Week Of Stimulation Research Articles

P-578 A combined analysis to establish the equipotency of corifollitropin alfa in comparison to daily recombinant FSH including individual data of 3292 IVF/ICSI patients

Abstract Study question What daily dose of follitropin beta provides a similar ovarian response as single dose of corifollitropin alfa (CFA) in women with different ovarian reserve? Summary answer Regardless of ovarian reserve, a single dose of CFA provides a similar ovarian response as 300 IU/day follitropin beta in IVF/ICSI patients. What is known already A single dose of CFA replaces the first week of stimulation with daily recFSH and provides robust ovarian stimulation due to its unique pharmacokinetic profile. Previous controlled trials in IVF/ICSI patients have demonstrated that CFA yields more oocytes than daily recFSH. In women up to 36 years, on average +2.5 oocytes were obtained in comparison to daily 150 IU recFSH and +1.2 oocytes in comparison to daily 200 IU recFSH, whereas this difference was only +0.5 oocytes in comparison to daily 300 IU recFSH in women aging 35 to 42 years. Study design, size, duration This was a retrospective analysis using individual patient data from 3 large, randomized trials, including 1715 IVF patients receiving a single injection of 100 or 150 mg CFA, followed by daily follitropin beta injections from day 8, and 1577 IVF patients treated with daily follitropin beta with a fixed starting dose of 150 IU, 200 IU or 300 IU for the first week of stimulation. Participants/materials, setting, methods The mean number of oocytes retrieved were estimated for each treatment and predicted response group (Low: AFC≤7 (n = 595), Normal: 8≥AFC≤14 (n = 1899), High: AFC≥15 (n = 808)). Pooling of the three trials was enabled by adjusting for AFC, age, body weight, and the interaction between AFC and age, all as continuous covariates. The dose of follitropin beta corresponding to CFA was estimated by including log(dose) as a covariate in the model. Main results and the role of chance There were similar positive associations between AFC and oocytes and negative associations between age and oocytes following CFA and daily recFSH treatment. There was no clear association between body weight and oocytes following either treatment. A clear increase in number of oocytes was observed with increasing daily doses of recFSH in predicted normal and predicted high responders, but not in predicted low responders. Accordingly, regardless the dose, CFA was providing an ovarian response higher than daily 150 IU or 200 IU recFSH in normal and high responders. The number of oocytes following 100 mg and 150 mg CFA was comparable in all three subsets of predicted responders and similar to the number of oocytes following daily treatment with 300 IU recFSH. The analysis estimated a single dose of 150 mg CFA to be equipotent to daily 300 IU recFSH (95% CI 251-359 IU) and a single dose of 100 mg CFA to be equipotent to 297 IU recFSH daily (95% CI 217-405 IU). Limitations, reasons for caution This retrospective analysis excludes patients with an irregular cycle, suffering from PCOS or having an AFC >20. Thus, the data cannot be extrapolated to these patients Wider implications of the findings Daily doses of recFSH provide dose-related increases of ovarian response in normal and high responders. With CFA treatment, the potential of a single IVF cycle is maximised with an ovarian response comparable to daily 300 IU recFSH, which can be safely managed by GnRH agonist triggering and a freeze-all strategy. Trial registration number NCT00696800, NCT00702845, NCT01144416

P-576 Pharmacokinetic and pharmacodynamic modelling to explore dosing regimens of corifollitropin alfa for ovarian stimulation without the need for additional daily recFSH injections

Abstract Study question Can ovarian stimulation in IVF patients be realized with one or two corifollitropin alfa (CFA) injections only? Summary answer For 94% of IVF patients, ovarian stimulation can be safely completed with a maximum of two CFA injections What is known already A single dose CFA replaces the first week of stimulation with daily recFSH, providing ovarian stimulation similar to daily 300 IU recFSH. Pharmacokinetic and pharmacodynamic (PK/PD) modelling has shown that a threshold serum FSH concentration of 1.1 ng/ml (∼ 6.72 IU/L) is required to maintain multiple follicular development, and that such FSH concentrations are maintained for 7 days following single injection. From day 8 onwards, most patients require daily recFSH injections to maintain serum FSH above threshold to complete the follicular growth. Patients requiring profound stimulation, e.g. prior to ‘freeze-all’, would benefit most from CFA only treatment, requiring less injections. Study design, size, duration This was a retrospective analysis using individual patient data from 4 large CFA trials, including totally 2397 IVF patients receiving a single injection of CFA followed by daily follitropin beta injections from day 8 of stimulation until triggering. Participants/materials, setting, methods A PK model developed for CFA was used to predict serum concentrations following different dosing regimens of CFA only. Clinical trial data from 2397 patients was used to estimate the distribution of the required length of stimulation and to evaluate the impact of different dosing regimens on the serum FSH concentrations up to the day of triggering. Main results and the role of chance At stimulation day 8, 21% of patients did not require additional FSH, whereas 25%, 27%, 14%, and 7% needed 1, 2, 3 or 4 days additional stimulation days to complete the cycle. Only 6% required more than 4 days additional stimulation. Patients below 60 kg remained longer above the threshold and additional dosing could have been delayed to stimulation day 9-11 depending on the initial dose (100 or 150 mg). In a 70 kg woman, daily doses of 7 mg CFA would be sufficient to maintain trough concentrations of FSH above the threshold, and a single dose of 15 and 30 mg on day 8 would sustain stimulation for another 2 and 4 days, respectively. A single dose of 30 mg on day 8 would increase FSH concentrations from 7 IU/L to a maximal level of approximately 12 IU/L, a fluctuation that is unlikely to recruit new small follicles during the late follicular phase. It is therefore suggested that patients can be safely treated with a second dose of 30 mg CFA on day 8 of stimulation, without risk of overdosing when receiving GnRH agonist triggering, and that 94% of patients will not need more than two doses. Limitations, reasons for caution The theoretical dosing regimens build upon this retrospective analysis and modelling needs to be validated in a clinical study to confirm that one additional dose of CFA is able to complete ovarian stimulation efficiently. Wider implications of the findings IVF patients planned to have ‘freeze-all’ following GnRH agonist triggering may be treated conveniently with one or max two injections of CFA for ovarian stimulation. Trial registration number not applicable

Coating of Neural Electrodes with Platinum Nanoparticles Reduces and Stabilizes Impedance In Vitro and In Vivo in a Rat Model

The efficacy of electrodes that are chronically implanted and used in the context of deep brain stimulation (DBS) for the treatment of neurological disorders critically depends on stable impedance. Platinum–iridium electrodes were coated with laser-generated platinum nanoparticle colloids (PtNPs) via electrophoretic deposition using pulsed direct currents (DC-EPD). Uncoated electrodes were used as controls. In vitro, electrodes were stimulated for four weeks in a 0.9% NaCl solution. For the in vivo (rats) study, coated electrodes were implanted in the left and uncoated control electrodes in the right subthalamic nucleus (STN). After two weeks of recovery, electrodes were stimulated for four weeks. Impedance measurements were conducted after each week of stimulation, both in vivo and in vitro. NP-coating resulted in a significant and long-lasting reduction in electrode impedance (p < 0.05) over four weeks of in vitro stimulation. Despite an initial increase in impedance after intracranial implantation, the impedance of the NP-coated electrodes was also reduced during in vivo stimulation over four weeks. NP-coated electrodes had a lower fluctuation of impedance during stimulation compared to uncoated electrodes both in vitro and in vivo (p < 0.05). Laser-generated PtNPs applied to electrodes by pulsed DC-EPD lead to lower and more stable electrode impedance during chronic stimulation, with the potential to enhance the performance of DBS systems during chronic use.

The effects of multi-day rTMS and cardiorespiratory fitness on working memory and local GABA concentration

Working memory (WM) refers to the capacity to temporarily retain and manipulate finite amounts of information; a critical process in complex behaviours such as reasoning, comprehension, and learning. This cognitive function is supported by a parietal-prefrontal network and linked to the activity of key neurotransmitters, such as gamma-aminobutyric acid (GABA). Impairments in WM are seen in a range of psychiatric and neurological disorders, and there are currently no effective treatments. In this study, we analysed secondary outcome measures from a trial investigating the effects of multi-day rTMS on cognition. Participants received four days of 20 Hz rTMS to an individualised region of left parietal cortex in one week, and an individualised region of pre-supplementary motor area (pre-SMA) in a separate week. We assessed changes to WM function before and after each week of stimulation (N = 39), and changes to GABA concentration before and after stimulation in week one using MR spectroscopy (N = 18 per stimulation condition). We hypothesised that parietal rTMS would enhance WM and alter GABA concentration at the site of stimulation, but this was not observed. Instead, we report some evidence of improved WM function following the first week of pre-SMA rTMS stimulation, and a generalised increase in GABA concentration across both parietal and pre-SMA voxels following pre-SMA rTMS. Additionally, we found that higher cardiorespiratory fitness was associated with greater WM improvement following pre-SMA stimulation. This study does not support the use of parietal multi-day rTMS for the enhancement of working memory. In contrast, the results suggest that increasing cardiorespiratory fitness may provide a novel approach to enhance the effects of pre-SMA rTMS on cognition.

Effects of Subthalamic Deep Brain Stimulation With Different Frequencies in a Parkinsonian Rat Model

ObjectiveSubthalamic deep brain stimulation (STN-DBS) could be an effective alternative treatment for patients with Parkinson’s disease (PD). However, the mechanisms of deep brain stimulation (DBS) at different frequencies are still unclear. In this study, diffusion tensor imaging (DTI) was used to detect parameter changes in different regions of rat brains after DBS, and rat exercise capacity and brain tissue immunohistochemistry were evaluated. Materials and MethodsThe 6-hydroxydopamine-induced hemi-parkinsonian rat models were made and divided into four groups: a control group, sham group, low-frequency group, and high-frequency group. Low-frequency (30 Hz) and high-frequency (130 Hz) DBS were given to the STN in rats. First, an open-field experiment was used to evaluate changes in exercise performance. Then, the DTI was used to measure parameter changes in the substantia nigra (SN). Finally, immunohistochemistry was used to analyze the expression of tyrosine hydroxylase (TH), NeuN, and α-synuclein (α-syn) in the SN in the rats. ResultsThere were significant differences in movement distance changes between the high-frequency stimulation (HFS) group and low-frequency stimulation (LFS) group, the HFS group and Ctrl group, and the Sham group and Ctrl group (all p < 0.05) after one week of stimulation. In the HFS group, the fractional anisotropy value of the SN was significantly higher than that of the other groups (p < 0.05), and the apparent diffusion coefficient and radial diffusion coefficient values were significantly lower than those of the other groups (p < 0.01). Immunohistochemical analysis showed that the integral optical density values of SN TH staining (p < 0.01) and NeuN staining (p < 0.05) in the HFS group were both significantly higher than those in the other groups. ConclusionSTN-HFS (130 Hz) and sham operation for one week can significantly improve the exercise performance of PD rats. The exercise performance of PD rats in LFS group (30 Hz) is worse compared with HFS group (130 Hz). HFS plays a role in neuroprotection and improvement of exercise performance of PD rats. Moreover, DTI can be used as an effective technique to assess the therapeutic effects and severity of PD.

Spinal Cord Stimulation for Chronic Refractory Neuropathic Pain: A Technical Note Initial Experience of Two cases

AbstractSpinal cord stimulation is an established procedure for relieving chronic neuropathic pain conditions. Although it has been over five decades since the first spinal cord stimulation (SCS) was developed, it has only been used in a few cases in India. It is primarily based on the “Gate Theory” of pain. The mechanism of its action is not exactly clear, but reports have suggested that it plays the main role in selectively stimulating the large diameter pain fibers in the dorsal aspect of spinal cord. SCS procedure involves a very careful case selection, and current evidence suggests that only a few conditions of chronic refractory neuropathic pain are its established indications. In these patients too, the efficacy rate remains around 50 to 75%. The overall pain relief observed is around 50% decrease in visual analog scale (VAS) scores. It is a technically simple procedure involving placement of electrodes over the dorsal aspect of spinal cord in the epidural space. The procedure is a staged one in which trial lead electrodes are first implanted and stimulated with an external pulse generator (EPG). If the trial is successful and patient has acceptable pain relief over 1 week of stimulation at various settings, the patient undergoes the permanent implantation of electrodes at the same position. The permanent electrodes are then stimulated by an implantable pulse generator (IPG) in the subcutaneous pocket (abdominal or gluteal). Complications are rare and are more related to hardware like lead migration and breakage. Since it is does not damage the cord per se, its acceptance as a procedure for pain is known quite well in the Western world. Its availability and cost of implants is the major hurdle in its use in a developing nation like India. Here, we present a technical note and our experience of two cases of thoracic spinal cord stimulation for chronic neuropathic pain at our institution.

Multi-day rTMS exerts site-specific effects on functional connectivity but does not influence associative memory performance

Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation technique with the capacity to modulate brain network connectivity and cognitive function. Recent studies have demonstrated long-lasting improvements in associative memory and resting-state connectivity following multi-day repetitive TMS (rTMS) to individualised parietal-hippocampal networks. We aimed to assess the reproducibility and network- and cognitive-specificity of these effects following multi-day rTMS. Participants received four days of 20 Hz rTMS to a subject-specific region of left lateral parietal cortex exhibiting peak functional connectivity to the left hippocampus. In a separate week, the same stimulation protocol was applied to a subject-specific region of pre-supplementary motor area (pre-SMA) exhibiting peak functional connectivity to the left putamen. We assessed changes to associative memory before and after each week of stimulation (N = 39), and changes to resting-state functional connectivity before and after stimulation in week one (N = 36). We found no evidence of long-lasting enhancement of associative memory or increased parieto-hippocampal connectivity following multi-day rTMS to the parietal cortex, nor increased pre-SMA-putamen connectivity following multi-day rTMS to pre-SMA. Instead, we observed some evidence of site-specific modulations of functional connectivity lasting ~24 h, with reduced connectivity within targeted networks and increased connectivity across distinct non-targeted networks. Our findings suggest a complex interplay between multi-day rTMS and network connectivity. Further work is required to develop reliable rTMS paradigms for driving changes in functional connectivity between cortical and subcortical regions.

Effect of Electro-Motor Stimulation on the Power Production of a Maximally Stretched Muscle

The effect of electro-motor stimulation (EMS) upon the increase in power production of the tibialis anterior muscle (TA) of healthy individuals in both the maximally stretched (ST group) and shortened (SH group) positions was investigated. The effect of cross-education upon the contralateral muscle was also examined. EMS with a frequency of 50 hertz, a duration of 0.2 miliseconds, and a rectangular wave was applied for ten seconds with a ten-second interval and repeated ten times per day for six weeks. The ST group gained significantly 9.4%, 15.5%, and 16.4% after two, four, and six weeks of stimulation, respectively, while the SH group also showed a significant gain of 5.1%, 8.3%, and 3.0%. When comparing the two groups at the end of the six-week period the ST group's gain was significantly greater. The increase of power production of the unstimulated TA was 5.5%, 8.0%, and 4.3% in the ST group, which was significant at the end of the second and fourth week of stimulation. The SH group, however, registered a non-significant increase of -2.7%, 1.8%, and -1.5%. Comparison between the two groups showed a significant increase in the power production of the unstimulated TA in the ST group commencing the second week.

Long-Term Efficacy of Deep Brain Stimulation of Bilateral Globus Pallidus Internus in Primary Meige Syndrome

Objective: Deep brain stimulation (DBS) of the internal segment of the globus pallidus (GPi) is an alternative therapy in ameliorating the clinical symptoms of primary Meige syndrome. Nevertheless, proof of its efficacy and safety is insufficient due to several case reports and small-sample clinical studies. This study aims to investigate postoperative long-term efficacy in patients undergoing DBS of the GPi for primary Meige syndrome. Methods: We performed a retrospective study to assess the efficacy and safety of bilateral GPi stimulation in 40 patients with primary Meige syndrome who responded poorly to medical treatments or botulinum toxin injections. All participants were postoperatively followed up at the outpatient clinic, and their motor functions were assessed using the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS). The severity of patients’ dystonia was evaluated before surgery and at follow-up neurostimu­lation. Results: The implanted stimulator was turned on 1 month after surgery. All 40 patients received monopolar stimulation using the following parameters: voltage 2.5–3.5 V (average: 2.6 ± 0.8 V), frequency 60–160 Hz (average: 88.0 ± 21.3 Hz), and pulse width 60–185 μS (average: 90.0 ± 21.1 μS). In 28 of 40 patients, the symptoms had signifi­cantly improved within 1 week of stimulation. Most of the patients had been followed up for 6–24 months (average: 15.0 ± 7.8 months). The clinical symptoms of all patients had significantly improved. At 6, 12, and 24 months after surgery, the BFMDRS subscores of eyes, mouth, speech, and swallowing were significantly lower, and subscores of mouth movement showed progressively decreased with prolonged stimulation time. The overall improvement rate was 83%. Five adverse events occurred in the 40 patients; all of these events resolved without permanent sequelae. Conclusions: Bilateral GPi-DBS demonstrated satisfactory long-term efficacy in the treatment of primary Meige syndrome and could serve as an effective and safe option.

INCLUSION OF AN INTELLECTUAL DISABILITY STUDENT IN PHYSICAL EDUCATION CLASSES

Neurodevelopmental Disorders is a set of changes that has its onset in the child's developmental period. One of the manifestations of this disorder is Intellectual Disability, which occurs during the child's development, causing motor, speech and social failures. The stimuli are extremely important to have an evolution in the cognitive, motor, affective and social development, besides promoting inclusion. Objective of this study was to identify the effectiveness of motor stimulation in a student with intellectual disabilities in physical education classes. The present study is a case report that developed in a 15 years old with intellectual disability Intellectual Development Disorder. The Francisco Rosa Neto Motor Development Scale was used as an assessment instrument. The tests were applied in 50-minute sections to apply all the tests in the manual, namely fine motor skills, overall motor skills, balance, body scheme, organization. spatial, temporal organization and laterality. After initial evaluation, two further evaluations were performed during the 10-week stimulation period, one on the 5th and the 10th week. Having some evolutions in certain abilities such as fine motor coordination, balance, body schema, temporal organization, being verified statistically significant improvement already in the 5th week of stimulation, the spatial organization showed statistically significant improvement in the 10th week and the body schema skills, temporal organization presented statistically significant improvement on week 5 and 10, indicating that there was a statistically significant improvement in both periods evaluated. In the evaluation of laterality, it was found that the individual is complete right-handed. It is concluded that motor stimulation acts positively on the motor skills of children with intellectual disabilities.

Randomized trial of transcranial alternating current stimulation for treatment of auditory hallucinations in schizophrenia

BackgroundApproximately 30% of patients with schizophrenia experience auditory hallucinations that are refractory to antipsychotic medications. Here, we evaluated the feasibility and efficacy of transcranial alternating current stimulation (tACS) that we hypothesized would improve auditory hallucination symptoms by enhancing synchronization between the frontal and temporo-parietal areas of the left hemisphere. Method22 participants were randomized to one of three arms and received twice daily, 20 min sessions of sham, 10 Hz 2 mA peak-to-peak tACS, or 2 mA tDCS over the course of 5 consecutive days. Symptom improvement was assessed using the Auditory Hallucination Rating Scale (AHRS) as the primary outcome measure. The Positive and Negative Syndrome Scale (PANSS) and the Brief Assessment of Cognition in Schizophrenia (BACS) were secondary outcomes. ResultsPrimary and secondary behavioral outcomes were not significantly different between the three arms. However, effect size analyses show that tACS had the greatest effect based on the auditory hallucinations scale for the week of stimulation (1.31 for tACS; 1.06 and 0.17, for sham and tDCS, respectively). Effect size analysis for the secondary outcomes revealed heterogeneous results across measures and stimulation conditions. ConclusionsTo our knowledge, this is the first clinical trial of tACS for the treatment of symptoms of a psychiatric condition. Further studies with larger sample sizes are needed to better understand the effect of tACS on auditory hallucinations.

Vagal nerve stimulation modifies neuronal activity and the proteome of excitatory synapses of amygdala/piriform cortex.

Vagal Nerve Stimulation (VNS) Therapy® is a United States Food and Drug Administration approved neurotherapeutic for medically refractory partial epilepsy and treatment-resistant depression. The molecular mechanisms underlying its beneficial effects are unclear. We hypothesized that one mechanism involves neuronal activity-dependent modifications of central nervous system excitatory synapses. To begin to test this hypothesis, we asked whether VNS modifies the activity of neurons in amygdala and hippocampus. Neuronal recordings from adult, freely moving rats revealed that activity in both amygdala and hippocampus was modified by VNS immediately after its application, and changes were detected following 1week of stimulation. To investigate whether VNS modifies the proteome of excitatory synapses, we established a label-free, quantitative liquid chromatography-tandem mass spectrometry workflow that enables global analysis of the constituents of the postsynaptic density (PSD) proteome. PSD proteins were biochemically purified from amygdala/piriform cortex of VNS- or dummy-treated rats following 1-week stimulation, and individual PSD protein levels were quantified by liquid chromatography-tandem mass spectrometry analysis. We identified 1899 unique peptides corresponding to 425 proteins in PSD fractions, of which expression levels of 22 proteins were differentially regulated by VNS with changes greater than 150%. Changes in a subset of these proteins, including significantly increased expression of neurexin-1α, cadherin 13 and voltage-dependent calcium channel α2δ1, the primary target of the antiepileptic drug gabapentin, and decreased expression of voltage-dependent calcium channel γ3, were confirmed by western blot analysis of PSD samples. These results demonstrate that VNS modulates excitatory synapses through regulating a subset of the PSD proteome. Our study reveals molecular targets of VNS and point to possible mechanisms underlying its beneficial effects, including activity-dependent formation of excitatory synapses.

Impact of gonadotropin type on progesterone elevation during ovarian stimulation in GnRH antagonist cycles.

Does hormonal stimulation with corifollitropin alpha (CFA) only, mimicking a step down protocol, result in lower incidence of progesterone elevation on the day of hCGtrigger as compared to sustained stimulation with recombinant FSH (rFSH)? The current findings support the concept that sustained FSH stimulus contributes to premature progesterone elevation in stimulated IVF cycles. Serum progesterone rise during the follicular phase of ovarian stimulation for IVF treatment seems to be related to a poorer reproductive outcome. However, the mechanism by which the rise in progesterone is caused is not yet fully understood. This study was a post hoc analysis of data from two multi-center, randomized, double-blind, double-dummy, active-controlled, non-inferiority trials, ENGAGE and PURSUE, conducted from June 2006 to January 2008 and from July 2010 to October 2012 respectively. In the ENGAGE-study, 1506 women, aged 18-36 years, were allocated to either a single injection of 150 mg CFA or daily injections of 200 IU rFSH in the first week of stimulation, using a standard GnRH antagonist protocol. In the PURSUE-study, a total of 1390 women, aged 35-42 years, were allocated to either a single injection of 150 mg of CFA or daily 300 IU of rFSH for the first week, again using a standard GnRH antagonist protocol. In both trials, daily rFSH was continued until three follicles reached >17 mm in size. All women had a body weight of between 50 and 90 kg, regular menstrual cycles and an indication for ovarian stimulation before IVF. The incidence of progesterone elevation on day of hCG-trigger in patients with CFA only or rFSH stimulation, and triggered on Day 8 of stimulation, was analyzed. Of patients with CFA only stimulation, 5.4% (13/239 patients) showed a progesterone elevation above 1.5 ng/ml on day of hCG-trigger, whereas patients with rFSH stimulation had a significant higher incidence of progesterone elevation (18.3%; 62/339 patients) (P<0.001). Post hoc analysis of data from previously published trials could be considered as a reason for caution. Future studies should evaluate whether it would be possible to prevent a premature progesterone rise in cycles stimulated with daily FSH by using a step down protocol towards the end of the follicular phase. Financial/Material Support was provided by Merck & Co., Inc., Kenilworth, NJ, USA. Davis Gates is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and may own stock and/or hold stock options in the company. Fabiola Beligotti is an employee of MSD, Italy, a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and may own stock and/or hold stock options in the company. Barbara Lawrenz, Nils Engelmann and Human M. Fatemi have no conflict of interest. ENGAGE study: ClinicalTrials.gov identifier NTC00696800. PURSUE-study: NCT01144416.

Deep brain stimulation of the medial forebrain bundle: Distinctive responses in resistant depression

BackgroundTreatment resistant depression (TRD) is a serious, disabling disease. Deep brain stimulation (DBS) to the superolateral branch of the medial forebrain bundle (MFB), as proposed by Schlaepfer et al. (2013), has led to rapid anti-depressant response but has not been replicated. MethodsIn this interim analysis of an ongoing pilot study of ten subjects, we assessed the efficacy of MFB-DBS in a cohort of four TRD patients over a 52-week period using the Montgomery-Åsberg Depression Rating Scale (MADRS) as the primary assessment tool. Implanted patients entered a 4-week single-blinded sham stimulation period prior to stimulation initiation. Deterministic fiber tracking analysis was performed to compare modulated fiber tracts between patients. ResultsIntraoperatively, responder patients displayed immediate increased signs of energy and motivation upon stimulation at target. There was no significant mean change in mood during sham stimulation phase. Three of 4 patients had >50% decrease in MADRS scores at 7 days post-stimulation initiation relative to baseline. One patient withdrew from study participation. At 26 weeks, two of 3 remaining patients continue to have >80% decrease in MADRS scores. One patient failed to have response; evaluation of modulated fiber tracts revealed reduced frontal connectivity to the target region. LimitationsThis is an interim report, with limited conclusions. ConclusionThis study of MFB-DBS shows similar rapid anti-depressant effects within the first week of stimulation as initially reported by Schlaepfer et al. (2013). Implementation of anhedonia measurements would greatly augment characterization of the striking motivational effects observed. We urge others to pursue this target to further prove efficacy.ClinicalTrials.gov (identifier: NCT02046330) https://clinicaltrials.gov/ct2/show/NCT02046330

ID 416 – Motor cortex stimulation for chronic pain relief using repetitive magnetic stimulation (rTMS): 20 Hz versus Theta-Burst, which is better?

Objective To compare the efficacy of two different modalities of rTMS (20 Hz and Theta-Burst) in relieving chronic neuropathic pain. Methods Thirty patients (mean age 55 ± 12) suffering from drug-resistant neuropathic pain received 20 Hz and Theta-Burst rTMS in randomized order. For each modality, every patient received one week of stimulation (daily sessions on 5 consecutive days), the two sessions being separated by a month. Patients rated different aspects of their pain (intensity, unpleasantness, sleep disturbances, etc) on a daily basis, using a numerical rating scale (NRS), one week before (baseline), during and for 2 weeks after the end of each stimulation week. Each week’s ratings were averaged and compared to each other. Results This preliminary analysis takes account exclusively of the ‘intensity’ pain scores. In these first 30 patients, only 20 Hz rTMS lead to a significant decrease of the NRS, compared to baseline, during the two weeks following stimulation onset. Conclusions 20 Hz rTMS appears superior to Theta-Burst for chronic neuropathic pain relief. The study will be running until 40 consecutive patients are studied.

P.2.b.007 Prevalence and psychiatric correlates of suicidal ideation in primary care patients: gender differences

Treatment resistant depression (TRD) is a serious, disabling disease. Deep brain stimulation (DBS) to the superolateral branch of the medial forebrain bundle (MFB), as proposed by Schlaepfer et al. (2013), has led to rapid anti-depressant response but has not been replicated.In this interim analysis of an ongoing pilot study of ten subjects, we assessed the efficacy of MFB-DBS in a cohort of four TRD patients over a 52-week period using the Montgomery-Åsberg Depression Rating Scale (MADRS) as the primary assessment tool. Implanted patients entered a 4-week single-blinded sham stimulation period prior to stimulation initiation. Deterministic fiber tracking analysis was performed to compare modulated fiber tracts between patients.Intraoperatively, responder patients displayed immediate increased signs of energy and motivation upon stimulation at target. There was no significant mean change in mood during sham stimulation phase. Three of 4 patients had >50% decrease in MADRS scores at 7 days post-stimulation initiation relative to baseline. One patient withdrew from study participation. At 26 weeks, two of 3 remaining patients continue to have >80% decrease in MADRS scores. One patient failed to have response; evaluation of modulated fiber tracts revealed reduced frontal connectivity to the target region.This is an interim report, with limited conclusions.This study of MFB-DBS shows similar rapid anti-depressant effects within the first week of stimulation as initially reported by Schlaepfer et al. (2013). Implementation of anhedonia measurements would greatly augment characterization of the striking motivational effects observed. We urge others to pursue this target to further prove efficacy.ClinicalTrials.gov (identifier: NCT02046330) https://clinicaltrials.gov/ct2/show/NCT02046330

Repetitive transcranial magnetic stimulation reduces cigarette consumption in schizophrenia patients

High-frequency repetitive transcranial magnetic stimulation (rTMS) over the left dorsolateral prefrontal cortex (DLPFC) seemed to decrease tobacco consumption and craving in nicotine-dependent people without psychiatric disorder or otherwise healthy people. Even if the prevalence of cigarette smoking in schizophrenia patients is high and estimated to be between 45% and 88%, this technique has not been systematically studied in this indication in schizophrenia yet. The aim of this study was to test the ability of high-frequency (10Hz) rTMS over the left DLPFC to decrease cigarette consumption in schizophrenia patients. The study included 35 male schizophrenia patients on stable antipsychotic medication. The patients were divided into two groups: the first (18 patients) were actively stimulated and the second (17 patients) underwent sham (placebo) stimulation. The sham rTMS was administered using a purpose-built sham coil that was identical in appearance to the real coil and made the same noise but did not deliver a substantial stimulus. The rTMS was administered at the stimulation parameters: location (left dorsolateral prefrontal cortex: DLPFC), intensity of magnetic stimulation in % of motor threshold (110%), stimulation frequency (10Hz), number of trains (20), single train duration (10s), inter-train interval (30s), and total number of stimulation sessions (21). In each stimulation session, 2000TMSpulses were given, with a total of 42,000pulses per treatment course. Patients noted the number of cigarettes smoked in the 7days before treatment, during the whole stimulation treatment (21days), and again for a 7-day period after treatment. Cigarette consumption was statistically significantly lower in the actively stimulated patients than in the sham rTMS group as early as the first week of stimulation. No statistically relevant correlations were found in the changes of ongoing negative or depressive schizophrenia symptoms and the number of cigarettes smoked. High-frequency rTMS over the left DLPFC has the ability to decrease the number of cigarettes smoked in schizophrenia patients.

Sustained cortical and subcortical neuromodulation induced by electrical tongue stimulation

This pilot study aimed to show that information-free stimulation of the tongue can improve behavioral measures and induce sustained neuromodulation of the balance-processing network in individuals with balance dysfunction. Twelve balance-impaired subjects received oneweek of cranial nerve non-invasive neuromodulation (CN-NINM). Before and after the week of stimulation, postural sway and fMRI activation were measured to monitor susceptibility to optic flow. Nine normal controls also underwent the postural sway and fMRI tests but did not receive CN-NINM. Results showed that before CN-NINM balance-impaired subjects swayed more than normal controls as expected (p ≤ 0.05), and that overall sway and susceptibility to optic flow decreased after CN-NINM (p ≤ 0.005 & p ≤ 0.05). fMRI showed upregulation of visual sensitivity to optic flow in balance-impaired subjects that decreased after CN-NINM. A region of interest analysis indicated that CN-NINM may induce neuromodulation by increasing activity within the dorsal pons (p ≤ 0.01).

Corifollitropin alfa in a long GnRH agonist protocol: proof of concept trial

Fifty healthy women, aged 18-39 years with no known risk of ovarian hyperstimulation were treated with 100 or 150 μg corifollitropin alfa (dependent on body weight) in a long GnRH agonist protocol. At these doses, corifollitropin alfa initiated and supported growth of a large cohort of follicles during the first week of ovarian stimulation.

A Pilot Study to Evaluate the Effect of Splanchnic Nerve Stimulation on Body Composition and Food Intake in Rats

Systemic sympathetic stimulation with caffeine and ephedrine increased metabolic rate, reduced food intake, and improved body composition but had systemic adverse events. We hypothesize that selective sympathetic stimulation of the upper gastrointestinal tract will preserve the advantages of systemic sympathetic stimulation without its adverse events. This study evaluated the effect of splanchnic nerve stimulation on metabolic rate, food intake, and body composition. Sixteen Sprague Dawley rats had monopolar electrodes placed on the superior common splanchnic nerve innervating the celiac ganglia. An indifferent electrode was placed subcutaneously on the back. The animals were placed on a 60% fat diet, and eight rats were stimulated for 6 weeks. The stimulation was advanced over 3 days from 0.6 mA to 3 mA. Metabolic rate and food intake were measured daily; weight change was monitored weekly, and body composition was determined by nuclear magnetic resonance (NMR) at the end of the study. Four of the eight animals had metabolic rate measured three times over 2-day periods at 0 mA, 1 mA, and 3 mA of stimulation in a metabolic chamber. Except for the first week of stimulation, there was no difference in body weight between the stimulated and control groups. Cumulative food intake was less in the stimulated group (p<0. 001). The lean-to-fat ratio was greater in the stimulated group (p<0. 01), and the animals that received incremental stimulation showed significantly augmented metabolic rate (p<0. 02). Splanchnic nerve stimulation decreased food intake, increased metabolic rate, and improved body composition.