Multi-Phase Interleaved AC-DC Step-Down Converter with Power Factor Improvement.

This paper presents the converter design of a single-phase non-isolated step-down controlled rectifier for power factor improvement and output voltage regulation. The converter consists of a full-bridge diode rectifier and a DC-DC interleaved buck converter of two or more switching cells that has an LC filter in its input. It is proposed that the interleaved switching cells operate in discontinuous conduction mode and the current through the input LC filter be continuous, avoiding switching frequency components to be injected into the grid. The controller, which has a simple structure and a small number of sensors, allows the system to achieve a high power factor. It also regulates the output voltage to a constant reference. An experimental prototype is built and tested to validate the analysis and proposed design. The closed-loop converter is evaluated both in a steady state and in transient conditions. At steady state, the converter achieves a power factor above 0.9 with a maximum of 45.4% THD at 110.1W. The main contributions of this paper are guidelines for the design of the converter, open-loop analysis, and converter control.

Real-world data of non-invasive stimulation of the human insula-prefrontal cortices using deep TMS to treat anxiety for occupational stress and generalized anxiety disorder.

Activation of the insula is found in all anxiety-related disorders and increased insular-prefrontal cortex (PFC) functional connectivity is associated with reduced anxiety. In this study, the combined stimulation of the insula and PFC using the dTMS H4 (insula+LPFC) and H2 (PFC) coils were used to reduce anxiety in 13 subjects experiencing occupational stress, and 55 participants suffering from generalized anxiety disorder (GAD). The combined HF stimulation of the insula and PFC significantly decreased anxiety scores according to the HARS, CAS, and STAI anxiety scales, leading to a reduction in anxiety according to HARS of 88.7% and 70.7% in participants with occupational stress and the clinical sample of participants diagnosed with GAD, respectively. The findings suggest that the prefrontal-insular axis is critical for the regulation of anxiety and its stimulation can be used for the treatment of anxiety in people suffering from occupational stress and GAD.

E.L., a modern-day Phineas Gage: Revisiting frontal lobe injury.

Background: How the prefrontal cortex (PFC) recovers its functionality following lesions remains a conundrum. Recent work has uncovered the importance of transient low-frequency oscillatory activity (LFO; < 4 Hz) for the recovery of an injured brain. We aimed to determine whether persistent cortical oscillatory dynamics contribute to brain capability to support 'normal life' following injury. Methods: In this 9-year prospective longitudinal study (08/2012-2021), we collected data from the patient E.L., a modern-day Phineas Gage, who suffered from lesions, impacting 11% of his total brain mass, to his right PFC and supplementary motor area after his skull was transfixed by an iron rod. A systematic evaluation of clinical, electrophysiologic, brain imaging, neuropsychological and behavioural testing were used to clarify the clinical significance of relationship between LFO discharge and executive dysfunctions and compare E.L.´s disorders to that attributed to Gage (1848), a landmark in the history of neurology and neuroscience. Findings: Selective recruitment of the non-injured left hemisphere during execution of unimanual right-hand movements resulted in the emergence of robust LFO, an EEG-detected marker for disconnection of brain areas, in the damaged right hemisphere. In contrast, recruitment of the damaged right hemisphere during contralateral hand movement, resulted in the co-activation of the left hemisphere and decreased right hemisphere LFO to levels of controls enabling performance, suggesting a target for neuromodulation. Similarly, transcranial magnetic stimulation (TMS), used to create a temporary virtual-lesion over E.L.'s healthy hemisphere, disrupted the modulation of contralateral LFO, disturbing behaviour and impairing executive function tasks. In contrast to Gage, reasoning, planning, working memory, social, sexual and family behaviours eluded clinical inspection by decreasing LFO in the delta frequency range during motor and executive functioning. Interpretation: Our study suggests that modulation of LFO dynamics is an important mechanism by which PFC accommodates neurological injuries, supporting the reports of Gage´s recovery, and represents an attractive target for therapeutic interventions. Funding: Fundação de Amparo Pesquisa Rio de Janeiro (FAPERJ), Universidade Federal do Rio de Janeiro (intramural), and Fiocruz/Ministery of Health (INOVA Fiocruz).

Presence of ethanol-sensitive and ethanol-insensitive glycine receptors in the ventral tegmental area and prefrontal cortex in mice.

BACKGROUND AND PURPOSE: Glycine receptors composed of α1 and ß subunits are primarily found in the spinal cord and brainstem and are potentiated by ethanol (10-100 mM). However, much less is known about the presence, composition and ethanol sensitivity of these receptors in higher CNS regions. Here, we examined two regions of the brain reward system, the ventral tegmental area (VTA) and the prefrontal cortex (PFC), to determine their glycine receptor subunit composition and sensitivity to ethanol. EXPERIMENTAL APPROACH: We used Western blot, immunohistochemistry and electrophysiological techniques in three different models: wild-type C57BL/6, glycine receptor subunit α1 knock-in and glycine receptor subunit α2 knockout mice. KEY RESULTS: Similar levels of α and ß receptor subunits were detected in both brain regions, and electrophysiological recordings demonstrated the presence of glycine-activated currents in both areas. Sensitivity of glycine receptors to glycine was lower in the PFC compared with VTA. Picrotoxin only partly blocked the glycine-activated current in the PFC and VTA, indicating that both regions express heteromeric αß receptors. Glycine receptors in VTA neurons, but not in PFC neurons, were potentiated by ethanol. CONCLUSION AND IMPLICATIONS: Glycine receptors in VTA neurons from WT and α2 KO mice were potentiated by ethanol, but not in neurons from the α1 KI mice, supporting the conclusion that α1 glycine receptors are predominantly expressed in the VTA. By contrast, glycine receptors in PFC neurons were not potentiated in any of the mouse models studied, suggesting the presence of α2/α3/α4, rather than α1 glycine receptor subunits.

Interneuron NMDA Receptor Ablation Induces Hippocampus-Prefrontal Cortex Functional Hypoconnectivity after Adolescence in a Mouse Model of Schizophrenia.

Although the etiology of schizophrenia is still unknown, it is accepted to be a neurodevelopmental disorder that results from the interaction of genetic vulnerabilities and environmental insults. Although schizophrenia's pathophysiology is still unclear, postmortem studies point toward a dysfunction of cortical interneurons as a central element. It has been suggested that alterations in parvalbumin-positive interneurons in schizophrenia are the consequence of a deficient signaling through NMDARs. Animal studies demonstrated that early postnatal ablation of the NMDAR in corticolimbic interneurons induces neurobiochemical, physiological, behavioral, and epidemiological phenotypes related to schizophrenia. Notably, the behavioral abnormalities emerge only after animals complete their maturation during adolescence and are absent if the NMDAR is deleted during adulthood. This suggests that interneuron dysfunction must interact with development to impact on behavior. Here, we assess in vivo how an early NMDAR ablation in corticolimbic interneurons impacts on mPFC and ventral hippocampus functional connectivity before and after adolescence. In juvenile male mice, NMDAR ablation results in several pathophysiological traits, including increased cortical activity and decreased entrainment to local gamma and distal hippocampal theta rhythms. In addition, adult male KO mice showed reduced ventral hippocampus-mPFC-evoked potentials and an augmented low-frequency stimulation LTD of the pathway, suggesting that there is a functional disconnection between both structures in adult KO mice. Our results demonstrate that early genetic abnormalities in interneurons can interact with postnatal development during adolescence, triggering pathophysiological mechanisms related to schizophrenia that exceed those caused by NMDAR interneuron hypofunction alone.SIGNIFICANCE STATEMENT NMDAR hypofunction in cortical interneurons has been linked to schizophrenia pathophysiology. How a dysfunction of GABAergic cortical interneurons interacts with maturation during adolescence has not been clarified yet. Here, we demonstrate in vivo that early postnatal ablation of the NMDAR in corticolimbic interneurons results in an overactive but desynchronized PFC before adolescence. Final postnatal maturation during this stage outspreads the impact of the genetic manipulation toward a functional disconnection of the ventral hippocampal-prefrontal pathway, probably as a consequence of an exacerbated propensity toward hippocampal-evoked depotentiation plasticity. Our results demonstrate a complex interaction between genetic and developmental factors affecting cortical interneurons and PFC function.

Alpha1-adrenergic drugs affect the development and expression of ethanol-induced behavioral sensitization.

BACKGROUND: According to the incentive sensitization theory, addiction is caused primarily by drug-induced sensitization in the brain mesocorticolimbic systems. After repeated ethanol administration, some animals develop psychomotor sensitization, a phenomenon which occurs simultaneously with the incentive sensitization. Recent evidence suggests the involvement of norepinephrine (NE) in drug addiction, with a critical role in the ethanol reinforcing properties. In this study we evaluated the influence of an agonist (phenylephrine) and an antagonist (prazosin) of alpha1-adrenergic receptors on the development and expression of behavioral sensitization to ethanol. Male Swiss mice, previously treated with ethanol or saline, were challenged with the combined administration of ethanol (or saline) with alpha1-adrenergic drugs. Prazosin (0.1; 0.5 and 1.0 mg/kg) and phenylephrine (1.0 and 2.0 mg/kg) administration blocked the expression of behavioral sensitization to ethanol. In another set of experiments, mice treated with 0.5mg/kg of prazosin+ethanol did not present the development of behavioral sensitization. However, when challenged with ethanol alone, they showed the same sensitized levels of locomotor activity of those presented by mice previously treated with ethanol and saline. Phenylephrine (1.0 mg/kg) treatment did not affect the development of behavioral sensitization. Based on this data, we concluded that the alteration of alpha1-adrenergic receptors functioning, by the administration agonists or antagonists, affected the locomotor sensitization to the stimulant effect of ethanol, suggesting that the normal functioning of the noradrenergic system is essential to its development and expression.

GABA-A receptor modulators alter emotionality and hippocampal theta rhythm in an animal model of long-lasting anxiety.

The cholinergic system is implicated in emotional regulation. The injection of non-convulsant doses of the muscarinic receptor agonist pilocarpine (PILO) induces long-lasting anxiogenic responses in rats evaluated at different time-points (24h to 3 months). To investigate the underlying mechanisms, rats treated with PILO (150mg/kg) were injected 24h or 1 month later with an anxiolytic (diazepam, 1mg/kg, DZP) or anxiogenic (pentylenetetrazole, 15mg/kg, PTZ) drug and evaluated in the elevated plus-maze (EPM). Prefrontal cortex (PFC) and hippocampal (HIP) electroencephalographic recordings and acetylcolinesterase (AChE) activity were also analyzed after PILO treatment. Anxiogenic responses observed in the EPM 24h or 1 month after PILO treatment (e.g., decreased time spent and number of entries into the open arms of the maze) were blocked by DZP but not affected by PTZ. No epileptiform events were registered in the HIP or PFC at 24h or 1 month after PILO injection, but enhanced theta activity was observed in the HIP. DZP decreased hippocampal theta of PILO-treated rats in contrast with PTZ, which increased this parameter in saline- and PILO-treated rats. The HIP and PFC AChE activity did not change after PILO treatment. Our findings demonstrate that the long-term effects on the emotionality of rats induced by PILO are associated with electrophysiological changes in the HIP and sensitive to pharmacological manipulation of the GABAergic system. The present work may support this new research model of long-lasting anxiety, while also highlighting the muscarinic system as a potential target involved in anxiety disorders.

Distribution of the Val108/158Met polymorphism of the COMT gene in healthy Mexican population.

Catechol-O-methyltransferase (COMT) inactivates the catecholamines adrenaline, noradrenaline and dopamine. On the other hand, some studies have reported that the enzymatic activity of COMT is partly genetically determined. With regard to the COMT gene, the most studied polymorphism is the functional variant Val108/158Met (rs4680), which results in substantial three- to four-fold variations in enzyme activity. To date, the rs4680 polymorphism of COMT has been associated with a number of disorders. In addition, this polymorphism has been found to have important differences in frequency according to the studied population. Therefore, the aim of the present study was to evaluate the frequency of a common single nucleotide polymorphism (SNP) Val108/158Met of the COMT gene in the Mexican population. Accordingly, we recruited 431 healthy volunteers. Our sample consisted of 111 healthy individuals from Mexico City and 320 individuals from the state of Tabasco, Mexico. We observed that Met was the most common allele, ranging from 57% (Tabasco) to 85% (Mexico City). In addition, we analyzed the frequency of Val108/158Met polymorphism of Caucasian (54% Met allele), Asian (29% Met allele) and African (34% Met allele) populations separately and also in comparison with Mexican (63% Met allele) population. In conclusion, the distribution of the Val108/158Met polymorphism distinguishes the Mexican population studied from other populations, but it is necessary to increase the size of the sample to get more conclusive results.

Ascending monoaminergic systems alterations in Alzheimer's disease. translating basic science into clinical care.

Extensive neuropathological studies have established a compelling link between abnormalities in structure and function of subcortical monoaminergic (MA-ergic) systems and the pathophysiology of Alzheimer's disease (AD). The main cell populations of these systems including the locus coeruleus, the raphe nuclei, and the tuberomamillary nucleus undergo significant degeneration in AD, thereby depriving the hippocampal and cortical neurons from their critical modulatory influence. These studies have been complemented by genome wide association studies linking polymorphisms in key genes involved in the MA-ergic systems and particular behavioral abnormalities in AD. Importantly, several recent studies have shown that improvement of the MA-ergic systems can both restore cognitive function and reduce AD-related pathology in animal models of neurodegeneration. This review aims to explore the link between abnormalities in the MA-ergic systems and AD symptomatology as well as the therapeutic strategies targeting these systems. Furthermore, we will examine possible mechanisms behind basic vulnerability of MA-ergic neurons in AD.