Аудит як процедура контролю за станом платіжної системи суб’єкта господарської діяльності

У статті розглядаються питання аудиту розрахункових операцій. Виділено різні види аудиторських процедур – аналітичні та альтернативні. Визначено порядок проведення аудиторської перевірки розрахунків.В статье рассматриваются вопросы аудита расчетных операций. Выделены различные виды аудиторских процедур – аналитические и альтернативные. Определен порядок проведения аудиторской проверки.In the article the issues of audit of payments are revealed. Various types of audit procedures – analytical and alternative are identified. The procedure for conducting the audit is stipulated

Reduced frontal brain volume in non-treatment-seeking cocaine-dependent individuals:Exploring the role of impulsivity, depression, and smoking

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

The novel antipsychotic brexpiprazole reverses a disruption of thalamocortical function induced by phencyclidine. Exploring the involvement of 5-HT1A and a1B-adrenergic receptors

Trabajo presentado en el 29th ECNP Congress, celebrado en Viena, Austria, del 17 al 20 de septiembre de 2016Peer Reviewe

The novel antipsychotic brexpiprazole partly reverses a disruption of thalamocortical function induced by phencyclidine

Trabajo presentado en el ECNP Workshop for Junior Scientists, celebrado en Miza, Francia, del 17 al 20 de marzo de 2016[Background] Brexpiprazole (BREX) is a novel compound with antipsychotic properties [1] recently approved for the treatment of schizophrenia and as adjunctive treatment of major depressive disorder (MDD). Compared to the classical and atypical antipsychotics, which primarily antagonize the dopamine D2 receptor and the serotonin 5-HT2A receptor, respectively, and which especially fail to improve negative and cognitive symptoms of schizophrenia, BREX possesses a different binding profile with superior affinity for 5-HT1A and ¿1B-adrenergic receptors [2]. Non-competitive NMDA receptor antagonists such as phencyclidine (PCP) are widely used as pharmacological models of schizophrenia. Previous work of our group has shown that PCP markedly disrupts thalamocortical activity, increasing excitatory neuron discharge and reducing low frequency oscillations (LFO; 0.15¿4 Hz) in both the prefrontal cortex (PFC) and the centromedial (CM) and mediodorsal (MD) nuclei of the rodent thalamus [3,4]. First and second generation antipsychotic drugs have been shown to reverse these effects [5]. Since the underlying mechanisms of BREX are still largely unknown, we aimed to clarify the neuronal circuits involved in the antipsychotic effects of BREX. For this purpose, we investigated the ability of BREX to reverse a disruption of thalamocortical function induced by PCP.[Methods] Single neuron and local field potential were recorded in the medial PFC (mPFC) and in the thalamic CM/ MD nuclei of the rat anesthetized with chloral hydrate to investigate the effects of BREX on neuronal firing rate and LFO. Two doses of BREX (0.25 mg/kg i.v. each) were administered after PCP (0.25¿0.5 mg/kg i.v.). Repeated measures one-way ANOVA analyses with post-hoc Newman-Keuls tests were performed to detect significant differences between conditions.[Results] In the thalamus, BREX reversed the PCP-induced increase in firing rate (0.25 mg/kg: partial reversal; 0.5 mg/kg:complete reversal, n = 13, p < 0.01 vs PCP) without affecting LFO. Conversely, BREX partially reversed the PCP-induced decrease in LFO in the mPFC (0.5 mg/kg, n = 16, p < 0.001 vs PCP) without affecting pyramidal neuron firing rate. Lack of effect on thalamic LFO might be explained by a decrease in LFO induced by BREX itself (0.125¿1.0 mg/kg), while LFO in the mPFC were only reduced after low doses of BREX (up to 0.5 mg/kg), returning to basal after a high dose (1.0 mg/kg). BREX on its own did not affect firing rate of both thalamic and mPFC pyramidal neurons.[Conclusions] BREX partly antagonizes thalamocortical hyperactivity associated with schizophrenia, with differential effects in the thalamus versus the mPFC. The stronger effects of BREX in the thalamus point to a primary action in this area, which would be in line with the abundant expression of ¿1B-adrenergic receptors in the thalamus. Whether these effects of BREX are mediated via ¿1B-adrenergic receptors as well as the potential involvement of 5-HT1A receptors will be investigated in following experiments.Peer Reviewe

The novel antipsychotic Brexpiprazole reverses a disruption of thalamocortical function induced by phencyclidine

Trabajo presentado en Barcelona Computational, Cognitive and Systems Neuroscience (BARCCSYN), celebrado del 16 al 17 de junio de 2016[Conclusions] BREX antagonizes thalamocortical hyperactivity associated with schizophrenia, with a stronger effect in the CD/MD thalamus, indicating a primary action in this area which is perhaps mediated by ¿1B¿adrenoceptor antagonism. A moderate excitation of pyramidal neurons induced by BREX -possibly mediated by 5¿HT1A receptors- might be related to its procognitive properties. Overall, these data provide more insight in the antipsychotic mechanisms of BREX.[Background] Brexpiprazole (BREX) is a novel compound with antipsychotic properties [1] recently approved for the treatment of schizophrenia and as adjunctive treatment of major depressive disorder (MDD). Compared to the classical and atypical antipsychotics, which primarily antagonize the dopamine D2 receptor and the serotonin 5-HT2A receptor, respectively, and which especially fail to improve negative and cognitive symptoms of schizophrenia, BREX possesses a different binding profile with superior affinity for 5¿HT1A and ¿1B-adrenergic receptors [2]. Non-competitive NMDA receptor antagonists such as phencyclidine (PCP) are widely used as pharmacological models of schizophrenia. Previous work of our group has shown that PCP markedly disrupts thalamocortical activity, increasing excitatory neuron discharge and reducing low frequency oscillations (LFO; 0.15-4 Hz) in both the prefrontal cortex (PFC) and the centromedial (CM) and mediodorsal (MD) nuclei of the rodent thalamus [3] and [4]. First and second generation antipsychotic drugs have been shown to reverse these effects [5]. Since the underlying mechanisms of BREX are still largely unknown, we aimed to clarify the neuronal circuits involved in the antipsychotic effects of BREX. For this purpose, we investigated the ability of BREX to reverse a disruption of thalamocortical function induced by PCP.[Methods] Neuronal discharge and local field potentials were recorded in the mPFC and CM/MD of chloral hydrate anesthetized rats. Pyramidal mPFC neurons were identified by antidromic stimulation from the midbrain. BREX (0.25-2 mg/kg i.v.) was administered after PCP (0.25-0.5 mg/kg i.v.).[Results] In the thalamus, BREX (0.5 mg/kg) reversed PCP-induced neuronal excitations without affecting LFO. In the mPFC, BREX reversed PCP-induced neuronal excitations and LFO decrease at a higher dose (2 mg/kg). Lack of effect on thalamic LFO might be explained by a decrease in LFO induced by BREX itself, while LFO in the mPFC were only reduced after low doses of BREX, returning to basal after a higher dose. In addition, low BREX doses (0.125-0.5 mg/kg) moderately excited mPFC pyramidal neurons.Peer Reviewe

The antipsychotic drug brexpiprazole reverses phencyclidine-induced disruptions of thalamocortical networks

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; 0.5 mg/kg) than in pyramidal medial prefrontal cortex neurons (mPFC, 2 mg/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.Work supported by a contract Grant from Lundbeck and grants SAF2015-68346-P (MINECO, FEDER EU) and (PI1200156 and PI1600287) Instituto de Salud Carlos III (Spanish Ministry of Economy and Competitiveness), co-financed by ERDF (European Regional Development Fund), “A way to build Europe”. The contribution of the following funds is also acknowledged: 2014SGR 798 (Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement de la Generalitat de Catalunya), CERCA Programme/Generalitat de Catalunya; Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM.Peer reviewe

Striatal activity during reactive inhibition is related to the expectation of stop-signals

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

Striatal activity during reactive inhibition is related to the expectation of stop-signals

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

Using subjective expectations to model the neural underpinnings of proactive inhibition

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

DRD2 schizophrenia-risk allele is associated with impaired striatal functioning in unaffected siblings of schizophrenia patients

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