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OBJECTIVE: To demonstrate clinical techniques for in vitro maturation (IVM) treatment, including stimulation recommendations, small follicle pick-up procedures, and compact cumulus-oocyte complex (COC) search practice. DESIGN: This video utilizes live-action footage from surgery and embryology practice for a representative IVM treatment cycle, with step-by-step instructions and recommendations for practice procedures. SETTING: In vitro fertilization (IVF) clinic. PATIENT(S): Patients undergoing IVM treatment. The patient(s) included in this video gave consent for publication of the video and posting of the video online, including on social media, the journal website, scientific literature websites, and other applicable sites. INTERVENTION(S): Identification of treatment cohorts, IVM definitions, and recommendations for stimulation treatments. A visual demonstration of COC extraction techniques from small antral follicles includes tubing, needle types, considerations when using double lumen or sheath needles, needle pressure, ultrasound, needle flushing, and aspiration technique. Visual demonstration of oocyte search and IVM preparation, including filtering follicular aspirate, prevention of COC cooling, identification of compact COCs, and general parameters of different IVM approaches. MAIN OUTCOME MEASURE(S): Clinical techniques for small follicle ovum pick up and compact COC identification for IVM treatment. RESULTS: Successful IVM treatment of patients can be achieved using minimal ovarian stimulation, effective small follicle retrieval, and efficient compact COC identification with flexibility in approach depending on clinical constraints and preference. CONCLUSION(S): In vitro maturation treatment is an efficacious and safe treatment for high ovarian reserve and hyper-responding patients undergoing IVF treatment, in which the retrieval of multiple immature COCs and their ex vivo maturation can be achieved with little to no in vivo stimulation. Practice procedures vary between treatment centers and IVM techniques. This video provides practice recommendations paired with a visual demonstration of techniques to assist in standardizing the approach and expanding the practice to more centers.

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BACKGROUND: While oocyte IVM is practiced sporadically it has not achieved widespread clinical practice globally. However, recently there have been some seminal advances in our understanding of basic aspects of oocyte biology and ovulation from animal studies that have led to novel approaches to IVM. A significant recent advance in IVM technology is the use of biphasic IVM approaches. These involve the collection of immature oocytes from small antral follicles from minimally stimulated patients/animals (without hCG-priming) and an ∼24 h pre-culture of oocytes in an advanced culture system ('pre-IVM') prior to IVM, followed by routine IVF procedures. If safe and efficacious, this novel procedure may stand to make a significant impact on human ART practices. OBJECTIVE AND RATIONALE: The objectives of this review are to examine the major scientific advances in ovarian biology with a unique focus on the development of pre-IVM methodologies, to provide an insight into biphasic IVM procedures, and to report on outcomes from animal and clinical human data, including safety data. The potential future impact of biphasic IVM on ART practice is discussed. SEARCH METHODS: Peer review original and review articles were selected from PubMed and Web of Science searches for this narrative review. Searches were performed using the following keywords: oocyte IVM, pre-IVM, biphasic IVM, CAPA-IVM, hCG-triggered/primed IVM, natural cycle IVF/M, ex-vivo IVM, OTO-IVM, oocyte maturation, meiotic competence, oocyte developmental competence, oocyte capacitation, follicle size, cumulus cell (CC), granulosa cell, COC, gap-junction communication, trans-zonal process, cAMP and IVM, cGMP and IVM, CNP and IVM, EGF-like peptide and IVM, minimal stimulation ART, PCOS. OUTCOMES: Minimizing gonadotrophin use means IVM oocytes will be collected from small antral (pre-dominant) follicles containing oocytes that are still developing. Standard IVM yields suboptimal clinical outcomes using such oocytes, whereas pre-IVM aims to continue the oocyte's development ex vivo, prior to IVM. Pre-IVM achieves this by eliciting profound cellular changes in the oocyte's CCs, which continue to meet the oocyte's developmental needs during the pre-IVM phase. The literature contains 25 years of animal research on various pre-IVM and biphasic IVM procedures, which serves as a large knowledge base for new approaches to human IVM. A pre-IVM procedure based on c-type natriuretic peptide (named 'capacitation-IVM' (CAPA-IVM)) has undergone pre-clinical human safety and efficacy trials and its adoption into clinical practice resulted in healthy live birth rates not different from conventional IVF. WIDER IMPLICATIONS: Over many decades, improvements in clinical IVM have been gradual and incremental but there has likely been a turning of the tide in the past few years, with landmark discoveries in animal oocyte biology finally making their way into clinical practice leading to improved outcomes for patients. Demonstration of favorable clinical results with CAPA-IVM, as the first clinically tested biphasic IVM system, has led to renewed interest in IVM as an alternative, low-intervention, low-cost, safe, patient-friendly ART approach, and especially for patients with PCOS. The same new approach is being used as part of fertility preservation in patients with cancer and holds promise for social oocyte freezing.

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The unitary postsynaptic response to presynaptic quantal glutamate release is the fundamental basis of excitatory information transfer between neurons. The view, however, of individual glutamatergic synaptic connections in a population as homogenous, fixed-strength units of neural communication is becoming increasingly scrutinized. Here, we used minimal stimulation of individual glutamatergic afferent axons to evoke single synapse resolution postsynaptic responses from central sensory lamina I neurons in an ex vivo adult rat spinal slice preparation. We detected unitary events exhibiting a NMDA receptor component with distinct kinetic properties across synapses conferred by specific GluN2 subunit composition, indicative of GluN2 subtype-based postsynaptic heterogeneity. GluN2A, 2A and 2B, or 2B and 2D synaptic predominance functioned on distinct lamina I neuron types to narrowly, intermediately, or widely tune, respectively, the duration of evoked unitary depolarization events from resting membrane potential, which enabled individual synapses to grade differentially depolarizing steps during temporally patterned afferent input. Our results lead to a model wherein a core locus of proteomic complexity prevails at this central glutamatergic sensory synapse that involves distinct GluN2 subtype configurations. These findings have major implications for subthreshold integrative capacity and transmission strength in spinal lamina I and other CNS regions.

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Introducción: En los últimos años, los tratamientos de FIV en ciclo natural y la FIV con estimulación ovárica “suave” están resurgiendo como una opción más segura, económica y cómoda para las pacien-tes. Definimos FIV en ciclo natural como el tratamiento en el que los ovocitos son obtenidos de un ciclo ovulatorio espontáneo. Cuando añadimos fármacos orales (citrato de clomifeno o letrozol), hablamos de estimulación “mínima”. El objetivo de este estudio es clarificar si la introducción de esta medicación es beneficiosa para las pacientes. Materials y métodos: Analizamos retrospectivamente los tratamientos de FIV en ciclo natural o con estimulación mínima llevados realizados en nuestro centro de enero 2016 a diciembre 2020.Resultados: Encontramos diferencias significativas entre los dos protocolos en el número de ovocitos obtenidos después de la punción folicular (1.03 vs 1.63, p<0.001), número de ovocitos maduros (0.9 vs 1.3, p < 0.01), ovocitos fecundados (0.7 vs 1.1, p < 0.01), y número de embriones disponibles para trans-ferencia (0.5 vs 0.7, p < 0.01). Sin embargo, no encontramos diferencias en la tasa de embarazo (26,3% vs 19,6%, p=0.251) ni en la tasa de recién nacido vivo (16.3% vs 14,3%, p=0.7806).Discusión: Añadir medicación oral a la FIV en ciclo natural no parece tener ningún impacto sobre los resultados clínicos del ciclo. Son necesarios más estudios, pero podríamos reconsiderar la necesidad de añadir esta medicación, ya que supone un mayor coste para los pacientes. (AU)

Introduction: In recent years, natural cycle IVF and minimal ovarian stimulation IVF had been under-going a revival, gaining recognition as safer, cheaper, and more comfortable options for patients. We define natural cicle IVF as the treatment in which oocytes are obtained from a spontaneous ovulatory cycle. When oral drugs are used (usually clomiphene citrate or letrozole), the process is referred to as minimal ovarian stimulation cycle IVF. The aim of this study is to clarify whether the introduction of oral medication is beneficial for patients.Methods: We retrospectively analysed all natural or minimal ovarian stimulation IVF treatments that took place in our clinic during the studied period (January 2016 - December 2020). Descriptive variables were analysed with a t-test, and a chi-square test was performed on result variables. Results: We found significant differences, between both protocols, in the number of oocytes obtained after oocyte retrieval (1.03 vs 1.63, p<0.001), number of mature oocytes (0.9 vs 1.3, p < 0.01), fertilized oocytes (0.7 vs 1.1, p < 0.01), and number of embryos available for transfer (0.5 vs 0.7, p < 0.01).Howe-ver, we did not found signficant differences in terms of pregnancy rate (26,3% vs 19,6%, p=0.251) or live birth rate (16.3% vs 14,3%, p=0.7806). (AU)

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BACKGROUND: We investigated the efficacy of progestin-primed ovarian stimulation (PPOS) and minimal stimulation using clomiphene citrate (CC) + gonadotropin (Gn) for in-vitro fertilization-embryo transfer (IVF-ET) in advanced maternal age (AMA) women with poor ovarian response (POR) according to the Patient-Oriented Strategies Encompassing Individualized Oocyte Number (POSEIDON) criteria. METHODS: A retrospective analysis was performed using the data of AMA patients who had received IVF-ET due to a low ovarian reserve. The enrolled patients were screened according to the POSEIDON group 4 criteria. 102 patients were included in the study, including 52 in the PPOS group and 50 in the minimal stimulation group (who received CC + Gn). The duration of Gn administration, Gn dose, estradiol (E2), and luteinizing hormone (LH) levels on the day of trigger, the cancellation rate of the oocyte retrieval cycle, the number of oocytes retrieved, the number of metaphase II (MII) oocytes, and IVF laboratory outcomes during ovarian stimulation were compared between the 2 groups. RESULTS: No significant differences were found in terms of age, infertility, body mass index (BMI), and basal follicle-stimulating hormone, LH, E2, AFC, and AMH between the 2 groups (all P>0.05). The duration of ovarian stimulation [(9.43±2.44) vs. (7.48±3.09) days, P<0.05] was significantly longer and the total Gn dose [(2,423.22±738.66) vs. (1,579.68±728.86) IU, P<0.05] were significantly higher in the PPOS group than the minimal stimulation group. The LH value on the day of trigger in the PPOS group (3.28 mIU/mL) was significantly lower than that in the minimal stimulation group (5.57 mIU/mL) (P<0.05). The number of oocytes retrieved, normal fertilization rate, number of good-quality embryos on day 3, number of transferable embryos, and number of frozen blastocysts did not differ significantly between the 2 groups (all P>0.05). The proportion of MII oocytes was significantly higher in the PPOS group than the minimal stimulation group (94.05% vs. 81.40%, P<0.05). CONCLUSIONS: For patients in the POSEIDON group 4, PPOS effectively blocked the premature LH surge and increased the proportion of mature oocytes. Thus, it is a feasible ovulation stimulation protocol for AMA women with POR.

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Oocyte in vitro maturation (IVM) is an assisted reproductive technology with a long and sometimes checked history. It is a minimally invasive technique involving the deliberate collection of immature oocytes from patients that have received no or minimal ovarian stimulation and the culture of oocytes to maturity in vitro, before standard procedures thereafter. Now, IVM is classified as nonexperimental and is primarily indicated for patients with a high antral follicle count, especially patients with polycystic ovaries or polycystic ovary syndrome, as well as for fertility preservation in cancer patients. In the recent past, IVM practice has had a confusing array of clinical protocols and has been slow to adapt to new scientific insights; however, recently, significant advances have been made in IVM culture methods based on new knowledge from animal studies, combined with defining a simple patient treatment protocol. These improvements have led to significant recent progress in IVM practice to the extent that IVM is now routinely practiced in a growing number of centers with specialized expertise around the world.

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Background: The optimal protocol for minimal stimulation in vitro fertilization (IVF) has yet to be established. This study aims to determine if the use of gonadotropin-releasing hormone (GnRH) antagonist during minimal stimulation improves outcomes. Materials and Methods: All cycles designated as minimal stimulation from 2014 to 2016 from the Society for Assisted Reproductive Technology Clinic Online Reporting System were identified. Cycles in which GnRH antagonist was administered (n = 5984) were compared to those that did not receive it (n = 7066). Wilcoxon's rank-sum test and chi-square test were used to analyze continuous and categorical variables. Results: A total of 6750 patients undergoing 13,050 cycles were included. GnRH antagonist use was associated with a significantly higher total gonadotropin dosage (median 975.0 [interquartile range, IQR, 600.0, 1575.0] vs. median 660.0 [IQR 375.0, 975.0], p < 0.001), lower cycle cancelation rate (11.3% vs. 13.6%, p < 0.001; OR 1.24, 95% CI 1.12-1.38, p < 0.001), and higher live birth rate (4.3% vs. 2.1%, p < 0.001; OR 0.47, 95% CI 0.39-0.58, p < 0.001). GnRH antagonist use was associated with a significantly higher live birth rate in women ≥35 years of age (2.7% vs. 0.9%, p < 0.001; OR 0.34, 95% CI 0.25-0.47, p < 0.001) and antimullerian hormone <1 (4.9% vs. 2.6%, p = 0.004; OR 0.52, 95% CI 0.33-0.81, p = 0.004). Conclusion: The use of GnRH antagonist suppression during minimal stimulation IVF is associated with an improved live birth rate, especially in older women and in women with diminished ovarian reserve. Although GnRH antagonist use may increase costs, it significantly decreases cancelation rate, increases number of embryos cryopreserved, and should be encouraged for minimal stimulation IVF.

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The substantia gelatinosa (SG, lamina II of spinal cord gray matter) is pivotal for modulating nociceptive information from the peripheral to the central nervous system. γ-Aminobutyric acid type B receptors (GABABRs), the metabotropic GABA receptor subtype, are widely expressed in pre- and postsynaptic structures of the SG. Activation of GABABRs by exogenous agonists induces both pre- and postsynaptic inhibition. However, the actions of endogenous GABA via presynaptic GABABRs on glutamatergic synapses, and the postsynaptic GABABRs interaction with glutamate, remain elusive. In the present study, first, using in vitro whole-cell recordings and taking minimal stimulation strategies, we found that in rat spinal cord glutamatergic synapses, blockade of presynaptic GABABRs switched "silent" synapses into active ones and increased the probability of glutamate release onto SG neurons; increasing ambient GABA concentration mimicked GABABRs activation on glutamatergic terminals. Next, using holographic photostimulation to uncage glutamate on postsynaptic SG neurons, we found that postsynaptic GABABRs modified glutamate-induced postsynaptic potentials. Taken together, our data identify that endogenous GABA heterosynaptically constrains glutamate release via persistently activating presynaptic GABABRs; and postsynaptically, GABABRs modulate glutamate responses. The results give new clues for endogenous GABA in modulating the nociception circuit of the spinal dorsal horn and shed fresh light on the postsynaptic interaction of glutamate and GABA.

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OBJECTIVE: To present our experience using four consecutive minimal COS (TetraStim) followed by oocyte retrieval and vitrification to increase the number of oocytes in patients with POR for whom oocyte donation is not an option. METHODS: We performed an observational study evaluating 128 poor responders submitted to TetraStim instead of oocyte donation cycles. Patients were submitted to four consecutive minimal COS started at luteal phase, oocyte retrieval, oocyte vitrification/warming, ICSI, endometrial priming and embryo transfer. We evaluated the number of vitrified oocytes, survival rate after warming, fertilization rate, cleavage rate, number of embryos transferred, clinical pregnancy rate, miscarriage rate and live birth rate. RESULTS: The mean age was 38.1 ± 3.1 years. A total of 791 oocytes were recovered (6.1 ± 2.7/patient), 682 (86.2%) Metaphase II (5.3 ± 2.4/patient) were vitrified, 95.3% survived warming (5.1 ± 2.3/patient), 82% showed normal fertilization after ICSI (4.2 ± 2/patient), 79.2% reached cleavage stage (3.3 ± 1.6/patient), 313 cleavage stage embryos were transferred to 115 patients (2.7 ± 0.7/patient) and 14.7% of the patients had surplus embryos that were vitrified. Clinical pregnancy rate per patient was 31.3% and live birth rate per patient was 22.6%. CONCLUSION: To our knowledge this is the first study that demonstrates that TetraStim can be an effective alternative for patients with POR with an indication to perform IVF with donated oocytes, but do not agree to use. TetraStim is a feasible alternative to increase the number of oocytes and embryos and improve pregnancy rates with no dropouts and very low cycle cancelation rate. However, randomized controlled studies must be performed to compare TetraStim with other treatments.

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Although it is well appreciated that ovarian stimulation protocols for in vitro fertilization (IVF) alter endometrial receptivity, the precise cellular mechanisms are not known. To gain insights into potential mechanisms by which different ovarian stimulation protocols alter the endometrium, we compared histologic and gene expression profiles of endometrium from women undergoing conventional ovarian stimulation for IVF (C-IVF) with those undergoing minimal stimulation with clomiphene citrate (MS-IVF). Sixteen women undergoing MS-IVF (n = 8) or C-IVF (n = 8) were recruited for endometrial biopsy at the time of oocyte retrieval. Endometrial glands were large, tortuous, and secretory with C-IVF but small and undifferentiated with MS-IVF. Whereas RNA sequencing did not reveal changes in estrogen receptor or its co-regulators or classic proliferation associated genes in MS-IVF, together with immunohistochemistry, Wnt signaling was disrupted in endometrium from MS-IVF cycles with significant upregulation of Wnt inhibitors. Secreted frizzled-related protein 1 (sFRP1) was increased fourfold (p < 0.01), and sFRP4 was upregulated sixfold (p < 0.01) relative to C-IVF. Further these proteins were localized to subepithelial endometrial stroma. These data indicate that MS-IVF protocols with CC do not seem to impact endometrial estrogen signaling as much as would be expected from the reported antiestrogenic properties of CC. Rather, the findings of this study highlight Wnt signaling as a major factor for endometrial development during IVF cycles.

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PURPOSE: To determine age-adjusted overall success rates for patients undergoing clomiphene citrate only minimal stimulation cycle (mini) in vitro fertilization (IVF) without any gonadotropin administration. METHODS: Eight hundred thirty-nine women (mean age: 38.4 ± 0.1 years; 2488 cycles) underwent clomiphene citrate only mini-IVF. Their first oocyte retrieval was between January 2009 and December 2009, with follow-up until December 2014. The cumulative live birth rate (CLBR) per oocyte retrieval cycle started and live birth rate per oocyte was retrospectively analyzed. The basic CLBR was calculated as the number of women who achieved a live birth divided by the total number of women who started oocyte retrieval. RESULTS: The mean number of oocytes retrieved was 1.5. The basic CLBRs for all ages after the first and third cycles were 22.6% and 39.2%, respectively. For ≤ 34 years, 35-37 years, 38-40 years, 41-42 years, and ≥ 43 years, CLBRs after the first and third cycles were 42.5% and 70.1%, 32.9% and 49.1%, 20.0% and 38.6%, 12.6% and 25.2%, and 4.4% and 8.8%, respectively. These rates had a significant relationship with age (P < 0.01). The LBR per oocyte for all ages was 9.6%. CONCLUSION: Acceptable overall IVF success rates can be achieved in clomiphene citrate only mini-IVF, as well as acceptable LBR. The CLBRs and LBRs per oocyte are evidently influenced by women's age.

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Resumen OBJETIVO: Evaluar los desenlaces de una estrategia combinada para fertilización in vitro: mínima estimulación ovárica, diagnóstico genético preimplantación para aneuploidias y transferencia de un solo embrión. MATERIALES Y MÉTODOS: Estudio de cohorte, retrospectivo, efectuado en dos centros de reproducción de México, en un periodo de tres años. Se incluyeron pacientes entre 25 y 45 años, en protocolo de fertilización in vitro, con mínima estimulación, diagnóstico genético preimplantación para aneuploidias (PGT-A) y transferencia de embrión único. El diagnóstico genético preimplantación se estableció mediante microarreglos y secuenciación de nueva generación (NGS). Para el análisis estadístico se integraron 5 grupos, según la edad de las pacientes: menores de 35 años; 35 a 37 años; 38 a 40 años; 41 a 42 años; y mayores de 42 años. Mediante estadística descriptiva se analizaron las variables numéricas y categóricas. RESULTADOS: Se analizaron 175 ciclos, en 125 pacientes (edad promedio: 39 años ± 5). Se obtuvieron, en promedio, 5 óvulos por ciclo. La tasa de fertilización fue de 86.5% y la de blastocisto por óvulo fertilizado de 50.7%. Se tomó biopsia para diagnóstico genético preimplantación para aneuploidias a 404 embriones. La tasa general de euploidia fue de 33%. Se efectuaron 69 transferencias de embrión único, con una tasa de embarazo por transferencia de 71%. La tasa de nacimiento por transferencia fue de 60.8% (42 nacimientos). CONCLUSIONES: La combinación de mínima estimulación, diagnóstico genético preimplantación para aneuploidias y transferencia de embrión único, es un procedimiento adecuado para alcanzar una tasa de nacimiento alta.

Abstract OBJECTIVE: To evaluate results of a combined approach in IVF, using minimal stimulation, preimplantation genetic testing for aneuploidy, and single blastocyst transfer. MATERIALS AND METHODS: Retrospective cohort study over a three years' period in two fertility centers in Mexico. A total of 125 patients were included, between 25 and 45 years old, with minimal stimulation IVF, preimplantation genetic testing for aneuploidy (PGT-A) and single euploid embryo transfer. PGT was performed using microarrays and next generation sequencing (NGS). RESULTS: A total of 175 cycles (mean age: 39 years old) were analyzed in 125 patients. On average, five eggs were collected per cycle; fertilization rate was 86.57%; blastocyst rate was 50.7% per fertilized egg. Only 33% of embryos were euploid. Pregnancy rate per transferred embryo was 71%. Live birth rate was 60.8% (42 births). CONCLUSIONS: A combination of minimal stimulation, PGT-A and single blastocyst embryo transfer can yield a high live birth rate.

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Background To determine whether a minimal stimulation (MS) or high-dose stimulation (HDS) protocol is a better option for patients classified as poor ovarian responders (POR) in terms of reproductive and pregnancy outcomes. Materials and methods A database search for evaluation of the study outcome by using meta-analysis method was carried out. The primary outcome was the clinical pregnancy (CP) rate for each of two groups, namely, the MS and HDS groups. The secondary outcomes were the gonadotropin dose used, duration of stimulation, cancellation rate, number of oocytes retrieved, number of fertilized oocytes, number of embryos transferred and live birth rates. Results Across five databases, 4670 potential studies for further screening were selected. But ultimately only six studies, three RCTs and three retrospective or case control studies were selected that meet the Bologna criteria for POR. In all there were 624 cycles. Our meta-analysis indicated that the CP rates, cycle cancellation rates, durations of stimulation, numbers of oocytes fertilized and numbers of embryos transferred were not statistically significant. Clearly, the number of oocytes retrieved in the MS group was significantly lower than in the HDS group, while the HDS group consumed significantly higher doses of gonadotropins than the MS group. The live birth rates were significantly higher in the MS group than in the HDS group. Conclusion MS should be the first-line protocol for managing POR because the live birth rate is significantly higher, even with fewer oocytes retrieved.

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Adaptive motor control critically depends on the interconnected nuclei of the basal ganglia in the CNS. A pivotal element of the basal ganglia is the subthalamic nucleus (STN), which serves as a therapeutic target for deep brain stimulation (DBS) in movement disorders, such as Parkinson's disease. The functional connectivity of the STN at the microcircuit level, however, still requires rigorous investigation. Here we combine multiple simultaneous whole-cell recordings with extracellular stimulation and post hoc neuroanatomical analysis to investigate intrinsic and afferent connectivity and synaptic properties of the STN in acute brain slices obtained from rats of both sexes. Our data reveal an absence of intrinsic connectivity and an afferent innervation with low divergence, suggesting that STN neurons operate as independent processing elements driven by upstream structures. Hence, synchrony in the STN, a hallmark of motor processing, exclusively depends on the interactions and dynamics of GABAergic and glutamatergic afferents. Importantly, these inputs are subject to differential short-term depression when stimulated at high, DBS-like frequencies, shifting the balance of excitation and inhibition toward inhibition. Thus, we present a mechanism for fast yet transient decoupling of the STN from synchronizing afferent control. Together, our study provides new insights into the microcircuit organization of the STN by identifying its neurons as parallel processing units and thus sets new constraints for future computational models of the basal ganglia. The observed differential short-term plasticity of afferent inputs further offers a basis to better understand and optimize DBS algorithms.SIGNIFICANCE STATEMENT The subthalamic nucleus (STN) is a pivotal element of the basal ganglia and serves as target for deep brain stimulation, but information on the functional connectivity of its neurons is limited. To investigate the STN microcircuitry, we combined multiple simultaneous patch-clamp recordings and neuroanatomical analysis. Our results provide new insights into the synaptic organization of the STN identifying its neurons as parallel processing units and thus set new constraints for future computational models of the basal ganglia. We further find that synaptic dynamics of afferent inputs result in a rapid yet transient decoupling of the STN when stimulated at high frequencies. These results offer a better understanding of deep brain stimulation mechanisms, promoting the development of optimized algorithms.

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OBJECTIVE: Minimal stimulation IVF is a treatment option that uses clomiphene citrate (CC). We sought to evaluate how CC impacts endometrial thickness during minimal stimulation IVF cycles. METHODS: We retrospectively analyzed a cohort of 230 cycles in 119 poor ovarian response patients. The IVF cycles were studied in three groups: 130 minimal stimulation cycles, 29 mild stimulation cycles, and 30 conventional high dose gonadotropin releasing hormone (GnRH) antagonist cycles. Thirty-three minimal stimulation IVF patients had 41 frozen embryo transfers (FET) which allowed us to study whether the CC effects were prolonged. RESULTS: Endometrial thickness in the minimal stimulation group was significantly lower than the mild and conventional stimulation groups (7.3±2.2mm versus 11.4±3.3mm versus 12.9±3.8mm, respectively, p<0.0001). In patients who underwent minimal stimulation IVF followed by FET, significantly thicker endometrial thickness was achieved during their FET cycles as compared to their minimal stimulation cycles (7.95±2.1mm versus 10.3±1.8mm, p<0.0001). CONCLUSION: We concluded that endometrial thickness is impacted during minimal stimulation IVF cycles. Since negative effects on endometrial thickness are not observed in the patients' subsequent FET cycle, a freeze-all approach is justified to mitigate adverse endometrial effects of CC in minimal stimulation IVF cycles.

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AIM OF STUDY: Over the last decade, the laboratory procedures in artificial reproduction have improved. Hyperstimulation causes an overload of eggs which will never be used. The present study was designed to evaluate the efficiency of a mild stimulation. To obtain oocytes for In Vitro Fertilization (IVF) a short antagonist protocol using Tamoxiphene and FSH was compared to conventional IVF. METHODS: A retrospective and observatory study including all patients with unexplained infertility. In total 720 cycles with mild stimulation protocol and 8,446 cycles with regular short antagonist IVF protocol were analysed. The observation period was from January 2011 until September 2017. All patients were recruited in the same time period and allocated to different treatments upon their request. Low stimulation using orally administrated anti-estrogenic drugs combined with FSH in the form of injections was used in order to obtain up to four mature follicles. RESULTS: The clinical pregnancy rate (CPR) per embryo transfer (ET) was 25% for the mild stimulation group. The CPR for the control group with conventional IVF was 23%. CONCLUSION: Mild stimulation may be an important step towards an easier IVF approach, more tolerable for women, easier and cheaper for the women and the society, while maintaining an acceptable success rate in terms of CPR. Large prospective studies need to be performed.

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Synaptic transmission and its activity-dependent modulation, known as synaptic plasticity, are fundamental processes in nervous system function. Neurons may receive thousands of synaptic contacts, but synaptic regulation may occur only at individual or discrete subsets of synapses, which may have important consequences on the spatial extension of the modulation of synaptic information. Moreover, while several electrophysiological methods are used to assess synaptic transmission at different levels of observation, i.e., through local field potential and individual whole-cell recordings, their experimental limitations to detect synapse-specific modulation is poorly defined. We have investigated how well-known synapse-specific short-term plasticity, where some synapses are regulated and others left unregulated, mediated by astrocytes and endocannabinoid (eCB) signaling can be assessed at different observational levels. Using hippocampal slices, we have combined local field potential and whole-cell recordings of CA3-CA1 synaptic activity evoked by Schaffer collateral stimulation of either multiple or single synapses through bulk or minimal stimulation, respectively, to test the ability to detect short-term synaptic changes induced by eCB signaling. We also developed a mathematical model assuming a bimodal distribution of regulated and unregulated synapses based on realistic experimental data to simulate physiological results and to predict the experimental requirements of the different recording methods to detect discrete changes in subsets of synapses. We show that eCB-induced depolarization-induced suppression of excitation (DSE) and astrocyte-mediated synaptic potentiation can be observed when monitoring single or few synapses, but are statistically concealed when recording the activity of a large number of synapses. These results indicate that the electrophysiological methodology is critical to properly assess synaptic changes occurring in subsets of synapses, and they suggest that relevant synapse-specific regulatory phenomena may be experimentally undetected but may have important implications in the spatial extension of synaptic plasticity phenomena.

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It has been proven that the use of high gonadotropin dose does not necessarily improve the final outcome of IVF. Mild ovarian stimulation is based on the principle of optimal utilization of competent oocytes/embryos and endometrial receptivity. There is growing evidence that the pregnancy or live birth rates with mild-stimulation protocols are comparable to those with conventional IVF; the cumulative pregnancy outcome has been shown to be no different, despite having fewer numbers of oocytes or embryos available with milder ovarian stimulation. Although equally effective, mild-stimulation IVF is associated with a greater safety profile, in terms of the incidence of ovarian hyperstimulation syndrome and venous thromboembolism. It is also found to be better tolerated by patients and less expensive. Emerging research evidence may lead to widespread acceptance of mild IVF, by both patients and IVF providers, and make IVF more accessible to women and couples worldwide.

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The first live birth after IVF was achieved in a purely natural cycle. Because early attempts at IVF were associated with low efficiency, ovarian stimulation was added to achieve a greater margin for error in oocyte retrieval, fertilization, and thus, overall pregnancy success. As technology improved, the intuitive appeal of the natural cycle led investigators to once again attempt IVF without antecedent gonadotropin stimulation. Triggering of ovulation with hCG was added to allow for accurate scheduling of oocyte retrieval and thus increased oocyte yield. When GnRH antagonists became available, premature ovulations could be prevented, albeit at the cost of adding some form of ovarian stimulation to continue follicle development until ovulation triggering. This type of cycle came to be known as the "modified natural cycle." These modified natural IVF cycles are associated with decreased medication costs, they produce acceptable pregnancy rates, and they may be particularly appropriate for patients at increased risk of ovarian hyperstimulation syndrome, poor responders, and those wishing to avoid supernumerary embryo production.

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There has been increasing interest in combining the oral agents clomiphene citrate (CC) and letrozole with gonadotropins in IVF: for poor responders to reduce the amount of gonadotropins used, and in normal responders to reduce the incidence of ovarian hyperstimulation (OHSS). In normal responders, mild stimulation with the use of CC and gonadotropins was found to decrease the number of oocytes retrieved and result in good pregnancy rates, but in most studies the cumulative pregnancy rate was lower compared with conventional ovarian stimulation when frozen embryo transfers were considered. Coadministration of letrozole and gonadotropins has mainly been used in patients with breast cancer to prevent the massive elevation of serum E2 concentrations with the use of standard controlled ovarian hyperstimulation. CC and letrozole have both been used with gonadotropins in poor responders and have been shown to reduce the amount of gonadotropin used without reducing the pregnancy rate. Letrozole use with gonadotropins in IVF cycles may increase endometrial receptivity by increasing integrin expression in the endometrium and by lowering estrogen concentrations to more physiologic levels.

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