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The incorporation of sex and gender (S/G) related factors is commonly acknowledged as a necessary step to advance towards more personalized diagnoses and treatments for somatic, psychiatric, and neurological diseases. Until now, most attempts to integrate S/G-related factors have been reduced to identifying average differences between females and males in behavioral/ biological variables. The present commentary questions this traditional approach by highlighting three main sets of limitations: 1) Issues stemming from the use of classic parametric methods to compare means; 2) challenges related to the ability of means to accurately represent the data within groups and differences between groups; 3) mean comparisons impose a results' binarization and a binary theoretical framework that precludes advancing towards precision medicine. Alternative methods free of these limitations are also discussed. We hope these arguments will contribute to reflecting on how research on S/G factors is conducted and could be improved.

Asunto(s)

Caracteres Sexuales , Humanos , Masculino , Femenino , Animales

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BACKGROUND: Sex differences in language-related abilities have been reported. It is generally assumed that these differences stem from a different organization of language in the brains of females and males. However, research in this area has been relatively scarce, methodologically heterogeneous and has yielded conflicting results. METHODS: Univariate and multivariate sex differences and similarities in gray matter volume (GMVOL) within 18 essential language-processing brain areas were assessed in a sex-balanced sample (N = 588) of right-handed young adults. Univariate analyses involved location, spread, and shape comparisons of the females' and males' distributions and were conducted with several robust statistical methods able to quantify the size of sex differences and similarities in a complementary way. Multivariate sex differences and similarities were estimated by the same methods in the continuous scores provided by two distinct multivariate procedures (logistic regression and a multivariate analog of the Wilcoxon-Mann-Whitney test). Additional analyses were addressed to compare the outcomes of these two multivariate analytical strategies and described their structure (that is, the relative contribution of each brain area to the multivariate effects). RESULTS: When not adjusted for total intracranial volume (TIV) variation, "large" univariate sex differences (males > females) were found in all 18 brain areas considered. In contrast, "small" differences (females > males) in just two of these brain areas were found when controlling for TIV. The two multivariate methods tested provided very similar results. Multivariate sex differences surpassed univariate differences, yielding "large" differences indicative of larger volumes in males when calculated from raw GMVOL estimates. Conversely, when calculated from TIV-adjusted GMVOL, multivariate differences were "medium" and indicative of larger volumes in females. Despite their distinct size and direction, multivariate sex differences in raw and TIV-adjusted GMVOL shared a similar structure and allowed us to identify the components of the SENT_CORE network which more likely contribute to the observed effects. CONCLUSIONS: Our results confirm and extend previous findings about univariate sex differences in language-processing areas, offering unprecedented evidence at the multivariate level. We also observed that the size and direction of these differences vary quite substantially depending on whether they are estimated from raw or TIV-adjusted GMVOL measurements.

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While it is generally assumed that there is a distinct organization of language in the brains of females and males, studies investigating potential sex-based differences in language-related neural circuits have been characterized by their methodological heterogeneity and yielded inconclusive results. In this study, we explored how the brains of men and women differ in a well-defined network of brain areas essential for basic language functions. We found that there are indeed differences in the size of certain brain regions involved in language, with men and women showing varying patterns of these differences. Interestingly, the way these differences were observed depended on whether they are assessed at the whole network or at individual brain regions. Also, when considering the size of these brain regions in relation to overall cranial volume, the differences changed. So, this study highlights that understanding these brain differences requires considering different factors, like existing sex differences in cranial size, and looking at local effects but also their interactions and relationships in the broader context of functional brain networks.

Asunto(s)

Sustancia Gris , Caracteres Sexuales , Adulto Joven , Humanos , Masculino , Femenino , Sustancia Gris/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Encéfalo , Lenguaje

RESUMEN

Background: Computerized training in persons with multiple sclerosis (PwMS) seems to enhance working memory (WM)/information processing (IP), but factors associated with the efficacy of the treatment have not been sufficiently explored. Objective: To identify clinical and radiological characteristics associated with positive WM/IP training responses. Methods: Radiological and neuropsychological assessments were carried out on a sample of 35 PwMs who were divided into "WM/IP-impaired" and "WM/IP-preserved." All participants underwent adaptive n-back training for 10 days and were assessed post-training. Between-group differences ("WM/IP-impaired" vs. "WM/IP-preserved") in training-induced cognitive improvement were assessed and exploratory correlational/ regression-based methods were employed to assess the relationship between cognitive improvement and clinical and radiological variables. Results: All PwMS exhibited WM/IP benefits after training, but those with preserved WM/IP functions showed greater positive effects as well as transfer effects to other WM/IP tests when compared to the impaired group. Additional analyses revealed that positive response to treatment was associated with WM/IP baseline capabilities and greater gray matter volume (GMVOL) in relevant areas such as the thalamus. Conclusions: Restorative cognitive training is suitable to improve cognition in PwMS but its effective outcome differs depending on the baseline WM/IP capabilities and GMVOL.

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Based on Social Cognitive Career Theory principles, the present study sought to investigate whether stereotype threat experiences could act as a barrier and reduce the persistence of women in math-intensive activities. More specifically, we assessed whether the experimental activation of stereotypes about women's lower math capabilities affected the performance, persistence, and self-selected difficulty of engineering students in a math task which required sustained effort. We also evaluated the relationships between these effects and the participants' pre-testing gender-science stereotypes and math self-concept. A sample of 340 engineering students (175 and 165 self-identified as males and females, respectively) were recruited and randomly assigned to a control (Con) or stereotype threat (StA) condition to form four similarly sized groups. All participants rated their self-concept in four academic domains (math, chemistry, physics, and coding), completed the gender-science Implicit Association Test, and a "reading comprehension task" that served to promote the stereotype threat manipulation immediately before facing a modified version of the Math Effort Task (M-MET). We observed that, in the control condition, M-MET performance, self-selected difficulty, and persistence were similar in female and male participants, independent of their gender-science implicit stereotypes but correlated to their math self-concept scores. In contrast, the StA condition triggered opposite effects in female and male students, so they showed decreased/enhanced M-MET performance and self-selected difficulty, respectively. This experimental condition also resulted in enhanced persistence of the male students without affecting the number of trials completed by female students. These effects were correlated with the strength of the participants' gender-science implicit stereotypes but not with their math self-concept scores. In fact, as revealed by finer-grain analyses, stereotype threat only had a significant impact on individuals harboring stereotypical gender-science implicit associations. Therefore, it is concluded that: (1) stereotypes can promote differences between male and female engineering students in their performance, self-confidence, and persistence in math-related activities; (2) These effects seem to be more prominent in individuals implicitly perceiving science as a masculine domain. The relevance of these findings to explain women's enhanced abandonment rates of math-intensive studies is discussed.

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OBJECTIVE: Depressive disorder occurs in up to 50% of persons with Multiple Sclerosis (PwMS). Accurate assessment of depression in MS is essential in clinical settings because depressive symptomatology can affect the clinical course of the disease. METHODS: We translated, adapted, and tested the Spanish version of the Chicago Multiscale Depression Inventory (CMDI), a specific test to assess depression in neurological disorders. We compare our results with those obtained with previous versions of the questionnaire (English and Italian). Finally, we also analyze the relationship between the results obtained on the CMDI and demographic, clinical, and cognitive variables. RESULTS: The results obtained with the Spanish version of the CMDI were similar to those observed in previous published versions. We also observed higher depression scores in PwMS (especially in progressive forms) compared with healthy controls. Moreover, depression symptomatology was related to higher disability and fatigue and worse cognitive performance in PwMS. CONCLUSIONS: The results support the validity of the CDMI in the Spanish population, as well as the association between depression and other characteristic symptoms of MS. These findings also emphasize the importance of good assessment and multidisciplinary treatment of depression in PwMS.

Asunto(s)

Esclerosis Múltiple , Humanos , Esclerosis Múltiple/psicología , Depresión/complicaciones , Depresión/diagnóstico , Chicago , Pruebas Neuropsicológicas , Reproducibilidad de los Resultados

RESUMEN

BACKGROUND: Cognitive deficits, especially in working memory (WM) and information processing (IP) efficiency, are common in people with multiple sclerosis (PwMS). Few studies have examined the efficacy of n-back training in improving these two cognitive functions in PwMS. In the present study, we examined the effects of an intensive n-back training program by measuring the gains on the trained task (2- and 3-back tasks), but we also studied possible near transfer effects to other tests that assess WM and IP, as well as far transfer effects or improvements in other cognitive functions. METHODS: A sample consisting of 35 PwMS with different cognitive statuses. All the participants underwent an adaptive n-back training for 10 days (60 min/day), and they were neuropsychologically assessed at baseline (D1) and after training (D10). The effectiveness of the training was tested: (1) by using mean-based comparisons and Cohen's d values; (2) by estimating and comparing the quartile values of the D1 and D10 distributions. Two indexes of improvement in individual performance were calculated, the net score improvement index (NSI) and the percent of maximum possible individualized improvement (PMPI). RESULTS: Repeat practice improves 2- and 3-back performance, showing more correct responses (CR) and lower reaction times (RT) on D10 compared to D1. These results were corroborated by the NSI and PMPI scores, but the gains after training were more statistically significant for the 3-back (observing higher CR and lower RT after training) than for the 2-back (observing gains in CR, but not in RT). We also observed a possible transference of this improvement on the n-back task to other WM/IPS tests. Specifically, statistically significant pre-post training differences were found in the values in three quartiles of the Paced Auditory Serial Addition Test (PASAT; q25, p < 0.03; q50, p < 0.001; q75, p < 0.002) and of the Symbol Digit Modalities Test (SDMT; q25, p < 0.03; q50, p < 0.001; q75, p < 0.001) as well as in two quartiles of the Letter-Number Sequencing Task (LNST; q50, p < 0.004; q75 p < 0.001), and in one quartile of the Digit Backwards Span Test (DSBT; q75, p < 0.001). Reliable change analyses confirmed these performance improvements on the PASAT, SDMT, and LNST. CONCLUSIONS: This study confirmed that the intensive and adaptive n-back training produced improvements in the trained task in PwMS with different cognitive statuses. Furthermore, these gains were not only observed on the trained task, but they seemed to be also transferred to other tests that measured WM and IP functions.

Asunto(s)

Memoria a Corto Plazo , Esclerosis Múltiple , Humanos , Memoria a Corto Plazo/fisiología , Esclerosis Múltiple/complicaciones , Aprendizaje , Pruebas Neuropsicológicas , Cognición/fisiología

RESUMEN

Previous studies have shown that machine-learning (ML) algorithms can "predict" sex based on brain anatomical/ functional features. The high classification accuracy achieved by ML algorithms is often interpreted as revealing large differences between the brains of males and females and as confirming the existence of "male/female brains". However, classification and estimation are different concepts, and using classification metrics as surrogate estimates of between-group differences may result in major statistical and interpretative distortions. The present study avoids these distortions and provides a novel and detailed assessment of multivariate sex differences in gray matter volume (GMVOL) that does not rely on classification metrics. Moreover, appropriate regression methods were used to identify the brain areas that contribute the most to these multivariate differences, and clustering techniques and analyses of similarities (ANOSIM) were employed to empirically assess whether they assemble into two sex-typical profiles. Results revealed that multivariate sex differences in GMVOL: (1) are "large" if not adjusted for total intracranial volume (TIV) variation, but "small" when controlling for this variable; (2) differ in size between individuals and also depends on the ML algorithm used for their calculation (3) do not stem from two sex-typical profiles, and so describing them in terms of "male/female brains" is misleading.

Asunto(s)

Encéfalo , Caracteres Sexuales , Corteza Cerebral , Femenino , Sustancia Gris/diagnóstico por imagen , Humanos , Aprendizaje Automático , Imagen por Resonancia Magnética/métodos , Masculino

RESUMEN

BACKGROUND: Working memory (WM) deficits are common in multiple sclerosis (MS) patients. Computerized cognitive training may enhance WM capabilities but its efficacy in MS patients has not been sufficiently explored. METHODS: This study examines the effects of n-back training on cognitive performance and functional connectivity (FC) in 29 MS patients and 29 healthy controls (HC). Baseline (S1) performance on 2- and 3-back tasks and FC within the fronto-parietal network were assessed before randomly splitting the sample into four subgroups: trained MS (MSt, n = 15), trained HC (HCt, n = 14), untrained MS (MSu, n = 14), and untrained HC (HCu, n = 15). The trained subgroups underwent adaptive n-back training (60 min/day; 4 days) and n-back task performance and FC were reassessed in a second session (S2). RESULTS: As revealed by mixed two-way ANOVAs, trained participants (MSt and HCt) exhibited a significant increase in the number of correct responses and significantly reduced reaction times in S2. These performance improvements were accompanied by an increase in FC in the fronto-parietal pathways and statistically significant correlations between both effects were found. CONCLUSIONS: Computerised WM training results in behavioural and neuroplasticity positive effects that may be useful when trying to prevent or attenuate cognitive decline in MS patients.

Asunto(s)

Memoria a Corto Plazo , Esclerosis Múltiple , Humanos , Aprendizaje , Plasticidad Neuronal , Tiempo de Reacción

RESUMEN

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

RESUMEN

Sex differences in 116 local gray matter volumes (GMVOL) were assessed in 444 males and 444 females without correcting for total intracranial volume (TIV) or after adjusting the data with the scaling, proportions, power-corrected proportions (PCP), and residuals methods. The results confirmed that only the residuals and PCP methods completely eliminate TIV-variation and result in sex-differences that are "small" (∣d∣ < 0.3). Moreover, as assessed using a totally independent sample, sex differences in PCP and residuals adjusted-data showed higher replicability ([Formula: see text] 93%) than scaling and proportions adjusted-data [Formula: see text] 68%) or raw data ([Formula: see text] 45%). The replicated effects were meta-analyzed together and confirmed that, when TIV-variation is adequately controlled, volumetric sex differences become "small" (∣d∣ < 0.3 in all cases). Finally, we assessed the utility of TIV-corrected/ TIV-uncorrected GMVOL features in predicting individuals' sex with 12 different machine learning classifiers. Sex could be reliably predicted (> 80%) when using raw local GMVOL, but also when using scaling or proportions adjusted-data or TIV as a single predictor. Conversely, after properly controlling TIV variation with the PCP and residuals' methods, prediction accuracy dropped to [Formula: see text] 60%. It is concluded that gross morphological differences account for most of the univariate and multivariate sex differences in GMVOL.

Asunto(s)

Corteza Cerebral/diagnóstico por imagen , Sustancia Gris/diagnóstico por imagen , Caracteres Sexuales , Adulto , Femenino , Humanos , Masculino

RESUMEN

BACKGROUND: Studies assessing volumetric sex differences have provided contradictory results. Total intracranial volume (TIV) is a major confounding factor when estimating local volumes of interest (VOIs). We investigated how the number, size, and direction of sex differences in gray matter volume (GMv) vary depending on how TIV variation is statistically handled. METHODS: Sex differences in the GMv of 116 VOIs were assessed in 356 participants (171 females) without correcting for TIV variation or after adjusting the data with 5 different methods (VBM8 non-linear-only modulation, proportions, power-corrected-proportions, covariation, and the residuals method). The outcomes obtained with these procedures were compared to each other and to those obtained in three criterial subsamples, one comparing female-male pairs matched on their TIV and two others comparing groups of either females or males with large/small TIVs. Linear regression was used to quantify TIV effects on raw GMv and the efficacy of each method in controlling for them. RESULTS: Males had larger raw GMv than females in all brain areas, but these differences were driven by direct TIV-VOIs relationships and more closely resembled the differences observed between individuals with large/small TIVs of sex-specific subsamples than the sex differences observed in the TIV-matched subsample. All TIV-adjustment methods reduced the number of sex differences but their results were very different. The VBM8- and the proportions-adjustment methods inverted TIV-VOIs relationships and resulted in larger adjusted volumes in females, promoting sex differences largely attributable to TIV variation and very distinct from those observed in the TIV-matched subsample. The other three methods provided results unrelated to TIV and very similar to those of the TIV-matched subsample. In these datasets, sex differences were bidirectional and achieved satisfactory replication rates in 19 VOIs, but they were "small" (d < ∣0.38∣) and most of them faded away after correcting for multiple comparisons. CONCLUSIONS: There is not just one answer to the question of how many and how large the sex differences in GMv are, but not all the possible answers are equally valid. When TIV effects are ruled out using appropriate adjustment methods, few sex differences (if any) remain statistically significant, and their size is quite reduced.

Asunto(s)

Sustancia Gris/anatomía & histología , Caracteres Sexuales , Adolescente , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven

RESUMEN

BACKGROUND/OBJECTIVE: To explore the effectiveness of a specific working memory (WM) training program in MS patients and healthy controls (HC). METHOD: 29 MS patients and 29 matched HC were enrolled in the study. MS and HC were randomly split into two groups: nontraining groups (15HC/14 MS) and training groups (14 HC/15 MS). Training groups underwent adaptive n-back training (60 min/day; 4 days). Functional magnetic resonance imaging (fMRI) was used to monitor brain activity during n-back performance (conditions: 0-back, 2-back, and 3-back) at 3 time points: (1) baseline, (2) post-training (+7days), and (3) follow-up (+35days). RESULTS: In post-training and follow-up fMRI sessions, trained groups (HC and MS patients) exhibited significant reaction time (RT) reductions and increases in Correct Responses (CRs) during 2-back and 3-back performance. This improvement of task performance was accompanied by a decrease in brain activation in the WM frontoparietal network. The two effects were significantly correlated. CONCLUSIONS: After WM training, both cognitively preserved MS patients and HC participants showed task performance improvement made possible by neuroplastic processes that enhanced neural efficiency.

RESUMEN

It is a common belief that males have superior visuospatial abilities and that differences in this and other cognitive domains (e.g., math) contribute to the reduced interest and low representation of girls and women in STEM education and professions. However, previous studies show that gender-related implicit associations and explicit beliefs, as well as situational variables, might affect cognitive performance in those gender-stereotyped domains and produce between-gender spurious differences. Therefore, the present study aimed to provide information on when, how and who might be affected by the situational reactivation of stereotypic gender-science beliefs/associations while performing a 3D mental rotation chronometric task (3DMRT). More specifically, we assessed the explicit beliefs and implicit associations (by the Implicit Association Test) held by female and male students of humanities and STEM majors and compared their performance in a 3DMRT after receiving stereotype- congruent, incongruent and nullifying experimental instructions. Our results show that implicit stereotypic gender-science associations correlate with 3DMRT performance in both females and males, but that inter-gender differences emerge only under stereotype-reactivating conditions. We also found that changes in self-confidence mediate these instructions' effects and that academic specialization moderates them, hence promoting 3DMRT performance differences between male and female humanities, but not STEM, students. Taken together, these observations suggest that the common statement "males have superior mental rotation abilities" simplifies a much more complex reality and might promote stereotypes which, in turn, might induce artefactual performance differences between females and males in such tasks.

RESUMEN

The present study aimed to investigate altered grey matter (GM) and functional connectivity (FC) in deep subcortical areas, such as the thalamus and basal ganglia, and their relationship with cognitive impairment (CI) in multiple sclerosis (MS). Thirty-six patients were neuropsychologically assessed, classified as cognitive preserved (CP) and CI, and were compared with 18 healthy controls. GM atrophy and FC were observed in 10 predefined functional areas of the thalamus and in six of basal ganglia. GM atrophy was prominent in the basal ganglia in CI patients compared with CP MS patients. Increased FC was observed between the right caudate and the bilateral orbitofrontal cortex in CI versus CP patients. The discriminant and correlation analyses showed that the enhanced FC observed between the right caudate and the orbitofrontal cortex was closely associated with CI in MS patients. In conclusion, reduced GM volume and enhanced frontobasal ganglia connectivity are related to cognition in MS patients.

Asunto(s)

Encéfalo/patología , Disfunción Cognitiva/patología , Sustancia Gris/patología , Esclerosis Múltiple/patología , Adulto , Atrofia , Encéfalo/diagnóstico por imagen , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/etiología , Femenino , Sustancia Gris/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/complicaciones , Esclerosis Múltiple/diagnóstico por imagen , Pruebas Neuropsicológicas , Adulto Joven

RESUMEN

One of the key mechanisms for the stabilization of synaptic changes near the end of critical periods for experience-dependent plasticity is the formation of specific lattice extracellular matrix structures called perineuronal nets (PNNs). The formation of drug memories depends on local circuits in the cerebellum, but it is unclear to what extent it may also relate to changes in their PNN. Here, we investigated changes in the PNNs of the cerebellum following cocaine-induced preference conditioning. The formation of cocaine-related preference memories increased expression of PNN-related proteins surrounding Golgi inhibitory interneurons as well as that of cFos in granule cells at the apex of the cerebellar cortex. In contrast, the expression of PNNs surrounding projection neurons in the medial deep cerebellar nucleus (DCN) was reduced in all cocaine-treated groups, independently of whether animals expressed a preference for cocaine-related cues. Discriminant function analysis confirmed that stronger PNNs in Golgi neurons and higher cFos levels in granule cells of the apex might be considered as the cerebellar hallmarks of cocaine-induced preference conditioning. Blocking the output of cerebellar granule cells in α6Cre-Cacna1a mutant mice prevented re-acquisition, but not acquisition, of cocaine-induced preference conditioning. Interestingly, this impairment in consolidation was selectively accompanied by a reduction in the expression of PNN proteins around Golgi cells. Our data suggest that PNNs surrounding Golgi interneurons play a role in consolidating drug-related memories.

Asunto(s)

Cerebelo/efectos de los fármacos , Cocaína/farmacología , Condicionamiento Clásico/efectos de los fármacos , Matriz Extracelular/efectos de los fármacos , Memoria/efectos de los fármacos , Nootrópicos/farmacología , Animales , Canales de Calcio Tipo N/genética , Canales de Calcio Tipo N/metabolismo , Cerebelo/metabolismo , Cerebelo/patología , Trastornos Relacionados con Cocaína/metabolismo , Trastornos Relacionados con Cocaína/patología , Condicionamiento Clásico/fisiología , Inhibidores de Captación de Dopamina/farmacología , Matriz Extracelular/metabolismo , Matriz Extracelular/patología , Femenino , Masculino , Memoria/fisiología , Ratones Transgénicos , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Proteínas Proto-Oncogénicas c-fos/metabolismo , Sinapsis/efectos de los fármacos , Sinapsis/metabolismo , Sinapsis/patología

RESUMEN

BACKGROUND: Reduced information-processing speed (IPS) is a primary cognitive deficit of multiple sclerosis (MS) patients. The neural efficiency hypothesis describes an inverse relationship between cognitive performance in a task and the amount of cognitive resources devoted to it. Previous studies have shown that the neural efficiency hypothesis provides an appropriate framework to explore cognitive dysfunction in neurological patients. OBJECTIVE: The aim of this study was to explore the neural efficiency hypothesis regarding IPS capabilities in cognitively preserved MS patients. METHODS: 16 MS patients and 17 healthy controls (HCs) were enrolled and neuropsychologically assessed. All participants also performed a functional magnetic resonance imaging (fMRI)-adapted version of the Symbol Digit Modalities Test (SDMT) at different interstimulus intervals (ISI: 1.5, 2, and 2.5 s). RESULTS: MS patients only displayed lower SDMT performance when the ISI was set at 1.5 s. However, MS patients' normal SDMT performance at larger ISIs was achieved at the cost of increased brain activation, hence revealing that they were less cognitively efficient than the HCs. Regression analyses confirmed this conclusion by showing an opposite relationship between SDMT performance and the amount of neural resources recruited in the HC and MS groups. Thus, while a positive relationship between both variables was observed in MS patients, this correlation was negative for the HC group. CONCLUSIONS: MS patients require more cognitive resources than HCs to achieve a normal SDMT performance, then revealing that they are less efficient regarding IPS capabilities.

Asunto(s)

Trastornos del Conocimiento/etiología , Imagen por Resonancia Magnética , Esclerosis Múltiple/complicaciones , Esclerosis Múltiple/diagnóstico por imagen , Pruebas Neuropsicológicas , Adulto , Análisis de Varianza , Encéfalo/diagnóstico por imagen , Trastornos del Conocimiento/diagnóstico por imagen , Evaluación de la Discapacidad , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Pruebas de Inteligencia , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/patología , Oxígeno/sangre , Adulto Joven

RESUMEN

RATIONALE: Previous studies have shown that repeated exposure to drugs of abuse is associated with changes in clock genes expression and that mice strains with various mutations in clock genes show alterations in drug-induced behaviors. OBJECTIVE: The objective of this study is to characterize the role of the clock gene mPer1 in the development of morphine-induced behaviors and a possible link to histone deacetylase (HDAC) activity. METHODS: In Per1 Brdm1 null mutant mice and wild-type (WT) littermates, we examined whether there were any differences in the development of morphine antinociception, tolerance to antinociception, withdrawal, sensitization to locomotion, and conditioned place preference (CPP). RESULTS: Per1 Brdm1 mutant mice did not show any difference in morphine antinociception, tolerance development, nor in physical withdrawal signs precipitated by naloxone administration compared to WT. However, morphine-induced locomotor sensitization and CPP were significantly impaired in Per1 Brdm1 mutant mice. Because a very similar dissociation between tolerance and dependence vs. sensitization and CPP was recently observed after the co-administration of morphine and the HDAC inhibitor sodium butyrate (NaBut), we studied a possible link between mPer1 and HDAC activity. As opposed to WT controls, Per1 Brdm1 mutant mice showed significantly enhanced striatal global HDAC activity within the striatum when exposed to a locomotor-sensitizing morphine administration regimen. Furthermore, the administration of the HDAC inhibitor NaBut restored the ability of morphine to promote locomotor sensitization and reward in Per1 Brdm1 mutant mice. CONCLUSIONS: Our results reveal that although the mPer1 gene does not alter morphine-induced antinociception nor withdrawal, it plays a prominent role in the development of morphine-induced behavioral sensitization and reward via inhibitory modulation of striatal HDAC activity. These data suggest that PER1 inhibits deacetylation to promote drug-induced neuroplastic changes.

Asunto(s)

Condicionamiento Psicológico/fisiología , Histona Desacetilasas/metabolismo , Locomoción/fisiología , Morfina/farmacología , Proteínas Circadianas Period/fisiología , Analgésicos Opioides/farmacología , Animales , Condicionamiento Psicológico/efectos de los fármacos , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/enzimología , Tolerancia a Medicamentos/fisiología , Activación Enzimática/efectos de los fármacos , Activación Enzimática/fisiología , Inhibidores de Histona Desacetilasas/farmacología , Locomoción/efectos de los fármacos , Masculino , Ratones , Ratones Noqueados , Ratones Transgénicos , Naloxona/farmacología

RESUMEN

BACKGROUND: Previous studies have suggested a relationship between neuroanatomical and neurofunctional hippocampal alterations and episodic memory impairments in multiple sclerosis (MS) patients. OBJECTIVE: We examined hippocampus volume and functional connectivity (FC) changes in MS patients with different episodic memory capabilities. METHODS: Hippocampal subfield volume and FC changes were compared in two subgroups of MS patients with and without episodic memory impairment (multiple sclerosis impaired (MSi) and multiple sclerosis preserved (MSp), respectively) and healthy controls (HC). A discriminant function (DF) analysis was used to identify which of these neuroanatomical and neurofunctional parameters were the most relevant components of the mnemonic profiles of HC, MSp, and MSi. RESULTS: MSi showed reduced volume in several hippocampal subfields compared to MSp and HC. Ordinal gradation (MSi > MSp > HC) was also observed for FC between the posterior hippocampus and several cortical areas. DF-based analyses revealed that reduced right fimbria volume and enhanced FC at the right posterior hippocampus were the main neural signatures of the episodic memory impairments observed in the MSi group. CONCLUSION: Before any sign of episodic memory alterations (MSp), FC increased on several pathways that connect the hippocampus with cortical areas. These changes further increased when the several hippocampal volumes reduced and memory deficits appeared (MSi).

Asunto(s)

Corteza Cerebral/fisiopatología , Conectoma/métodos , Progresión de la Enfermedad , Hipocampo/fisiopatología , Trastornos de la Memoria/fisiopatología , Memoria Episódica , Esclerosis Múltiple/fisiopatología , Adulto , Corteza Cerebral/diagnóstico por imagen , Femenino , Hipocampo/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Masculino , Trastornos de la Memoria/diagnóstico por imagen , Trastornos de la Memoria/etiología , Persona de Mediana Edad , Esclerosis Múltiple/complicaciones , Esclerosis Múltiple/diagnóstico por imagen , Adulto Joven

RESUMEN

Among mammals, every cell has a biological sex, and the sex of an individual pervades its body and brain. In this review, we describe the processes through which mammals become phenotypically male or female by organizational and activational influences of genes and hormones throughout development. We emphasized that the molecular and cellular changes triggered by sex chromosomes and steroid hormones may generate sex differences in overt physiological functions and behavior, but they may alternatively promote end-point convergences between males and females. Clinical and pre-clinical evidences suggest that sex and gender differences modulate drug consumption as well as of the transition towards drug-promoted pathological states such as dependence and addiction. Additionally, sex differences in drug pharmacokinetics and pharmacodynamics will also influence dependence and addiction as well as side effects of drugs. These effects will further interact with socially gendered factors to result in sex differences in the access to, engagement in and efficacy of any therapeutic attempt. Finally, we maintain that 'sex sameness' is as important as 'sex differences' when building a complete understanding of biology for both males and females and provide a framework with which to classify and guide investigation into the mechanisms mediating sex differences and sex sameness.

Asunto(s)

Conducta Adictiva/fisiopatología , Investigación , Caracteres Sexuales , Animales , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Factores Sexuales

RESUMEN

Addiction involves alterations in multiple brain regions that are associated with functions such as memory, motivation and executive control. Indeed, it is now well accepted that addictive drugs produce long-lasting molecular and structural plasticity changes in corticostriatal-limbic loops. However, there are brain regions that might be relevant to addiction other than the prefrontal cortex, amygdala, hippocampus and basal ganglia. In addition to these circuits, a growing amount of data suggests the involvement of the cerebellum in many of the brain functions affected in addicts, though this region has been overlooked, traditionally, in the addiction field. Therefore, in the present review we provide seven arguments as to why we should consider the cerebellum in drug addiction. We present and discuss compelling evidence about the effects of drugs of abuse on cerebellar plasticity, the involvement of the cerebellum in drug-induced cue-related memories, and several findings showing that the instrumental memory and executive functions also recruit the cerebellar circuitry. In addition, a hypothetical model of the cerebellum's role relative to other areas within corticostriatal-limbic networks is also provided. Our goal is not to review animal and human studies exhaustively but to support the inclusion of cerebellar alterations as a part of the physiopathology of addiction disorder.

Asunto(s)

Conducta Adictiva/fisiopatología , Cerebelo/fisiopatología , Trastornos Relacionados con Sustancias/fisiopatología , Animales , Conducta Adictiva/psicología , Humanos , Vías Nerviosas/fisiopatología , Trastornos Relacionados con Sustancias/psicología