This study was financially supported by LivaNova, Inc.

The following protocol provides a step-by-step manual for using VNS in the continuous treatment of TRD. The protocol is mainly based on the experiences and recommendations of the authors from different psychiatric centers in Germany. The protocol follows the guidelines of our institution&#39;s human research ethics committee.
1. Pre-operative Examination
NOTE: Before performing pre-operative steps, patients must be evaluated for solid compliance and willingness to attend regular (and likely irregular) control and tuning visitations after the implantation. In particular, aspects of compliance after implantation require careful consideration.
<ol>
	<li>Contraindications
	<ol>
		<li>Before implantation, exclude contraindications for VNS therapy such as acute suicidality, substance addiction, and documented and difficult-to-treat non-compliance or non-adherence during previous psychiatric and/or somatic treatments. 
		NOTE: Bipolar disorders and psychotic depressive symptoms are not contraindications for VNS therapy.</li>
	</ol>
	</li>
	<li>Neurosurgical examination
	<ol>
		<li>After positive psychiatric indication and evaluation, refer the probands to surgical evaluation to determine contraindications from a surgical perspective, then evaluate the eligibility for general anesthesia.</li>
	</ol>
	</li>
</ol>
2. Surgical Procedure
<ol>
	<li>Implantation
	<ol>
		<li>Administer general endo-tracheal anesthesia to the patient using standard techniques. Use propofol (4&#8211;12 mg/kg/h iv) for general anesthesia. Add an analgesic drug (e.g., remifentanyl at 1 &#181;g/kg/min iv) and a muscle relaxant (e.g., rocuronium at 0.6 mg/kg iv).</li>
		<li>Position the patient supine on the operating table. Turn the head slightly to the right. Prepare the left side of the neck for supraclavicular lead implantation and an infraclavicular or axillar approach for the generator.
		<ol>
			<li>Use a specific agent for skin preparation to avoid surgical side infection. Scrub the skin with an aqueous-based iodophor such as povidone-iodine (PVP-I).</li>
			<li>Perform an axillary incision by following a skin line. After hemostasis, bluntly dissect the subcutaneous fat to free the pectoralis major fascia and form a space for the generator.</li>
		</ol>
		</li>
		<li>Make an oblique skin incision of 4 cm approximately halfway between the mastoid and clavicle, with the medial border of the sternocleidomastoid muscle at the center. Then, divide the platysma muscle and dissect the cervical fascia.</li>
		<li>Palpate the carotid artery to safely identify the correct neuro-vascular compartment. After opening the deep layer of the cervical fascia, carefully retract the carotid artery and internal jugular vein. The vagus nerve can be found between and below the vessels. 
		NOTE: At this point, we usually continue the procedure with operating microscopes.</li>
		<li>Dissect the vagus nerve longitudinally for approximately 4&#8211;5 cm, carefully sparing all branches and avoiding damage to the vasa nervorum.
		<ol>
			<li>Bring the lead in place from infra- to supra-clavicular using the tunneller device, enabling implantation.</li>
		</ol>
		</li>
		<li>Carefully wrap the inferior anchor tether of the VNS lead around the caudal aspect of the vagus nerve, then fix both positive and negative contact electrodes at the nerve. Insert the connector pin into the generator infraclavicularly.</li>
		<li>After testing (see below), fix the lead with the tie-downs, facilitating a &#34;spare loop&#34;. This allows the patient to move the head without tethering the probe. Suture the generator to the pectoralis major muscle fascia. 
		NOTE: It is important to place the electrodes inferior to the cardiac branches of the vagus nerve to avoid cardiac side effects.</li>
	</ol>
	</li>
	<li>Intraoperative lead testing 
	NOTE: It is necessary to first perform an intraoperative (lead) test, which should exclude the most common and serious side effects. Most notably, asystole can occur when the VNS is activated intraoperatively.
	<ol>
		<li>In situ testing
		<ol>
			<li>Connect the programming wand of the VNS while maintaining sterility intraoperatively in situ. Perform lead testing with a minimum of 10 seconds of stimulation of 0.5&#8211;1.0 mA and 25 Hz. If no serious cardiac side effects occur, proceed to impedance testing.</li>
		</ol>
		</li>
	</ol>
	</li>
	<li>Intraoperative impedance testing interpretation
	<ol>
		<li>Check the impedance during the in situ testing of the device. Check repeatedly. 
		NOTE: High impedances (&#62;1,700&#8211;2,000 &#937;) indicate poor contact between the helical electrodes and the nerve. During this phase, the anesthesiologist should be prepared for the occurrence of bradycardia or even asystole. Impedance is tested for a maximum of five seconds with an output current of 2.00&#8211;3.00 mA and should be under 100 &#937;.</li>
	</ol>
	</li>
	<li>Fixing the electrodes after implantation
	<ol>
		<li>Use a tunneller to position the stimulator lead by passing it from the subcutaneous thoracic pocket into the cervical incision.</li>
		<li>Tunnel the wire, and finally, secure the loops around the nerve to reduce the probability of dislodging the electrode.</li>
	</ol>
	</li>
	<li>Finishing the operative procedures
	<ol>
		<li>Create a strain relief bend to provide slack during movements of the neck.</li>
		<li>Secure the electrode by tacking nonabsorbable sutures to silicone head holders at the deep cervical fascia and near the sternocleidomastoid muscle.</li>
		<li>Fix the battery to the lead electrode and anchor it with nonabsorbable sutures in the fascia. Close the incisions by standard techniques.</li>
	</ol>
	</li>
</ol>
3. Post-surgical Treatment and Dosing
<ol>
	<li>Discharge
	<ol>
		<li>Discharge the patient one day after surgery, following an X-ray to ensure regular positioning of the device.</li>
	</ol>
	</li>
	<li>VNS dosing
	<ol>
		<li>Commence regular VNS dosing 2 weeks after implantation using the recommended stimulation settings (1.5&#8211;3.0 mA; 500 &#181;s pulse width; 20&#8211;30 Hz; 30 s on, 5 min off), which must be gradually reached with 0.25&#8211;0.5 mA increases per week.</li>
		<li>Start dosing (recommended) at 0.25 mA intervals as needed, and increase up to 2.00&#8211;3.00 mA. Most patients (&#62;90%) will require dosing no higher than 2.00 mA.</li>
	</ol>
	</li>
	<li>Dosing in cases of persisting depressive symptoms
	<ol>
		<li>Set the on/off time to 30 s on/5 min off.</li>
		<li>End dosing when a response to VNS is achieved, after a maximum of 9&#8211;12 months.</li>
	</ol>
	</li>
	<li>Dosing alternatives in cases of non-response or partial response
	<ol>
		<li>In cases of non-response or partial response, as an alternative to increasing the output current (mA), change the signal frequency (Hz) tuning (typically by decreasing from 30 to 20 Hz) or reduce the off time to 3 min.</li>
	</ol>
	</li>
	<li>Dosing in cases of side effects
	<ol>
		<li>If side effects occur (mainly laryngopharyngeal dysfunction such as hoarseness, dyspnea, and coughing), which tend to be transitory and directly associated with stimulation of the inferior (recurrent) laryngeal nerve, reduce the maximum mA tuning (typically no lower than 0.75 mA) and/or change the on/off timing. 
		NOTE: An additional overview of the protocol is provided in Table 2.</li>
	</ol>
	</li>
</ol>

Sebastian Moeller received a research grant from LivaNova, Inc. Christian Heinen received a speaker&#39;s honorarium from LivaNova, Inc. Bettina H. Bewernick received a speaker&#39;s honorarium from LivaNova, Inc. and was member of an adivsory board of LivaNova, Inc. Merve Aydin, Alexandra Philomena Lam, Teja W. Gr&#246;mer, Caroline L&#252;cke, and Alexandra Philipsen have no competing interests. Helge H.O. M&#252;ller served as an advisory board member of LivaNova, Inc. and received speaker&#39;s compensation from LivaNova, Inc.

VNS is a neurostimulation tool for chronic depression and TRD in patients aged 18 years or older who do not respond to other antidepressant treatments. VNS has been approved for use in the European Union and the United States22. VNS has been shown to be effective as an adjunctive treatment in TRD22; moreover, it has antisuicidal effects and improves quality of life22.
In this article, we present a protocol and additional information to help clinicians properly implement VNS in patients with TRD. The treating psychiatrist is responsible for the optimal dosing of the vagus nerve stimulator and for considering all aspects of the therapy, including the safety, tolerability, and efficacy of VNS in patients with TRD.
VNS requires an implantable pulse generator, which is surgically inserted under the skin of the chest, as described in the protocol. The VNS therapy pulse generator for depression treatment is placed subcutaneously in the left chest wall. Standard wound care is recommended during the first week after the procedure34,35. The repeated stimulation of the vagus nerve sends impulses from the peripheral nervous system, where the electrode is placed to the brain. The negative electrode generates action potentials that travel afferently via sensory fibers, while efferently traveling action potentials are mostly blocked by the positive electrode. Unblocked action potentials can cause side effects. A distance of approximately eight millimeters between the negative and positive electrodes is recommended36.
It is suggested not to use the right vagus nerve because of the risk of severe bradycardia and arrhythmias. In contrast, no such side effects have been reported when the left vagus nerve was used; however, several patients have had right-sided implants with good results. Surgical implantation is performed by means of minor surgery (mainly neurosurgical)37,38. The most frequent acute complications of vagus nerve stimulator implantation include temporary salivation, coughing, paralysis of the vocal cords, and lower facial weakness. Bradycardia occurs rarely, and asystole occurs very rarely. The risk for infection at the VNS site can be approximated to be between 1.1 and 3.9%36.
Regarding psychiatric adverse effects, the rate of stimulation-induced switch to mania or hypomania in the VNS trials was low (i.e., &#60;0.01% at one year), and those symptoms diminished after modifying the stimulation parameters29. Side effects are generally fully reversible37,39. Adverse events reported during the first and second years on VNS therapy are summarized in Table 133.
During surgery, the vagus nerve stimulator is regularly switched on to 0.5 mA to check whether the device is working properly and to avoid side effects such as asystole. After functionality has been verified, the device is switched off again. At least two weeks (depending on the potential side effects of tuning the VNS) after the device has been implanted, the vagus nerve stimulator is switched on again. Normal-mode stimulation is applied 24 h per day.
The stimulation amplitude is optimized with respect to the therapeutic effect and/or tolerability. The device is activated telemetrically by a wand connected to a handheld computerized device during psychiatric in-office visits. In general, the dose (i.e., the amplitude) is set to a level that the patient can tolerate (see Table 2). Adjustment of the treatment parameters, including output current, signal frequency, pulse width, signal on time, and signal off time, is non-invasively performed using the external interface. Importantly, the patient can stop the VNS stimulation by placing a magnet over the generator. After the magnet is removed, the generator restarts in normal-mode stimulation. The normal-mode output current can be increased to a therapeutic range as quickly as tolerable. More frequent visits (approximately 1 to 2 visits per week) at the beginning of the stimulation are recommended. Usually, stimulation is increased by 0.25 mA per visit. However, multiple 0.25 mA increases may be made at a single visit to reach the therapeutic range more quickly. Nevertheless, it is essential to ensure patient tolerance before making additional adjustments. The therapeutic range is usually between 1.0 and 2.0 mA. In some patients, it is necessary to use higher output currents to receive additional efficacy. The effect of VNS is based on distinct mechanisms and is related to the anatomy of the vagus nerve.
The vagus nerve has anatomical connections, including those to the nucleus tractus solitaries, locus coeruleus, raphe nuclei, amygdala, hypothalamus, and orbitofrontal cortex40. VNS can increase the metabolic activity in the main serotonin- and noradrenalin-producing nuclei, resulting in augmented neurotransmitter concentrations in the CSF41,42. Thus, the mode of action of VNS works analogously to most antidepressants.
Neuroimaging studies have shown that activity in the thalamus and cortex of depressed patients is changed by VNS therapy. Changed activity in the orbital and ventromedial prefrontal cortices has also been recorded43,44. Several imaging studies have suggested that VNS therapy is associated with decreased metabolic activity in the right hemisphere and increased metabolic activity in the left hemisphere, thus attenuating the hemispheric imbalance in depressive patients40,45,46,47. Vagal afferents express IL-1&#946; receptors that convey inflammatory signals to the hypothalamus, leading to a release of hypophysis adreno-corticotrophin hormones. This pathway also stimulates glucocorticoid release by the adrenal glands via a decrease in peripheral inflammation processes. In the vaso-vagal-inflammatory reflex loop, vagal afferents activate vagal efferents, which release acetylcholine (ACh) at the distal end of the vagus nerve, inhibiting the release of pro-inflammatory cytokines such as TNF&#945;48. In summary, the short- and medium-term antidepressant effects of VNS may be related to the increased availability of serotonin and noradrenalin, similar to the mechanism of antidepressive medication49. Long-term VNS has different effects than short-term VNS. The long-term antidepressant effects of VNS may be related to mitigation of the interhemispheric imbalance associated with depression (i.e., right-sided inhibition and left-sided activation)45. Moreover, VNS may reduce inflammation that contributes to depression50, though not all the mechanisms of action of VNS are completely understood yet. The effects are thought to be gradual and acting with latency; consequently, VNS is usually not indicated for the relief of acute depressive symptoms32.
Up to 60% of patients with TRD show reduction in their depressive symptoms22,23,49,51,52. Long-term follow-ups also indicate fewer suicide attempts and lower levels of suicidal ideations and thoughts. Also documented are fewer hospitalizations in patients treated with VNS in addition to pharmacotherapy compared to patients with the same level of depression symptom severity who were only taking medications22,29,53.
Antidepressant and relapse prevention effects can even be observed after a long-term follow-up of 5 years22,23. Recently, in a large sample of patients with TRD, Aaronson and colleagues have shown significantly higher 5 year cumulative response rates and significantly higher remission rates in patients treated with VNS compared to patients who were only TAU22. The best-responding group consisted of patients with a history of good responses to ECT before receiving VNS22. The number needed to treat (NNT) for VNS ranges from 4 to 10. Given the high level of treatment resistance in this population of patients, the NNT remains clinically significant32.
Therefore, the long-term results of VNS are distinctly promising, suggesting that VNS might be particularly useful for patients with chronic depression for whom treatment resistance is a challenge20. Thus, after approximately 3 to 6 months of VNS therapy, treatment results can be expected.
The common definition of TRD is treatment failure of at least two antidepressants17,18,19. However, most patients with TRD who are treated with VNS have undergone more than two treatment trials of antidepressant medication before device implantation22. For example, in the longitudinal study by Aaranson et al. (2017)22, patients who were treated with VNS failed an average of 8 treatments. The findings suggest that VNS might also be particularly useful in much heavier states of TRD. Antidepressive VNS therapy is mostly based on modifications to the output current and signal frequency. Changing the settings of on/off time parameters usually leads to a reduction in side effects.
Similar to TRD, VNS has been evaluated for its possible use for other psychiatric diseases, such as bipolar major depressive disorder, Alzheimer&#39;s disease, schizophrenia, obsessive compulsive disorder, panic disorder, post-traumatic stress disorder, treatment-resistant rapid-cycling bipolar disorder, fibromyalgia, and Prader-Willi syndrome54. The efficacy of VNS for affective disorders has been clearly demonstrated20,22,23,54; however, for other psychiatric conditions, there have not yet been reports of either no effect or only preliminary data on efficacy54. Thus, no final conclusion about the efficacy of VNS in these psychiatric indications can be made currently. However, there may be potential for future therapeutic approaches54. Moreover, VNS is not only in the psychiatric armamentarium, as it is a common treatment method for treatment-refractory epilepsy55. In epilepsy patients, the stimulation parameters of the vagus nerve stimulator are similar to the settings in patients with TRD.
Initially, mood improvement in epilepsy patients with VNS led to the conclusion that VNS might also be useful in affective disorders32. VNS has also been assessed for the treatment of tinnitus56, inflammatory bowel diseases57, heart failure58, rheumatoid arthritis59, and many other conditions. Although preliminary data are promising, future evaluations are necessary for understanding the possible mechanisms and therapeutic potential in various clinical conditions and diseases.
Nevertheless, approximately one-third of patients with TRD do not adequately respond to VNS23. Moreover, the abovementioned side effects of VNS can limit its therapeutic action32. However, in cases of insufficient response or intolerable side effects, clinicians can modify the setup of the vagus nerve stimulator. Fine-tuning of the vagus nerve stimulator offers various possibilities for generating desirable responses to different medical conditions. Future perspectives to improve VNS efficacy and reduce side effects, such as including increasing the battery life, shortening the response time, transcutaneous stimulation, and identification of prognostic factors for valuable responses, should be further investigated.

Major depressive disease (MDD) is a frequently recurring or chronic psychiatric disease with high prevalence1,2 and is characterized by alterations in affect and mood. Of utmost importance is the association of MDD with high rates of suicidality and mortality3,4,5,6. Pharmacological treatment strategies include monoamine neurotransmitter reuptake inhibition [e.g., treatment with selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs)], lithium augmentation, or atypical antipsychotic augmentation strategies7,8. In addition to pharmacological treatment, psychotherapeutic approaches and supplemental noninvasive strategies are used to treat MDD8,9,10. Alternative strategies such as light-based therapy, exercise, acupuncture, and yoga have also been successfully used in treatment of MDD8,9,11,12; although, these are not approved methods. However, up to 30&#8211;50% of all patients with MDD do not achieve remission with currently available treatment options13. This subtype of MDD is called therapy-resistant depression (TRD)14,15,16. TRD is defined as the failure of two successive trials of antidepressant treatment administered at an appropriate dose and for a sufficient duration17,18,19.
The high rate of TRD poses a challenge in the overall management of patients with MDD13; thus, innovative add-on therapies for TRD are urgently needed. Neurostimulation tools such as electroconvulsive therapy (ECT), transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), deep brain stimulation (DBS), magnetic seizure therapy (MST), cranial electrotherapy (CES), and vagus nerve stimulation (VNS) are clinically available and promising tools in the psychiatric armamentarium for patients with TRD20. VNS is particularly useful in TRD and exhibits antidepressant and mood stabilizing effects. During long-term treatment (&#62;12 months), up to two-thirds of patients have responded favorably21,22,23. The American Psychiatric Association recommends the use of VNS as a treatment option after four treatment failures22.
In this study, we outline a protocol for clinicians, describing how to use and set up the VNS instrument for the continuous treatment of TRD. Additional notes on hardware components are included to help readers choose the product that best suits a patient&#39;s needs.

<table><tbody><tr><td>VNS Therapy AspireSR Model 106 Generator</td><td>LivaNova Inc.</td><td>Primary DI Number: 05425025750061</td><td>Implantable Pulse Generator</td></tr><tr><td>VNS Therapy Programming Wand Model 2000</td><td>LivaNova Inc.</td><td>Primary DI Number: 05425025750177</td><td>Programming Wand</td></tr><tr><td>VNS Therapy Demipulse Model 103 Generator</td><td>LivaNova Inc.</td><td>Primary DI Number: 05425025750030</td><td>Implantable Pulse Generator</td></tr><tr><td>Cyberonics Tunneler Model 402&amp;nbsp;</td><td>LivaNova Inc.</td><td>Primary DI Number: 05425025750238</td><td>Tunneler</td></tr><tr><td>VNS Therapy Model 502 Accessory Pack</td><td>LivaNova Inc.</td><td>Primary DI Number: 05425025750245</td><td>VNS Therapy Accessory Pack&amp;nbsp;</td></tr><tr><td>VNS Therapy Model 302 Lead</td><td>LivaNova Inc.</td><td>Primary DI Number: 05425025750108</td><td>Implantable Bipolar Lead</td></tr><tr><td>Propofol</td><td>Merck</td><td>CAS Number: 2078-54-8</td><td>[(CH&lt;sub&gt;3&lt;/sub&gt;)&lt;sub&gt;2&lt;/sub&gt;CH]&lt;sub&gt;2&lt;/sub&gt;C&lt;sub&gt;6&lt;/sub&gt;H&lt;sub&gt;3&lt;/sub&gt;OH</td></tr><tr><td>Remifentanyl</td><td>Merck</td><td>CAS Number: 132539-07-2</td><td>C20H28N2O5 &amp;middot; HCl</td></tr><tr><td>Rocoronium bromide</td><td>Merck</td><td>CAS Number: 119302-91-9</td><td>C&lt;sub&gt;32&lt;/sub&gt;H&lt;sub&gt;53&lt;/sub&gt;BrN&lt;sub&gt;2&lt;/sub&gt;O&lt;sub&gt;4&lt;/sub&gt;</td></tr></tbody></table>

vagus nerve stimulation as an adjunctive neurostimulation tool in treatment-resistant depression

Vagus nerve stimulation (VNS) is an approved neurostimulation therapy. The purpose of the method is to treat patients with therapy-resistant depression (TRD). VNS exhibits antidepressive and stabilizing effects. This method is particularly useful as a long-term treatment, in which up to two-thirds of patients respond. The vagus nerve stimulator is positioned on the left vagus nerve during a surgical procedure and is activated telemetrically by a wand connected to a handheld computerized device. The treating physician can perform various adjustments of the vagus nerve stimulator during in-office visits (e.g., by modifying stimulation intensity or stimulation frequency) to achieve maximum therapeutic effects with low side effects. Set-up of the device usually takes several months. Typical side effects include wound infection, temporary salivation, coughing, paralysis of the vocal cords, bradycardia, or even asystole. The patient can stop the VNS by placing a magnet over the generator. The current protocol describes delivery of the specific stimulation tool and methods for adjusting the tuning parameters to achieve the best remission rates in patients with TRD.

The outcome measurements of VNS effectiveness usually include a decline in depressive symptoms, measured by observer-rated scales and/or self-rated assessment instruments [e.g., the Hamilton Depression Rating Scale, the Montgomery-&#197;sberg Depression Rating Scale, or the Beck Depression Inventory (BDI)]6.
The first trial that systematically examined VNS in patients with major depressive episodes was conducted by Rush et al.24, who used VNS as an augmentation strategy with a 10 week combination VNS treatment alongside patients&#39; normal medication. The average baseline 28 item Hamilton Depression Rating Scale score was 38.0. Forty percent of patients responded favorably, while 17% showed remission24. Sackheim et al.25 combined the initial study cohort with an additional 30 patients who were monitored for twelve weeks. The authors observed a response rate of 30% and a remission rate of 15%. Schlaepfer and colleagues examined the antidepressive effects of VNS in an open, uncontrolled European multicenter study. Response and remission rates were 37% and 17%, respectively26. Notably, in long-term follow-ups, an increase in both response and remission rates could be observed (Figure 1)23,27,28. In a sham-controlled, multicenter study, no significant difference between active and sham groups was observed29. However, the authors only performed ten weeks of active or sham VNS. Again, follow-up observations with higher remission and response rates suggest that VNS treatment has a beneficial effect over time30,31. The TRD registry followed the clinical course and outcome for TRD patients treated with and without adjunctive VNS22. In the observational study of unipolar or bipolar depression, the outcomes of 500 patients with VNS and 300 with treatment as usual (TAU) patients were compared. The subjects were permitted to choose between VNS and TAU at the time of screening. Registry results indicated that the adjunctive VNS group had better clinical outcomes than the TAU group. The 5 year cumulative response rate (67.6% compared to 40.9%) and remission rate (43.3% compared to 25.7%) were significantly higher in the VNS + TAU group than in the TAU-only group (Figure 2 and Figure 3)22. Moreover, the findings in the literature suggest decreased suicide attempts, reduced levels of suicidal ideation, and fewer hospitalizations due to depression in patients with VNS than in those with the same severity of disease but who are taking medications22,32.
In the following, we present three clinical cases to highlight the potential benefits as well as possible difficulties of providing VNS therapy to patients with TRD.
A 53 year-old woman with a 20 year history of TRD was referred to our office. Her treatment included ineffective trials of tricyclic antidepressants, serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and adjunctive treatments with antipsychotic agents and anxiolytics. She had also received a series of ECT. Although suicidality initially remitted, she remained depressed and required further ECT. ECT was continued, but her improved mood was unstable and did not result in a meaningful decrease in antidepressant medications. Her psychopathological characteristics included feelings of worthlessness, low self-esteem, and a daily lack of energy and motivation. The patient&#39;s long course of treatment-resistant major depressive episodes made her a candidate for VNS therapy. The patient underwent VNS therapy device implantation by a neurosurgeon during a 1.5 h procedure. The VNS was checked for functionality upon insertion. Stimulation was reactivated during an office visit within several weeks. At that time, the patient additionally received sertraline (200 mg/day). During the first stimulation visit, the vagus nerve stimulator was adjusted to 1.00 mA, 25 Hz, and 30 s on/5 min off. During the second office visit, the dosing was increased to 1.50 mA, and multiple 0.25 mA increases were performed. The patient did not report any side effects. Within three months, the current had been titrated up to an output of 1.5 mA, with a standard signal frequency of 30 Hz, pulse width of 500 &#181;s, and signal time of 30 s on/5 min off. However, at that time, the patient experienced only minor improvements in mood and quality of life. The BDI showed a slight reduction of depression. The current output was set at 2.25 mA, and during the following two weeks, an improvement was observed. We then added lithium at a dosage of 900 mg/day to her medications and decreased the VNS off time to 2 min. During the next three months, the patient described an improvement of her mood and energy levels. Her BDI sum score showed a remission (i.e., the patient no longer met the criteria for major depression). Fortunately, she did not experience adverse events or side effects. Her medication was reduced to sertraline (100 mg/day). Perhaps the most significant improvement since the device adjustment was the reduction in medication use. The patient is now maintained on antidepressant therapy with sertraline and lithium. The device settings have not been changed again. After successful adjustment of the vagus nerve stimulator, the patient now participates every six months for control visits.
A 58-year-old chronically depressed patient was referred to our office. She had experienced ongoing depressive episodes since the age of 15, requiring several courses of ECT. With each relapse of severe depression, she presented in a characteristic way, namely with periods of emotional non-response, unresponsiveness, an expressionless face, and staring eyes. When depressed, she would not care for herself, resulting in poor oral intake and rapid weight loss. She also socially disengaged from people and refused to take medication. She received several sessions of emergency ECT and showed a good response. During the last ECT session, the patient again showed marked improvement. Her BDI score was 46 before ECT and 18 afterwards. However, she refused to undergo maintenance ECT. She reported experiencing severe headache and memory loss after ECT. The patient&#39;s long and excellent response to ECT in terms of antidepressant effects made her a candidate for VNS therapy22. The patient underwent VNS therapy device implantation. The VNS was checked for functionality when it was inserted. Stimulation was reactivated during an office visit later that month. At the time of VNS initiation, the patient received citalopram (30 mg/day) and mirtazapine (60 mg/day). During this visit, the vagus nerve stimulator was adjusted to 1.00 mA. Within five months, the current had been titrated up to an output of 2 mA, standard signal frequency of 25 Hz, pulse width of 250 &#181;s, and signal time of 30 s on/5 min off. Six months after implantation of the VNS device, the patient was taking several antidepressants, including lithium and citalopram. The device was implanted 13 years ago. Since then, the patient&#39;s depressive symptoms have remained stable. She has reported subjective well-being and no side effects of VNS.
A 62-year-old man was referred to our office with a 40 year history of TRD. Due to the severity of the disease, he had been a patient in psychiatric hospitals and had made several severe suicide attempts. His depressive symptoms included melancholic mood, anhedonia, loss of appetite with consecutive weight loss, decreased energy, hopelessness, nihilistic delusion, and suicidal intentions. Somatic comorbidities consisted of controlled hypothyroidism and controlled epilepsy. The first seizure occurred after a closed head trauma when he was 49 years old. The patient had on average 3 seizures per year (tonic-clonic) between his 49th and 53th birthdays. Over the previous years, the patient had received treatments with different combinations of 2&#8211;5 antidepressants (e.g., citalopram, paroxetine, fluvoxamine, imipramine, amitriptyline, and venlafaxine extended release) without complete remittance. Remittance also failed with antidepressant augmentation trials with lithium, aripiprazole, and olanzapine. He also had 19 courses of ECT (bilateral and unilateral) during the period from 1980 to 2005. The ECT effect was mostly short-lasting, as no sustained or long-term benefit from ECT was observed. He then underwent implantation with a VNS device for TRD in 2010. Previously, his prescribed medications (i.e., duloxetine, quetiapine, lithium, and topiramate) were unchanged. The vagus nerve stimulator was checked for functionality at the time of insertion. Stimulation was reactivated during an office visit later that month. During that visit, the vagus nerve stimulator was adjusted to 1.75 mA. At the second in-office visit, dosing was increased to 2.00 mA. The patient reported no side effects. Within 14 weeks, the current had been titrated up to 2.5 mA with a standard signal frequency of 30 Hz, pulse width of 500 &#181;s, and signal time of 30 s on/5 min off. However, during an in-office visit, the patient reported an unusual globus sensation and hoarseness. Depressive symptoms markedly improved. The BDI score before implantation was 46, but only 15 at 14 weeks post-implantation. Because of the remarkable antidepressant effect of VNS in this patient, we only made minor changes to the VNS setup. Moreover, the patient did not have any seizures after implantation of the VNS device. During the following three visits, which occurred over 2 weeks, we adapted the output to 2 mA and signal frequency to 40 Hz and adopted an extraordinary off time of 8 min. With this setup, mild side effects occurred, but the antidepressant effect persisted. In accordance with the patient&#39;s wishes, we did not change the device settings.
These three patients, as well as our other patients receiving VNS, were prepared as required so that individual needs were addressed within the first six months after device implantation. After the first 6 months, follow-up appointments should be scheduled after 9, 12, and 24 months, or when an adjustment of dosing or device maintenance is necessary. The setup must be adapted to the patient&#39;s psychopathology, compatibility, psychological examination, somatic status (including history of side effects), laboratory, ECG, and (if necessary) imaging results.
<img alt="Figure 1" class="xfigimg" src="/files/ftp_upload/58264/58264fig1.jpg" /> 
Figure 1: Development of depression severity (p &#60; 0.001) under VNS treatment compared to baseline (before VNS stimulation). The depression severity is coded as: 0 = no depression, 1 = mild depression, 2 = moderate depression, and 3 = severe depression. Treatment varied between 3 and 200 months (mean 104.9 months). This figure has been modified from Muller et al. (2017)23 with permission. The sample size was 18 (6 female, 12 male; mean age 54). Hamilton Depression Rating Scale raw scores were translated into an ordinal classification of depression severity. Differences in depression severity (pre- and post-treatment) were compared using a paired sample t-test. Pearson&#39;s product-moment correlation coefficient was computed to assess the relationship between VNS stimulation parameters and depression severity. <a href="https://www.jove.com/files/ftp_upload/58264/58264fig1large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 2" class="xfigimg" src="/files/ftp_upload/58264/58264fig2.jpg" /> 
Figure 2: First-time response rate after 5 years based on the Montgomery-&#197;sberg Depression Rating Scale (MADRS). This figure has been modified with permission from Aaronson et al.22. A total of 765 patients (489 in the VNS group and 276 in the TAU group) was included in the efficacy analyses. <a href="https://www.jove.com/files/ftp_upload/58264/58264fig2large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 3" class="xfigimg" src="/files/ftp_upload/58264/58264fig3.jpg" /> 
Figure 3: First-time remission rate based on the MADRS (&#8804;9). This figure has been modified with permission22. A total of 765 patients (489 in the VNS group and 276 in the TAU group) was included in the efficacy analyses. <a href="https://www.jove.com/files/ftp_upload/58264/58264fig3large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>Adverse event, n (%)</td>
			<td>Year 1 (N = 700)</td>
			<td>Year 2 (N = 344)</td>
		</tr>
		<tr>
			<td>Voice alteration</td>
			<td>485 (69.29)</td>
			<td>179 (52.03)</td>
		</tr>
		<tr>
			<td>Dyspnea</td>
			<td>211 (30.14)</td>
			<td>71 (20.64)</td>
		</tr>
		<tr>
			<td>Pain</td>
			<td>199 (28.43)</td>
			<td>41 (11.92)</td>
		</tr>
		<tr>
			<td>Increased cough</td>
			<td>185 (26.43)</td>
			<td>47 (13.66)</td>
		</tr>
		<tr>
			<td>Incision pain</td>
			<td>181 (25.86)</td>
			<td>15 (4.36)</td>
		</tr>
		<tr>
			<td>Paresthesia</td>
			<td>159 (22.71)</td>
			<td>39 (11.34)</td>
		</tr>
		<tr>
			<td>Headache</td>
			<td>153 (21.86)</td>
			<td>29 (8.43)</td>
		</tr>
		<tr>
			<td>Neck pain</td>
			<td>139 (19.86)</td>
			<td>55 (15.99)</td>
		</tr>
		<tr>
			<td>Pharyngitis</td>
			<td>122 (17.43)</td>
			<td>25 (7.27)</td>
		</tr>
		<tr>
			<td>Depression</td>
			<td>121 (17.29)</td>
			<td>46 (13.37)</td>
		</tr>
		<tr>
			<td>Dysphagia</td>
			<td>115 (16.43)</td>
			<td>32 (9.30)</td>
		</tr>
		<tr>
			<td>Incision-site reaction</td>
			<td>113 (16.14)</td>
			<td>15 (4.36)</td>
		</tr>
		<tr>
			<td>Nausea</td>
			<td>107 (15.29)</td>
			<td>12 (3.49)</td>
		</tr>
		<tr>
			<td>Device-site pain</td>
			<td>98 (14.00)</td>
			<td>11 (3.20)</td>
		</tr>
		<tr>
			<td>Hypertonia</td>
			<td>92 (13.14)</td>
			<td>31 (9.01)</td>
		</tr>
		<tr>
			<td>Device-site reaction</td>
			<td>82 (11.71)</td>
			<td>27 (7.85)</td>
		</tr>
		<tr>
			<td>Insomnia</td>
			<td>75 (10.71)</td>
			<td>22 (6.40)</td>
		</tr>
	</tbody>
</table>
Table 1: Adverse events [n (%)] reported during the first and second years on VNS treatment. This table has been modified with permission from Berry et al.33.
<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>Parameter</td>
			<td>Units</td>
			<td>Range</td>
			<td>Target Range</td>
			<td>Maximum Therapeutic Dosing</td>
			<td>note</td>
		</tr>
		<tr>
			<td>Output Current</td>
			<td>Milliampere (mA)</td>
			<td>0 &#8211; 3.50</td>
			<td>1.0 &#8211; 2.0</td>
			<td>2.5</td>
			<td>Stepwise&#160; increase after first dosing test (lead-test), 0.25 every two weeks (if tolerated)</td>
		</tr>
		<tr>
			<td>Signal Frequency</td>
			<td>Hertz (Hz)</td>
			<td>1 &#8211; 30</td>
			<td>20</td>
			<td>20-30</td>
			<td>Modulation range 20-30 Hz (for antidepressive mode of action)</td>
		</tr>
		<tr>
			<td>Pulse Width</td>
			<td>Microseconds (&#181;s)</td>
			<td>130 &#8211; 1000</td>
			<td>250</td>
			<td>500</td>
			<td></td>
		</tr>
		<tr>
			<td>Signal On-Time</td>
			<td>Seconds (s)</td>
			<td>7 &#8211; 60</td>
			<td>30</td>
			<td>60</td>
			<td>Decrease when side-effects occur</td>
		</tr>
		<tr>
			<td>Signal Off-Time</td>
			<td>Minutes (min)</td>
			<td>0.2 &#8211; 180</td>
			<td>5</td>
			<td>180</td>
			<td>Increase when side-effects occur</td>
		</tr>
	</tbody>
</table>
Table 2: Dosing recommendation for VNS. Normal-mode stimulation: stimulation 24 h/day and 7 days/week. Dosing is optimized for therapeutic effect and/or tolerability.

Watch this Scientific Journal Video about Vagus Nerve Stimulation As an Adjunctive Neurostimulation Tool in Treatment-resistant Depression at JoVE.com

Vagus Nerve Stimulation As an Adjunctive Neurostimulation Tool in Treatment-resistant Depression

Vagus nerve stimulation (VNS) has been shown to be effective as an adjunct treatment for treatment-resistant depression (TRD). VNS leads to antidepressive and antisuicidal effects and quality of life improvements. This protocol offers a step-by-step guide to managing and adjusting a vagus nerve stimulator for efficient treatment of TRD.

Vagus nerve stimulation (VNS) is an approved neurostimulation therapy. The purpose of the method is to treat patients with therapy-resistant depression ...

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28.4K Views.  Carl von Ossietzky Universität Oldenburg. Deze methode kan de kwaliteit van leven aanzienlijk verbeteren bij patiënten met therapie-resistente depressie. Het belangrijkste voordeel van deze techniek is dat het met succes kan worden gebruikt, zelfs als meerdere antidepressieve drug regimenten hebben gefaald. Visuele demonstratie van deze methode is niet moeilijk, als de verschillende stappen van nervus nervus stimulatie, of VNS, tuning zijn gemakkelijk te leren.Het aantonen van de procedure zal Dr.Merve Aydin, een clinicus van...

Video: Vagus Nerve Stimulation As an Adjunctive Neurostimulation Tool in Treatment-resistant Depression

Vagus Nerve Stimulation as a Tool to Induce Plasticity in Pathways Relevant for Extinction Learning

Extinction describes the process of attenuating behavioral responses to neutral stimuli when they no longer provide the reinforcement that has been maintaining the behavior. There is close correspondence between fear and human anxiety, and therefore studies of extinction learning might provide insight into the biological nature of anxiety-related disorders such as post-traumatic stress disorder, and they might help to develop strategies to treat them. Preclinical research aims to aid extinction learning and to induce targeted plasticity in extinction circuits to consolidate the newly formed memory. Vagus nerve stimulation (VNS) is a powerful approach that provides tight temporal and circuit-specific release of neurotransmitters, resulting in modulation of neuronal networks engaged in an ongoing task. VNS enhances memory consolidation in both rats and humans, and pairing VNS with exposure to conditioned cues enhances the consolidation of extinction learning in rats. Here, we provide a detailed protocol for the preparation of custom-made parts and the surgical procedures required for VNS in rats. Using this protocol we show how VNS can facilitate the extinction of conditioned fear responses in an auditory fear conditioning task. In addition, we provide evidence that VNS modulates synaptic plasticity in the pathway between the infralimbic (IL) medial prefrontal cortex and the basolateral complex of the amygdala (BLA), which is involved in the expression and modulation of extinction memory.

Vagus nerve stimulation (VNS) has emerged as a tool to induce targeted synaptic plasticity in the forebrain to modify a range of behaviors. This protocol describes how to implement VNS to facilitate the consolidation of fear extinction memory.

Extinction describes the process of attenuating behavioral responses to neutral stimuli when they no longer provide the reinforcement that has been ...

Behavior

Individualized rTMS Treatment for Depression using an fMRI-Based Targeting Method

To achieve greater clinical efficacy, a revolution in treatment for major depressive disorder (MDD) is highly anticipated. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive and safe neuromodulation technique that immediately changes brain activity. Despite its wide application in the treatment for MDD, the treatment response remains different among individuals, which may be attributable to the inaccurate positioning of the stimulation target. Our study aims to examine whether the functional magnetic resonance imaging (fMRI)-assisted positioning improves the efficacy of rTMS in treating depression. We intend to identify and stimulate the subregion of dorsolateral prefrontal cortex (DLPFC) in MDD with strongest anti-correlation with the subgenual anterior cingulate cortex (sgACC), and to conduct a comparative investigation of this novel method and the traditional 5-cm rule. To achieve more precise stimulation, both methods were applied under the guidance of neuronavigation system. We expected that the TMS treatment with individualized positioning based on resting state functional connectivity may show better clinical efficacy than the 5-cm method.

The present protocol describes the application of repetitive transcranial magnetic stimulation (rTMS), where a subregion of the dorsolateral prefrontal cortex (DLPFC) with the strongest functional anticorrelation with the subgenual anterior cingulate cortex (sgACC) was located as the stimulation target under the assistance of a fMRI-based neuronavigation system.

To achieve greater clinical efficacy, a revolution in treatment for major depressive disorder (MDD) is highly anticipated. Repetitive transcranial ...

Increased Recovery Time and Decreased LPS Administration to Study the Vagus Nerve Stimulation Mechanisms in Limited Inflammatory Responses

Inflammation is a local response to infection and tissue damage mediated by activated macrophages, monocytes, and other immune cells that release cytokines and other mediators of inflammation. For a long time, humoral and cellular mechanisms have been studied for their role in regulating the immune response, but recent advances in the field of immunology and neuroscience have also unraveled specific neural mechanisms with interesting therapeutic potential. The so-called cholinergic anti-inflammatory pathway (CAP) has been described to control innate immune responses and inflammation in a very potent manner. In the early 2000s, Tracey and collaborators developed a technique that stimulates the vagus nerve and mimics the effect of the pathway. The methodology is based on the electrical stimulation of the vagus nerve at low voltage and frequency, in order to avoid any side effects of overstimulation, such as deregulation of heart rate variability. Electrical devices for stimulation are now available, making it easy to set up the methodology in the laboratory. The goal of this research was to investigate the potential involvement of prostaglandins in the CAP. Unfortunately, based on earlier attempts, we failed to use the original protocol, as the induced inflammatory response either was too high or was not suitable for enzymatic metabolism properties. The different settings of the original surgery protocol remained mostly unchanged, but the conditions regarding inflammatory induction and the time point before sacrifice were improved to fit our purposes (i.e., to investigate the involvement of the CAP in more limited inflammatory responses). 
The modified version of the original protocol, presented here, includes a longer time range between vagus nerve stimulation and analysis, which is associated with a lower induction of inflammatory responses. Additionally, while decreasing the level of lipopolysaccharides (LPS) to inject, we also came across new observations regarding mechanistic properties in the spleen.

Vagus nerve stimulation has proven to have a strong efficacy for decreasing peripheral inflammation. Here, we present a modified vagus nerve stimulation protocol that allows for further examinations of the cholinergic anti-inflammatory mechanisms in limited inflammatory responses.

Inflammation is a local response to infection and tissue damage mediated by activated macrophages, monocytes, and other immune cells that release ...

Immunology and Infection

MRI-guided dmPFC-rTMS as a Treatment for Treatment-resistant Major Depressive Disorder

Here we outline the protocol for magnetic resonance imaging (MRI) guided repetitive transcranial magnetic stimulation (rTMS) to the dorsal medial prefrontal cortex (dmPFC) in patients with major depressive disorder (MDD). Technicians used a neuronavigation system to process patient MRIs to generate a 3-dimensional head model. The head model was subsequently used to identify patient-specific stimulatory targets. The dmPFC was stimulated daily for 20 sessions. Stimulation intensity was titrated to address scalp pain associated with rTMS. Weekly assessments were conducted on the patients using the Hamilton Rating Scale for Depression (HamD17) and Beck Depression Index II (BDI-II). Treatment-resistant MDD patients achieved significant improvements on both HAMD and BDI-II. Of note, angled, double-cone coil rTMS at 120% resting motor threshold allows for optimal stimulation of deeper midline prefrontal regions, which results in a possible therapeutic application for MDD. One major limitation of the rTMS field is the heterogeneity of treatment parameters across studies, including duty cycle, number of pulses per session and intensity. Further work should be done to clarify the effect of stimulation parameters on outcome. Future dmPFC-rTMS work should include sham-controlled studies to confirm its clinical efficacy in MDD.

Here we outline the procedure for MRI-guided repetitive transcranial magnetic stimulation to the dorsomedial prefrontal cortex as an experimental treatment for major depressive disorder.

Here we outline the protocol for magnetic resonance imaging (MRI) guided repetitive transcranial magnetic stimulation (rTMS) to the dorsal medial ...

Laboratory Administration of Transcutaneous Auricular Vagus Nerve Stimulation (taVNS): Technique, Targeting, and Considerations

Non-invasive vagus nerve stimulation (VNS) may be administered via a novel, emerging neuromodulatory technique known as transcutaneous auricular vagus nerve stimulation (taVNS). Unlike cervically-implanted VNS, taVNS is an inexpensive and non-surgical method used to modulate the vagus system. taVNS is appealing as it allows for rapid translation of basic VNS research and serves as a safe, inexpensive, and portable neurostimulation system for the future treatment of central and peripheral disease. The background and rationale for taVNS is described, along with electrical and parametric considerations, proper ear targeting and attachment of stimulation electrodes, individual dosing via determination of perception threshold (PT), and safe administration of taVNS.

Laboratory Administration of Transcutaneous Auricular Vagus Nerve Stimulation taVNS: Technique, Targeting, and Considerations

A methodological description of the technique, potential targets, and proper administration of transcutaneous auricular vagus nerve stimulation (taVNS) on the human ear is described.

Non-invasive vagus nerve stimulation (VNS) may be administered via a novel, emerging neuromodulatory technique known as transcutaneous auricular vagus ...

Neuroscience

Preparation of Peripheral Nerve Stimulation Electrodes for Chronic Implantation in Rats

Peripheral nerve cuff electrodes have long been used in the neurosciences and related fields for stimulation of, for example, vagus or sciatic nerves. Several recent studies have demonstrated the effectiveness of chronic VNS in enhancing central nervous system plasticity to improve motor rehabilitation, extinction learning, and sensory discrimination. Construction of chronically implantable devices for use in such studies is challenging due to rats&#8217; small size, and typical protocols require extensive training of personnel and time-consuming microfabrication methods. Alternatively, commercially available implantable cuff electrodes can be purchased at a significantly higher cost. In this protocol, we present a simple, low-cost method for construction of small, chronically implantable peripheral nerve cuff electrodes for use in rats. We validate the short and long-term reliability of our cuff electrodes by demonstrating that VNS in ketamine/xylazine anesthetized rats produces decreases in breathing rate consistent with activation of the Hering-Breuer reflex, both at the time of implantation and up to 10 weeks after device implantation. We further demonstrate the suitability of the cuff electrodes for use in chronic stimulation studies by pairing VNS with skilled lever press performance to induce motor cortical map plasticity.

Existing approaches for constructing chronically implantable peripheral nerve cuff electrodes for use in small rodents often require specialized equipment and/or highly trained personnel. In this protocol we demonstrate a simple, low-cost approach for fabricating chronically implantable cuff electrodes, and demonstrate their effectiveness for vagus nerve stimulation (VNS) in rats.

Peripheral nerve cuff electrodes have long been used in the neurosciences and related fields for stimulation of, for example, vagus or sciatic nerves. ...

Deep Brain Stimulation for Treatment of Major Depression

Closed-Loop Neurostimulation for Biomarker-Driven, Personalized Treatment of Major Depressive Disorder

Deep brain stimulation involves the administration of electrical stimulation to targeted brain regions for therapeutic benefit. In the context of major depressive disorder (MDD), most studies to date have administered continuous or open-loop stimulation with promising but mixed results. One factor contributing to these mixed results may stem from when the stimulation is applied. Stimulation administration specific to high-symptom states in a personalized and responsive manner may be more effective at reducing symptoms compared to continuous stimulation and may avoid diminished therapeutic effects related to habituation. Additionally, a lower total duration of stimulation per day is advantageous for reducing device energy consumption. This protocol describes an experimental workflow using a chronically implanted neurostimulation device to achieve closed-loop stimulation for individuals with treatment-refractory MDD. This paradigm hinges on determining a patient-specific neural biomarker that is related to states of high symptoms and programming the device detectors, such that stimulation is triggered by this read-out of symptom state. The described procedures include how to obtain neural recordings concurrent with patient symptom reports, how to use these data in a state-space model approach to differentiate low- and high-symptom states and corresponding neural features, and how to subsequently program and tune the device to deliver closed-loop stimulation therapy.

Author Spotlight: Therapeutic Benefit of Closed-Loop Deep Brain Stimulation in Depression Treatment 

Deep brain stimulation triggered by a patient-specific neural biomarker of a high-symptom state may better control symptoms of major depressive disorder compared to continuous, open-loop stimulation. This protocol provides a workflow for identifying a patient-specific neural biomarker and controlling the delivery of therapeutic stimulation based on the identified biomarker.

Deep brain stimulation involves the administration of electrical stimulation to targeted brain regions for therapeutic benefit. In the context of major ...

Measurement of Neuromodulation by Transcutaneous Auricular Vagus Nerve  Stimulation

Understanding the Effects of Non&#45;Invasive Transauricular Vagus Nerve Stimulation on EEG and HRV

Several studies have demonstrated promising results of transcutaneous auricular vagus nerve stimulation (taVNS) in treating various disorders; however, no mechanistic studies have investigated this technique's neural network and autonomic nervous system effects. This study aims to describe how taVNS can affect EEG metrics, HRV, and pain levels. Healthy subjects were randomly allocated into two groups: the active taVNS group and the sham taVNS group. Electroencephalography (EEG) and Heart Rate Variability (HRV) were recorded at baseline, 30 min, and after 60 min of 30 Hz, 200-250 &#181;s taVNS, or sham stimulation, and the differences between the metrics were calculated. Regarding vagal projections, some studies have demonstrated the role of the vagus nerve in modulating brain activity, the autonomic system, and pain pathways. However, more data is still needed to understand the mechanisms of taVNS on these systems. In this context, this study presents methods to provide data for a deeper discussion about the physiological impacts of this technique, which can help future therapeutic investigations in various conditions.

Author Spotlight: Exploring the Effects of Transauricular Vagus Nerve Stimulation

This protocol provides information on how to apply transcutaneous auricular vagus nerve stimulation (taVNS) in a clinical trial, including potential biomarkers such as EEG metrics and heart rate variability (HRV) to measure the effect of this treatment on the autonomic nervous system.

Several studies have demonstrated promising results of transcutaneous auricular vagus nerve stimulation (taVNS) in treating various disorders; however, no ...

Abdominal VNS for Treating Inflammatory Conditions in Rat Models

Implantation Surgery for Abdominal Vagus Nerve Stimulation and Recording Studies in Awake Rats

Abdominal vagus nerve stimulation (VNS) can be applied to the subdiaphragmatic branch of the vagus nerve of rats. Due to its anatomical location, it does not have any respiratory and cardiac off-target effects commonly associated with cervical VNS. The lack of respiratory and cardiac off-target effects means that the intensity of stimulation does not need to be lowered to reduce side effects commonly experienced during cervical VNS. Few recent studies demonstrate the anti-inflammatory effects of abdominal VNS in rat models of inflammatory bowel disease, rheumatoid arthritis, and glycemia reduction in a rat model of type 2 diabetes. Rat is a great model to explore the potential of this technology because of the well-established anatomy of the vagus nerve, the large size of the nerve that allows easy handling, and the availability of many disease models. Here, we describe the methods for cleaning and sterilizing the abdominal VNS electrode array and surgical protocol in rats. We also describe the technology required for confirmation of suprathreshold stimulation by recording evoked compound action potentials. Abdominal VNS has the potential to offer selective, effective treatment for a variety of conditions, including inflammatory diseases, and the application is expected to expand similarly to cervical VNS.

Author Spotlight: Exploring Abdominal VNS for Inflammatory Conditions

The present protocol describes the surgical technique for implanting an electrode array onto the abdominal vagus nerve in rats, along with methods for chronic electrophysiology testing and stimulation using the implanted device.

Abdominal vagus nerve stimulation (VNS) can be applied to the subdiaphragmatic branch of the vagus nerve of rats. Due to its anatomical location, it does ...

Assessing the Efficacy of Cranial Electrical Stimulation in Fibromyalgia

A Randomized, Sham-Controlled Trial of Cranial Electrical Stimulation for Fibromyalgia Pain and Physical Function, Using Brain Imaging Biomarkers

Fibromyalgia is a chronic pain syndrome that presents with a constellation of broad symptoms, including decreased physical function, fatigue, cognitive disturbances, and other somatic complaints. Available therapies are often insufficient in treating symptoms, with inadequate pain control commonly leading to opioid usage for attempted management. Cranial electrical stimulation (CES) is a promising non-pharmacologic treatment option for pain conditions that uses pulsed electrical current stimulation to modify&#160;brain function via transcutaneous electrodes. These neural mechanisms and the applications of CES in fibromyalgia symptom relief require further exploration.
A total of 50 participants from the Atlanta Veterans Affairs Healthcare System (VAHCS) diagnosed with fibromyalgia were enrolled and then block-randomized into either a placebo plus standard therapy or active CES plus standard therapy group. Baseline assessments were obtained prior to the start of treatment. Both interventions occurred over 12 weeks, and participants were assessed at 6 weeks and 12 weeks after treatment initiation. The primary outcome investigated whether pain and functional improvements occur with the application of CES. Additionally, baseline and follow-up resting state functional connectivity magnetic resonance imaging (rs-fcMRI) were obtained at the 6-week and 12-week time points to assess for clinical applications of neural connectivity biomarkers and the underlying neural associations related to treatment effects.
This is a randomized, placebo-controlled trial to determine the efficacy of CES for improving pain and function in fibromyalgia and further develop rs-fcMRI as a clinical tool to assess the neural correlates and mechanisms of chronic pain and analgesic response.

Author Spotlight: Methodologies and Advancements of Chronic Pain Management Research

The current study is a randomized, placebo-controlled trial to determine the efficacy of cranial electrical stimulation (CES) for improving pain and function in fibromyalgia and further develop resting functional connectivity magnetic resonance imaging (rs-fcMRI) as a clinical tool to assess the neural correlates and mechanisms of chronic pain and analgesic response.

Fibromyalgia is a chronic pain syndrome that presents with a constellation of broad symptoms, including decreased physical function, fatigue, cognitive ...

Vagus Nerve Stimulation As an Adjunctive Neurostimulation Tool in Treatment-resistant Depression

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