Impulsivity is an endophenotype of vulnerability for compulsive behaviors. However, the neural mechanisms whereby impulsivity facilitates the development of compulsive disorders, such as addiction or obsessive compulsive disorder, remain unknown. We first investigated, in rats, anatomical and functional correlates of impulsivity in the anterior insular (AI) cortex by measuring both the thickness of, and cellular plasticity markers in, the AI with magnetic resonance imaging and in situ hybridization of the immediate early gene zif268, respectively. We then investigated the influence of bilateral AI cortex lesions on the high impulsivity trait, as measured in the five-choice serial reaction time task (5-CSRTT), and the associated propensity to develop compulsivity as measured by high drinking levels in a schedule-induced polydipsia procedure (SIP). We demonstrate that the AI cortex causally contributes to individual vulnerability to impulsive-compulsive behavior in rats. Motor impulsivity, as measured by premature responses in the 5-CSRTT, was shown to correlate with the thinness of the anterior region of the insular cortex, in which highly impulsive (HI) rats expressed lower zif268 mRNA levels. Lesions of AI reduced impulsive behavior in HI rats, which were also highly susceptible to develop compulsive behavior as measured in a SIP procedure. AI lesions also attenuated both the development and the expression of SIP. This study thus identifies the AI as a novel neural substrate of maladaptive impulse control mechanisms that may facilitate the development of compulsive disorders.
When a flashed stimulus is followed by a backward mask, subjects fail to perceive it unless the target-mask interval exceeds a threshold duration of about 50 ms. Models of conscious access postulate that this threshold is associated with the time needed to establish sustained activity in recurrent cortical loops, but the brain areas involved and their timing remain debated. We used high-density recordings of event- related potentials (ERPs) and cortical source reconstruction to assess the time course of human brain activity evoked by masked stimuli and to determine neural events during which brain activity correlates with conscious reports. Target- mask stimulus onset asynchrony (SOA) was varied in small steps, allowing us to ask which ERP events show the characteristic nonlinear dependence with SOA seen in subjective and objective reports. The results separate distinct stages in mask-target interactions, indicating that a considerable amount of subliminal processing can occur early on in the occipito-temporal pathway (270 ms) and highly distributed fronto-parieto-temporal activation as a correlate of conscious reportability.
In order to investigate the mechanism of the reaction catalyzed by HindIII, structures of HindIII–DNA complexes with varying durations of soaking time in cryoprotectant buffer containing manganese ions were determined by the freeze‐trap method. In the crystal structures of the complexes obtained after soaking for a longer duration, two manganese ions, indicated by relatively higher electron density, are clearly observed at the two metal ion‐binding sites in the active site of HindIII. The increase in the electron density of the two metal‐ion peaks followed distinct pathways with increasing soaking times, suggesting variation in the binding rate constant for the two metal sites. DNA cleavage is observed when the second manganese ion appears, suggesting that HindIII uses the two‐metal‐ion mechanism, or alternatively that its reactivity is enhanced by the binding of the second metal ion. In addition, conformational change in a loop near the active site accompanies the catalytic reaction.
•Nitrate rich diets may slow the rate of cognitive decline.•People with type 2 diabetes have accelerated cognitive decline with ageing.•Dietary nitrate improved reaction time in subjects with type 2 diabetes.•Novel nitrate depleted placebo beetroot juice developed and characterised. In this substudy of the effect of dietary nitrate on blood pressure, endothelial function, and insulin sensitivity in type 2 diabetes, we report the development of a novel nitrate depleted beetroot juice for use clinical trials and determine if dietary nitrate supplementation improved cognitive function in patients with type 2 diabetes mellitus. Beetroot juice was treated with the anion exchange resin Purolite A520e. UV–vis-spectrophotometry, and a blind taste test were performed along with determination of sugar content, measurement of ascorbate and dehydroascorbate, the ionic composition of juice and Proton NMR. Subsequently, 27 patients, age 67.2±4.9years, (18 male) were recruited for a double blind, randomised, placebo-controlled crossover trial. Participants were randomised to begin in either order beetroot juice (nitrate content 7.5mmol per 250ml) or placebo (nitrate depleted beetroot juice nitrate content 0.002mmol per 250ml). At the end of each 2week supplementation period cognitive function was assessed using E-prime, E-Studio software with 5 separate tests being performed. The tests utilised in the present study have been adapted from the Cambridge Neuropsychological Test Automated Battery (CANTAB). The differences in the UV–vis spectra were comparable to the natural variation found in differing cultivars. There were no discernable differences in taste, sugar content, or Proton NMR. Ascorbate and dehydroascorbate were undetectable in either juice. After 2weeks of beetroot juice simple reaction time was significantly quicker in the active arm at 327±40ms versus 341.8±52.7ms in the placebo arm, mean difference 13.9±25.6ms (95% CI 3.8–24.0ms), p=0.009. No other measures of cognitive function differed between treatment arms. We have developed an effective placebo beetroot juice for use in trials of supplementation of dietary nitrate. Two weeks supplementation of the diet with 7.5mmol of nitrate per day caused a significant improvement in simple reaction time in individuals with T2DM.
Growing evidence suggests that distributed spatial attention may invoke theta (3–9 Hz) rhythmic sampling processes. The neuronal basis of such attentional sampling is, however, not fully understood. Here we show using array recordings in visual cortical area V4 of two awake macaques that presenting separate visual stimuli to the excitatory center and suppressive surround of neuronal receptive fields (RFs) elicits rhythmic multi-unit activity (MUA) at 3–6 Hz. This neuronal rhythm did not depend on small fixational eye movements. In the context of a distributed spatial attention task, during which the monkeys detected a spatially and temporally uncertain target, reaction times (RTs) exhibited similar rhythmic fluctuations. RTs were fast or slow depending on the target occurrence during high or low MUA, resulting in rhythmic MUA-RT cross-correlations at theta frequencies. These findings show that theta rhythmic neuronal activity can arise from competitive RF interactions and that this rhythm may result in rhythmic RTs potentially subserving attentional sampling. •Receptive field interactions induce theta rhythmic activation in visual cortex•The neuronal rhythm does not depend on small fixational eye movements•Reaction time fluctuations lock to the neuronal rhythm under distributed attention Kienitz et al. show that receptive field interactions induce theta rhythmic neuronal activity in visual area V4 that is independent of eye movements. Under distributed attention, periodic reaction times were locked to the neuronal rhythm. Rhythmic modulation of neuronal sensitivity could thus explain attentional dynamics during visual competition.
Alcohol craving, in combination with impaired impulse control, often leads to relapse. The dopamine system mediates the rewarding properties of alcohol but is also involved in regulating impulsive behavior. The monoamine stabilizer (−)‐OSU6162 (OSU6162) has the ability to stabilize dopamine activity depending on the prevailing dopaminergic tone and may therefore normalize the dopaminergic transmission regulating both alcohol use disorder and impulsivity. We have recently showed that OSU6162 attenuates voluntary alcohol consumption, operant alcohol self‐administration, alcohol withdrawal symptoms and cue‐induced reinstatement of alcohol seeking in rats. Here, we evaluated OSU6162's effects on motor impulsivity in Wistar rats that had voluntarily consumed alcohol or water for 10 weeks. The five‐choice serial reaction time task was used to measure motor impulsivity, and a prolonged waiting period (changed from 5 to 7 seconds) was applied to induce premature responses. OSU6162‐testing was conducted twice a week (Tuesdays and Fridays), every other week with regular baseline training sessions in between. We also tested OSU6162's effects on the alcohol deprivation effect in long‐term alcohol drinking Wistar rats. The results showed that OSU6162 (30 mg/kg) pre‐treatment significantly improved motor impulsivity in the five‐choice serial reaction time task in both alcohol and alcohol‐naïve rats. Moreover, OSU6162 (30 mg/kg) pre‐treatment prevented the alcohol deprivation effect, i.e. relapse‐like drinking behavior after a forced period of abstinence in long‐term drinking rats. In conclusion, our results provide further support for OSU6162 as a novel treatment for alcohol use disorder. The results further indicate that improvement of motor impulse control might be one mechanism behind OSU6162's ability to attenuate alcohol‐mediated behaviors. A main problem in the treatment of alcohol use disorder (AUD) is the long‐lasting vulnerability to relapse. Impaired impulse control, often seen in AUD individuals, contribute to relapse to alcohol drinking. Here, we showed that the monoamine stabilizer OSU6162 improved motor impulsivity (i.e. decreased premature responses) in both alcohol‐naive and alcohol drinking rats as measured with the five‐choice serial reaction time task. These results provide further support for the potential of OSU6162 as a novel medication for AUD.
Voluntary movement is accompanied by changes in the degree to which neurons in the brain synchronize their activity within discrete frequency ranges. Two patterns of movement-related oscillatory activity stand out in human cortical motor areas. Activity in the beta frequency (15–30 Hz) band is prominent during tonic contractions but is attenuated prior to and during voluntary movement . Without such attenuation, movement may be slowed, leading to the suggestion that beta activity promotes postural and tonic contraction, possibly at a cost to the generation of new movements [2, 3]. In contrast, activity in the gamma (60–90 Hz) band increases during movement . The direction of change suggests that gamma activity might facilitate motor processing. In correspondence with this, increased frontal gamma activity is related with reduced reaction times . Yet the possibility remains that these functional correlations reflect an epiphenomenal rather than causal relationship. Here we provide strong evidence that oscillatory activities at the cortical level are mechanistically involved in determining motor behavior and can even improve performance. By driving cortical oscillations using noninvasive electrical stimulation, we show opposing effects at beta and gamma frequencies and interactions with motor task that reveal the potential quantitative importance of oscillations in motor behavior. ► Cortical driving at 20 and 70 Hz slows and speeds voluntary force generation ► Performance can be enhanced even during contractions made as fast as possible ► Scale of effects of cortical driving depend on the nature of the cued motor task
In primates, both the dorsal anterior cingulate cortex (dACC) and the dorsolateral prefrontal cortex (dlPFC) are key regions of the frontoparietal cognitive control network. To study the role of the dACC and its communication with the dlPFC in cognitive control, we recorded local field potentials (LFPs) from the dlPFC before and during the reversible deactivation of the dACC, in macaque monkeys engaging in uncued switches between 2 stimulus-response rules, namely prosaccade and antisaccade. Cryogenic dACC deactivation impaired response accuracy during maintenance of-but not the initial switching to-the cognitively demanding antisaccade rule, which coincided with a reduction in task-related theta activity and the correct-error (C-E) difference in dlPFC beta-band power. During both rule switching and maintenance, dACC deactivation prolonged the animals' reaction time and reduced task-related alpha power in the dlPFC. Our findings support a role of the dACC in prefrontal oscillatory activities that are involved the maintenance of a new, challenging task rule.
The ability to plan and execute appropriately timed responses to external stimuli is based on a well-orchestrated balance between movement initiation and inhibition. In impulse control disorders involving the prefrontal cortex (PFC) , this balance is disturbed, emphasizing the critical role that PFC plays in appropriately timing actions [2–4]. Here, we employed optogenetic and electrophysiological techniques to systematically analyze the functional role of five key subareas of the rat medial PFC (mPFC) and orbitofrontal cortex (OFC) in action control [5–9]. Inactivation of mPFC subareas induced drastic changes in performance, namely an increase (prelimbic cortex, PL) or decrease (infralimbic cortex, IL) of premature responses. Additionally, electrophysiology revealed a significant decrease in neuronal activity of a PL subpopulation prior to premature responses. In contrast, inhibition of OFC subareas (mainly the ventral OFC, i.e., VO) significantly impaired the ability to respond rapidly after external cues. Consistent with these findings, mPFC activity during response preparation predicted trial outcomes and reaction times significantly better than OFC activity. These data support the concept of opposing roles of IL and PL in directing proactive behavior and argue for an involvement of OFC in predominantly reactive movement control. By attributing defined roles to rodent PFC sections, this study contributes to a deeper understanding of the functional heterogeneity of this brain area and thus may guide medically relevant studies of PFC-associated impulse control disorders in this animal model for neural disorders [10–12]. [Display omitted] •Optogenetic PL/IL inhibition promotes/suppresses early responses, respectively•Optogenetic VO inhibition results in more late releases and longer reaction times•mPFC/OFC contribute in a more proactive/reactive way, respectively•Specialized neuronal subpopulations contribute to behavioral inhibition/execution Planning and execution of precisely timed actions is based on a well-orchestrated balance between movement initiation and inhibition. By combining optogenetic and electrophysiological techniques in trained rats, Hardung et al. show that prefrontal subsections play distinct roles in proactive and reactive motor control.
Impulsivity is a risk factor for alcoholism, and long-term alcohol exposure may further impair impulse control in a manner that propels problematic alcohol use. The present study employed the rat 5-choice serial reaction time task (5-CSRTT) to measure behavioral inhibition and attentional capacity during abstinence from repeated 5-day cycles of alcohol liquid diet consumption. Task performance was not disrupted following the first cycle of alcohol exposure; however, evidence of impaired behavioral inhibition emerged following the third cycle of alcohol exposure. In comparison with controls, alcoholic rats exhibited deficits in inhibitory control during cognitively challenging 5-CSRTT tests employing variable intertrial interval (varITI). This behavioral disruption was not present during early abstinence (3 days) but was evident by 7 days of abstinence and persisted for at least 34 days. Interestingly, renewed alcohol consumption ameliorated these disruptions in impulse control, although deficient behavioral inhibition re-emerged during subsequent abstinence. Indices of increased impulsivity were no longer present in tests conducted after 49 days of abstinence. Alcohol-related impairments in impulse control were not evident in sessions employing highly familiar task parameters regardless of the abstinence period, and control experiments confirmed that performance deficits during the challenge sessions were unlikely to result from alcohol-related disruption in the adaptation to repeated varITI testing. Together, the current findings demonstrate that chronic intermittent alcohol consumption results in decreased behavioral inhibition in rats that is temporally similar to clinical observations of disrupted impulsive control in abstinent alcoholics performing tasks of behavioral inhibition. The present study employed the 5-Choice Serial Reaction Time Task (5-CSRTT) to evaluate the effects of prior chronic alcohol exposure on the impulsive-like behavior in rats. Alcohol-exposed rats exhibited deficits in inhibitory control and increased perseverative behavior during 5-CSRTT tests employing variable inter-trial intervals. These disruptions were not present during early abstinence (3d) but emerged by 7d abstinence and persisted for at least 34d. Renewed alcohol consumption ameliorated these disruptions, though deficient behavioral inhibition re-emerged during subsequent abstinence.