cases. In this review, we examined different pathophysiological mechanisms and current pharmacological and non-pharmacological approaches for the treatment of PSD.

Patients with cancer are at greater risk of developing depression in comparison to the general population and this is associated with serious adverse effects, such as poorer quality of life, worse prognosis and higher mortality. Although the relationship between depression and cancer is now well established, a common underlying pathophysiological mechanism between the two conditions is yet to be elucidated. Existing theories of depression, based on monoamine neurotransmitter system dysfunction, are insufficient as explanations of the disorder. Recent advances have implicated neuroinflammatory mechanisms in the etiology of depression and it has been demonstrated that inflammation at a peripheral level may be mirrored centrally in astrocytes and microglia serving to promote chronic levels of inflammation in the brain. Three major routes to depression in cancer in which proinflammatory mediators are implicated, seem likely. Activation of the kynurenine pathway involving cytokines, increases tryptophan catabolism, resulting in diminished levels of serotonin which is widely acknowledged as being the hallmark of depression. It also results in neurotoxic effects on brain regions thought to be involved in the evolution of major depression. Proinflammatory mediators also play a crucial role in impairing regulatory glucocorticoid mediated feedback of the hypothalamic-pituitary-adrenal axis, which is activated by stress and considered to be involved in both depression and cancer. The third route is via the glutamatergic pathway, whereby glutamate excitotoxicity may lead to depression associated with cancer. A better understanding of the mechanisms underlying these dysregulated and other newly emerging pathways may provide a rationale for therapeutic targeting, serving to improve the care of cancer patients.

Depression is a worldwide disease causing severe disability, morbidity, and mortality. Despite abundant studies, the precise mechanisms underlying the pathophysiology of depression remain elusive. Recently, cumulate research suggests that a disturbance of microbiota-gut-brain axis may play a vital role in the etiology of depression while correcting this disturbance could alleviate depression symptoms. The vagus nerve, linking brain and gut through its afferent and efferent branches, is a critical route in the bidirectional communication of this axis. Directly or indirectly, the vagus afferent fibers can sense and relay gut microbiota signals to the brain and induce brain disorders including depression. Also, brain changes in response to stress may result in gut hyperpermeability and inflammation mediating by the vagal efferents, which may be detrimental to depression. Notably, vagus nerve stimulation owns an anti-inflammatory effect and was proved for depression treatment. Nevertheless, depression was accompanied by a low vagal tone, which may derive from response to stress and contribute to pathogenesis of depression. In this review, we aim to explore the role of the vagus nerve in depression from the perspective of the microbiota-gut-brain axis, highlighting the relationship among the vagal tone, the gut hyperpermeability, inflammation, and depression.

Objective.Vagus nerve stimulation (VNS) is Food and Drug Administration-approved for epilepsy, depression, and obesity, and stroke rehabilitation; however, the morphological anatomy of the vagus nerve targeted by stimulatation is poorly understood. Here, we used microCT to quantify the fascicular structure and neuroanatomy of human cervical vagus nerves (cVNs).Approach.We collected eight mid-cVN specimens from five fixed cadavers (three left nerves, five right nerves). Analysis focused on the 'surgical window': 5 cm of length, centered around the VNS implant location. Tissue was stained with osmium tetroxide, embedded in paraffin, and imaged on a microCT scanner. We visualized and quantified the merging and splitting of fascicles, and report a morphometric analysis of fascicles: count, diameter, and area.Main results.In our sample of human cVNs, a fascicle split or merge event was observed every ∼560µm (17.8 ± 6.1 events cm-1). Mean morphological outcomes included: fascicle count (6.6 ± 2.8 fascicles; range 1-15), fascicle diameter (514 ± 142µm; range 147-1360µm), and total cross-sectional fascicular area (1.32 ± 0.41 mm2; range 0.58-2.27 mm).Significance.The high degree of fascicular splitting and merging, along with wide range in key fascicular morphological parameters across humans may help to explain the clinical heterogeneity in patient responses to VNS. These data will enable modeling and experimental efforts to determine the clinical effect size of such variation. These data will also enable efforts to design improved VNS electrodes.

The 'neurogenesis hypothesis of depression' emphasizes the importance of upregulated hippocampal neurogenesis for the efficacy of antidepressant treatment. Neuromodulation is a promising therapeutic method that stimulates neural circuitries to treat neuropsychiatric illnesses. We conducted a scoping review on the neurogenic and antidepressant outcomes of neuromodulation in animal models of depression. PubMed, Web of Science, and PsycInfo were comprehensively searched for full-text English articles from inception to October 5, 2021. Data screening and extraction were conducted independently by two researchers. Seventeen eligible studies were included in this review. The majority of studies used non-invasive neuromodulation (n = 14) and assessed neurogenesis using neural proliferation (n = 16) and differentiation markers (n = 9). Limited reports (n = 2) used neurogenic inhibitors to evaluate the role of neurogenesis on the depressive-like behavioral outcomes. Overall, neuromodulation substantially effectuated both hippocampal cell proliferation and antidepressant-like behavior in animal models of depression, with some providing evidence for enhanced neuronal differentiation and maturation. The proposed neurogenic-related mechanisms mediating the neuromodulation efficacies included neurotrophic processes, anti-apoptotic pathways, and normalization of HPA axis functions. Further research is warranted to explore the role of neuromodulation-induced neurogenic effects on treatment efficacies and to elucidate the underlying molecular mechanisms.

Electrical stimulation of peripheral nerves is a cornerstone of bioelectronic medicine. Effective ways to accomplish peripheral nerve stimulation (PNS) noninvasively without surgically implanted devices are enabling for fundamental research and clinical translation. Here, it is demonstrated how relatively high-frequency sine-wave carriers (3 kHz) emitted by two pairs of cutaneous electrodes can temporally interfere at deep peripheral nerve targets. The effective stimulation frequency is equal to the offset frequency (0.5 - 4 Hz) between the two carriers. This principle of temporal interference nerve stimulation (TINS) in vivo using the murine sciatic nerve model is validated. Effective actuation is delivered at significantly lower current amplitudes than standard transcutaneous electrical stimulation. Further, how flexible and conformable on-skin multielectrode arrays can facilitate precise alignment of TINS onto a nerve is demonstrated. This method is simple, relying on the repurposing of existing clinically-approved hardware. TINS opens the possibility of precise noninvasive stimulation with depth and efficiency previously impossible with transcutaneous techniques.

The aim of this study was to investigate whether transauricular vagus nerve stimulation (taVNS) could decrease the incidence of delayed neurocognitive recovery (dNCR) in elderly adults after total joint arthroplasty (TJA).

A prospective, randomized, double-blind, sham-controlled trial was designed. In total, 124 elderly patients undergoing TJA were enrolled and randomly assigned to taVNS group (n = 62), who received taVNS at 1 h before anesthetic induction until the end of surgery, or sham stimulation (SS) group (n = 62), who received SS in the same manner. Neuropsychological batteries were performed before and at 1 week after surgery to assess the incidence of dNCR. Blood samples were collected before surgery and at 1 day after surgery to detect the activity of cholinesterase (AChE and BChE), as well as the levels of inflammatory factors (TNF-α, IL-1β, IL-6, and HMGB1) and brain damage factor S100β.

Of 124 patients, 119 completed 1 week neuropsychological tests. The incidence of dNCR was significantly decreased in taVNS group [10% (6/60)] compared with the SS group [27.1% (16/59)] (P < 0.05). Patients who received taVNS had lower blood levels of AChE, BChE, IL-6, HMGB1, and S100β after surgery (P < 0.05), as compared with those in the SS group. There was no difference in TNF-α between the two groups.

The taVNS can decrease the incidence of dNCR after TJA in elderly patients, which may be related to the inhibition of inflammatory cytokine production and the reduction of cholinesterase activity.

Previous studies in animals and humans indicated that transcutaneous vagus nerve stimulation (tVNS) and transcutaneous electrical acupoint stimulation (TEAS) on trigeminal nerve-innervated forehead acupoints can relief the symptoms of depression. However, due to the limited investigations on these two interventions, more research are needed to confirm their efficacy in depression. To improve the efficacy of the single treatment, we combined two treatments and created a novel non-invasive stimulation, transcutaneous electrical cranial-auricular acupoint stimulation (TECAS). To assess the efficacy and safety of TECAS, we compare it with a selective serotonin reuptake inhibitor (SSRI), escitalopram, for the treatment of depression.

This is a multi-center, non-inferiority, randomized controlled trial that will involve 470 patients with mild to moderate depression. Patients will be randomly assigned to either the TECAS group or the escitalopram group in a 1:1 ratio. The TEAS group will receive two sessions of treatments per day for 8 consecutive weeks, and the escitalopram group will receive 8 weeks of oral escitalopram tablets prescribed by clinical psychiatrists as appropriate for their condition. The primary outcome is the clinical response as determined by Montgomery-Åsberg Depression Rating Scale (MADRS) scores at week 8, with -10% as the non-inferior margin. The secondary outcomes include the response rate determined by 17-item Hamilton Depression Rating Scale (HAMD-17), remission rate, changes from baseline in the scores on the MADRS, the HAMD-17, the Hamilton Anxiety Rating Scale (HAMA), the Pittsburgh Sleep Quality Index (PSQI), and the Short Form 36 Health Survey (SF-36).

This will be the first randomized controlled trial to compare the efficacy of TECAS with escitalopram for depression. If effective, this novel intervention could have significant clinical and research implications for patients with depression.

[ClinicalTrials.gov], identifier [NCT03909217].

The effects of non-invasive, non-convulsive electrical neuromodulation (NINCEN) on depression, anxiety and sleep disturbance are inconsistent in different studies. Previous meta-analyses on transcranial direct current stimulation (tDCS) and cerebral electrotherapy stimulation (CES) suggested that these methods are effective on depression. However, not all types of NINECN were included; results on anxiety and sleep disturbance were lacking and the influence of different populations and treatment parameters was not completely analyzed. We searched PubMed, Embase, PsycInfo, PsycArticles and CINAHL before March 2021 and included published randomized clinical trials of all types of NINCEN for symptoms of depression, anxiety and sleep in clinical and non-clinical populations. Data were pooled using a random-effects model. The main outcome was change in the severity of depressive symptoms after NINCEN treatment. A total of 58 studies on NINCEN were included in the meta-analysis. Active tDCS showed a significant effect on depressive symptoms (Hedges' g = 0.544), anxiety (Hedges' g = 0.667) and response rate (odds ratio = 1.9594) compared to sham control. CES also had a significant effect on depression (Hedges' g = 0.654) and anxiety (Hedges' g = 0.711). For all types of NINCEN, active stimulation was significantly effective on depression, anxiety, sleep efficiency, sleep latency, total sleep time, etc. Our results showed that tDCS has significant effects on both depression and anxiety and that these effects are robust for different populations and treatment parameters. The rational expectation of the tDCS effect is 'response' rather than 'remission'. CES also is effective for depression and anxiety, especially in patients with disorders of low severity.

Vagus nerve stimulation (VNS) is reemerging as an exciting form of brain stimulation, due in part to the development of its noninvasive counterpart transcutaneous auricular VNS. As the field grows, it is important to understand where VNS emerged from, including its history and the studies that were conducted over the past four decades. Here, we offer a comprehensive review of the history of VNS in the treatment of major depression.

Using PubMed, we reviewed the history of VNS and aggregated the literature into a narrative review of four key VNS epochs: 1) early invention and development of VNS, 2) path to Food and Drug Administration (FDA) approval for depression, 3) refinement of VNS treatment parameters, and 4) neuroimaging of VNS.

VNS was described in the literature in the early 1900s; however, gained traction in the 1980s as Zabara and colleagues developed an implantable neurocybernetic prosthesis to treat epilepsy. As epilepsy trials proceed in the 1990s, promising mood effects emerged and were studied, ultimately leading to the approval of VNS for depression in 2005. Since then, there have been advances in understanding the mechanism of action. Imaging techniques like functional magnetic resonance imaging and positron emission tomography further aid in understanding direct brain effects of VNS.

The mood effects of VNS were discovered from clinical trials investigating the use of VNS for reducing seizures in epileptic patients. Since then, VNS has gone on to be FDA approved for depression. The field of VNS is growing, and as noninvasive VNS quickly advances, it is important to consider a historical perspective to develop future brain stimulation therapies.

Major depressive disorder (MDD) is one of the most common mental illnesses. This study aims to investigate the effectiveness of transcutaneous auricular vagus nerve stimulation (taVNS) compared with the effectiveness of citalopram, a commonly used antidepressant, in patients with depression.

A total of 107 male and female patients with MDD (55 in the taVNS group and 52 in the citalopram group) were enrolled in a prospective 12-week, single-blind, comparative effectiveness trial. Participants were recruited from the outpatient departments of three hospitals in China. Participants were randomly assigned to either taVNS treatment (eight weeks, twice per day, with an additional four-week follow-up) or citalopram treatment (12 weeks, 40 mg/d). The primary outcome was the 17-item Hamilton Depression Rating Scale (HAM-D₁₇) measured every two weeks by trained interviewers blinded to the treatment assignment. The secondary end points included the 14-item Hamilton Anxiety Scale and peripheral blood biochemical indexes.

The HAM-D₁₇ scores were reduced in both treatment groups; however, there was no significant group-by-time interaction (95% CI: -0.07 to 0.15, p = 0.79). Nevertheless, we found that taVNS produced a significantly higher remission rate at week four and week six than citalopram. Both treatments were associated with significant changes in the peripheral blood levels of 5-hydroxytryptamine, dopamine, γ-aminobutyric acid, and noradrenaline, but there was no significant difference between the two groups.

taVNS resulted in symptom improvement similar to that of citalopram; thus, taVNS should be considered as a therapeutic option in the multidisciplinary management of MDD. Nevertheless, owing to the design of this study, it cannot be ruled out that the reduction in depression severity in both treatment groups could be a placebo effect.

Neuropsychiatric symptoms are prevalent in neurologic practice, but their complexity makes them challenging to manage. Many cognitive, affective, behavioral, and perceptual symptoms span multiple neurologic diagnoses-and there is prominent variability in neuropsychiatric symptom burden for a given condition. There is also a relative lack of robust controlled clinical trial evidence and expert consensus recommendations for a range of neuropsychiatric symptom presentations. Thus, the categorical approach (e.g., a discrete diagnosis equals a specific set of medication interventions) used in many other medical conditions can sometimes have limited utility in commonly encountered neuropsychiatric clinical scenarios. In this review, we explore medication management for a range of neuropsychiatric symptoms using a dimensional transdiagnostic approach applied to the neurological patient. This approach allows the clinician to think beyond the boundaries of a discrete diagnosis and treat specific symptom domains (e.g., apathy, impulsivity). Pharmacologic considerations, including mechanisms of action and their application to various neurotransmitter systems and brain networks, are discussed, as well as general recommendations to optimize medication adherence and rapport with the patient. The dimensional, transdiagnostic approach to pharmacological management of patients with neurological conditions will help the clinician treat neuropsychiatric symptoms safely, effectively, and confidently.

Conventional monoamine-based pharmacotherapy, considered the first-line treatment for major depressive disorder (MDD), has several challenges, including high rates of non-response. To address these challenges, preclinical and clinical studies have sought to characterize antidepressant response through monoamine-independent mechanisms. One striking example is glutamate, the brain's foremost excitatory neurotransmitter: since the 1990s, studies have consistently reported altered levels of glutamate in MDD, as well as antidepressant effects following molecular targeting of glutamatergic receptors. Therapeutically, this has led to advances in the discovery, testing, and clinical application of a wide array of glutamatergic agents, particularly ketamine. Notably, ketamine has been demonstrated to rapidly improve mood symptoms, unlike monoamine-based interventions, and the neurobiological basis behind this rapid antidepressant response is under active investigation. Advances in brain imaging techniques, including functional magnetic resonance imaging, magnetic resonance spectroscopy, and positron emission tomography, enable the identification of the brain network-based characteristics distinguishing rapid glutamatergic modulation from the effect of slow-acting conventional monoamine-based pharmacology. Here, we review brain imaging studies that examine brain connectivity features associated with rapid antidepressant response in MDD patients treated with glutamatergic pharmacotherapies in contrast with patients treated with slow-acting monoamine-based treatments. Trends in recent brain imaging literature suggest that the activity of brain regions is organized into coherent functionally distinct networks, termed intrinsic connectivity networks (ICNs). We provide an overview of major ICNs implicated in depression and explore how treatment response following glutamatergic modulation alters functional connectivity of limbic, cognitive, and executive nodes within ICNs, with well-characterized anti-anhedonic effects and the enhancement of "top-down" executive control. Alterations within and between the core ICNs could potentially exert downstream effects on the nodes within other brain networks of relevance to MDD that are structurally and functionally interconnected through glutamatergic synapses. Understanding similarities and differences in brain ICNs features underlying treatment response will positively impact the trajectory and outcomes for adults suffering from MDD and will facilitate the development of biomarkers to enable glutamate-based precision therapeutics.

The vagus nerve provides motor, sensory, and autonomic innervation of multiple organs, and electrical vagus nerve stimulation (VNS) provides an adjunctive treatment option for e.g. medication-refractory epilepsy and treatment-resistant depression. The mechanisms of action for VNS are not known, and high-resolution anatomical mapping of the human vagus nerve is needed to better understand its functional organization. Electron microscopy (EM) is required for the detection of both myelinated and unmyelinated axons, but access to well-preserved human vagus nerves for ultrastructural studies is sparse. Intact human vagus nerve samples were procured intra-operatively from deceased organ donors, and tissues were immediately immersion fixed and processed for EM. Ultrastructural studies of cervical and sub-diaphragmatic vagus nerve segments showed excellent preservation of the lamellated wall of myelin sheaths, and the axolemma of myelinated and unmyelinated fibers were intact. Microtubules, neurofilaments, and mitochondria were readily identified in the axoplasm, and the ultrastructural integrity of Schwann cell nuclei, Remak bundles, and basal lamina was also well preserved. Digital segmentation of myelinated and unmyelinated axons allowed for determination of fiber size and myelination. We propose a novel source of human vagus nerve tissues for detailed ultrastructural studies and mapping to support efforts to refine neuromodulation strategies, including VNS.

Background: Extensive research has reported that electroconvulsive therapy (ECT) can be highly effective in approximately 80% of patients suffering from depression. Its clinical use is mainly limited by historical objections and the concern about unwanted adverse effects (AEs), including serious and potentially life-threatening adverse events (pLTAEs), induced either by ECT or by anesthesia. Objective risk estimation is, therefore, a decisive factor in determining an indication for ECT. Methods: This paper presents a retrospective analysis of 3-year safety protocols and patient files of 157 patients who received a total of 3,106 ECT applications in a psychiatric inpatient setting at a psychiatric community hospital. This patient group comprises 5.3% of inpatients admitted with comparable diagnoses. Adverse events were analyzed from standardized safety protocols and patient files with a focus on pLTAEs. Results: Adverse events were reported for 30 (19.1%) of the 157 participants during 39 (6.1%) of 641 hospital stays. Serious pLTAEs occurred during three electroconvulsive stimulations in three patients, who needed action through the administration of medication or mechanical respiration. No patient suffered permanent damage to health, and no patient died. The incidence of these and other AEs was independent of sex, age, and diagnosis of patients, and anesthesia medication. Minor AEs occurred more often with higher stimulus doses and an increasing number of treatments. Conclusion: The low incidence rate of 0.097% of serious pLTAEs that require medical action may allow the conclusion that ECT is a rather safe treatment when performed in a controlled setting. The beneficial risk profile of ECT performed in the standard care of psychiatric hospitals suggests a more generous indication of this treatment method. We recommend that ECT facilities collect individual safety data to allow a reliable judgment of their institutional ECT risk profile.