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This PrimeView highlights the utility of designer receptors exclusively activated by designer drugs (DREADDs) in neuroscience to study neuronal activity and signalling in cells, rodents and non-human primates.

Transcranial low-intensity ultrasound is a promising neuromodulation modality, with the advantages of noninvasiveness, deep penetration, and high spatiotemporal accuracy. However, the underlying biological mechanism of ultrasonic neuromodulation remains unclear, hindering the development of efficacious treatments. Here, the well-known Piezo1 was studied through a conditional knockout mouse model as a major mediator for ultrasound neuromodulation ex vivo and in vivo. We showed that Piezo1 knockout (P1KO) in the right motor cortex of mice significantly reduced ultrasound-induced neuronal calcium responses, limb movement, and muscle electromyogram (EMG) responses. We also detected higher Piezo1 expression in the central amygdala (CEA), which was found to be more sensitive to ultrasound stimulation than the cortex was. Knocking out the Piezo1 in CEA neurons showed a significant reduction of response under ultrasound stimulation, while knocking out astrocytic Piezo1 showed no-obvious changes in neuronal responses. Additionally, we excluded an auditory confound by monitoring auditory cortical activation and using smooth waveform ultrasound with randomized parameters to stimulate P1KO ipsilateral and contralateral regions of the same brain and recording evoked movement in the corresponding limb. Thus, we demonstrate that Piezo1 is functionally expressed in different brain regions and that it is an important mediator of ultrasound neuromodulation in the brain, laying the ground for further mechanistic studies of ultrasound.

Purpose of Review The number of applications for peripheral nerve stimulation (PNS) in the pain management field is ever-growing. With the increasing number of clinical applications for peripheral nerve stimulation, the purpose of this article is to review the mechanism of action surrounding PNS, the recent literature from January 2018 to January 2021, and pertinent clinical outcomes. Recent Findings The authors searched articles identified from PubMed (January 2018–January 2021), Cochrane Central Register of Controlled Trials databases (January 2018–January 2021), and Scopus (January 2018–January 2021) databases, and manually searched references of identified publications. Broad MeSH terms and Boolean operators were queried in each search, including the following terms and their respective synonyms: peripheral nerve stimulation, mechanism of action, biochemical pathway, and pain pathway. 15 consensus articles were selected for in-depth review and inclusion for qualitative analysis. Summary PNS may activate and modulate higher central nervous system (CNS) centers, including the dorsal lateral prefrontal cortex, somatosensory cortex, anterior cingulate cortex, and parahippocampal areas. Neuromodulatory effects from PNS may also extend into the spinal columns. Also, PNS may lead to changes in endogenous neurotransmitters and affect the plasticity of NMDA pathways.

Purpose of Review Neuromodulation techniques currently available for headache management are reviewed in this article, with a focus on recent advances in non-invasive devices for migraine and trigeminal autonomic cephalalgias. Recent Findings The currently available FDA-cleared non-invasive devices for migraine include transcutaneous supraorbital and supratrochlear nerve stimulation, single-pulse transcranial magnetic stimulation (sTMS), external concurrent occipital and trigeminal neurostimulation (eCOT-NS), remote electrical neuromodulation (REN), and non-invasive vagal nerve stimulation (nVNS) with indications for migraine and trigeminal autonomic cephalalgias. Emerging non-invasive techniques being explored for use in migraine include transcranial direct current stimulation (tDCS), kinetic oscillation stimulation (KOS), and auricular transcutaneous vagal nerve stimulation (at-VNS). In addition to primary headache, non-invasive neuromodulation is being investigated for comorbid conditions such as depression. Summary Non-invasive neuromodulation devices remain a safe, well-tolerated, and effective therapy for patients with primarily migraine and trigeminal autonomic cephalalgias. Ongoing research is needed to determine efficacy in other headache disorders and comorbid conditions.

Abstract The cerebellum is involved in multiple closed-loops circuitry which connect the cerebellar modules with the motor cortex, prefrontal, temporal, and parietal cortical areas, and contribute to motor control, cognitive processes, emotional processing, and behavior. Among them, the cerebello-thalamo-cortical pathway represents the anatomical substratum of cerebellum-motor cortex inhibition (CBI). However, the cerebellum is also connected with basal ganglia by disynaptic pathways, and cerebellar involvement in disorders commonly associated with basal ganglia dysfunction (e.g., Parkinson’s disease and dystonia) has been suggested. Lately, cerebellar activity has been targeted by non-invasive brain stimulation (NIBS) techniques including transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) to indirectly affect and tune dysfunctional circuitry in the brain. Although the results are promising, several questions remain still unsolved. Here, a panel of experts from different specialties (neurophysiology, neurology, neurosurgery, neuropsychology) reviews the current results on cerebellar NIBS with the aim to derive the future steps and directions needed. We discuss the effects of TMS in the field of cerebellar neurophysiology, the potentials of cerebellar tDCS, the role of animal models in cerebellar NIBS applications, and the possible application of cerebellar NIBS in motor learning, stroke recovery, speech and language functions, neuropsychiatric and movement disorders.

Purpose of Review Neuromodulation devices have become an attractive alternative to traditional pharmacotherapy for migraine, especially for patients intolerant to medication or who prefer non-pharmacological options. In the past decades, many studies demonstrated the efficacy of neuromodulation devices in patients with episodic migraine (EM). However, the benefit of these devices on chronic migraine (CM), which is typically more debilitating and refractory than EM, remains not well studied. Recent Findings We reviewed the literature within the last five years on using FDA-cleared and investigational devices for CM. There were eight randomized controlled trials and 15 open-label observational studies on ten neuromodulation devices. Summary Neuromodulation is promising for use in CM, although efficacy varies among devices or individuals. Noninvasive devices are usually considered safe with minimal adverse events. However, stimulation protocol and methodology differ between studies. More well-designed studies adhering to the guideline may facilitate FDA clearance and better insurance coverage.

Purpose of Review Low back pain (LBP) is a prevalent condition that is associated with diminished physical function, poor mental health outcomes, and reduced quality of life. Peripheral nerve stimulation (PNS) is an emerging modality that has been utilized to treat LBP. The primary objective of this systematic review is to appraise the level of evidence on the efficacy of PNS for treatment of LBP. Recent Findings Twenty-nine articles were included in this systematic review, consisting of 828 total participants utilizing PNS as the primary modality for LBP and 173 participants using PNS as salvage or adjunctive therapy for LBP after SCS placement. Different modalities of PNS therapy were reported across studies, including conventional PNS systems stimulating the lumbar medial branch nerves, peripheral nerve field stimulation (PNFS), and restorative neuromuscular stimulation of the multifidus muscles. All studies consistently reported positive modest to moderate improvement in pain intensity with PNS therapy when comparing baseline pain intensity to each study’s respective primary follow-up period. There was a very low GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) quality of evidence supporting this finding. Inconsistency was present in some comparative studies that demonstrated no difference between PNS therapy versus control cohorts (sham or SCS therapy alone), which therefore highlighted the potential for placebo effect. Summary This systematic review highlights that PNS, PNFS, and neuromuscular stimulation may provide modest to moderate pain relief in patients with LBP, although evidence is currently limited due to risk of bias, clinical and methodological heterogeneity, and inconsistency in data.

BackgroundDepression is common among elective lumbar spine surgery candidates and is associated with worse postoperative outcomes. Home-based transcranial direct current stimulation (tDCS) has demonstrated safety and feasibility, with evidence of antidepressant effects in remote randomized and open-label studies of major depressive disorder (MDD). Whether this approach can be feasibly and acceptably implemented as a preoperative intervention in lumbar spine surgical populations is unknown.MethodsWe propose a prospective, open-label, single-arm feasibility study evaluating preoperative, home-based tDCS for elective, non-revision lumbar spine surgery candidates with MDD. Adults aged 22–75 years with DSM-5 MDD and at least moderate depressive symptom severity [self-reported Montgomery–Åsberg Depression Rating Scale (MADRS-S) ≥ 20] being evaluated for elective lumbar spine surgery will receive home-based tDCS. Key exclusion criteria include history of seizure disorder, implanted cranial electronic or metallic devices, clinically unstable psychiatric conditions, prior brain stimulation therapy, and use of medications that significantly affect cortical excitability. Pre-surgical treatment follows a standardized cadence (5 sessions/week for 3 weeks, then 3 sessions/week) for a minimum of 4 weeks, continuing until surgery or up to 10 weeks. Feasibility will be assessed using a pre-specified tiered exposure framework based on the number of sessions completed before surgery.Anticipated resultsPrimary outcomes are feasibility and acceptability of preoperative home-based tDCS delivery. The principal exploratory clinical outcome is change in depressive symptom severity measured using MADRS-S. Exploratory perioperative recovery outcomes include spine-related disability, pain intensity, functional status, and opioid utilization. For participants who proceed to surgery, postoperative outcomes will be followed up to 12 months.DiscussionThis pilot study will generate feasibility, acceptability, and preliminary signal data to inform the design of future randomized controlled trials of preoperative neuromodulation in surgical populations.

Purpose of Review Chronic facial pain is considered one of the conditions that affect quality of daily life of patients significantly and makes them seek medical help. Intractable facial pain with failed trials of medical treatment and other pain management therapies presents a challenge for neurologists, pain specialists, and neurosurgeons. We describe the possibility of proposing peripheral nerve stimulation of the supraorbital nerves to treat patients with medically intractable facial pain. Stimulation of the supraorbital nerves is performed using percutaneously inserted electrodes that are positioned in the epi-fascial plane, traversing the course of the supraorbital nerves. The procedure has two phases starting with a trial by temporary electrodes that are inserted under fluoroscopic guidance and are anchored to the skin. This trial usually lasts for a few days to 2 weeks. If successful, we proceed to the insertion of a permanent electrode that is tunneled under the skin behind the ear toward the infraclavicular region in which we make a pocket for the implantable pulse generator. Recent Findings This procedure has been used in multiple patients with promising results which was published in literature. Literature shows that it provides relief of medically intractable pain, without the need for destructive procedures or more central modulation approaches with a preferable safety profile compared to other invasive procedures. Summary Supraorbital nerve stimulation is now considered a valid modality of treatment for patients with medically intractable facial pain and can be offered as a reliable alternative for the patients while discussing the proper plan of management.

Purpose of Review Painful diabetic neuropathy (PDN) is a prevalent and debilitating condition, characterized by severe burning, tingling, and lancinating pain usually located in the distal lower extremities. In addition to manifesting with severe pain, PDN may also be associated with poor quality of life and sleep, mood disorders, burns, falls, and social withdrawal. The authors appraised the current body of literature for evidence on neuromodulation interventions for PDN. Recent Findings In patients with refractory PDN unresponsive to conventional medical management (glucose optimization and oral analgesic medications), there is level I evidence supporting the use of 10-kHz and tonic dorsal column spinal cord stimulation (SCS). Included studies reported significant associations between 10-kHz and tonic dorsal column SCS and superior analgesic outcomes, physical functioning, and patient satisfaction. Current level of evidence remains limited for other modalities of neuromodulation for PDN including burst SCS (level II-3), dorsal root ganglion SCS (level III), and peripheral nerve stimulation (level II-3). Some studies reported improvements in neurological physical examination, sensory testing, and/or reflex testing in patients undergoing 10-kHz SCS for treatment of PDN. Summary In summary, the purpose of this review is to equip provider with important updates on the use of neuromodulation interventions for the treatment of PDN that is refractory to conventional medical therapy, with current level I evidence supporting use of 10-kHz and tonic SCS for PDN.