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Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience


Despite extensive research on inhibitory control (IC) and its neural systems, the questions of whether IC can be improved with training and how the associated neural systems change are understudied. Behavioral evidence suggests that performance on IC tasks improves with training but that these gains do not transfer to other tasks, and almost nothing is known about how activation in IC-related brain regions changes with training. Human participants were randomly assigned to receive IC training (N = 30) on an adaptive version of the stop-signal task (SST) or an active sham-training (N = 30) during 10 sessions across 3 weeks. Neural activation during the SST before and after training was assessed in both groups using functional magnetic resonance imaging. Performance on the SST improved significantly more in the training group than in the control group. The pattern of neuroimaging results was consistent with a proactive control model such that activity in key parts of the IC network shifted earlier in time within the trial, becoming associated with cues that anticipated the upcoming need for IC. Specifically, activity in the inferior frontal gyrus decreased during the implementation of control (i.e., stopping) and increased during cues that preceded the implementation of IC from pretraining to post-training. Also, steeper behavioral improvement in the training group correlated with activation increases during the cue phase and decreases during implementation in the dorsolateral prefrontal cortex. These results are the first to uncover the neural pathways for training-related improvements in IC and can explain previous null findings of IC training transfer.

Concepts: Better, Brain, Improve, Magnetic resonance imaging, Cerebrum, Attention versus memory in prefrontal cortex, Frontal lobe, Brodmann area


We previously found that Mertk and its ligand Gas6, astrocytic genes involved in phagocytosis, are upregulated after acute sleep deprivation. These results suggested that astrocytes may engage in phagocytic activity during extended wake, but direct evidence was lacking. Studies in humans and rodents also found that sleep loss increases peripheral markers of inflammation, but whether these changes are associated with neuroinflammation and/or activation of microglia, the brain’s resident innate immune cells, was unknown. Here we used serial block-face scanning electron microscopy to obtain 3D volume measurements of synapses and surrounding astrocytic processes in mouse frontal cortex after 6-8 h of sleep, spontaneous wake, or sleep deprivation (SD) and after chronic (∼5 d) sleep restriction (CSR). Astrocytic phagocytosis, mainly of presynaptic components of large synapses, increased after both acute and chronic sleep loss relative to sleep and wake. MERTK expression and lipid peroxidation in synaptoneurosomes also increased to a similar extent after short and long sleep loss, suggesting that astrocytic phagocytosis may represent the brain’s response to the increase in synaptic activity associated with prolonged wake, clearing worn components of heavily used synapses. Using confocal microscopy, we then found that CSR but not SD mice show morphological signs of microglial activation and enhanced microglial phagocytosis of synaptic elements, without obvious signs of neuroinflammation in the CSF. Because low-level sustained microglia activation can lead to abnormal responses to a secondary insult, these results suggest that chronic sleep loss, through microglia priming, may predispose the brain to further damage.SIGNIFICANCE STATEMENT We find that astrocytic phagocytosis of synaptic elements, mostly of presynaptic origin and in large synapses, is upregulated already after a few hours of sleep deprivation and shows a further significant increase after prolonged and severe sleep loss, suggesting that it may promote the housekeeping of heavily used and strong synapses in response to the increased neuronal activity of extended wake. By contrast, chronic sleep restriction but not acute sleep loss activates microglia, promotes their phagocytic activity, and does so in the absence of overt signs of neuroinflammation, suggesting that like many other stressors, extended sleep disruption may lead to a state of sustained microglia activation, perhaps increasing the brain’s susceptibility to other forms of damage.

Concepts: Immune system, Neuron, Brain, Sleep deprivation, Human brain, Cerebral cortex, Cerebrum, Frontal lobe


Noninvasive brain stimulation provides a potential tool for affecting brain functions in the typical and atypical brain and offers in several cases an alternative to pharmaceutical intervention. Some studies have suggested that transcranial electrical stimulation (TES), a form of noninvasive brain stimulation, can also be used to enhance cognitive performance. Critically, research so far has primarily focused on optimizing protocols for effective stimulation, or assessing potential physical side effects of TES while neglecting the possibility of cognitive side effects. We assessed this possibility by targeting the high-level cognitive abilities of learning and automaticity in the mathematical domain. Notably, learning and automaticity represent critical abilities for potential cognitive enhancement in typical and atypical populations. Over 6 d, healthy human adults underwent cognitive training on a new numerical notation while receiving TES to the posterior parietal cortex or the dorsolateral prefrontal cortex. Stimulation to the the posterior parietal cortex facilitated numerical learning, whereas automaticity for the learned material was impaired. In contrast, stimulation to the dorsolateral prefrontal cortex impaired the learning process, whereas automaticity for the learned material was enhanced. The observed double dissociation indicates that cognitive enhancement through TES can occur at the expense of other cognitive functions. These findings have important implications for the future use of enhancement technologies for neurointervention and performance improvement in healthy populations.

Concepts: Psychology, Brain, Cognition, Cerebrum, Educational psychology, Knowledge, Frontal lobe, Parietal lobe


17β-estradiol (E2) is produced from androgens via the action of the enzyme aromatase. E2 is known to be made in neurons in the brain, but its precise functions in the brain are unclear. Here, we utilized a forebrain neuron-specific aromatase knockout (FBN-ARO-KO) mouse model to deplete neuron-derived E2 in the forebrain of mice and thereby elucidate its functions. FBN-ARO-KO mice showed a 70-80% decrease in aromatase and forebrain E2 levels, as compared to FLOX controls. Male and female FBN-ARO-KO mice exhibited significant deficits in forebrain spine and synaptic density, as well as hippocampal-dependent spatial reference memory, recognition memory and contextual fear memory, but had normal locomotor function and anxiety levels. Reinstating forebrain E2 levels via exogenous in vivo E2 administration was able to rescue both the molecular and behavioral defects in FBN-ARO-KO mice. Furthermore, in vitro studies using FBN-ARO-KO hippocampal slices revealed that while induction of long-term potentiation (LTP) was normal, the amplitude was significantly decreased. Intriguingly, the LTP defect could be fully rescued by acute E2 treatment in vitro Mechanistic studies revealed that FBN-ARO-KO mice had compromised rapid kinase (AKT, ERK) and CREB-BDNF signaling in the hippocampus and cerebral cortex. In addition, acute E2 rescue of LTP in hippocampal FBN-ARO-KO slices could be blocked by administration of a MEK/ERK inhibitor, further suggesting a key role for rapid ERK signaling in neuronal E2 effects. In conclusion, the findings provide evidence of a critical role for neuron-derived E2 in regulating synaptic plasticity and cognitive function in the male and female brain.SIGNIFICANCE STATEMENTThe steroid hormone, 17β-Estradiol (E2) is well known to be produced in the ovaries in females. Intriguingly, forebrain neurons also express aromatase, the E2 biosynthetic enzyme, but the precise functions of neuron-derived E2 is unclear. Using a novel forebrain neuron-specific aromatase knockout mouse model to deplete neuron-derived E2, the current study provides direct genetic evidence of a critical role for neuron-derived E2 to regulate rapid AKT-ERK and CREB-BDNF signaling in the mouse forebrain, and demonstrates that neuron-derived E2 is essential for normal expression of long term potentiation, synaptic plasticity, and cognitive function in both the male and female brain. These findings suggest that neuron-derived E2 functions as a novel neuromodulator in the forebrain to control synaptic plasticity and cognitive function.


The need to breathe links the mammalian olfactory system inextricably to the respiratory rhythms that draw air through the nose. In rodents and other small animals, slow oscillations of local field potential activity are driven at the rate of breathing (∼2-12 Hz) in olfactory bulb and cortex, and faster oscillatory bursts are coupled to specific phases of the respiratory cycle. These dynamic rhythms are thought to regulate cortical excitability and coordinate network interactions, helping to shape olfactory coding, memory, and behavior. However, while respiratory oscillations are a ubiquitous hallmark of olfactory system function in animals, direct evidence for such patterns is lacking in humans. In this study, we acquired intracranial EEG data from rare patients (Ps) with medically refractory epilepsy, enabling us to test the hypothesis that cortical oscillatory activity would be entrained to the human respiratory cycle, albeit at the much slower rhythm of ∼0.16-0.33 Hz. Our results reveal that natural breathing synchronizes electrical activity in human piriform (olfactory) cortex, as well as in limbic-related brain areas, including amygdala and hippocampus. Notably, oscillatory power peaked during inspiration and dissipated when breathing was diverted from nose to mouth. Parallel behavioral experiments showed that breathing phase enhances fear discrimination and memory retrieval. Our findings provide a unique framework for understanding the pivotal role of nasal breathing in coordinating neuronal oscillations to support stimulus processing and behavior.

Concepts: Psychology, Brain, Cerebrum, Hippocampus, Olfactory bulb, Olfaction, Limbic system, Nasal cavity


To find objects of interest in a cluttered and continually changing visual environment, humans must often ignore salient stimuli that are not currently relevant to the task at hand. Recent neuroimaging results indicate that the ability to prevent salience-driven distraction depends on the current level of attentional control activity in frontal cortex, but the specific mechanism by which this control activity prevents salience-driven distraction is still poorly understood. Here, we asked whether salience-driven distraction is prevented by suppressing salient distractors or by preferentially up-weighting the relevant visual dimension. We found that salient distractors were suppressed even when they resided in the same feature dimension as the target (that is, when dimensional weighting was not a viable selection strategy). Our neurophysiological measure of suppression-the PD component of the event-related potential-was associated with variations in the amount of time it took to perform the search task: distractors triggered the PD on fast-response trials, but on slow-response trials they triggered activity associated with working memory representation instead. These results demonstrate that during search salience-driven distraction is mitigated by a suppressive mechanism that reduces the salience of potentially distracting visual objects.

Concepts: Attention, Cognitive psychology, Neuroscience, Frontal lobe, Suppression, Suppression of dissent, Distraction, Attention span


In human participants, the intensive practice of particular cognitive activities can induce sustained improvements in cognitive performance, which in some cases transfer to benefits on untrained activities. Despite the growing body of research examining the behavioral effects of cognitive training in children, no studies have explored directly the neural basis of these training effects in a systematic, controlled fashion. Therefore, the impact of training on brain neurophysiology in childhood, and the mechanisms by which benefits may be achieved, are unknown. Here, we apply new methods to examine dynamic neurophysiological connectivity in the context of a randomized trial of adaptive working memory training undertaken in children. After training, connectivity between frontoparietal networks and both lateral occipital complex and inferior temporal cortex was altered. Furthermore, improvements in working memory after training were associated with increased strength of neural connectivity at rest, with the magnitude of these specific neurophysiological changes being mirrored by individual gains in untrained working memory performance.

Concepts: Psychology, Brain, Neuroscience, Human brain, Cerebral cortex, Cerebrum, Hippocampus, Skull


Receiving social feedback such as praise or blame for one’s character traits is a key component of everyday human interactions. It has been proposed that humans are positively biased when integrating social feedback into their self-concept. However, a mechanistic description of how humans process self-relevant feedback is lacking. Here, participants received feedback from peers after a real-life interaction. Participants processed feedback in a positively biased way, i.e., they changed their self-evaluations more toward desirable than toward undesirable feedback. Using functional magnetic resonance imaging we investigated two feedback components. First, the reward-related component correlated with activity in ventral striatum and in anterior cingulate cortex/medial prefrontal cortex (ACC/MPFC). Second, the comparison-related component correlated with activity in the mentalizing network, including the MPFC, the temporoparietal junction, the superior temporal sulcus, the temporal pole, and the inferior frontal gyrus. This comparison-related activity within the mentalizing system has a parsimonious interpretation, i.e., activity correlated with the differences between participants' own evaluation and feedback. Importantly, activity within the MPFC that integrated reward-related and comparison-related components predicted the self-related positive updating bias across participants offering a mechanistic account of positively biased feedback processing. Thus, theories on both reward and mentalizing are important for a better understanding of how social information is integrated into the human self-concept.

Concepts: Brain, Interaction, Magnetic resonance imaging, Cerebrum, Limbic system, Frontal lobe, Feedback, Inferior frontal gyrus


Autism is hypothesized to result in a cortical excitatory and inhibitory imbalance driven by inhibitory interneuron dysfunction, which is associated with the generation of gamma oscillations. On the other hand, impaired motor control has been widely reported in autism. However, no study has focused on the gamma oscillations during motor control in autism. In the present study, we investigated the motor-related gamma oscillations in autism using magnetoencephalography. Magnetoencephalographic signals were recorded from 14 right-handed human children with autism (5 female), aged 5–7 years, and age- and IQ-matched 15 typically developing children during a motor task using their right index finger. Consistent with previous studies, the autism group showed a significantly longer button response time and reduced amplitude of motor-evoked magnetic fields. We observed that the autism group exhibited a low peak frequency of motor-related gamma oscillations from the contralateral primary motor cortex, and these were associated with the severity of autism symptoms. The autism group showed a reduced power of motor-related gamma oscillations in the bilateral primary motor cortex. A linear discriminant analysis using the button response time and gamma oscillations showed a high classification performance (86.2% accuracy). The alterations of the gamma oscillations in autism might reflect the cortical excitatory and inhibitory imbalance. Our findings provide an important clue into the behavioral and neurophysiological alterations in autism and a potential biomarker for autism.SIGNIFICANCE STATEMENTCurrently, the diagnosis of autism has been based on behavioral assessments, and a crucial issue in the diagnosis of autism is to identify objective and quantifiable clinical biomarkers. A key hypothesis of the neurophysiology of autism is an excitatory and inhibitory imbalance in the brain, which is associated with the generation of gamma oscillations. On the other hand, motor deficits have also been widely reported in autism. This is the first study to demonstrate low motor performance and altered motor-related gamma oscillations in autism, reflecting a brain excitatory and inhibitory imbalance. Using these behavioral and neurophysiological parameters, we classified autism and control group with good accuracy. This work provides important information on behavioral and neurophysiological alterations in patients with autism.


How much we like something, whether it be a bottle of wine or a new film, is affected by the opinions of others. However, the social information we receive can be contradictory and vary in its reliability. Here we test whether the brain incorporates these statistics when judging value and confidence. Participants provided value judgments about consumer goods in the presence of online reviews. We found participants updated their initial value and confidence judgments in a Bayesian fashion, taking into account both the uncertainty of their initial beliefs and the reliability of the social information. Activity in dorsomedial prefrontal cortex tracked the degree of belief update. We find, analogous to how lower-level perceptual information is integrated, that when judging value and confidence the human brain integrates social information according to its reliability.SIGNIFICANCE STATEMENTThe field of perceptual decision making has shown that the sensory system integrates different sources of information according to their respective reliability, as predicted by a Bayesian inference scheme. In this work we hypothesized that a similar coding scheme is implemented by the human brain to process social signals and guide complex value-based decisions. We provide experimental evidence that the human prefrontal cortex’s activity is consistent with a Bayesian computation that integrate social information that differs in reliability and that this integration affects the neural representation of value and confidence.

Concepts: Scientific method, Neuron, Brain, Human brain, Cerebral cortex, Cerebellum, Frontal lobe, Prefrontal cortex