RESUMEN
A novel series of spirocyclic-diamine based, isoform non-selective inhibitors of acetyl-CoA carboxylase (ACC) is described. These spirodiamine derivatives were discovered by design of a library to mimic the structural rigidity and hydrogen-bonding pattern observed in the co-crystal structure of spirochromanone inhibitor I. The lead compound 3.5.1 inhibited de novo lipogenesis in rat hepatocytes, with an IC50 of 0.30 µM.
Asunto(s)
Acetilcoenzima A/metabolismo , Acetil-CoA Carboxilasa/antagonistas & inhibidores , Descubrimiento de Drogas , Hepatocitos/efectos de los fármacos , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Animales , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Hepatocitos/enzimología , Humanos , Concentración 50 Inhibidora , Modelos Biológicos , Estructura Molecular , Ratas , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacologíaRESUMEN
The melanocortin-4 receptor (MC4R) is a centrally expressed, class A GPCR that plays a key role in the regulation of appetite and food intake. Deficiencies in MC4R signaling result in hyperphagia and increased body mass in humans. Antagonism of MC4R signaling has the potential to mitigate decreased appetite and body weight loss in the setting of anorexia or cachexia due to underlying disease. Herein, we report on the identification of a series of orally bioavailable, small-molecule MC4R antagonists using a focused hit identification effort and the optimization of these antagonists to provide clinical candidate 23. Introduction of a spirocyclic conformational constraint allowed for simultaneous optimization of MC4R potency and ADME attributes while avoiding the production of hERG active metabolites observed in early series leads. Compound 23 is a potent and selective MC4R antagonist with robust efficacy in an aged rat model of cachexia and has progressed into clinical trials.
Asunto(s)
Apetito , Receptor de Melanocortina Tipo 4 , Ratas , Humanos , Animales , Caquexia/tratamiento farmacológico , Anorexia/tratamiento farmacológico , Conformación MolecularRESUMEN
In people with mental health issues, approximately 20% have co-occurring substance use, often involving cannabis. Although emotion regulation can be affected both by major depressive disorder (MDD) and by cannabis use, the relationship among all three factors is unknown. In this study, we used fMRI to evaluate the effect that cannabis use and MDD have on brain activation during an emotion regulation task. Differences were assessed in 74 emerging adults aged 16-23 with and without MDD who either used or did not use cannabis. Severity of depressive symptoms, emotion regulation style, and age of cannabis use onset were also measured. Both MDD and cannabis use interacted with the emotion regulation task in the left temporal lobe, however the location of the interaction differed for each factor. Specifically, MDD showed an interaction with emotion regulation in the middle temporal gyrus, whereas cannabis use showed an interaction in the superior temporal gyrus. Emotion regulation style predicted activity in the right superior frontal gyrus, however, this did not interact with MDD or cannabis use. Severity of depressive symptoms interacted with the emotion regulation task in the left middle temporal gyrus. The results highlight the influence of cannabis use and MDD on emotion regulation processing, suggesting that both may have a broader impact on the brain than previously thought.
Asunto(s)
Cannabis , Trastorno Depresivo Mayor , Regulación Emocional , Adulto , Encéfalo/diagnóstico por imagen , Emociones , Humanos , Imagen por Resonancia MagnéticaRESUMEN
Most of our knowledge about the functional organization of the nonhuman primate brain has come from single neuron recordings, whereas functional magnetic resonance imaging (fMRI) has rapidly become the method of choice for the study of the human brain. In some cases these two methods have resulted in conflicting models of frontal lobe function. Based on the finding that the frontal eye fields (FEF) exhibit a higher blood-oxygenation-level dependent (BOLD) activation for anti-saccades compared with pro-saccades, it has been proposed that this area is more involved in voluntary than automatic saccade generation. This model has been questioned by the finding of decreased single neuron activity in FEF for anti-compared with pro-saccades in monkeys. To reconcile these findings, we employed fMRI to compare BOLD activation between anti-saccades and pro-saccades in monkeys. FEF and a number of other cortical and subcortical areas showed an increased activation for anti-saccades. The results indicate that previous contrary findings between single neuron recordings and fMRI were due to differences between these techniques and were not related to differences between the two primate species.
Asunto(s)
Mapeo Encefálico/métodos , Potenciales Evocados Visuales/fisiología , Fijación Ocular/fisiología , Lóbulo Frontal/fisiología , Imagen por Resonancia Magnética/métodos , Movimientos Sacádicos/fisiología , Animales , Humanos , Macaca mulatta , Masculino , Especificidad de la EspecieRESUMEN
The basal ganglia (BG) play a central role in movement and it has been demonstrated that the discharge rate of neurons in these structures are modulated by the behavioral context of a given task. Here we used the antisaccade task, in which a saccade toward a flashed visual stimulus must be inhibited in favor of a saccade to the opposite location, to investigate the role of the caudate nucleus, a major input structure of the BG, in flexible behavior. In this study, we recorded extracellular neuronal activity while monkeys performed pro- and antisaccade trials. We identified two populations of neurons: those that preferred contralateral saccades (CSNs) and those that preferred ipsilateral saccades (ISNs). CSNs increased their firing rates for prosaccades, but not for antisaccades, and ISNs increased their firing rates for antisaccades, but not for prosaccades. We propose a model in which CSNs project to the direct BG pathway, facilitating saccades, and ISNs project to the indirect pathway, suppressing saccades. This model suggests one possible mechanism by which these neuronal populations could be modulating activity in the superior colliculus.
Asunto(s)
Núcleo Caudado/fisiología , Neuronas/fisiología , Movimientos Sacádicos/fisiología , Potenciales de Acción , Análisis de Varianza , Animales , Señales (Psicología) , Lateralidad Funcional , Macaca mulatta , Masculino , Microelectrodos , Modelos Neurológicos , Actividad Motora/fisiología , Estimulación Luminosa , Tiempo de ReacciónRESUMEN
Recent evidence suggests that the P2X(7) receptor may play a role in the pathophysiology of preclinical models of pain and inflammation. Therefore, pharmacological agents that target this receptor may potentially have clinical utility as anti-inflammatory and analgesic therapy. We investigated and characterized the previously reported P2X(7) antagonist N-(adamantan-1-ylmethyl)-5-[(3R-amino-pyrrolidin-1-yl)methyl]-2-chloro-benzamide, hydrochloride salt (AACBA; GSK314181A). In vitro, AACBA was a relatively potent inhibitor of both human P2X(7)-mediated calcium flux and quinolinium,4-[(3-methyl-2(3H)-benzoxazolylidene)methyl]-1-[3-(triemethylammonio)propyl]-diiodide (YO-PRO-1) uptake assays, with IC(50) values of approximately 18 and 85 nM, respectively. Compared with the human receptor, AACBA was less potent at the rat P2X(7) receptor, with IC(50) values of 29 and 980 nM in the calcium flux and YO-PRO-1 assays, respectively. In acute in vivo models of pain and inflammation, AACBA dose-dependently reduced lipopolysaccharide-induced plasma interleukin-6 release and prevented or reversed carrageenan-induced paw edema and mechanical hypersensitivity. In chronic in vivo models of pain and inflammation, AACBA produced a prophylactic, but not therapeutic-like, prevention of the clinical signs and histopathological damage of collagen-induced arthritis. Finally, AACBA could not reverse L(5) spinal nerve ligation-induced tactile allodynia when given therapeutically. Consistent with previous literature, these results suggest that P2X(7) receptors do play a role in animal models of pain and inflammation. Further study of P2X(7) antagonists both in preclinical and clinical studies will help elucidate the role of the P2X(7) receptor in pain and inflammatory mechanisms and may help identify potential clinical benefits of such molecules.
Asunto(s)
Adamantano/análogos & derivados , Antiinflamatorios no Esteroideos/farmacología , Benzamidas/farmacología , Inflamación/tratamiento farmacológico , Dolor/tratamiento farmacológico , Antagonistas del Receptor Purinérgico P2 , Adamantano/farmacología , Animales , Artritis/inducido químicamente , Artritis/tratamiento farmacológico , Benzoxazoles , Calcio/metabolismo , Modelos Animales de Enfermedad , Humanos , Concentración 50 Inhibidora , Compuestos de Quinolinio , Ratas , Receptores Purinérgicos P2X7RESUMEN
Studies have linked the serine-threonine kinase MAP4K4 to the regulation of a number of biological processes and/or diseases, including diabetes, cancer, inflammation, and angiogenesis. With a majority of the members of our lead series (e.g., 1) suffering from time-dependent inhibition (TDI) of CYP3A4, we sought design avenues that would eliminate this risk. One such approach arose from the observation that carboxylic acid-based intermediates employed in our discovery efforts retained high MAP4K4 inhibitory potency and were devoid of the TDI risk. The medicinal chemistry effort that led to the discovery of this central nervous system-impaired inhibitor together with its preclinical safety profile is described.
Asunto(s)
Aminopiridinas/síntesis química , Aminopiridinas/farmacología , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Aminopiridinas/efectos adversos , Animales , Disponibilidad Biológica , Ácidos Carboxílicos/química , Inhibidores del Citocromo P-450 CYP3A/síntesis química , Inhibidores del Citocromo P-450 CYP3A/farmacología , Descubrimiento de Drogas , Semivida , Lipopolisacáridos/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Conformación Molecular , Inhibidores de Proteínas Quinasas/efectos adversos , Ratas , Ratas Wistar , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/sangreRESUMEN
Anomalies in the medial prefrontal cortex, anterior insulae, and large-scale brain networks associated with them have been proposed to underlie the pathophysiology of schizophrenia and major depressive disorder (MDD). In this study, we examined the connectivity of the medial prefrontal cortices and anterior insulae in 24 healthy controls, 24 patients with schizophrenia, and 24 patients with MDD early in illness with seed-based resting state functional magnetic resonance imaging analysis using Statistical Probability Mapping. As hypothesized, reduced connectivity was found between the medial prefrontal cortex and the dorsal anterior cingulate cortex and other nodes associated with directed effort in patients with schizophrenia compared to controls while patients with MDD had reduced connectivity between the medial prefrontal cortex and ventral prefrontal emotional encoding regions compared to controls. Reduced connectivity was found between the anterior insulae and the medial prefrontal cortex in schizophrenia compared to controls, but contrary to some models emotion processing regions failed to demonstrate increased connectivity with the medial prefrontal cortex in MDD compared to controls. Although, not statistically significant after correction for multiple comparisons, patients with schizophrenia tended to demonstrate decreased connectivity between basal ganglia-thalamocortical regions and the medial prefrontal cortex compared to patients with MDD, which might be expected as these regions effect action. Results were interpreted to support anomalies in nodes associated with directed effort in schizophrenia and nodes associated with emotional encoding network in MDD compared to healthy controls.
RESUMEN
Recent studies in adipose tissue, pancreas, muscle, and macrophages suggest that MAP4K4, a serine/threonine protein kinase may be a viable target for antidiabetic drugs. As part of the evaluation of MAP4K4 as a novel antidiabetic target, a tool compound, 16 (PF-6260933) and a lead 17 possessing excellent kinome selectivity and suitable properties were delivered to establish proof of concept in vivo. The medicinal chemistry effort that led to the discovery of these lead compounds is described herein together with in vivo pharmacokinetic properties and activity in a model of insulin resistance.
RESUMEN
Non-suicidal self-injury (NSSI) is increasingly common in young psychiatric patients. It is unclear why pain, which should be aversive, becomes reinforcing in this context. We hypothesized that pain- and/or reward-processing neurocircuitry would be abnormal in NSSI patients compared with non-NSSI patients. Using functional magnetic resonance imaging, we administered a painfully cold and comparison cool stimulus under two conditions: self-administered and experimenter-administered (as a control). Participants comprised 13 NSSI patients and 15 non-NSSI control patients, who were matched for sex, age, medications, symptoms, and diagnoses. Whole-brain analyses of main effects, as well as correlational analyses with subjective pain and "relief" (suggesting reward), were performed. Significant main effects of group showed greater blood oxygenation level-dependent (BOLD) response for NSSI than controls in right midbrain/pons; culmen; amygdala; and parahippocampal, inferior frontal and superior temporal gyri; as well as orbital frontal cortex (OFC). The correlation between BOLD signal and "relief" was greater in NSSI patients in areas associated with reward/pain and addiction including thalamus, dorsal striatum and anterior precuneus. Post hoc analysis showed reduced functional connectivity between right OFC and anterior cingulate cortex in NSSI youth, implying possible deficits in the neuroregulation of emotional behavior. These findings help inform how pain is associated with reward for NSSI patients but not for non-NSSI patients.
Asunto(s)
Corteza Cerebral/fisiopatología , Dolor/fisiopatología , Dolor/psicología , Recompensa , Conducta Autodestructiva/fisiopatología , Ideación Suicida , Adolescente , Adulto , Estudios de Casos y Controles , Frío , Femenino , Giro del Cíngulo/fisiopatología , Humanos , Imagen por Resonancia Magnética , Masculino , Corteza Prefrontal/fisiopatología , Conducta Autodestructiva/psicología , Adulto JovenRESUMEN
Prior research has shown a relationship between early onset marijuana (MJ) use and depression; however, this relationship is complex and poorly understood. Here, we utilized passive music listening and fMRI to examine functional brain activation to a rewarding stimulus in 75 participants [healthy controls (HC), patients with major depressive disorder (MDD), frequent MJ users, and the combination of MDD and MJ (MDD + MJ)]. For each participant, a preferred and neutral piece of instrumental music was determined (utilizing ratings on a standardized scale), and each completed two 6-min fMRI scans of a passive music listening task. Data underwent pre-processing and 61 participants were carried forward for analysis (17 HC, 15 MDD, 15 MJ, 14 MDD + MJ). Two statistical analyses were performed using SPM8, an analysis of covariance with two factors (group × music type) and a whole brain, multiple regression analysis incorporating two predictors of interest [MJ use in past 28 days; and Beck Depression Inventory (BDI) score]. We identified a significant group × music type interaction. Post hoc comparisons showed that the preferred music had significantly greater activation in the MDD + MJ group in areas including the right middle and inferior frontal gyri extending into the claustrum and putamen and the anterior cingulate. No significant differences were identified in MDD, MJ, or HC groups. Multiple regression analysis showed that activation in medial frontal cortex was positively correlated with amount of MJ use, and activation in areas including the insula was negatively correlated with BDI score. Results showed modulation in brain activation during passive music listening specific to MDD, frequent MJ users. This supports the suggestion that frequent MJ use, when combined with MDD, is associated with changes in neurocircuitry involved in reward processing in ways that are absent with either frequent MJ use or MDD alone. This could help inform clinical recommendations for youth with MDD.
RESUMEN
BACKGROUND: Major Depressive Disorder (MDD) and Bipolar Disorder (BD) can be difficult to differentiate, as both feature depressive episodes. Here we have utilized fMRI and a measure of trait bipolarity to examine resting-state functional connectivity of brain activation in the default mode network in youth with MDD and BD to isolate trait-specific patterns. METHODS: We collected resting-state fMRI scans from thirty youth (15 MDD; 15 BD, Type 1). The Bipolarity Index (BI) was completed by each patient's treating psychiatrist. Independent components analysis was used to extract a default mode network component from each participant, and then multiple regression was used to identify correlations between bipolarity and network activation. RESULTS: Activation in putamen/claustrum/insula correlated positively with BI; activation in the postcentral gyrus/posterior cingulate gyrus correlated negatively with BI. These correlations did not appear to be driven by movement in the scanner, state depression, gender or lithium use. LIMITATIONS: There were group differences in state depression and sex that needed to be statistically covaried; differences in medication use existed between the groups; sample size was not large. CONCLUSIONS: The identification of the putamen/claustrum in our positive correlation may indicate a potential trait marker for the psychomotor activation unique to bipolar mania. The negative correlation in the postcentral gyrus/posterior cingulate suggests that this functional inactivation is more specific to MDD and is consistent with previous research. Ultimately, this approach may help to develop techniques to minimize the current clinical dilemma by facilitating the classification between BD and MDD.
Asunto(s)
Trastorno Bipolar/fisiopatología , Encéfalo/fisiopatología , Trastornos del Humor/fisiopatología , Adolescente , Ganglios Basales/fisiopatología , Trastorno Depresivo Mayor/fisiopatología , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Desempeño Psicomotor , Putamen/fisiopatologíaRESUMEN
In order to study diversification and microevolution in Phlox, we developed nine polymorphic microsatellite loci. In 20 individuals of Phlox pilosa from a single population, the average number of alleles per locus was 10.0 ± 5.1, and average observed and expected heterozygosities were 0.611 ± 0.234 and 0.769 ± 0.170, respectively. Most of these markers amplified successfully in 11 additional species of Phlox, representing a broad diversity of the genus, and some also amplified in more distantly related members of the Polemoniaceae. These microsatellite markers will be valuable for investigation of evolutionary processes in this important study system.
RESUMEN
Flexible, adaptive behavior often requires the inhibition of automatic responses in favor of voluntary response generation. The antisaccade task requires active inhibition of the automatic saccade to a peripheral stimulus followed by generation of a voluntary antisaccade to the opposite location. Previous studies demonstrated greater functional magnetic resonance imaging (fMRI) activation for antisaccades than prosaccades in cortical saccade areas but did not distinguish the relative contributions of saccadic inhibition and generation. To address this question, we compared prosaccades, antisaccades, and nogo trials in a rapid event-related fMRI experiment with ten human subjects (6 female, 4 male). Trials were compound, containing a colored fixation point to cue trial type, followed by a 200-ms gap and then peripheral stimulus presentation and response. Required responses for prosaccade, antisaccade, and nogo trials, respectively, were to generate a saccade to the stimulus, look away from it, and inhibit the automatic saccade while maintaining central fixation. Frontal and supplementary eye fields, anterior cingulate cortex, intraparietal sulcus, and precuneus, exhibited surprisingly similar activation patterns for prosaccade and nogo responses, suggesting that BOLD signal in cortical saccade regions might predominantly reflect visual detection and attention processes rather than saccade generation or inhibition. These regions displayed greater activation for antisaccade responses versus prosaccade or nogo responses, possibly due to visuospatial remapping or increased attention levels in the antisaccade task. In right superior frontal sulcus, right supramarginal gyrus, and posterior cingulate sulcus, activation was greater for nogo compared to prosaccade responses, suggesting a role in active saccadic inhibition.
Asunto(s)
Mapeo Encefálico , Potenciales Evocados/fisiología , Imagen por Resonancia Magnética/métodos , Movimientos Sacádicos/fisiología , Adulto , Femenino , Humanos , Cinética , Masculino , Estimulación Luminosa , Tiempo de Reacción , Valores de ReferenciaRESUMEN
P2X3 purinergic receptors are predominantly expressed in dorsal root ganglion (DRG) neurons and play an important role in pain sensation. P2X3-specific antagonists are currently being sought to ameliorate pain in several indications. Understanding how antagonists interact with the P2X3 receptor can aid in the discovery and development of P2X3-specific antagonists. We studied the activity of the noncompetitive antagonist P1, P5-di[inosine-5'] pentaphosphate (IP5I) at the P2X3 receptor, compared with the well studied competitive antagonist TNP-ATP, using a whole-cell voltage-clamp technique in dissociated rat DRG neurons. IP5I blocked alphabeta-methylene ATP (alphabeta-meATP)-evoked P2X3 responses in a concentration-dependent manner (IC50 = 0.6 +/- 0.1 microM). IP5I effectively inhibited P2X3 currents when pre-exposed to desensitized but not unbound receptors. Furthermore, IP5I equally blocked 1 and 10 microM alphabeta-meATP-evoked currents and had no effect on the desensitization rate constant of these currents. This supports the action of IP5I as a noncompetitive antagonist that interacts with the desensitized state of the P2X3 receptor. In contrast, TNP-ATP inhibited the current evoked by 1 microM alphabeta-meATP significantly more than the one evoked by 10 microM alphabeta-meATP. It also significantly slowed down the desensitization rate constant of the current. These results suggest that TNP-ATP acts as a competitive antagonist and competes with alphabeta-meATP at the P2X3 agonist binding site. These findings may help to explain why IP5I acts selectively at the fast-desensitizing P2X1 and P2X3 subtypes of the P2X purinoceptor, while having much less potency at slow-desensitizing P2X2 and P2X(2/3) subtypes that lack the fast desensitized conformational state.
Asunto(s)
Fosfatos de Dinucleósidos/metabolismo , Ganglios Espinales/metabolismo , Antagonistas del Receptor Purinérgico P2 , Adenosina Trifosfato/análogos & derivados , Adenosina Trifosfato/farmacología , Animales , Unión Competitiva , Fosfatos de Dinucleósidos/farmacología , Relación Dosis-Respuesta a Droga , Ratas , Ratas Sprague-Dawley , Receptores Purinérgicos P2/metabolismo , Receptores Purinérgicos P2X3RESUMEN
Under conditions of genomic stress, the Mdm locus in human and in mouse is prone to instability manifested as amplification and oncogenesis. The Mdm2 gene is a known oncogene that is amplified in approximately one-third of sarcomas and whose protein product interacts with the tumor suppressor p53. Concimitant with such gene amplification events is the activation and mobilization of endogenous retroelements, typically through the relaxation of epigenetic controlling mechanisms. Processed pseudogenes, which can be formed through endogenous LINE retroelement activity, may indicate increased genomic instability. We have isolated processed pseudogenes for Mdm2 in Mus caroli DNA, likely formed from independent events in different individuals. This is the first identification and characterization of an Mdm2 pseudogene in any organism. Multiple retrotransposition events are suggested by the variable sequence and genomic structure of the identified pseudogenes across all exons and the 3'UTR. The high degree of similarity between the gene and each pseudogene, as well as the lack of evidence for an Mdm2 pseudogene in several other species of Mus, indicate evolutionarily recent retrotransposition events leading to the formation of the Mdm2 pseudogenes in M. caroli. Previous studies on the Mdm2 locus in Mus caroli showed amplification and overexpression of this gene on double minute chromosomes in a Mus musculus x Mus caroli interspecific hybrid. The identification of an Mdm2 retropseudogene within this species further highlights the predisposition to instability for this region of the genome.
Asunto(s)
Secuencia de ADN Inestable , Ratones/genética , Proteínas Proto-Oncogénicas c-mdm2/genética , Seudogenes , Regiones no Traducidas 3' , Animales , Exones , Amplificación de Genes , Oncogenes , RetroelementosRESUMEN
One of the hallmarks of cognitive control is the suppression of prepotent but inappropriate responses. Here we used event-related functional MRI to measure functional brain activation during a stimulus-response incompatibility task. Subjects were instructed before a stimulus appeared either to look at the stimulus (prosaccade) or to look away from the stimulus (antisaccade). Eye movements were recorded so that functional brain activation could be grouped into prosaccades, correct antisaccades, and errors (saccades toward the stimulus on antisaccade trials). Correct antisaccade trials were associated with significantly more activation in frontal and parietal cortical areas compared with prosaccade trials during the late preparatory period before stimulus appearance. Correct antisaccades evoked more activation than errors in the right dorsolateral prefrontal cortex, anterior cingulate cortex (ACC), and presupplementary eye fields during this period. No significant differences were found for any comparisons early in the preparatory period. Our data suggest that the preparation of an antisaccade activates a large frontal and parietal network that may be involved in presetting the oculomotor system for the antisaccade task. These findings indicate that a large network of frontal and posterior areas is modulated during the latter component of the preparatory period on antisaccade compared with prosaccade trials. The results further suggest that the activation level of frontal cortical areas before stimulus presentation is associated with subjects' performance in the antisaccade task. In contrast, we found no areas that were more active for correct antisaccades than prosaccades or for correct antisaccades than error antisaccades during the stimulus-response period. In fact, a number of posterior cortical areas and a few areas in the superior frontal lobe were more active during the stimulus-response period on prosaccade trials than on antisaccade trials. Error antisaccades showed a larger activation in the ACC during the stimulus-response period compared with correct antisaccades.
Asunto(s)
Mapeo Encefálico , Corteza Cerebral/irrigación sanguínea , Corteza Cerebral/fisiología , Potenciales Evocados Visuales/fisiología , Imagen por Resonancia Magnética , Movimientos Sacádicos/fisiología , Adulto , Corteza Cerebral/anatomía & histología , Femenino , Lateralidad Funcional/fisiología , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Oxígeno/sangre , Estimulación Luminosa/métodos , Desempeño Psicomotor/fisiología , Tiempo de Reacción/fisiología , Análisis y Desempeño de TareasRESUMEN
Visually guided arm movements such as reaching or pointing are accompanied by saccadic eye movements that typically begin prior to motion of the arm. In the past, some degree of coupling between the oculomotor and limb motor systems has been demonstrated by assessing the relative onset times of eye and arm movement, and by the demonstration of a gap effect for arm movement reaction times. However, measures of limb movement onset time based on kinematics are affected by factors such as the relatively high inertia of the limb and neuromechanical delays. The goal of the present study was thus to assess the relative timing of rapid eye and arm movements made to visual targets by examining electromyographic (EMG) activity of limb muscles in conjunction with eye and arm position measures. The observation of a positive correlation between eye and limb EMG onset latencies, and the presence of a gap effect for limb EMG onset times (a reduction in reaction time when a temporal gap is introduced between the disappearance of a central fixation point and the appearance of a new target) both support the idea that eye and arm movement initiation are linked. However, limb EMG onset in most cases precedes saccade onset, and the magnitude of EMG activity prior to eye movement is correlated with both the direction and amplitude of the upcoming arm movement. This suggests that, for the rapid movements studied here, arm movement direction and distance are specified prior to the onset of saccades.
Asunto(s)
Mano/fisiología , Desempeño Psicomotor/fisiología , Brazo/fisiología , Electromiografía , Femenino , Humanos , Masculino , Movimiento/fisiología , Tiempo de Reacción , Movimientos Sacádicos/fisiologíaRESUMEN
It has been shown that saccade-related neurons in the superior colliculus (SC) display an increased level of prestimulus activity and a higher stimulus-related burst in action potentials preceding direction errors in the anti-saccade task compared with correct anti-saccades. From this, it has been hypothesized that errors occur when the incoming visual signal in the SC passes a threshold and triggers a reflexive saccade. This hypothesis predicts that an attenuated visual signal will reduce the number of direction errors. Since ethanol has been shown to have a suppressive effect on cortical visual event-related potentials (ERPs), the purpose of the present study was to investigate the effects of moderate ethanol consumption on anti-saccade performance. Under both placebo and ethanol conditions, we recorded ERPs and measured eye movements in male subjects during the performance of an anti-saccade task in which the fixation point disappeared 200 ms prior to stimulus presentation. Compared with the placebo condition, we found in the ethanol condition: (1). a decrease in ERP amplitudes during the gap period and after stimulus presentation, (2). an increase in the latencies of anti-saccades, and (3). a decrease in the percentage of direction errors. These data demonstrate the effects of ethanol on anti-saccade task performance and provide further support for the hypothesis that errors in the anti-saccade task are triggered by the incoming visual signal.
Asunto(s)
Etanol/farmacología , Potenciales Evocados/efectos de los fármacos , Neuronas/efectos de los fármacos , Desempeño Psicomotor/efectos de los fármacos , Movimientos Sacádicos/fisiología , Colículos Superiores/efectos de los fármacos , Vías Visuales/efectos de los fármacos , Adulto , Potenciales Evocados/fisiología , Fijación Ocular/efectos de los fármacos , Fijación Ocular/fisiología , Humanos , Masculino , Modelos Neurológicos , Inhibición Neural/efectos de los fármacos , Inhibición Neural/fisiología , Neuronas/fisiología , Trastornos de la Motilidad Ocular/inducido químicamente , Trastornos de la Motilidad Ocular/fisiopatología , Desempeño Psicomotor/fisiología , Tiempo de Reacción/efectos de los fármacos , Tiempo de Reacción/fisiología , Colículos Superiores/fisiología , Vías Visuales/fisiologíaRESUMEN
Subjects sometimes fail to suppress a reflexive saccade towards the flashed stimulus in an anti-saccade task. Here, we studied how error rates in the anti-saccade task varied as a function of saccadic probability. Ten subjects performed 200 anti-saccade trials for each of three saccade-direction probability conditions (20%, 50%, and 80%). We found that as the likelihood of a saccade in a given direction increased, the percentage of pro-saccade errors also increased for stimulus presentations in this direction. These results provide support for the hypothesis that errors in the anti-saccade task are the result of an increased level of motor preparation.