BACKGROUND:Neuromodulation through external trigeminal nerve stimulation (eTNS) is an emerging noninvasive wearable treatment for neuropsychiatric disorders including attention deficit disorder, epilepsy, and major depression. eTNS is now US Food and Drug Administration approved for attention deficit disorder and investigational for the treatment of epilepsy, major depression, and other neuropsychiatric disorders. Rodent studies indicate eTNS activates key brainstem nuclei, in addition to the amygdala and hippocampus. However, the effect of eTNS on cortical blood flow and metabolism is not known. A better understanding of which brain areas are activated or deactivated by eTNS would provide a scientific basis for current applications and could provide a roadmap to identify new disease targets and interventions. OBJECTIVES:This study aimed to investigate the effect of eTNS on brain blood flow using oxygen-15 labeled water positron emission tomography ([15O]H2O PET) to advance the understanding of the networks, pathways, and mechanisms of action of eTNS in humans. MATERIAL AND METHODS:Institutional review board approval and informed consent were obtained. Five subjects underwent eTNS using electrodes positioned 2.5 cm from the nasal midline to stimulate the paired supraorbital branches of the trigeminal nerve. [15O]H2O brain PET scans were performed using a Siemens-CTI HR+ EXACT system at the University of California Los Angeles Laboratory of Neuroimaging. Three scans were performed with trigeminal stimulation ON (scans 1, 3, and 6), and three scans were performed with trigeminal stimulation OFF (scans 2, 4, and 5). Data were analyzed comparing stimulus ON with stimulus OFF scans. Adjustments for multiple comparisons were performed using the family-wise error correction. RESULTS:eTNS of the supraorbital branches of the trigeminal nerve produced significant activations (increased cerebral blood flow) in bilateral anterior cingulate gyri; bilateral parieto-temporal cortex; left inferior frontal gyrus; and right medial and middle frontal gyri. The most significant deactivations (decreased blood flow) occurred in the left parahippocampal gyrus, right sensorimotor cortex, right superior parietal area, bilateral temporo-occipital cortex, and bilateral visual cortex. CONCLUSIONS:eTNS of bilateral supraorbital nerves (V1 division) generates significant activations during [15O]H2O PET imaging in regions associated with major depression and attention deficit disorder. Deactivations of cortical regions including the parahippocampal gyrus, sensorimotor cortex, and others provide a rationale for some of the antiseizure effects of trigeminal nerve stimulation. The results of this study advance our understanding of mechanisms of action of trigeminal nerve stimulation in neuropsychiatric disorders and epilepsy.

Background: Sudden unexpected death in epilepsy (SUDEP) is a major cause of death in those with drug-resistant epilepsy (DRE). There is a need for inventories and biomarkers associated with the risk for SUDEP.Objective: To explore the revised SUDEP Risk Inventory (SUDEP-7) in a cohort with DRE and determine the association with Heart Rate and other covariates.Methods: Twenty-five subjects with severe DRE were enrolled in a clinical trial for epilepsy. Baseline demographics, duration of epilepsy, seizure types, seizure frequency, seizure severity, AEDs, and vital signs were collected. Heart rate variability (HRV) was calculated from 1-h recordings of ECG. A SUDEP Risk Inventory (SUDEP-7) was administered, which included seven validated and weighted risk factors initially identified by Walczak et al. as factors associated with SUDEP risk.Results: The total score on the revised SUDEP-7 ranged from 1 to 7, mean = 3.4 (SD 1.8). The SUDEP Risk Inventory score was inversely correlated with RMSSD (Pearson r = -0.45, p = 0.027). The following variables were significantly associated with RMSSD: epilepsy duration (p = 0.02), age (p = 0.03), and developmental intellectual disability (p <0.001). The correlation between RMSSD and SUDEP-7 tended to persist also after the adjustment for patient age (r = -0.40, p = 0.05). Two subjects died of SUDEP: their SUDEP-7 scores were above average and in the upper twenty-fifth and fiftieth percentiles, respectively (6 and 4, mean = 3.4).Conclusion: RMSSD, a measure of low frequency HRV, was significantly associated with SUDEP Risk Inventory (SUDEP-7) scores. Using a multivariate model, the covariates of developmental intellectual disability, age, and duration of epilepsy were also significantly associated with decreased HRV. The correlation between decreased HRV and a higher SUDEP-7 score remained unchanged even after the adjustment for patient age. The results suggest that older age, greater duration of epilepsy, and the presence of developmental intellectual disability may increase the risk of SUDEP through their direct influence on decreasing the vagus nerve-mediated HRV. Further validation of the SUDEP-7 inventory is indicated.

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.

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 (V1 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.

BACKGROUND:Tinnitus, a profoundly widespread auditory disorder, is characterized by the perception of sound in the absence of external stimulation. The aim of this work is to review the various surgical treatment options for tinnitus, targeting the various disruption sites along the auditory pathway, as well as to indicate novel neuromodulatory techniques as a mode of tinnitus control.METHODS:A comprehensive analysis was conducted on published clinical and basic neuroscience research examining the pathophysiology and treatment options of tinnitus.RESULTS:Stereotactic radiosurgery methods and microvascular decompressions are indicated for tinnitus caused by underlying pathologies such as vestibular schwannomas or neurovascular conflicts of the vestibulocochlear nerve at the level of the brainstem. However, subsequent hearing loss and secondary tinnitus may occur. In patients with subjective tinnitus and concomitant sensorineural hearing loss, cochlear implantation is indicated. Surgical ablation of the cochlea, vestibulocochlear nerve, or dorsal cochlear nucleus, though previously suggested in earlier literature as viable treatment options for tinnitus, has been shown to be ineffective and contraindicated. Recently, emerging research has shown the neuromodulatory capacity of the somatosensory system at the level of the trigeminal nerve on the auditory pathway through its inputs at various nuclei in the central auditory pathway.CONCLUSION:Tinnitus remains to be a difficult disorder to treat despite the many surgical interventions aimed at eliminating the aberrant neuronal activity in the auditory system. A promising novel neuromodulatory approach using the trigeminal system to control such a bothersome and difficult-to-treat disorder deserves further investigation and controlled clinical trials.

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 V1 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.

1288 Objectives The aim of this study was to evaluate effects on regional cerebral blood flow of trigeminal nerve stimulation (TNS), an investigational neuromodulation intervention, in treatment-resistant epilepsy and depression patients. Methods A total of 24 [O15]water-PET scans from 4 depressed adults (mean±SD, age: 46.9±5.8, yrs of education: 17.3±1.5, 2M:2F, all right-handed, severity of the 17-item Hamilton Depression Rating Scale 19.5±4.4) were examined. Half of the scans for each subset were acquired while receiving 60 seconds of TNS at maximally tolerated current intensity, and half were acquired while the same apparatus was in place but current was set to zero. During each scan, the onset of TNS occurred at the time the [O15]water bolus was pushed. PET data were analyzed by standardized volume of interest (sVOI) and statistical parametric mapping (spm) methods. Results The bilateral temporo-occipital cortex (TOC) (in the vicinity of Brodman’s areas 37 and 39) was the brain region demonstrating the most significant decrease in blood flow during TNS (right TOC p Conclusions TNS was associated with deactivation in TOC, superior parietal, and sensorimotor cortex, and activation in medial frontal cortical areas. Though effects were bilateral, all of the major changes occurring in regional cerebral blood flow during TNS were more striking in the right hemisphere

Objective: The goal of this study was to determine if specific measures of heart rate variability (HRV) are associated with the total score on a new seven-item inventory for sudden unexplained death in epilepsy (SUDEP).Methods: Nineteen subjects with intractable partial seizures, at least three per month, were enrolled in a randomized clinical trial of omega-3 fatty acids in epilepsy. At study entry, subjects underwent a 1-hour ECG recording for the determination of HRV. To estimate the risk of SUDEP, we assembled a seven-item inventory (the SUDEP-7 Inventory) from risk factors prospectively validated by T.S. Walczak, I.E. Leppik, M. D'Amelio M, et al. (Neurology 2001:56:519-25). The SUDEP-7 score was then correlated with measures of HRV using the Pearson correlation and other parametric and nonparametric methods.Results: Subjects had highly drug-resistant seizures, with a mean seizure frequency of 22.8 seizures per month. Scores on the SUDEP-7 inventory ranged from 1 to 7 of a maximum possible score of 12. RMSSD, a measure of high-frequency HRV, was inversely correlated with the SUDEP-7 score, r=-0.64, P=0.004. Subjects with higher SUDEP-7 scores had reduced levels of HRV (RMSSD). Other time-dependent measures of HRV (SDNN, SDANN) were not significantly correlated with SUDEP risk scores.Conclusions: RMSSD, a measure of HRV, which reflects the integrity of vagus nerve-mediated autonomic control of the heart, is highly associated with the total score on a new seven-item SUDEP risk inventory. Lower RMSSD values were associated with higher risk scores on the new SUDEP risk inventory. This provides new evidence that HRV (specifically RMSSD) is a marker of SUDEP risk. (C) 2010 Elsevier Inc. All rights reserved.

Objective: The goal of the work described here was to determine the effect of high-dose n-3 fatty acids (eicosapentanoic acid + docosahexanoic acid, fish oil) on several outcomes in subjects with refractory epilepsy, including seizure severity, seizure frequency, cardiac risk factors, and heart rate variability, in a pilot, exploratory planning trial.Methods: Pilot, randomized, double-blind two-period crossover clinical trial of high-dose fish oil (9600 mg of fish oil/day, 2880 mg of n-3 fatty acids) in 11 subjects with refractory seizures. Outcomes included seizure frequency, seizure severity, lipid panel, and heart rate variability as measured by SDNN and SDANN (defined as the standard deviation of all normal R-R intervals for 1 h, and the standard deviation of all R-R intervals in each successive 5-min epoch, respectively).Results: Preliminary data identified trends towards lower seizure severity, lower triglycerides, higher HDL, and increased SDNN/SDANN in those with low SDNN/SDANN at baseline (Spearman's correlation = -0.65, P = 0.03). No positive effect on seizure frequency was identified.Conclusions: Further study of the effect of n-3 fatty acids is indicated in people with epilepsy, as favorable trends were identified on cardiac risk factors (triglycerides) and in a subgroup with low heart rate variability (low SDNN/SDANN), a marker of sudden death risk. To our knowledge, this is the first trial to explore the beneficial effects of n-3 fatty acids on cardiac risk factors and heart rate variability in people with epilepsy. (C) 2008 Elsevier Inc. All rights reserved.

Eliminating infected female mosquitoes by aerial applications of ultra-low volume adulticides is the intervention strategy currently recommended to interrupt the epidemic transmission of encephalitis viruses, including West Nile. The current research optimized pyrethrin formulations and evaluated their efficacy in the desert environment of the Coachella Valley, Riverside County, California. After seven trials during 2004, a 1:2 by volume mixture of Pyrenone 25-5 in BVA oil optimized particle size, droplet descent to ground level, and kill of sentinel mosquitoes. Three subsequent experiments used 3 aerial applications of the 1:2 Pyrenone 25-5:BVA oil mixture on alternate nights to suppress Culex tarsalis Coquillett host-seeking abundance over a 1-square-mile target area. Mortality patterns among caged sentinel mosquitoes varied among sites and replicate sprays, indicating variable particle dispersion at ground level within the target area. In addition, mortality was observed for sentinels up to 1 mile downwind from the target area, indicating considerable particle drift. Geometric mean abundance of host-seeking Cx. tarsalis females collected at dry ice-baited traps within each of 3 sprayed and 2 unsprayed negative control strata varied similarly over time, indicating that our sprays minimally impacted the target population or that drift combined with other factors led to widespread area control. Experiments during March and June when recruitment rates were minimal showed general area-wide suppression of abundance following spray, whereas an experiment during September when recruitment rates were high from newly flooded marshes failed to prevent an area-wide increase in abundance. Clearly additional research is needed to standardize the efficacy of aerial applications of pyrethrins in hot dry desert environments.