Lara M. Schrader

Trigeminal nerve stimulation in major depressive disorder: First proof of concept in an open pilot trial

Modulation of brain activity via trigeminal nerve stimulation is an emerging therapy in drug-resistant epilepsy. This cranial nerve also projects to structures implicated in depression (such as the nucleus tractus solitarius and locus coeruleus). We examined the effects of external trigeminal nerve stimulation in major depressive disorder as an adjunct to pharmacotherapy. Five adults (mean age 49.6, SD 10.9, three females and two males) participated in an 8-week open-label outpatient trial; all had persistent symptoms despite adequate pharmacotherapy, with a mean score on the 28-item Hamilton Depression Rating Scale of 25.4 (SD=3.9) at entry. Nightly stimulation over the V(1) branch was well tolerated. Both the clinician-rated 28-item Hamilton Depression Rating Scale (P=0.006) and the self-rated Beck Depression Inventory (P=0.0004) detected significant symptomatic improvement. This novel neuromodulation approach may have use as an adjunct to pharmacotherapy in major depressive disorder. Additional larger trials are needed to delineate efficacy and tolerability with greater reliability.

Trigeminal nerve stimulation in major depressive disorder: acute outcomes in an open pilot study.

Most patients with major depressive disorder (MDD) do not recover with initial pharmacotherapy, and many pursue combination treatments. Combining a medication with neuromodulation offers an alternative to purely pharmacologic strategies. In prior open and double-blind controlled trials for drug-resistant epilepsy, adjunctive external trigeminal nerve stimulation (eTNS) was found to be safe and well tolerated, to significantly reduce seizures, and to be associated with an improvement in depressive symptoms. Here, we present a comprehensive description of the first open pilot investigation in MDD. In this 8-week trial, eleven adults with unipolar MDD received nightly stimulation (V(1) branch). All entered with moderate to severe symptom levels despite at least two antidepressant medication trials in this episode. All the eleven adults completed the acute trial, without serious adverse events. Symptoms of depression improved significantly, whether assessed with clinician- or self-rated scales (all p < 0.01; effect sizes d 1.0-1.8), as did quality of life (p < 0.02). Four of the 11 achieved remission. These improvements from nightly adjunctive eTNS in treatment-resistant depression merit replication under double-blind conditions.

Trigeminal Nerve Stimulation: Seminal Animal and Human Studies for Epilepsy and Depression

The unique ability to stimulate bilaterally, extracranially, and non-invasively may represent a significant advantage to invasive neuromodulation therapies. In humans thus far the technique has been applied noninvasively, and is termed external trigeminal nerve stimulation (eTNSTM).

Fish oil (n-3 fatty acids) in drug resistant epilepsy: a randomised placebo-controlled crossover study

Abstract Background n-3 fatty acids inhibit neuronal excitability and reduce seizures in animal models. High-dose fish oil has been explored in two randomised trials in drug resistant epilepsy with negative results. We performed a phase II randomised controlled crossover trial of low-dose and high-dose fish oil in participants with drug resistant epilepsy to explore whether low-dose or high-dose fish oil reduces seizures or improves cardiovascular health. Methods Randomised placebo-controlled trial of low-dose and high-dose fish oil versus placebo (corn oil, linoleic acid) in 24 participants with drug resistant epilepsy. A three-period crossover design was utilised lasting 42 weeks, with three 10-week treatment periods and two 6-week washout periods. All participants were randomised in double-blind fashion to receive placebo, high dose or low dose in different sequences. The primary outcome was per cent change in total seizure frequency. Findings Low-dose fish oil (3 capsules/day, 1080 mg eicosapentaenoic acid+docosahexaenoic acid) was associated with a 33.6% reduction in seizure frequency compared with placebo. Low-dose fish oil was also associated with a mild but significant reduction in blood pressure. High-dose fish oil was no different than placebo in reducing seizures or improving cardiac risk factors. Interpretation In this phase II randomised crossover trial, low-dose fish oil was effective in reducing seizures compared with placebo. The magnitude of improvement is similar to that of recent antiepileptic drug trials in drug resistant epilepsy (DRE). The results indicate that low-dose fish oil may reduce seizures and improve the health of people with epilepsy. These findings justify a large multicentre randomised trial of low-dose fish oil (n-3 fatty acids <1080 mg/day) in drug resistant epilepsy. Trial registration number NCT00871377.

Reduced anesthetization during the intracarotid amobarbital (Wada) test in patients taking carbonic anhydrase-inhibiting medications

Summary:  Purpose: Failure to show adequate anesthetization during the intracarotid amobarbital procedure (IAP or “Wada test”) is a rare complication. After an unusually high rate of recent anesthetization failures, we sought to determine the frequency of reduced anesthetization and any common factors underlying these failures.

A lack of effect from transcranial magnetic stimulation (TMS) on the vagus nerve stimulator (VNS)

OBJECTIVE The effects of transcranial magnetic stimulation (TMS) on vagus nerve stimulation (VNS) are unknown. Understanding these effects is important before exposing individuals with an implanted VNS to TMS, as could occur in epilepsy or depression TMS research. To explore this issue, the TMS-induced current in VNS leads and whether TMS has an effect on the VNS pulse generator was assessed. METHODS Ex vivo measurement of current in VNS leads during single-pulse TMS and pulse generator function before, during, and after single-pulse TMS was assessed. RESULTS At the highest intensity and with the TMS coil held approximately 5 mm from the VNS wires, a 200 nA, 1.0 ms current was induced by TMS. This translates to an induced charge density of 3.3 nC/cm2/phase. The function of the pulse generator was unaffected by single-pulse TMS, even when its case was directly stimulated by the coil. CONCLUSIONS TMS-induced current in VNS electrodes was not only well outside of the range known to be injurious to peripheral nerve, but also below the activation threshold of nerve fibers. SIGNIFICANCE Using single-pulse TMS in individuals with VNS should not result in nerve stimulation or damage. Furthermore, single-pulse TMS does not affect the VNS pulse generators function.

AR2, a novel automatic muscle artifact reduction software method for ictal EEG interpretation: Validation and comparison of performance with commercially available software.

Objective: To develop a novel software method (AR2) for reducing muscle contamination of ictal scalp electroencephalogram (EEG), and validate this method on the basis of its performance in comparison to a commercially available software method (AR1) to accurately depict seizure-onset location. Methods: A blinded investigation used 23 EEG recordings of seizures from 8 patients. Each recording was uninterpretable with digital filtering because of muscle artifact and processed using AR1 and AR2 and reviewed by 26 EEG specialists. EEG readers assessed seizure-onset time, lateralization, and region, and specified confidence for each determination. The two methods were validated on the basis of the number of readers able to render assignments, confidence, the intra-class correlation (ICC), and agreement with other clinical findings. Results: Among the 23 seizures, two-thirds of the readers were able to delineate seizure-onset time in 10 of 23 using AR1, and 15 of 23 using AR2 (p<0.01). Fewer readers could lateralize seizure-onset (p<0.05). The confidence measures of the assignments were low (probable-unlikely), but increased using AR2 (p<0.05). The ICC for identifying the time of seizure-onset was 0.15 (95% confidence interval (CI), 0.11-0.18) using AR1 and 0.26 (95% CI 0.21-0.30) using AR2. The EEG interpretations were often consistent with behavioral, neurophysiological, and neuro-radiological findings, with left sided assignments correct in 95.9% (CI 85.7-98.9%, n=4) of cases using AR2, and 91.9% (77.0-97.5%) (n=4) of cases using AR1. Conclusions: EEG artifact reduction methods for localizing seizure-onset does not result in high rates of interpretability, reader confidence, and inter-reader agreement. However, the assignments by groups of readers are often congruent with other clinical data. Utilization of the AR2 software method may improve the validity of ictal EEG artifact reduction.

Direct cortical stimulation to localize sensory, motor and language function

Publisher Summary This chapter reviews that the goal of brain surgery is to remove as much pathological tissue as possible, yet preserve brain function. Brain surgery in or near eloquent cortex requires understanding of the anatomic localization of eloquent brain function in these regions prior to resection of brain tissue. It discusses that brain mapping with direct cortical electrical stimulation essentially involves assessing whether electrical stimulation to a small region of cortical surface results in a neurological change in the patient, such as a movement or speech arrest. The chapter reviews that the reliability of electrocortical stimulation mapping for predicting the postoperative functional outcomes depends on whether the stimulation used is sufficient to alter the cortical activity, the effects of stimulation are focal, and the appropriate task is chosen to test the function of the cortical region stimulated. Direct cortical stimulation for brain mapping can be done extraoperatively using implanted subdural electrodes, as is often done in patients undergoing an epilepsy surgery evaluation or intraoperatively. Both the techniques generally employ the same principles toward mapping the brain function but differ somewhat with regard to their benefits and limitations. This chapter focuses on the technical aspects of intraoperative brain mapping using direct cortical stimulation.

Somatosensory-Evoked Potential Monitoring

Somatosensory-evoked potentials (SEPs) are an excellent modality for spinal cord monitoring during surgery. They cover much territory, including the peripheral, spinal, brain stem, thalamic, and cortical levels of sensory pathways. They are used for monitoring for both spinal cord and cerebral injury during various types of surgery.

P20-27 Investigation of low frequency repetitive transcranial magnetic stimulation (LF-rTMS) parameters on motor cortex excitability in normal subjects

Background: It has been shown that rTMS to the primary motor cortex (M1) or dorsolateral prefrontal cortex (DLPFC) can reduce pain in experimental models in healthy subjects. The mechanisms may depend on the activation of pain modulation systems. Due to the major role of endogenous opioids systems (EOS) in pain modulation, we hypothesized that EOS are involved in the analgesic action of rTMS. Methods: To investigate the role of EOS in rTMS-induced analgesia, we compared the analgesic effects of M1 or DLPFC stimulation before and after naloxone or placebo, using a randomized double-blind design. Twelve healthy volunteers were randomly assigned to three groups and received either active stimulation of the right M1, active stimulation of the right DLPFC (frequency 10 Hz, 80% of the motor threshold, 1500 pulses/session) or sham stimulation, during two experimental sessions within two weeks interval. Based on our previous results showing that rTMS acts preferentially on cold pain [1], measurements of cold pain thresholds were used to evaluate the analgesic effects of rTMS. During each session, cold pain thresholds were measured on the left thenar eminence before and one hour after iv injection of naloxone or saline (bolus of 0.1 mg/kg then continuous infusion of 0.1 mg/kg/h up to the end of rTMS). Results: Compared with the sham stimulation, both the stimulation of M1 and DLPFC induced a significant decrease in cold pain (i.e. analgesia) after saline injection. Naloxone significantly reduced the analgesic effects of M1, but not of DLPFC stimulation. Conclusions: We showed for the first time that EOS are involved in the analgesic effects of rTMS. The differential effects of naloxone on M1 and DLPFC stimulation indicate that, despite their apparent similarity, the analgesic effects evoked by stimulation of these cortical sites involve distinct mechanisms.