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BACKGROUND: The impulsive choice is characterized by the preference for a small immediate reward over a bigger delayed one. The mechanisms underlying impulsive choices are linked to the activity in the Nucleus Accumbens (NAc), the orbitofrontal cortex (OFC), and the dorsolateral striatum (DLS). While the study of functional connectivity between brain areas has been key to understanding a variety of cognitive processes, it remains unclear whether functional connectivity differentiates impulsive-control decisions. METHODS: To study the functional connectivity both between and within NAc, OFC, and DLS during a delay discounting task, we concurrently recorded local field potential in NAc, OFC, and DLS in rats. We then quantified the degree of phase-amplitude coupling (PAC), coherence, and Granger Causality between oscillatory activities in animals exhibiting either a high (HI) or low (LI) tendency for impulsive choices. RESULTS: Our results showed a differential pattern of PAC during decision-making in OFC and NAc, but not in DLS. While theta-gamma PAC in OFC was associated with self-control decisions, a higher delta-gamma PAC in both OFC and NAc biased decisions toward impulsive choices in both HI and LI groups. Furthermore, during the reward event, Granger Causality analysis indicated a stronger NAc➔OFC gamma contribution in the HI group, while the LI group showed a higher OFC➔NAc gamma contribution. CONCLUSIONS: The overactivity in NAc during reward in the HI group suggests that exacerbated contribution of NAcCore can lead to an overvaluation of reward that biases the behavior toward the impulsive choice.

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Intermittent ethanol consumption changes the neuronal activity of the orbitofrontal cortex (OFC) in rodents, which has been attributed to important participation in the development of addiction, particularly alcoholism. The OFC participates in gustatory sensory integration. However, it is unknown whether this region can encode chemosensory elements of oral ethanol administration independently of the consumption movement (orofacial motor response) when administered for the first time (naïve mice). To answer this question, we used a sedated mouse model and a temporary analysis protocol to register extracellular neuronal responses during the oral administration of ethanol. Our results show an increase in neuronal frequency (in the first 500 ms) when low (0.6, 1, and 2.1 M) and high (3.2, 4.3, and 8.6 M) concentrations of ethanol are orally administered. The modulatory effect of ethanol was observed from low and high concentrations and differed from the tastants. There was consistent neuronal activity independent of the concentration of ethanol. Our results demonstrate a sensory representation of oral ethanol stimulation in the OFC neurons of naïve mice under sedation.

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BACKGROUND: There have been significant challenges in understanding functional brain connectivity associated with adolescent depression, including the need for a more comprehensive approach to defining risk, the lack of representation of participants from low- and middle-income countries, and the need for network-based approaches to model connectivity. The current study aimed to address these challenges by examining resting-state functional connectivity of frontolimbic circuitry associated with the risk and presence of depression in adolescents in Brazil. METHODS: Adolescents in Brazil ages 14 to 16 years were classified into low-risk, high-risk, and depressed groups using a clinical assessment and composite risk score that integrates 11 sociodemographic risk variables. After excluding participants with excessive head movement, resting-state functional magnetic resonance imaging data of 126 adolescents were analyzed. We compared group differences in frontolimbic network connectivity using region of interest-to-region of interest, graph theory, and seed-based connectivity analyses. Associations between self-reported depressive symptoms and brain connectivity were also explored. RESULTS: Adolescents with depression showed greater dorsal anterior cingulate cortex (ACC) connectivity with the orbitofrontal cortex compared with the 2 risk groups and greater dorsal ACC global efficiency than the low-risk group. Adolescents with depression also showed reduced local efficiency and a lower clustering coefficient of the subgenual ACC compared with the 2 risk groups. The high-risk group also showed a lower subgenual ACC clustering coefficient relative to the low-risk group. CONCLUSIONS: These findings highlight altered connectivity and topology of the ACC within frontolimbic circuitry as potential neural correlates and risk factors of developing depression in adolescents in Brazil. This study broadens our understanding of the neural connectivity associated with adolescent depression in a global context.

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The objective of the study was to determine if sex plays a moderating role in the relationship between executive functions and academic procrastination in 106 university students of both genders (28.3% male and 71.7% female) between the ages of 18 and 30 years (M = 19.7; SD = 2.7). The Academic Procrastination Scale and the Neuropsychological Battery of Executive Functions and Frontal Lobes (BANFE-2) were used to measure the variables. The results of the study showed that the degree of prediction of the tasks linked to the orbitomedial cortex (involves the orbitofrontal cortex [OFC] and the medial prefrontal cortex [mPFC]) on academic procrastination is significantly moderated by the sex of the university students (ß3 = 0.53; p < 0.01). For men, the estimated effect of the tasks linked to the orbitomedial cortex on the degree of academic procrastination is -0.81. For women, the estimated effect of the tasks linked to the orbitomedial cortex on the degree of academic procrastination is -0.28. In addition, it was shown that sex does not play a moderating role in the relationship between the tasks linked to the dorsolateral prefrontal cortex (dlPFC) and academic procrastination (ß3 = 0.12; p > 0.05). It was also determined that sex does not play a moderating role in the relationship between the tasks linked to the anterior prefrontal cortex (aPFC) and academic procrastination (ß3 = 0.05; p > 0.05). It is concluded that only the executive functions associated with the orbitomedial cortex are moderated by the sex of the university students, where the impact of the tasks linked to the orbitomedial cortex on academic procrastination in men is significantly greater than in women.

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Introduction: Prenatal growth impairment leads to higher preference for palatable foods in comparison to normal prenatal growth subjects, which can contribute to increased body fat mass and a higher risk for developing chronic diseases in small-for-gestational-age (SGA) individuals throughout life. This study aimed to investigate the effect of SGA on feeding behavior in children and adolescents, as well as resting-state connectivity between areas related to reward, self-control, and value determination, such as orbitofrontal cortex (OFC), dorsolateral prefrontal cortex (DL-PFC), amygdala and dorsal striatum (DS). Methods: Caregivers and their offspring were recruited from two independent cohorts in Brazil (PROTAIA) and Canada (MAVAN). Both cohorts included anthropometric measurements, food choice tasks, and resting-state functional magnetic resonance imaging (fMRI) data. Results: In the Brazilian sample (17 ± 0.28 years, n=70), 21.4% of adolescents were classified as SGA. They exhibited lower monetary-related expenditure to buy a snack compared to controls in the food choice test. Decreased functional connectivity (n=40) between left OFC and left DL-PFC; and between right OFC and: left amygdala, right DS, and left DS were observed in the Brazilian SGA participants. Canadian SGA participants (14.9%) had non-significant differences in comparison with controls in a food choice task at 4 years old ( ± 0.01, n=315). At a follow-up brain scan visit (10.21 ± 0.140 years, n=49), SGA participants (28.6%) exhibited higher connectivity between the left OFC and left DL-PFC, also higher connectivity between the left OFC and right DL-PFC. We did not observe significant anthropometric neither nutrients' intake differences between groups in both samples. Conclusions: Resting-state fMRI results showed that SGA individuals had altered connectivity between areas involved in encoding the subjective value for available goods and decision-making in both samples, which can pose them in disadvantage when facing food options daily. Over the years, the cumulative exposure to particular food cues together with the altered behavior towards food, such as food purchasing, as seen in the adolescent cohort, can play a role in the long-term risk for developing chronic non-communicable diseases.

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The orexin peptides promote hedonic intake and other reward behaviors through different brain sites. The opioid dynorphin peptides are co-released with orexin peptides but block their effects on reward in the ventral tegmental area (VTA). We previously showed that in the paraventricular hypothalamic nucleus (PVN), dynorphin and not orexin peptides enhance hedonic intake, suggesting they have brain-site-specific effects. Obesity alters the expression of orexin and dynorphin receptors, but whether their expression across different brain sites is important to hedonic intake is unclear. We hypothesized that hedonic intake is regulated by orexin and dynorphin peptides in PVN and that hedonic intake in obesity correlates with expression of their receptors. Here we show that in mice, injection of DYN-A1-13 (an opioid dynorphin peptide) in the PVN enhanced hedonic intake, whereas in the VTA, injection of OXA (orexin-A, an orexin peptide) enhanced hedonic intake. In PVN, OXA blunted the increase in hedonic intake caused by DYN-A1-13. In PVN, injection of norBNI (opioid receptor antagonist) reduced hedonic intake but a subsequent OXA injection failed to increase hedonic intake, suggesting that OXA activity in PVN is not influenced by endogenous opioid activity. In the PVN, DYN-A1-13 increased the intake of the less-preferred food in a two-food choice task. In obese mice fed a cafeteria diet, orexin 1 receptor mRNA across brain sites involved in hedonic intake correlated with fat preference but not caloric intake. Together, these data support that orexin and dynorphin peptides regulate hedonic intake in an opposing manner with brain-site-specific effects.

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Methylphenidate (MPH) has been widely misused by children and adolescents who do not meet all diagnostic criteria for attention-deficit/hyperactivity disorder without a consensus about the consequences. Here, we evaluate the effect of MPH treatment on glucose metabolism and metabolic network in the rat brain, as well as on performance in behavioral tests. Wistar male rats received intraperitoneal injections of MPH (2.0 mg/kg) or an equivalent volume of 0.9% saline solution (controls), once a day, from the 15th to the 44th postnatal day. Fluorodeoxyglucose-18 was used to investigate cerebral metabolism, and a cross-correlation matrix was used to examine the brain metabolic network in MPH-treated rats using micro-positron emission tomography imaging. Performance in the light-dark transition box, eating-related depression, and sucrose preference tests was also evaluated. While MPH provoked glucose hypermetabolism in the auditory, parietal, retrosplenial, somatosensory, and visual cortices, hypometabolism was identified in the left orbitofrontal cortex. MPH-treated rats show a brain metabolic network more efficient and connected, but careful analyses reveal that the MPH interrupts the communication of the orbitofrontal cortex with other brain areas. Anxiety-like behavior was also observed in MPH-treated rats. This study shows that glucose metabolism evaluated by micro-positron emission tomography in the brain can be affected by MPH in different ways according to the region of the brain studied. It may be related, at least in part, to a rewiring in the brain the metabolic network and behavioral changes observed, representing an important step in exploring the mechanisms and consequences of MPH treatment.

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Abstract Background: Migraine is a prevalent neurological disease that leads to severe headaches. Moreover, it is the commonest among the primary headaches that cause medication overuse headache (MOH). The orbitofrontal cortex (OFC) is one of the structures most associated with medication overuse. Objective: To determine microstructural changes in the OFC among migraine patients who developed MOH, through the diffusion tensor imaging (DTI) technique. Methods: Fifty-eight patients who had been diagnosed with migraine based on the Classification of Headache Disorders (ICHD-III-B) were included in the study. Patients were sub-classified into two groups, with and without MOH, based on the MOH criteria of ICHD-III-B. DTI was applied to each patient. The OFC fractional anisotropy (FA), and apparent diffusion coefficient (ADC) values of the two groups were compared. Results: The mean age of all the patients was 35.98±7.92 years (range: 18-65), and 84.5% (n=49) of them were female. The two groups, with MOH (n=25) and without (n=33), were alike in terms of age, gender, family history, migraine with or without aura and duration of illness. It was found that there was a significant difference in FA values of the left OFC between the two groups (0.32±0.01 versus 0.29±0.01; p=0.04). Conclusions: An association was found between MOH and changes to OFC microstructure. Determination of neuropathology and factors associated with medication overuse among migraine patients is crucial in terms of identifying the at-risk patient population and improving proper treatment strategies specific to these patients.

RESUMO Introdução: A migrânea é uma doença neurológica prevalente que causa fortes dores de cabeça. Além disso, é a mais comum entre as cefaleias primárias que causam cefaleia por uso excessivo de medicamentos (CUEM). O córtex orbitofrontal (OF) é uma das estruturas mais associadas ao uso excessivo de medicamentos. Objetivo: Determinar alterações microestruturais no córtex OF em pacientes com migrânea que desenvolveram CUEM, por meio da técnica de imagem por tensor de difusão (ITD). Métodos: Cinquenta e oito pacientes com diagnóstico de migrânea, com base na Classificação das Cefaleias (ICHD-III-B), foram incluídos no estudo. Os pacientes foram subclassificados em dois grupos, com e sem CUEM, com base nos critérios de CUEM da ICHD-III-B. A ITD foi aplicada a cada paciente. Os valores de anisotropia fracionada OFC (AF) e coeficiente de difusão aparente (CDA) dos dois grupos foram comparados. Resultados: A média de idade de todos os pacientes foi de 35,98±7,92 anos (variação: 18‒65), sendo 84,5% (n=49) do sexo feminino. Os dois grupos, com CUEM (n=25) e sem (n=33), são semelhantes em termos de idade, sexo, história familiar, migrânea com ou sem aura e duração da doença. Verificou-se que houve diferença significativa nos valores de AF do córtex OF esquerdo entre os dois grupos (0,32±0,01 versus 0,29±0,01; p=0,04). Conclusões: Foi encontrada associação entre o CUEM e as alterações na microestrutura do córtex OF. A determinação da neuropatologia e dos fatores associados ao uso excessivo de medicamentos entre pacientes com migrânea é crucial para identificar a população de pacientes em risco e melhorar as estratégias de tratamento adequadas específicas para esses pacientes.

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Abstract Executive dysfunction is associated with the inability to control aberrant behaviors, such as chronic overeating (Moore, Sabino, Koob, & Cottone, 2017). Obese individuals often report great difficulties controlling eating behaviors, despite a desire to successfully lose weight (Dohle, Diel, & Hofmann, 2018). However, current literature lacks a systematic review about the relationship between executive dysfunction and Obesity. The aim of this study is to present the most important findings about this matter. First, a bibliometric analysis shows the evolution of the topic. Then, the Tree of Science tool is used to show a chronological review that provides a general description of the roots and current perspectives of the state of literature. Finally, clustering analysis of the co-citation network was employed to identify the different perspectives of the topic. The main findings suggest four approaches: (1) effects of body mass index on executive functioning, (2) executive functioning in children with overweight and obesity, (3) physical activity for adult obesity and (4) structural and functional brain changes in obesity. Preliminary data state that in obesity, poor food choices may be associated with frontal cognitive impairments that contribute to reduced orbitofrontal cortex volume.

Resumen Las alteraciones en el funcionamiento ejecutivo están relacionadas con la incapacidad de controlar conductas como comer en exceso. Pacientes con diagnóstico de obesidad reportan dificultades para controlar las conductas alimentarias, a pesar del deseo de perder peso. Sin embargo, la literatura actual carece de una revisión sistemática sobre la relación entre las alteraciones del funcionamiento ejecutivo y la obesidad. El objetivo de este estudio es presentar los hallazgos más importantes sobre este tema. Primero, un análisis bibliométrico muestra la evolución del tema. Luego, desde la herramienta Tree of Science se presenta una revisión cronológica que proporciona una descripción general de estudios seminales y perspectivas actuales del estado de la literatura. Finalmente, se empleó el análisis de agrupamiento de la red de co-citaciones para identificar las diferentes perspectivas del tema. Los hallazgos sugieren cuatro perspectivas: (1) los efectos del índice de masa corporal en el funcionamiento ejecutivo, (2) el funcionamiento ejecutivo en niños con sobrepeso y obesidad, (3) la actividad física en adultos con obesidad y (4) los cambios cerebrales estructurales y funcionales en la obesidad. Los datos preliminares sugieren que, en la obesidad, la mala elección de alimentos puede asociarse con deficiencias cognitivas frontales que pueden ser el resultado de disminuciones en el volumen de la corteza orbitofrontal.

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The right orbitofrontal cortex (rOFC) has been proposed as the region where conscious olfactory perception arises; however, evidence supporting this hypothesis has all been collected from neuroimaging and lesion studies in which only correlation and not a temporal pattern can be established. Continuous theta burst stimulation (cTBS) causes a reversible disruption of cortical activity and has been used successfully to disrupt orbitofrontal activity. To overcome intrinsic limitations of current experimental research, a crossover, double-blind, prospective and longitudinal study was carried out in which cTBS was applied over the rOFC to evaluate its effect on odorant stimuli detection. All subjects received real and sham cTBS. Experimental procedures were done in two different sessions with a separation of at least one week between them to avoid carryover and learning effects. A total of 15 subjects completed the experiment, and their data were included in the final analysis (10 women, 5 men, mean age 22.40 ± 3.41). Every session consisted of two different measures of the conscious olfactory perception task: A baseline measure and one 5 min after cTBS/sham. Compared to baseline, marks in the olfactory task during the sham cTBS session increased (p = 0.010), while marks during the real cTBS session decreased (p = 0.017). Our results support the hypothesis that rOFC is an important node of a complex network required for conscious olfactory perception to arise. However, the exact mechanism that explains our results is unclear and could be explained by the disruption of other cognitive functions related to the rOFC.

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Previous clinical and pre-clinical studies suggest the involvement of ventromedial orbitofrontal cortex (vmOFC) and glutamatergic neurotransmission in obsessive-compulsive disorder (OCD). Ketamine, an NMDA glutamatergic receptor antagonist, has shown a rapid and long-lasting antidepressant effect, but its anti-compulsive effect has been scarcely investigated. The antidepressant effect of ketamine involves NMDA receptor blockade, AMPA receptor activation, increased serotonin (5-HT) release and attenuation of nitric oxide (NO) synthesis. It is not known if these mechanisms are involved in ketamine-induced anti-compulsive effect. Therefore, we firstly investigated the effect of S-ketamine in the marble-burying test (MBT), a model for screening of drugs with potential to treat OCD. Then, we evaluated whether ketamine effects in the MBT would involve the vmOFC, be dependent on AMPA receptors, facilitation of serotonergic neurotransmission and inhibition of nitrergic pathway. Our results showed that single systemic (10 mg/kg) and intra-vmOFC (10 nmol/side) administration of S-ketamine reduces marble burying behaviour (MBB) without affecting spontaneous locomotors activity. Pre-treatment with NBQX (3 mg/kg; AMPA receptor antagonist) blocked the reduction of MBB induced by S-ketamine. However, pre-treatment with p-CPA (150 mg/kg/day; a 5-HT synthesis inhibitor), WAY100635 (3 mg/kg; a 5-HT1A receptor antagonist), or L-arginine (500 mg/kg; a nitric oxide precursor) did not counteract S-ketamine effect in the MBT. In contrast, associating sub-effective doses of L-NAME (10 mg/kg; NOS inhibitor) and S-ketamine (3 mg/kg) decreased MBB. In conclusion, the reduction of MBB by S-ketamine strengthens its possible anti-compulsive effect. The vmOFC is involved in this S-ketamine effect, which is dependent on the activation of AMPA receptors.

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Amyotrophic lateral sclerosis (ALS) is characterised by frontostriatal grey matter changes similar to those in frontotemporal dementia (FTD). However, these changes are usually detected at a group level, and simple visual magnetic resonance imaging (MRI) cortical atrophy scales may further elucidate frontostriatal changes in ALS. OBJECTIVE: To investigate whether frontostriatal changes are detectable using simple visual MRI atrophy rating scales applied at an individual patient level in ALS. METHODS: 21 ALS patients and 17 controls were recruited and underwent an MRI scan. Prefrontal cortex sub-regions of the medial orbitofrontal cortex (MOFC), lateral orbitofrontal cortex (LOFC) and anterior cingulate cortex (ACC), striatal sub-regions of the caudate nucleus (CN) and nucleus accumbens (NAcc) were rated using visual grey matter atrophy 5-point Likert scales. RESULTS: Significantly higher atrophy ratings in the bilateral MOFC only in ALS patients versus controls was observed (p<.05). Patients with greater MOFC atrophy had significantly higher atrophy of the CN (p<.05) and LOFC (p<.05). CONCLUSION: Use of simple visual atrophy rating scales on an individual level reliably detects frontostriatal deficits specific to ALS, showing MOFC atrophy differences with associated CN and LOFC atrophy. This is an applicable method that could be used to support clinical diagnosis and management.

A esclerose lateral amiotrófica (ELA) é caracterizada por alterações na substância cinzenta frontostriatal, semelhantes às da demência frontotemporal (DFT). No entanto, essas alterações geralmente são detectadas em nível de grupo, e as escalas simples de atrofia cortical por ressonância magnética visual (MRI) podem elucidar ainda mais as alterações frontostriatais na ELA. OBJETIVO: Investigar se as alterações frontostriatais são detectáveis usando escalas de classificação de atrofia MRI visuais simples aplicadas em um nível de paciente individual em ELA. MÉTODOS: 21 pacientes com ELA e 17 controles foram recrutados e submetidos a uma ressonância magnética. Sub-regiões do córtex pré-frontal do córtex orbitofrontal medial (MOFC), córtex orbitofrontal lateral (LOFC) e córtex cingulado anterior (ACC), sub-regiões estriadas do núcleo caudado (NC) e nucleus accumbens (NAcc) foram classificadas usando escalas de atrofia de substância cinzenta visuais de Likert de 5 pontos. RESULTADOS: Observações de atrofia significativamente maiores no MOFC bilateral em pacientes com ELA versus controles foram observadas apenas (p <0,05). Pacientes com maior atrofia do MOFC tiveram atrofia significativamente maior do CN (p <0,05) e LOFC (p <0,05). CONCLUSÃO: O uso de escalas de avaliação de atrofia visuais simples em um nível individual detecta de forma confiável déficits frontostriatais específicos para ELA, mostrando diferenças de atrofia MOFC com atrofia associada de CN e LOFC. Este é um método aplicável que pode ser usado para apoiar o diagnóstico e o gerenciamento clínico.

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ABSTRACT: Amyotrophic lateral sclerosis (ALS) is characterised by frontostriatal grey matter changes similar to those in frontotemporal dementia (FTD). However, these changes are usually detected at a group level, and simple visual magnetic resonance imaging (MRI) cortical atrophy scales may further elucidate frontostriatal changes in ALS. Objective: To investigate whether frontostriatal changes are detectable using simple visual MRI atrophy rating scales applied at an individual patient level in ALS. Methods: 21 ALS patients and 17 controls were recruited and underwent an MRI scan. Prefrontal cortex sub-regions of the medial orbitofrontal cortex (MOFC), lateral orbitofrontal cortex (LOFC) and anterior cingulate cortex (ACC), striatal sub-regions of the caudate nucleus (CN) and nucleus accumbens (NAcc) were rated using visual grey matter atrophy 5-point Likert scales. Results: Significantly higher atrophy ratings in the bilateral MOFC only in ALS patients versus controls was observed (p<.05). Patients with greater MOFC atrophy had significantly higher atrophy of the CN (p<.05) and LOFC (p<.05). Conclusion: Use of simple visual atrophy rating scales on an individual level reliably detects frontostriatal deficits specific to ALS, showing MOFC atrophy differences with associated CN and LOFC atrophy. This is an applicable method that could be used to support clinical diagnosis and management.

RESUMO: A esclerose lateral amiotrófica (ELA) é caracterizada por alterações na substância cinzenta frontostriatal, semelhantes às da demência frontotemporal (DFT). No entanto, essas alterações geralmente são detectadas em nível de grupo, e as escalas simples de atrofia cortical por ressonância magnética visual (MRI) podem elucidar ainda mais as alterações frontostriatais na ELA. Objetivo: Investigar se as alterações frontostriatais são detectáveis usando escalas de classificação de atrofia MRI visuais simples aplicadas em um nível de paciente individual em ELA. Métodos: 21 pacientes com ELA e 17 controles foram recrutados e submetidos a uma ressonância magnética. Sub-regiões do córtex pré-frontal do córtex orbitofrontal medial (MOFC), córtex orbitofrontal lateral (LOFC) e córtex cingulado anterior (ACC), sub-regiões estriadas do núcleo caudado (NC) e nucleus accumbens (NAcc) foram classificadas usando escalas de atrofia de substância cinzenta visuais de Likert de 5 pontos. Resultados: Observações de atrofia significativamente maiores no MOFC bilateral em pacientes com ELA versus controles foram observadas apenas (p <0,05). Pacientes com maior atrofia do MOFC tiveram atrofia significativamente maior do CN (p <0,05) e LOFC (p <0,05). Conclusão: O uso de escalas de avaliação de atrofia visuais simples em um nível individual detecta de forma confiável déficits frontostriatais específicos para ELA, mostrando diferenças de atrofia MOFC com atrofia associada de CN e LOFC. Este é um método aplicável que pode ser usado para apoiar o diagnóstico e o gerenciamento clínico.

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Schizophrenia is a chronic and incurable neuropsychiatric disorder that affects about one percent of the world population. The proteomic characterization of the synaptosome fraction of the orbitofrontal cortex is useful for providing valuable information about the molecular mechanisms of synaptic functions in these patients. Quantitative analyses of synaptic proteins were made with eight paranoid schizophrenia patients and a pool of eight healthy controls free of mental diseases. Label-free and iTRAQ labeling identified a total of 2018 protein groups. Statistical analyses revealed 12 and 55 significantly dysregulated proteins by iTRAQ and label-free, respectively. Quantitative proteome analyses showed an imbalance in the calcium signaling pathway and proteins such as reticulon-1 and cytochrome c, related to endoplasmic reticulum stress and programmed cell death. Also, it was found that there is a significant increase in limbic-system-associated membrane protein and α-calcium/calmodulin-dependent protein kinase II, associated with the regulation of human behavior. Our data contribute to a better understanding about apoptosis as a possible pathophysiological mechanism of this disease as well as neural systems supporting social behavior in schizophrenia. This study also is a joint effort of the Chr 15 C-HPP team and the Human Brain Proteome Project of B/D-HPP. All MS proteomics data are deposited in the ProteomeXchange Repository under PXD006798.

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BACKGROUND: Obsessive-compulsive disorder is treated with exposure with response prevention (ERP) therapy, in which patients are repeatedly exposed to compulsive triggers but prevented from expressing their compulsions. Many compulsions are an attempt to avoid perceived dangers, and the intent of ERP is to extinguish compulsions. Patients failing ERP therapy are candidates for deep brain stimulation (DBS) of the ventral capsule/ventral striatum, which facilitates patients' response to ERP therapy. An animal model of ERP would be useful for understanding the neural mechanisms of extinction in obsessive-compulsive disorder. METHODS: Using a platform-mediated signaled avoidance task, we developed a rodent model of ERP called extinction with response prevention (Ext-RP), in which avoidance-conditioned rats are given extinction trials while blocking access to the avoidance platform. Following 3 days of Ext-RP, rats were tested with the platform unblocked to evaluate persistent avoidance. We then assessed if pharmacologic inactivation of lateral orbitofrontal cortex (lOFC) or DBS of the ventral striatum reduced persistent avoidance. RESULTS: Following Ext-RP training, most rats showed reduced avoidance at test (Ext-RP success), but a subset persisted in their avoidance (Ext-RP failure). Pharmacologic inactivation of lOFC eliminated persistent avoidance, as did DBS applied to the ventral striatum during Ext-RP. CONCLUSIONS: DBS of ventral striatum has been previously shown to inhibit lOFC activity. Thus, activity in lOFC, which is known to be hyperactive in obsessive-compulsive disorder, may be responsible for impairing patients' response to ERP therapy.

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A hipótese de “miopia emocional” constitui uma reflexão teórica de compreensão da vulnerabilidade psicológica identificada em muitos toxicodependentes. Propõe-se uma cooperação, mas não incorporação, de níveis de conhecimento em torno dos determinantes do neurodesenvolvimento, de perspectivas psicanalíticas e de vinculação e de modelos psicobiológicos das toxicodependências. Salientam-se influências ambientais sobre as mudanças na morfologia cerebral, não apenas o trauma precoce ou a privação de cuidados, mas também as decorrentes de consumos abusivos como cernes de vulnerabilidade. Propõe-se que a hipótese Damasiana dos marcadores somáticos participe nessa formulação. A parca qualidade das interações precoces pode sustentar o desligamento afetivo progressivo, a hipomaturação do cérebro social, o incremento de um padrão alexitímico e a procura urgente de sensações, todos potenciais propiciadores da busca do prazer nas drogas.

The “emotional myopia” hypothesis is a theoretical reflection to increase the understanding of the psychological vulnerability showed by many drug addicts Instead of an incorporation, a cooperation is proposed of levels of knowledge on the determinants of the neurodevelopment, psychoanalytical and attachment perspectives and psychobiological models of drug addictions. Environmental inputs that change brain morphology are highlighted, not only early trauma or care deprivation but also others derived from the long-term use of drugs as the core of vulnerability. We propose that Damasio’s hypothesis of somatic markers forms part of this theoretical formulation. The low quality of early social interactions may support an increasing emotional disengagement, a poor maturation of the social brain, an increase of alexithymic patterns and novelty-seeking behaviours, all potential triggers for searching for pleasure in drugs.

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The reinforcement omission effect (ROE), reflected by response rates that are higher after reinforcement omission than after reinforcement delivery, has been attributed to both motivational and attentional consequences of the surprising reinforcement omission. These processes depend on the operation of separate amygdala areas and their connections with other brain systems. The interaction between the amygdala and orbitofrontal cortex has been suggested to be important in the modulation of motivational processes. The present study sought to verify whether the mechanisms involved in the ROE depend on the integrity of the orbitofrontal cortex. Prior to acquisition training, rats received bilateral excitotoxic lesions of the orbitofrontal cortex or sham lesions. Following postoperative recovery, the rats were trained on a fixed-interval 12 s limited-hold 6 s signaled schedule of reinforcement. After the acquisition of stable performance, the training was changed from a 100% to 50% schedule of reinforcement. The results showed that rats in both groups exhibited the ROE, with no differences in performance between groups following nonreinforcement. These data do not support the hypothesis that the orbitofrontal cortex is included in the neural substrates related to ROE modulation. The results also showed no difference in response rates between groups in the periods that preceded and followed nonreinforcement. These findings confirm previous studies that showed that the ROE is not related to the facilitation of behavior induced by nonreinforcement...

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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.

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RESUMO

Eating is a behavior oriented to get the energy necessary for the organism to survive and to contend with the demands of its environment. Food, besides of energy, provides structure and function, as amino acids are converted into structural or secretion proteins or enzymes. These proteins are synthesized following a strict genetic code. Variants in the genome happen frequently, but only those changes that result in a poor adaptive phenotype are well documented. There are other changes that may go unnoticed due to culture influence, and they may be seen as adaptive because they seem to favor individuals in the short-term. A child that overeats and becomes overweighed is culturally appreciated as a healthy child. However, systematic studies have shown that these feeding styles influenced by culture, in the long-term, result on an irreversible damage to the individual. Food selection also depends on the functioning of homeostatic and hedonistic systems. The homeostatic system involves the hypothalamus that includes nuclei that promote both appetite and satiety. The hedonic system is constituted by the ventral tegmental area and the nucleus accumbens. Stimulation of the ventral tegmental area induces the release of dopamine into the nucleus accumbens, making the individual to experience pleasure. This system also interacts with the hypothalamic systems that promote appetite. As it can be seen, food intake is regulated by diverse cerebral systems that are under the influence of one another. Failure in one of these systems may lead the subject to a compulsive, or defective, food intake. We have allowed media and mercantilist interests to govern our diet, instead of allowing our brain and its systems to do it. We should have psycoeducation as a priority in medicine to improve our capacity to select better quality food to eat, without compromising the pleasure of eating.

Comer es una conducta dirigida a conseguir la energía para llevar a cabo las funciones que mantienen al organismo y le permiten contender contra las demandas del medio. Debido a que nuestro organismo evolucionó dentro de un ambiente con escasez de alimentos, los genes que nos adaptaron al medio fueron los que promueven el almacenamiento y optimización de los nutrientes, así como aquellos que promueven la habilidad de generar estrategias de cacería y otras conductas orientadas a ese objetivo. Estos mecanismos fisiológicos y bioquímicos incluyen una amplia variedad de genes, desde aquellos que codifican para enzimas que almacenan el glucógeno hasta enzimas que sintetizan o degradan a los neurotransmisores. Diversos sistemas cerebrales regulan la ingestión del alimento: El homeostásico involucra al hipotálamo lateral como promotor de la ingestión de alimento por medio de neuronas orexinérgicas y MCHérgicas, al núcleo arcuato que sintetiza y libera neuropéptido Y y al péptido relacionado al gen agouti y como promotor de la saciedad a través de la POMC y del CART. Diferentes hormonas y proteínas hipotalámicas participan en la función del sistema hedónico compuesto por el área ventral tegmental y el núcleo accumbens, produciéndose un diálogo entre los sistemas homeostásico y hedónico. Otros sistemas cerebrales que participan son la amígdala y el lóbulo de la ínsula que promueven la selección de los alimentos con base en la experiencia. La corteza prefrontal participa en la preferencia por los alimentos y la toma de decisiones tales como qué, cuándo y dónde comer. Es importante reconocer que los sistemas neuroquímicos que regulan la ingestión del alimento también participan en funciones cognitivas y que la falla en estos sistemas afecta la forma en que el individuo elige su alimentación y, a su vez, el estado cognitivo del sujeto. Por lo tanto, la psicoeducación para regular los hábitos alimenticios debe ser una prioridad en el campo de la medicina.

RESUMO

OBJECTIVE: Stimulation of the inferior thalamic peduncle (ITP) is emerging as a promising new therapeutic target in certain psychiatric disorders. The circuitry that includes the nonspecific thalamic system (NSTS), which projects via the ITP to the orbitofrontal cortex (OFC), is involved in the physiopathology of major depression disorder (MDD) and obsessive compulsive disorder (OCD). The safety and efficacy of chronic ITP stimulation in cases of MDD and OCD refractory to medical treatment is presented. MATERIALS AND METHODS: Six patients with OCD and one with MDD were implanted with tetrapolar deep brain stimulation electrodes in the ITP (x = 3.5 mm lateral to the ventricular wall, y = 5 mm behind the anterior commissure, and z = at the intercommissural plane, i.e., anterior commissure-posterior commissure [AC-PC] level). The effect of chronic stimulation at 130 Hz, 450 µs, and 5.0 V on OCD was evaluated before and 3, 6, and 12 months after initiation of electrical stimulation through the Yale-Brown Obsessive Compulsive Scale, Hamilton Depression Rating Scale, and Global Assessment of Function scale. RESULTS: Chronic ITP electrical stimulation in OCD patients decreased the mean Yale-Brown Obsessive Compulsive Scale score to around 51% for the group at the 12-month follow-up, and increased the mean Global Assessment of Function scale score to 68% for a significant improvement (P = 0.026). Three of 6 patients returned to work. The Hamilton Depression Rating Scale score of the only patient with MDD treated to date went from 42 to 6. This condition of the patient, who had been incapacitated for 5 years prior to surgery, has not relapsed for 9 years. Three OCD patients with drug addiction continued to consume drugs in spite of their improvement in OCD. CONCLUSION: Deep brain stimulation in the ITP is safe and may be effective in the treatment of OCD. A multicenter evaluation of the safety and efficacy of ITP in OCD is currently in process.

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