Facial nerve stimulation in normal pigs and healthy human volunteers: transitional development of a medical device for the emergency treatment of ischemic stroke.

BACKGROUND: Magnetic stimulation of the facial nerve has been tested in preclinical studies as a new, non-invasive emergency treatment of ischemic stroke that acts by increasing cerebral blood flow (CBF). The objective of the studies reported herein was to identify minimal stimulation parameters that increase CBF in large animals and then test those stimulation parameters in healthy volunteers for safety, tolerability, and effectiveness at increasing CBF. This translational research is necessary preparation for clinical studies in ischemic stroke patients. METHODS: Initial experiments in anesthetized Yorkshire pigs were undertaken in order to identify the lowest stimulus power and duration that increase CBF. A full 3 × 3 factorial design was used to evaluate magnetic stimulation of the facial nerve at various stimulation powers (1.3, 1.6, and 1.9 Tesla field strength at coil surface) and for various durations (2, 3.5, and 5 min). CBF was measured with contrast MRI perfusion imaging and the internal carotid arteries were assessed with MR angiography. Magnetic facial nerve stimulation with parameters identified in the pig study was then applied to 35 healthy volunteers. Safety was assessed with adverse event reports and by medical examination. Tolerability was defined as each volunteer's ability to withstand at least 2 min of stimulation. Volunteers could determine the maximum power of stimulation they received during a ramp-up period. RESULTS: In pigs, unilateral facial nerve stimulation increased CBF by as much as 77% over pre-stimulation baseline when administered across a range of 1.3-1.9 Tesla power and for 2- to 5-min duration. No clear dose-response relationship could be observed across this range, but lower powers and durations than these were markedly less effective. The effect of a single stimulation lasted 90 min. A second stimulation delivered 100 min after the first stimulation sustained the increased CBF without evidence of tachyphylaxis. In human, bilateral facial nerve stimulation caused only non-serious adverse events that were limited to the 2-min stimulation period. Tolerability was greatly improved by gentle encouragement from the study staff, which enabled most volunteers to tolerate 1.6-1.8 Tesla of stimulation power. CBF measures taken approximately 10 min after stimulation demonstrated on average a 32 ± 6% increase in CBF, with ≥ 25% increases in CBF occurring in 10 of the 31 volunteers who had adequate CBF measurements. CONCLUSIONS: The minimal effective stimulation parameters defined by increased CBF, as identified in the pig study, translated into safe, tolerable, and effective stimulation of healthy volunteers. These results support the future development and evaluation of non-invasive facial nerve stimulation for the emergency treatment of ischemic stroke. Trial Registration retrospectively registered with clinicaltrials.gov NRV_P1_01_15 on June 6, 2017.

Effects of noninvasive facial nerve stimulation in the dog middle cerebral artery occlusion model of ischemic stroke.

BACKGROUND AND PURPOSE: Facial nerve stimulation has been proposed as a new treatment of ischemic stroke because autonomic components of the nerve dilate cerebral arteries and increase cerebral blood flow when activated. A noninvasive facial nerve stimulator device based on pulsed magnetic stimulation was tested in a dog middle cerebral artery occlusion model. METHODS: We used an ischemic stroke dog model involving injection of autologous blood clot into the internal carotid artery that reliably embolizes to the middle cerebral artery. Thirty minutes after middle cerebral artery occlusion, the geniculate ganglion region of the facial nerve was stimulated for 5 minutes. Brain perfusion was measured using gadolinium-enhanced contrast MRI, and ATP and total phosphate levels were measured using 31P spectroscopy. Separately, a dog model of brain hemorrhage involving puncture of the intracranial internal carotid artery served as an initial examination of facial nerve stimulation safety. RESULTS: Facial nerve stimulation caused a significant improvement in perfusion in the hemisphere affected by ischemic stroke and a reduction in ischemic core volume in comparison to sham stimulation control. The ATP/total phosphate ratio showed a large decrease poststroke in the control group versus a normal level in the stimulation group. The same stimulation administered to dogs with brain hemorrhage did not cause hematoma enlargement. CONCLUSIONS: These results support the development and evaluation of a noninvasive facial nerve stimulator device as a treatment of ischemic stroke.

The SLC16A11 risk haplotype is associated with decreased insulin action, higher transaminases and large-size adipocytes.

Objective A haplotype at chromosome 17p13 that reduces expression and function of the solute carrier transporter SLC16A11 is associated with increased risk for type 2 diabetes in Mexicans. We aim to investigate the detailed metabolic profile of SLC16A11 risk haplotype carriers to identify potential physiological mechanisms explaining the increased type 2 diabetes risk. Design Cross-sectional study. Methods We evaluated carriers (n = 72) and non-carriers (n = 75) of the SLC16A11 risk haplotype, with or without type 2 diabetes. An independent sample of 1069 subjects was used to replicate biochemical findings. The evaluation included euglycemic-hyperinsulinemic clamp, frequently sampled intravenous glucose tolerance test (FSIVGTT), dual-energy X-ray absorptiometry (DXA), MRI and spectroscopy and subcutaneous abdominal adipose tissue biopsies. Results Fat-free mass (FFM)-adjusted M value was lower in carriers of the SLC16A11 risk haplotype after adjusting for age and type 2 diabetes status (ß = -0.164, P = 0.04). Subjects with type 2 diabetes and the risk haplotype demonstrated an increase of 8.76 U/L in alanine aminotransferase (ALT) (P = 0.02) and of 7.34 U/L in gamma-glutamyltransferase (GGT) (P = 0.05) compared with non-carriers and after adjusting for gender, age and ancestry. Among women with the risk haplotype and normal BMI, the adipocyte size was higher (P < 0.001). Conclusions Individuals carrying the SLC16A11 risk haplotype exhibited decreased insulin action. Higher serum ALT and GGT levels were found in carriers with type 2 diabetes, and larger adipocytes in subcutaneous fat in the size distribution in carrier women with normal weight.

Restored brain perfusion after non-invasive stimulation of the facial nerve in a canine stroke model.

Ischemic stroke affects over 15 million patients per year and is a leading cause of death worldwide. Currently available treatments are indicated for less than 5% of patients. Stimulation of the facial nerve has been proposed as a possible new treatment of ischemic stroke that acts by increasing blood flow to the brain and thereby restoring perfusion through collateral vessels. The objective of this project was to evaluate the changes in brain perfusion, following facial nerve stimulation in an animal stroke model using MRI measures of cerebral blood flow. Autologous blood clot was injected in the internal carotid artery to occlude the middle cerebral artery (MCA) in 17 mongrel dogs. Occlusion in the MCA was verified using fluoroscopy and MRI angiography. Following baseline and post-stroke MRI images, the facial nerve at the site of the geniculate ganglion was located and then stimulated using a transcranial magnetic stimulator and a neuro-navigation system in 11 animals. Six animals followed the same procedure but were not stimulated (control group). The perfusion index of both sides of the brain was measured using gadolinium contrast MRI before and after stroke, and at 30 minute intervals after stimulation. Results show a significant and persistent increase in perfusion in the stroke side of the brain relative to the non-stroke / contralateral side, after stimulation, when compared to the control group. These results strongly support the future development and evaluation of a non-invasive facial nerve stimulator device for the early treatment of ischemic stroke.

Effect of pulsed magnetic stimulation of the facial nerve on cerebral blood flow.

In these experiments we define an effective means of pulsed magnetic stimulation of the facial nerve for the purpose of increasing cerebral blood flow (CBF). In normal anesthetized dog and sheep, a focal magnetic field was directed toward the facial nerve within the temporal bone by placing a 6.5 cm figure-8 stimulation coil over the ear. In an initial set of experiments, CBF was measured by laser Doppler flowmetry and the cerebral vasculature was visualized by angiography. The effect of facial nerve stimulation was found to be dependent on stimulation power, frequency, and the precise positioning of the stimulation coil. Furthermore, an increase in CBF was not observed after direct electrical stimulation in the middle ear space, indicating that non-specific stimulation of the tympanic plexus, an intervening neural structure with vasoactive effects, was not responsible for the increase in CBF after pulsed magnetic stimulation. Subsequent experiments using perfusion MRI demonstrated reproducible increases in CBF throughout the forebrain that manifested bilaterally, albeit with an ipsilateral predominance. These experiments support the development of a non-invasive pulsed magnetic facial nerve stimulator that will increase CBF as a treatment of ischemic stroke.

Negative effects of obesity analyzed through bioimpedance, indirect calorimetry, the sympathovagal index and the orthoclinostatic test.

Early analysis of the negative effects of obesity is important to prevent the development of chronic diseases related to this condition. There is a need to monitor these effects through simple instrumentation that measures fat-free mass (FFM) catabolism. Obesity leads to a decrease in the FFM energy expenditure and to an increase in the autonomic nervous system (ANS) activity. Thus, the measurement of FFM dynamic catabolism can provide information regarding the effects of obesity. The hypothesis is that this increased ANS activity produces an increase of energy expenditure of carbohydrates and fats when the subjects are under stress; in this case after an 8-hour fast and while they are undergoing an orthoclinostatic test. A pilot study was conducted on 29 volunteers, 16 women and 13 men. The results show significant statistical differences (p<0.1) in fat and carbohydrate utilization during the orthoclinostatic tests: A move from the clinostatic to the orthostatic positions produced the following: Fat metabolism varied from 97.2 to 105.9 gr/day of fat for women and 24.9 to 35.7 gr/day of fat for men; carbohydrate metabolism changed from 38 to 39 gr/day for women and 239 to 277 gr/day for men; FFM averages were 47 Kg for women and 57.6 Kg for men; changes in the sympathovagal index (SVI) averages were 0.4 to 1.8 for women and 0.8 to 2.7 for men. The conclusions show that the methodology's sensitivity is such that gender differences can be used as a model to prove FFM metabolic differences. We believe that further studies will lead to the development of a robust methodology for the early detection of the negative effects of obesity.

Method to observe hemodynamic and metabolic changes during hemodiafiltration therapy with exercise.

Intradyalitic exercise programas are important to improve patient's hemodynamic stability. Blood pressure and metabolic changes are correlated when heat accumulation is due to increment of the body core temperature (+1.0 °C). However, increase in temperature could be controlled by lowering dialysate's temperature using two main modalities techniques (isothermic and thermoneural) with different patient's thermal balance consequences, not yet well studied. In this work, a new method to observe the main physiological parameters (hearth rate variability (HRV), blood pressure, BTM dialysate temperature control and substrate utilization by indirect calorimtery) which are involved in hemodiafitration (HDF), are displayd. An experiment was carried out in a group of 5 patients waiting kidney transplant. In each patient, EE was assessed as well as the HRV during isothermic and thermoneutral modalities as a manner of cross and prospective study (a) at before therapy, (b) during therapy and (c) at the end of the HDF therapy. Power extraction was also measured by a BTM (Blood Temperature Monitor from Fresenius Inc), in order to determine how the dialysate temperature was controlled. The results showed important method's advantages which place the BTM performance as unstable control system with the possibility to produce undesirable HRV changes as the vagotonical response. However more patient cases are needed in order to identify the real advantage of this new method.

Active metabolic weight estimation using bioimpedance, indirect calorimetry and the clino-ortho maneuver.

The resting energy expenditure (REE) and substrate utilization are computed by indirect calorimetry technique (ICT). The REE represents 80-85% of the total energy expenditure (TEE) but only accounts for the 7% of the actual body weight (ABW). The TEE is produced by the organs plus muscles, whereas the REE accounts only for the main organs. An important problem comes up when the REE is computed throughout the fat free mass (FFM) computation or anthropometric measurements because they do not explain the tremendous catabolic variability by ICT when subjects show the same body composition. Therefore, the aim of this work is to develop a method to compute the metabolic active weight (MAW) as a new form that may help to understand the catabolic activity of the body composition. The premise was the clino-ortho maneuver can split the ABW in two parts: one in which the MAW reflects the FFM catabolism while the second part was not considered since there is not energy requirement in it. The experiment design studied 37 young volunteers undergoing the clino-ortho maneuver during fast and postprandial conditions. The results showed REE increments of 21% during phase I (fast), while in phase II (postprandial) only 14% was achieved in ortho-postprandial. Therefore, the computed MAWs were 65.5Kg and 58Kg, respectively, when the ABW average was 70 Kg and the FFM was 50 Kg. One first conclusion was that the 15.5 Kg of the MAW above the FFM could explain a catabolic equivalence which can be exclusively related to the fast-ortho position which can help to classify exclusively the dynamic over activity of the FFM.

Game motivated and constraint induced therapy in late stroke with FMRI studies pre and post therapy.

20 patients with stroke more than one year earlier were evaluated, admitted to a novel therapy including constraint-induced and computer game-motivated therapy. Statistically significant improvements after 4 weeks of late therapy were seen in all 20 patients on nine out of eleven quantified clinical evaluation scales. The patients looked forward to and enjoyed the therapy. These same late stroke patients were studied via fMRI BOLD immediately before therapy and post therapy. fMRI BOLD studies confirm brain functional reorganization; 3 of the 20 fMRI cases are presented here. We propose that fMRI can help in the process of designing effective stroke therapy programs based on biological principles of brain plasticity.