RESUMEN
Proactive inhibition - the anticipation of having to stop a response - relies on objective information contained in cue-related contingencies in the environment, as well as on the subjective interpretation derived from these cues. To date, most studies of brain areas underlying proactive inhibition have exclusively considered the objective predictive value of environmental cues, by varying the probability of stop-signals. However, by only taking into account the effect of different cues on brain activation, the subjective component of how cues affect behavior is ignored. We used a modified stop-signal response task that includes a measurement for subjective expectation, to investigate the effect of this subjective interpretation. After presenting a cue indicating the probability that a stop-signal will occur, subjects were asked whether they expected a stop-signal to occur. Furthermore, response time was used to retrospectively model brain activation related to stop-expectation. We found more activation during the cue period for 50% stop-signal probability, when contrasting with 0%, in the mid and inferior frontal gyrus, inferior parietal lobe and putamen. When contrasting expected vs. unexpected trials, we found modest effects in the mid frontal gyrus, parietal, and occipital areas. With our third contrast, we modeled brain activation during the cue with trial-by-trial variances in response times. This yielded activation in the putamen, inferior parietal lobe, and mid frontal gyrus. Our study is the first to use the behavioral effects of proactive inhibition to identify the underlying brain regions, by employing an unbiased task-design that temporally separates cue and response.
Asunto(s)
Anticipación Psicológica/fisiología , Encéfalo/fisiología , Modelos Neurológicos , Actividad Motora/fisiología , Inhibición Proactiva , Encéfalo/diagnóstico por imagen , Mapeo Encefálico , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Tiempo de Reacción , Adulto JovenRESUMEN
OBJECTIVES: Stimulant use is associated with increased anxiety and a single administration of dexamphetamine increases amygdala activation to biologically salient stimuli in healthy individuals. Here, we investigate how current cocaine use affects amygdala activity and amygdala connectivity with the prefrontal cortex in response to biologically salient stimuli in an emotional face matching task (EFMT). EXPERIMENTAL DESIGN: Amygdala activity and amygdala connectivity during the EFMT were assessed in 51 cocaine using males and 32 non-drug-using healthy males using functional magnetic resonance imaging (fMRI). Within the cocaine use group, we explored whether amygdala activation was associated with age of first use of cocaine and duration of cocaine use to distinguish between amygdala activation alterations as a cause or a consequence of cocaine use. PRINCIPAL OBSERVATIONS: We observed hyperactivity of the amygdala, thalamus, and hippocampus and reduced amygdala connectivity with the anterior cingulate gyrus in response to angry and fearful facial expressions in current cocaine users compared to controls. Increased amygdala activation was independently associated with earlier age of first cocaine use and with longer exposure to cocaine. CONCLUSIONS: Our findings suggest that amygdala hyperactivity to biologically salient stimuli may represent a risk factor for an early onset of cocaine use and that prolonged cocaine use may further sensitize amygdala activation. High amygdala activation to emotional face processing in current cocaine users may result from low prefrontal control of the amygdala response to such stimuli.
Asunto(s)
Amígdala del Cerebelo/patología , Trastornos Relacionados con Cocaína/patología , Trastornos Relacionados con Cocaína/psicología , Vías Nerviosas/patología , Corteza Prefrontal/patología , Adulto , Edad de Inicio , Ira , Mapeo Encefálico , Expresión Facial , Miedo , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Factores de Riesgo , Percepción Social , Trastornos Relacionados con Sustancias/patología , Trastornos Relacionados con Sustancias/psicología , Adulto JovenRESUMEN
Motivational states consist of cognitive, emotional, and physiological components controlled by multiple brain regions. An integral component of this neural circuitry is the bed nucleus of the stria terminalis (BNST). Here, we identify that neurons within BNST that express the gene prepronociceptin (PnocBNST) modulate rapid changes in physiological arousal that occur upon exposure to motivationally salient stimuli. Using in vivo two-photon calcium imaging, we find that PnocBNST neuronal responses directly correspond with rapid increases in pupillary size when mice are exposed to aversive and rewarding odors. Furthermore, optogenetic activation of these neurons increases pupillary size and anxiety-like behaviors but does not induce approach, avoidance, or locomotion. These findings suggest that excitatory responses in PnocBNST neurons encode rapid arousal responses that modulate anxiety states. Further histological, electrophysiological, and single-cell RNA sequencing data reveal that PnocBNST neurons are composed of genetically and anatomically identifiable subpopulations that may differentially tune rapid arousal responses to motivational stimuli.
Asunto(s)
Amígdala del Cerebelo/metabolismo , Conducta Animal/fisiología , Neuronas/metabolismo , Precursores de Proteínas/metabolismo , Receptores Opioides/metabolismo , Animales , Nivel de Alerta , Masculino , RatonesRESUMEN
The current obesity epidemic is a major worldwide health concern. Despite the consensus that the brain regulates energy homeostasis, the neural adaptations governing obesity are unknown. Using a combination of high-throughput single-cell RNA sequencing and longitudinal in vivo two-photon calcium imaging, we surveyed functional alterations of the lateral hypothalamic area (LHA)-a highly conserved brain region that orchestrates feeding-in a mouse model of obesity. The transcriptional profile of LHA glutamatergic neurons was affected by obesity, exhibiting changes indicative of altered neuronal activity. Encoding properties of individual LHA glutamatergic neurons were then tracked throughout obesity, revealing greatly attenuated reward responses. These data demonstrate how diet disrupts the function of an endogenous feeding suppression system to promote overeating and obesity.
Asunto(s)
Área Hipotalámica Lateral/metabolismo , Área Hipotalámica Lateral/fisiopatología , Obesidad/genética , Obesidad/fisiopatología , Transcriptoma , Animales , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Ácido Glutámico/metabolismo , Ratones , Neuronas , Obesidad/psicología , Recompensa , Proteína 2 de Transporte Vesicular de Glutamato/genéticaRESUMEN
Successful response inhibition relies on the suppression of motor cortex activity. The striatum has previously been linked to motor cortex suppression during the act of inhibition (reactive), but activation was also seen during anticipation of stop signals (proactive). More specifically, striatal activation increased with a higher stop probability. Using functional magnetic resonance imaging with specific regions of interest, we investigate for the first time whether activation in the striatum during reactive inhibition is related to previously formed expectations. We used a modified stop-signal response task in which subjects were asked trial by trial, after being presented a stop-signal probability cue, whether they actually expected a stop to occur. This enabled us to investigate the subjective expectation of a stop signal during each trial. We found that striatal activity during reactive inhibition was higher when subjects expected stop signals. These results help explain conflicting findings of previous studies on the association between striatal activation and inhibition, since we demonstrate a crucial role of the subjects' expectation of a stop signal and thus their ability to prepare for a stop in advance. In conclusion, the current results show for the first time that striatal contributions to reactive response inhibition are, in part, related to subjective anticipation.
Asunto(s)
Mapeo Encefálico , Cuerpo Estriado/fisiología , Corteza Motora/fisiología , Desempeño Psicomotor/fisiología , Adulto , Anticipación Psicológica/fisiología , Función Ejecutiva/fisiología , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Neostriado/fisiología , Tiempo de Reacción/fisiología , Inhibición ReactivaRESUMEN
Brexpiprazole (BREX), a recently approved antipsychotic drug in the US and Canada, improves cognitive dysfunction in animal models, by still largely unknown mechanisms. BREX is a partial agonist at 5-HT1A and D2 receptors and antagonist at α1B- and α2C-adrenergic and 5-HT2A receptors all with a similar potency. The NMDA receptor antagonist phencyclidine (PCP), used as pharmacological model of schizophrenia, activates thalamocortical networks and decreases low frequency oscillations (LFO; <4 Hz). These effects are reversed by antipsychotics. Here we assessed the ability of BREX to reverse PCP-induced hyperactivity of thalamocortical circuits, and the involvement of 5-HT1A receptors in its therapeutic action. BREX reversed PCP-induced neuronal activation at a lower dose in centromedial/mediodorsal thalamic nuclei (CM/MD; 0.5mg/kg) than in pyramidal medial prefrontal cortex neurons (mPFC, 2mg/kg), perhaps due to antagonism at α1B-adrenoceptors, abundantly expressed in the thalamus. Conversely, a cumulative 0.5 mg/kg dose reversed a PCP-induced LFO decrease in mPFC but not in CM/MD. BREX reduced LFO in both areas, yet with a different dose-response, and moderately excited mPFC neurons. The latter effect was reversed by the 5-HT1A receptor antagonist WAY-100635. Thus, BREX partly antagonizes PCP-induced thalamocortical hyperactivity, differentially in mPFC versus CM/MD. This regional selectivity may be related to the differential expression of α1B-, α2C-adrenergic and 5-HT2A receptors in both regions and/or different neuronal types. Furthermore, the pro-cognitive properties of BREX may be related to the 5-HT1A receptor-mediated increase in mPFC pyramidal neuron activity. Overall, the present data provide new insight on the brain elements involved in BREX's therapeutic actions.
Asunto(s)
Antipsicóticos/farmacología , Vías Nerviosas/efectos de los fármacos , Neuronas/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Quinolonas/farmacología , Núcleos Talámicos/efectos de los fármacos , Tiofenos/farmacología , Potenciales de Acción/efectos de los fármacos , Animales , Ondas Encefálicas/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Antagonistas de Aminoácidos Excitadores/farmacología , Análisis de Fourier , Masculino , Vías Nerviosas/fisiología , Fenciclidina/farmacología , Piperazinas/farmacología , Corteza Prefrontal/citología , Piridinas/farmacología , Ratas , Ratas Wistar , Antagonistas de la Serotonina/farmacología , Núcleos Talámicos/citologíaRESUMEN
Schizophrenia is a severe psychiatric disorder associated with impaired fronto-striatal functioning. Similar deficits are observed in unaffected siblings of patients, indicating that these deficits are linked to a familial risk for the disorder. Fronto-striatal deficits may arise during adolescence and precede clinical manifestation of the disorder. However, the development of the fronto-striatal network in adolescents at increased familial risk for schizophrenia is still poorly understood. In this cross-sectional study, we investigate the impact of familial risk on fronto-striatal functioning across age related to reward anticipation and receipt in 25 adolescent offspring of schizophrenia patients (SZ offspring) and 36 age-matched healthy controls (range 10-19years). Subjects performed a reward task while being scanned with functional MRI. Overall response times and the amount of money won did not differ between the groups. Striatal activation during reward anticipation decreased across age in the SZ offspring, while it did not in the healthy controls. Activation in the orbitofrontal cortex during reward receipt did not differ between the groups. These results, taken together with data from adult schizophrenia patients and their siblings, indicate that the diminishing striatal activation across adolescence may signify a familial vulnerability for schizophrenia.
Asunto(s)
Desarrollo del Adolescente/fisiología , Anticipación Psicológica/fisiología , Hijo de Padres Discapacitados/psicología , Cuerpo Estriado/fisiopatología , Recompensa , Esquizofrenia/fisiopatología , Adolescente , Mapeo Encefálico , Niño , Cuerpo Estriado/crecimiento & desarrollo , Estudios Transversales , Predisposición Genética a la Enfermedad , Humanos , Imagen por Resonancia Magnética , Pruebas Neuropsicológicas , Tiempo de ReacciónRESUMEN
A recent Genome-Wide Association Study showed that the rs2514218 single nucleotide polymorphism (SNP) in close proximity to dopamine receptor D2 is strongly associated with schizophrenia. Further, an in silico experiment showed that rs2514218 has a cis expression quantitative trait locus effect in the basal ganglia. To date, however, the functional consequence of this SNP is unknown. Here, we used functional Magnetic resonance imaging to investigate the impact of this risk allele on striatal activation during proactive and reactive response inhibition in 45 unaffected siblings of schizophrenia patients. We included siblings to circumvent the illness specific confounds affecting striatal functioning independent from gene effects. Behavioral analyses revealed no differences between the carriers (n= 21) and noncarriers (n= 24). Risk allele carriers showed a diminished striatal response to increasing proactive inhibitory control demands, whereas overall level of striatal activation in carriers was elevated compared to noncarriers. Finally, risk allele carriers showed a blunted striatal response during successful reactive inhibition compared to the noncarriers. These data are consistent with earlier reports showing similar deficits in schizophrenia patients, and point to a failure to flexibly engage the striatum in response to contextual cues. This is the first study to demonstrate an association between impaired striatal functioning and the rs2514218 polymorphism. We take our findings to indicate that striatal functioning is impaired in carriers of the DRD2 risk allele, likely due to dopamine dysregulation at the DRD2 location.
Asunto(s)
Función Ejecutiva/fisiología , Inhibición Psicológica , Neostriado/fisiopatología , Receptores de Dopamina D2/genética , Esquizofrenia/genética , Esquizofrenia/fisiopatología , Hermanos , Adulto , Alelos , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , RiesgoRESUMEN
In cocaine-dependent patients, gray matter (GM) volume reductions have been observed in the frontal lobes that are associated with the duration of cocaine use. Studies are mostly restricted to treatment-seekers and studies in non-treatment-seeking cocaine abusers are sparse. Here, we assessed GM volume differences between 30 non-treatment-seeking cocaine-dependent individuals and 33 non-drug using controls using voxel-based morphometry. Additionally, within the group of non-treatment-seeking cocaine-dependent individuals, we explored the role of frequently co-occurring features such as trait impulsivity (Barratt Impulsivity Scale, BIS), smoking, and depressive symptoms (Beck Depression Inventory), as well as the role of cocaine use duration, on frontal GM volume. Smaller GM volumes in non-treatment-seeking cocaine-dependent individuals were observed in the left middle frontal gyrus. Moreover, within the group of cocaine users, trait impulsivity was associated with reduced GM volume in the right orbitofrontal cortex, the left precentral gyrus, and the right superior frontal gyrus, whereas no effect of smoking severity, depressive symptoms, or duration of cocaine use was observed on regional GM volumes. Our data show an important association between trait impulsivity and frontal GM volumes in cocaine-dependent individuals. In contrast to previous studies with treatment-seeking cocaine-dependent patients, no significant effects of smoking severity, depressive symptoms, or duration of cocaine use on frontal GM volume were observed. Reduced frontal GM volumes in non-treatment-seeking cocaine-dependent subjects are associated with trait impulsivity and are not associated with co-occurring nicotine dependence or depression.
RESUMEN
In general, clinical trials in developing countries are met with resistance because the people are particularly vulnerable and medical assistance is often unaffordable. The prospect of free medication can then lead to exploitation since the local population can be persuaded to participate in trials that would never be allowed in Western countries due to ethical concerns. Placebo-controlled research that tests cheaper alternatives for treatments already registered could greatly improve the situation in developing countries, however. Expensive registered treatments are often unavailable in these countries. Therefore, I call for allowing such studies when the registered treatment is locally unavailable. This should be based on the four most important principles of medical ethics: the duty to help patients, avoid harm, justice and respect for autonomy. On the condition, however, that the population in developing countries benefits in the long term.