Sexually satiated male rats exhibit long-lasting physiological changes, suggestive of brain plasticity, the most conspicuous of which are a sexual behaviour inhibition and a generalised drug hypersensitivity. Copulation activates the mesolimbic circuit increasing dopamine (DA) release in the nucleus accumbens (NAcc) and, enhanced midbrain DA neuron activity promotes endocannabinoid (eCB) release in the ventral tegmental area (VTA). The objective of this work was to explore the possible participation of DA and/or eCB transmission in the induction of these two long-lasting phenomena. To this aim we analysed the effect of blocking DA or CB1 receptors during the process of copulation to exhaustion, on the expression 24 h later, of the sexual inhibitory state and the hypersensitivity to two different drugs: 8-OH-DPAT, a 5-HT1A receptor agonist, and yohimbine, an α2-adrenoceptor antagonist. Blockade of DA receptors failed to prevent these phenomena, while blockade of CB1 receptors interfered with the appearance of the sexual inhibition and the hypersensitivity to both drugs in the sexually satiated animals. Specific blockade of CB1 receptors in the VTA during copulation to satiety mimicked these results, suggesting that both eCB-mediated effects were exerted in this brain region. It is concluded that eCBs play a role in the induction of behavioural and physiological changes, triggered by copulation to satiety, by acting at the VTA, while increased NAcc DA levels appear not to contribute to the changes induced by intense copulation. Results pose sexual satiety as a useful model for the study of brain plasticity phenomena induced by natural rewards.

The known effects of aging on the brain and behavior include impaired cognition, increases in anxiety and depressive-like behaviors, and reduced locomotor activity. Environmental exposures and interventions also influence brain functions during aging. We investigated the effects of normal aging under controlled environmental conditions and in the absence of external interventions on locomotor activity, cognition, anxiety and depressive-like behaviors, immune function and hippocampal gene expression in C57BL/6 mice. Healthy mice at 4, 9, and 14 months of age underwent behavioral testing using an established behavioral battery, followed by cellular and molecular analysis using flow cytometry, immunohistochemistry, and quantitative PCR. We found that 14-month-old mice showed significantly reduced baseline locomotion, increased anxiety, and impaired spatial memory compared to younger counterparts. However, no significant differences were observed for depressive-like behavior in the forced-swim test. Microglia numbers in the dentate gyrus, as well as CD8+ memory T cells increased towards late middle age. Aging processes exerted a significant effect on the expression of 43 genes of interest in the hippocampus. We conclude that aging is associated with specific changes in locomotor activity, cognition, anxiety-like behaviors, neuroimmune responses and hippocampal gene expression.

Systemic inflammation induces cognitive impairments via unclear mechanisms. Accumulating evidence has demonstrated that a subset of neurons that express parvalbumin (PV) play a critical role in regulation of cognitive and emotional behavior. Thus, the aim of the present study was to test whether disruption of PV interneuron mediates systemic inflammation–induced depression-like behavior and working memory impairment by lipopolysaccharide (LPS) challenge. Here we showed that LPS induces depression-like behavior and working memory impairment, coinciding with increased PV expression, enhanced GABAergic transmission, and impaired long-term potentiation (LTP) in the hippocampus. Notably, systemic administration of NMDA (N–methyl–D–aspartate) receptor (NMDAR) antagonist ketamine was able to interfere with PV expression and reverse depression-like behavior and working memory impairment, which is probably mediated by reversing impaired LTP. In addition, flumazenil, a competitive antagonist acting at the benzodiazepine binding site of the GABAA receptor, also ameliorated these abnormal behaviors. Collectively, our study added growing evidence to the limited studies that overinhibition mediated by PV interneurons might play a critical role in LPS–induced depression-like behavior and working memory impairment.

Levels of weight gain have hit an epidemic level with rates of overweight and obesity diagnoses topping all-time highs. Elevated body weight has been linked to increased rates of cardiac problems, blood pressure issues, and risk of developing type 2 diabetes. Leptin, a hormone produced by the body that is involved in energy balance by inhibiting hunger has been implicated as an underlying mechanism that differentially contributes to food-seeking motivation. Using a scientifically validated animal model of obesity, the fatty Zucker rat, which has mutated leptin receptor genes, leptin’s role in behavioral motivation can be assessed. Animals were on a 2 -h food access restriction with one-hour access to rewards in session and one hour of free-feeding access. Pre-session and post-session food access differences were evaluated in looking at motivation for food rewards during satiation while responding on differing levels of fixed-ratio schedules. The results showed robust differential behavior from satiation, demonstrating a basis for a biological mechanism involving leptin sensitivity that could underlie obesity. Although further experimentation is needed, understanding leptin could help bridge the gap in our understanding of satiation and non-satiation.

The startle reflex, which interferes with on-going cognitive/behavioral activities, is of important protective function for humans and animals. Prepulse inhibition (PPI), as an operational measure of sensorimotor gating, is the suppression of the startle reflex in response to an intense startling stimulus (pulse) when this startling stimulus is shortly preceded by a weaker non-startling stimulus (prepulse). In both humans and laboratory animals, PPI can be enhanced by facilitating selective attention to the prepulse, suggesting that higher-order cognitive/perceptual processes modulate PPI. It has been well known that both the cholinergic system located in the basal forebrain and the deep layers of the superior colliculus in the PPI-mediating circuit are top-down modulated by the medial agranular cortex (AGm), which is a subdivision of the medial prefrontal cortex (PFC) and has wide axonal connections with both cortical regions (including the posterior parietal cortex) and subcortical structures critical for attention/orientation processes. This study investigated whether the AGm is involved in attentional modulation of PPI. The results showed that PPI was enhanced by fear conditioning of the prepulse, and then further enhanced by perceived spatial separation between the conditioned prepulse and a back-ground masking noise based on the auditory precedence effect. Bilateral injection of 2-mM kynurenic acid, a broad spectrum antagonist of glutamate receptors, into the AGm, but not the primary somatosensory cortex, eliminated these two types of attentional enhancement of PPI. Thus, the AGm plays a role in facilitating attention to the prepulse and is involved in the top-down modulation of PPI.

Adolescence represents a key developmental period in terms of both mood and overweight and is linked to disturbed eating behavior. Therefore, it is essential to investigate the basis of food intake in healthy adolescents by considering mood impacts which remain largely unexplored. Hence this study aims to investigate the impact of hunger and mood on cerebral blood flow (CBF) changes in healthy adolescents. Fifteen participants underwent two MRI sessions including a 3D pseudo-continuous arterial spin labeling sequence: pre-lunch (hunger) and post-lunch (satiety). Mood was assessed using the Multiscore Depression Inventory for Children. We found higher CBF values in the posterior insula in response to hunger compared to satiety, an area of the brain which contributes to the anticipation and motivation of feeding. In response to satiation, we observed higher CBF values in the precuneus, lingual gyrus and cuneus which are involved in the aspects of response inhibition related to food intake. Furthermore, we show that correlation between mood assessment and CBF is modulated by appetite in the precuneus, anterior cingulate gyrus, anterior orbitofrontal gyrus, occipital gyrus and cuneus, suggesting that participants affected by depressed mood could use ruminative processing in order to evaluate the reward of an upcoming meal.

Methylphenidate (MPD) is commonly used to treat attention-deficit hyperactivity disorder (ADHD). Recently, it is being abused for cognitive enhancement and recreation leading to concerns regarding its addictive potential. The prefrontal cortex (PFC) and caudate nucleus (CN) are two of the brain structures involved in the motive/reward circuit most affected by MPD and are also thought to be responsible for ADHD phenomena. This study is unique in that it investigated acute and chronic, dose-response MPD exposure on animals’ behavior activity concomitantly with PFC and CN neuronal circuitry in freely behaving adult animals without the interference of anesthesia. Further, it compared acute and chronic MPD action on over 1,000 subcortical and cortical neurons simultaneously, allowing for a more accurate interpretation of drug action on corticostriatal neuronal circuitry. For this experiment, four groups of animals were used: saline (control), 0.6, 2.5, and 10.0 mg/kg MPD following acute and repetitive exposure. The data shows that the same MPD dose elicits behavioral sensitization in some animals and tolerance in others and that the PFC and CN neuronal activity correlates with the animals' behavioral responses to MPD. The expression of sensitization and tolerance are experimental biomarkers indicating that a drug has addictive potential. In general, a greater percentage of CN units responded to both acute and chronic MPD exposure as compared to PFC units. Dose response differences between the PFC and the CN units were observed. The dichotomy that some PFC and CN units responded to the same MPD dose by excitation and other units by attenuation in neuronal firing rate is discussed. In conclusion, to understand the mechanism of action of the drug, it is essential to study, simultaneously, on more than one brain site, the electrophysiological and behavioral effects of acute and chronic drug exposure, as sensitization and tolerance are experimental biomarkers indicating that a drug has addictive potential. The behavioral and neuronal data obtained from this study indicates that chronic MPD exposure results in behavioral and biochemical changes consistent with a substance abuse disorder.

Effects of xenon (Xe) on whole-cell currents induced by glutamate (Glu), its three ionotropic subtypes, and GABA, as well as on the fast synaptic glutamatergic and GABAergic transmissions, were studied in the mechanically dissociated “synapse bouton preparation” of rat spinal sacral dorsal commissural nucleus (SDCN) neurons. This technique evaluates pure single or multi-synapse responses from native functional nerve endings and enables us to quantify how Xe influences pre- and postsynaptic transmissions accurately. Effects of Xe on glutamate (Glu)-, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-, kainate (KA)- and N-methyl-d-aspartate (NMDA)- and GABAA receptor-mediated whole-cell currents were investigated by the conventional whole-cell patch configuration. Excitatory and inhibitory postsynaptic currents (EPSCs and IPSCs) were measured as spontaneous (s) and evoked (e) EPSCs and IPSCs. Evoked synaptic currents were elicited by paired-pulse focal electric stimulation. Xe decreased Glu, AMPA, KA, and NMDA receptor-mediated whole-cell currents but did not change GABAA receptor-mediated whole-cell currents. Xe decreased the frequency and amplitude but did not affect the 1/e decay time of the glutamatergic sEPSCs. Xe decreased the frequency without affecting the amplitude and 1/e decay time of GABAergic sIPSCs. Xe decreased the amplitude and increased the failure rate (Rf) and paired-pulse ratio (PPR) without altering the 1/e decay time of both eEPSC and eIPSC, suggesting that Xe acts on the presynaptic side of the synapse. The presynaptic inhibition was greater in eEPSCs than in eIPSCs. We conclude that Xe decreases glutamatergic and GABAergic spontaneous and evoked transmissions at the presynaptic level. The glutamatergic presynaptic responses are the main target of anesthesia-induced neuronal responses. In contrast, GABAergic responses minimally contribute to Xe anesthesia.

Purpose Radiation-induced optic neuropathy (RION) is a serious complication that occurs after radiation therapy of tumors in the vicinity of the optic nerve, yet its mechanism and imaging features are poorly understood. In this study, we employed manganese-enhanced MRI (MEMRI) to assess optic nerve axonal transport in tree shrews and rats after irradiation. Materials and methods A comparison of normal visual projections in tree shrews and rats was conducted by intravitreal MnCl2 injection followed by MRI. Adult male tree shrews and rats received a total dose of 20 Gy delivered in two fractions (10 Gy per fraction) within 5 days. Longitudinal MEMRI was conducted 5, 10, 20 and 30 weeks after radiation. At the end of observation, motor proteins involved in axonal transport were detected by western blotting, and the axon cytoskeleton was assessed by immunofluorescence. Results The eyeballs, lens sizes, vitreous volumes, optic nerves and superior colliculi of tree shrews were significantly larger than those of rats on MEMRI (P < 0.05). The Mn2+-enhancement of the optic nerve showed no significant changes at 5 and 10 weeks (P > 0.05) but decreased gradually from 20 to 30 weeks postirradiation (P < 0.05). The enhancement of the superior colliculus gradually decreased from 5 weeks to 30 weeks, and the decrease was most significant at 30 weeks (P < 0.05). The levels of the motor proteins cytoplasmic dynein-1, kinesin-1 and kinesin-2 in the experimental group were significantly decreased (P < 0.05). The immunofluorescence results showed that the α-tubulin, β-tubulin and SMI 31 levels in the experimental groups and control groups were not significantly different (P > 0.05). Conclusion Tree shrews show great advantages in visual neuroscience research involving MEMRI. The main cause of the decline in axonal transport in RION is an insufficient level of motor protein rather than damage to the axonal cytoskeletal structure. Longitudinal MEMRI can be used to detect changes in axonal transport function and to observe the relatively intact axon structure from the early to late stages after radiation administration.

We report two experiments that suggest that syntactic category plays a key role in limiting competition in lexical access in speaking. We introduce a novel sentence-picture interference (SPI) paradigm, and we show that nouns (e.g., running as a noun) do not compete with verbs (e.g., walking as a verb) and verbs do not compete with nouns in sentence production, regardless of their conceptual similarity. Based on this finding, we argue that lexical competition in production is limited by syntactic category. We also suggest that even complex words containing category-changing derivational morphology can be stored and accessed together with their final syntactic category information. We discuss the potential underlying mechanism and how it may enable us to speak relatively fluently.

Objective The spontaneous action potential of isolated sinoatrial node cells is regulated by a coupled-clock system of two clocks: the calcium clock and membrane clock. However, it remains unclear whether calcium clock inhibitors have a direct effect on the membrane clock. The purpose of this study was to investigate the direct effect of cyclopiazonic acid (CPA), a selective calcium clock inhibitor, on the function of the membrane clock of sinoatrial node cells. Methods Rat sinoatrial node cells were isolated by trypsinization and identified based on morphology and electrophysiology. If and HCN currents were recorded via patch clamp technique. The expression of the HCN channel protein was determined by Western blotting analysis. Results The diastolic depolarization rate of spontaneous action potentials and the current densities of If were reduced by exposure to 10 μM CPA. The inhibitory effect of CPA was concentration-dependent with an IC50 value of 16.3 μM and a Hill coefficient of 0.98. The effect of CPA on If current was also time-dependent, and the If current amplitude was partially restored after washout. Furthermore, the steady-state activation curve of the If current was shifted to a negative potential, indicating that channel activation slowed down. Finally, the protein expression of HCN4 in HEK293 cells was markedly downregulated by CPA. Conclusions These results indicate that the direct inhibition effect of CPA on the If current in SAN cells is both concentration- and time-dependent. The underlying mechanisms may involve slowing down steady-state activation and the downregulation of pacemaker channel protein expression.

In this study we used fMRI to examine whether defining a stimulus as a target affects brain activation associated with a verbal working memory task. Seventeen healthy right-handed volunteers performed a Sternberg task with 3 consonants as memory set. We performed a region of interest based fMRI analysis to examine differences in brain activity patterns between targets and non-targets. Non-target brain activity was subtracted from target activity and hemispheric and fronto-parietal differences were tested by conducting a MANOVA. Participants responded correctly to 97.5% of the stimuli. FMRI results showed a hemisphere by fronto-parietal location interaction, where targets evoked increased activity in the right frontal regions compared to non-targets, whereas the left frontal task activation did not differ between targets and non-targets. In the parietal regions, targets evoked increased activity compared to non-targets in the lateral anterior, but not the medial posterior part. Our study revealed that defining a stimulus as a target within a verbal working memory task evokes an increase in brain activity in right frontal brain regions, compared to non-targets. Our results suggest an important hemispheric differentiation in target processing, in which the right frontal cortex is predominantly involved in processes associated with target stimuli. The left frontal cortex does not differentiate between processing target and non-target stimuli, suggesting involvement in working memory processes that are independent of stimulus type. Parietal, the lateral anterior part is predominantly involved in target processing, while the medial posterior part does not differentiate between target and non-target processing.

In the last 50 years, our vision of the cerebellum has vastly evolved starting with Jan Voogd’s (1967) description of extracerebellar projections’ terminations and how the projection maps transformed the presumptive homogeneity of the cerebellar cortex into a more complex center subdivided into transverse and longitudinal distinct functional zones. The picture became still more complex with Richard Hawkes and colleagues’ (Gravel et al., 1987) discovery of the biochemical heterogeneity of Purkinje cells (PCs), by screening their molecular identities with monoclonal antibodies. Antigens were expressed in a parasagittal pattern with subsets of PCs either possessing or lacking the respective antigens, which divided the cerebellar cortex into precise longitudinal compartments that are congruent with the projection maps. The correlation of these two maps in adult cerebellum shows a perfect matching of developmental mechanisms. This review discusses a series of arguments in favor of the essential role played by PCs in organizing the microzonation of the cerebellum during development (the “matching” hypothesis).

Objective Motor learning is relevant in chronic stroke for acquiring compensatory strategies to motor control deficits. However, the neurophysiological mechanisms underlying motor skill acquisition with the paretic upper limb have received little systematic investigation. The aim of this study was to assess the modulation of corticomotor excitability and intracortical inhibition within ipsilesional primary motor cortex (M1) during motor skill learning. Methods Ten people at the chronic stage after stroke and twelve healthy controls trained on a sequential visuomotor isometric wrist extension task. Skill was quantified before, immediately after, 24 hours and 7 days post-training. Transcranial magnetic stimulation was used to examine corticomotor excitability and short- and long-interval intracortical inhibition (SICI and LICI) pre- and post-training. Results The patient group exhibited successful skill acquisition and retention, although absolute skill level was lower compared with controls. In contrast to controls, patients’ ipsilesional corticomotor excitability was not modulated during skill acquisition, which may be attributed to excessive ipsilesional LICI relative to controls. SICI decreased after training for both patient and control groups. Conclusions Our findings indicate distinct inhibitory networks within M1 that may be relevant for motor learning after stroke. Significance These findings have potential clinical relevance for neurorehabilitation adjuvants aimed at augmenting the recovery of motor function.

Objective To investigate whether the effects of HD-tDCS and conventional tDCS of the right IFG are superior to the effects of sham stimulation for the improvement of working memory performance in ADHD. Methods 15 ADHD patients between 10 and 16 years underwent three tDCS sessions in which conventional, HD and sham tDCS of the right IFG were applied. In all sessions a 2-back working memory task was solved and EEG was recorded. Baseline data were assessed from 15 age matched healthy controls. Results In ADHD patients, increased positive values of P300 and N200 mean amplitudes were found after conventional and HD-tDCS. Thus, both components were more in resemblance to ERPs in healthy controls. Behavioral performance was not generally influenced by tDCS but effects of HD-tDCS depended on individual hyperactive/impulsive symptom load. The rate of responders for HD-tDCS was equivalent to the responder rate for conventional tDCS. Conclusions ERP data indicate that HD-tDCS is equally suitable as conventional tDCS for the recruitment of the right IFG in the context of working memory processing. Significance HD-tDCS of the right IFG is a promising approach for neuromodulation in ADHD but further research is necessary to develop adaptations that produce reliable behavioral benefits.

Adults and children recruit a specific network of brain regions when engaged in “Theory of Mind” (ToM) reasoning. Recently, fMRI studies of adults have used multivariate analyses to provide a deeper characterization of responses in these regions. These analyses characterize representational distinctions within the social domain, rather than comparing responses across preferred (social) and non-preferred stimuli. Here, we conducted opportunistic multivariate analyses in two previously collected datasets (Experiment 1: n = 20 5–11 year old children and n = 37 adults; Experiment 2: n = 76 neurotypical and n = 29 5–12 year old children diagnosed with Autism Spectrum Disorder (ASD)) in order to characterize the structure of representations in the developing social brain, and in order to discover if this structure is disrupted in ASD. Children listened to stories that described characters' mental states (Mental), non-mentalistic social information (Social), and causal events in the environment (Physical), while undergoing fMRI. We measured the extent to which neural responses in ToM brain regions were organized according to two ToM-relevant models: 1) a condition model, which reflected the experimenter-generated condition labels, and 2) a data-driven emotion model, which organized stimuli according to their emotion content. We additionally constructed two control models based on linguistic and narrative features of the stories. In both experiments, the two ToM-relevant models outperformed the control models. The fit of the condition model increased with age in neurotypical children. Moreover, the fit of the condition model to neural response patterns was reduced in the RTPJ in children diagnosed with ASD. These results provide a first glimpse into the conceptual structure of information in ToM brain regions in childhood, and suggest that there are real, stable features that predict responses in these regions in children. Multivariate analyses are a promising approach for sensitively measuring conceptual and neural developmental change and individual differences in ToM.

Humans can experience a wide variety of different thoughts and feelings in the course of everyday life. To successfully navigate the social world, people need to perceive, understand, and predict others' mental states. Previous research suggests that people use three dimensions to represent mental states: rationality, social impact, and valence. This 3d Mind Model allows people to efficiently “see” the state of another person's mind by considering whether that state is rational or emotional, more or less socially impactful, and positive or negative. In the current investigation, we validate this model using neural, behavioral, and linguistic evidence. First, we examine the robustness of the 3d Mind Model by conducting a mega-analysis of four fMRI studies in which participants considered others' mental states. We find evidence that rationality, social impact, and valence each contribute to explaining the neural representation of mental states. Second, we test whether the 3d Mind Model offers the optimal combination of dimensions for describing neural representations of mental state. Results reveal that the 3d Mind Model achieve the best performance among a large set of candidate dimensions. Indeed, it offers a highly explanatory account of mental state representation, explaining over 80% of reliable neural variance. Finally, we demonstrate that all three dimensions of the model likewise capture convergent behavioral and linguistic measures of mental state representation. Together, these findings provide strong support for the 3d Mind Model, indicating that is it is a robust and generalizable account of how people think about mental states.

Previous studies have identified a collection of brain areas that show neural selectivity for the distinction between human-to-human and human-to-object interactions, including regions implicated in sensory and social processing. It remains largely unknown, however, how the functional communication between these areas changes with the type of interaction. Combining a generalized psychophysiological interaction (gPPI) analysis and independent component analysis (ICA), the current study sought to identify the context-sensitive modulation of the functional network architecture during touch observation. Thirty-seven participants watched 75 video clips displaying social and non-social touch events during a functional imaging scan. A gPPI analysis of pre-defined regions of interest revealed that social-cognitive brain regions show enhanced interregional coupling during social touch observation, both among social-cognitive brain regions and between social-cognitive regions and sensory regions. Conversely, during non-social touch observation, a significantly stronger coupling among brain areas within the system that processes the unimodal sensory information was observed. At the level of large-scale brain networks extracted with ICA, stronger connectivity between 11 pairs of networks, including default mode networks, was observed during social touch observation, while only three pairs of networks showed stronger connectivity during non-social touch observation. The current study identifies the presence of context-dependent changes in functional brain architecture based on whether the touch recipient is a person or an object, highlighting an increased exchange of neural information for social processing.

Understanding others in everyday situations requires multiple types of information processing (visual, auditory, higher order…) which implicates the use of multiple neural circuits of the human brain. Here, using a multisensory paradigm we investigate one aspect of social understanding less explored in the literature: instead of focusing on the capacity to infer what a specific person is thinking, we explore here how people with high functioning autism (HFA) and matched controls with typical development (TD) infer the “population thinking”. For this we created an audio-visual ‘social norm inference’ task. Participants were required to imagine how most people would judge the appropriateness of vocal utterances in relation to different emotional visual contexts. Behavioral findings demonstrated that HFA individuals show more interindividual variability in these judgments despite equal within-participant reliability relative to TD. This was also the case for judgements of the valence of these vocalizations when presented in isolation. At the neural level, multivoxel pattern analysis of functional magnetic resonance imaging data revealed strikingly similar neural representations between HFA and TD participants at the group level across different hierarchical levels and neural systems. However, analyses at the individual-participant level revealed that the “Temporal Voice Area” (TVA) shows more interindividual variability in the HFA group, both for neural representations and functional connectivity. Thus, this larger neural idiosyncrasy in a high-level auditory area matches with the larger behavioral idiosyncrasy in HFA individuals, when judging auditory valence and its adequacy in different social scenarios. These results suggest that idiosyncrasy in task-relevant sensory areas in HFA participants could underlie their greater difficulties to estimate how others can think.

While cognitive fatigue is experienced by up to 80% of individuals with traumatic brain injury (TBI), little is known about its neural underpinnings. We previously hypothesized that presentation of rewarding outcomes leads to cognitive fatigue reduction and activation of the striatum, a brain region shown to be associated with cognitive fatigue in clinical populations and processing of rewarding outcomes. We have demonstrated this in individuals with multiple sclerosis. Here, we tested this hypothesis in individuals with TBI. Twenty-one individuals with TBI and 24 healthy participants underwent functional magnetic resonance imaging. Participants performed a task during which they were presented with 1) the Outcome condition where they were exposed to monetary rewards, and 2) the No Outcome condition that served as the control condition and was not associated with monetary rewards. In accordance with our hypothesis, results showed that attainment of rewarding outcomes leads to cognitive fatigue reduction in individuals with TBI, as well as activation of the striatum. Specifically, we observed a significant group by condition interaction on fatigue scores driven by the TBI group reporting lower levels of fatigue after the Outcome condition. fMRI data revealed a significant main-effect of condition in regions previously implicated in outcome processing, while a significant group by condition interaction was observed in the left ventral striatum as revealed by a priori region of interest analysis. Results suggest that a salient motivator can significantly reduce fatigue and that outcome presentation leads to increased activation of the ventral striatum in TBI. These findings can inform the development of future non-pharmacological cognitive fatigue treatment methods and contribute to the growing body of evidence showing the association between cognitive fatigue and the striatum.

Abnormality of inhibitory control is considered to be a potential cognitive marker of tics in Tourette disorder (TD), attention deficit hyperactivity disorder (ADHD), and impulse control disorders. The results of the studies on inhibitory control in TD showed discrepant results. The aim of the present study was to assess reactive inhibitory control in adult TD patients with and without antipsychotic medication, and under emotional stimulation (visual images with positive, neutral and negative content). We assessed 31 unmedicated and 19 medicated TD patients and 26 matched healthy controls using the stop signal task as an index of reactive motor impulsivity and emotional stimulation with the aim to increase impulsivity. We performed a multimodal neuroimaging analysis using a regions of interest approach on grey matter signal, resting-state spontaneous brain activity and functional connectivity analyses. We found a higher reactive motor impulsivity in TD patients medicated with antipsychotics compared to unmedicated TD patients and controls. This propensity for reactive motor impulsivity in medicated TD patients was not influenced by ADHD or emotional stimulation. Neuroimaging results in medicated TD patients suggested that reactive motor impulsivity was underpinned by an increased grey matter signal from the right supplementary motor area and inferior frontal gyrus; decreased resting-state spontaneous activity of the left putamen; higher functional connectivity between the inferior frontal gyrus and the superior temporal gyri (bilaterally); lower functional connectivity between the cerebellum and the right subthalamic nucleus. Taken together, our data suggested (i) a deficit in reactive motor impulsivity in TD patients medicated with atypical antipsychotics that was unrelated to ADHD and (ii) that motor impulsivity was underpinned by structures and by functional connectivity of the fronto-temporo-basal ganglia-cerebellar pathway.

Objective Tourette syndrome is a neurodevelopmental disorder putatively associated with a hyperdopaminergic state. Therefore, it seems plausible that excessive dopamine transmission in Tourette syndrome alters the ability to learn based on rewards and punishments. We tested whether Tourette syndrome patients exhibited altered reinforcement learning and corresponding feedback-related EEG deflections. Methods We used a reinforcement learning task providing factual and counterfactual feedback in a sample of 15 Tourette syndrome patients and matched healthy controls whilst recording EEG. The paradigm presented various reward probabilities to enforce adaptive adjustments. We employed a computational model to derive estimates of the prediction error, which we used for single-trial regression analysis of the EEG data. Results We found that Tourette syndrome patients showed increased choice stochasticity compared to controls. The feedback-related negativity represented an axiomatic prediction error for factual feedback, yet did not differ between groups. We observed attenuated P3a modulation specifically for factual feedback in Tourette syndrome patients, representing impaired coding of attention allocation. Conclusion Our findings indicate that cortical prediction error coding is unaffected by Tourette syndrome. Nonetheless, the transfer of learned values into choice formation is degraded, in line with increased tonic dopamine in Tourette syndrome.

Modelling behavioural deficits based on structural lesion imaging is a popular approach to map functions in the human brain, and efforts to translationally apply lesion-behaviour modelling to predict post-stroke outcomes are on the rise. The high-dimensional complexity of lesion data, however, evokes challenges in both lesion behaviour mapping and post stroke outcome prediction. This paper aims to deepen the understanding of this complexity by reframing it from the perspective of causal and non-causal dependencies in the data, and by discussing what this complexity implies for different data modelling approaches. By means of theoretical discussion and empirical examination, several common strategies and views are challenged, and future research perspectives are outlined. A main conclusion is that lesion-behaviour inference is subject to a lesion-anatomical bias that cannot be overcome by using multivariate models or any other algorithm that is blind to causality behind relations in the data. This affects the validity of lesion behaviour mapping and might even wrongfully identify paradoxical effects of lesion-induced functional facilitation – but, as this paper argues, only to a minor degree. Thus, multivariate lesion-brain inference appears to be a valuable tool to deepen our understanding of the human brain, but only because it takes into account the functional relation between brain areas. The perspective of causality and inter-variable dependence is further used to point out challenges in improving lesion behaviour models. Firstly, the dependencies in the data open up different possible strategies of data reduction, and considering those might improve post-stroke outcome prediction. Secondly, the role of non-topographical causal predictors of post stroke behaviour is discussed. The present article argues that, given these predictors, different strategies are required in the evaluation of model quality in lesion behaviour mapping and post stroke outcome prediction.

In the healthy human brain, the processing of language is strongly lateralised, usually to the left hemisphere, while the processing of complex non-linguistic sounds recruits brain regions bilaterally. Here we asked whether the anterior temporal lobes, strongly implicated in semantic processing, are critical to this special treatment of spoken words. Nine patients with semantic dementia (SD) and fourteen age-matched controls underwent magnetoencephalography and structural MRI. Voxel based morphometry demonstrated the stereotypical pattern of SD: severe grey matter loss restricted to the anterior temporal lobes, with the left side more affected. During magnetoencephalography, participants listened to word sets in which identity and meaning were ambiguous until word completion, for example played vs plate. Whereas left-hemispheric responses were similar across groups, patients demonstrated increased right hemisphere activity 174-294ms after stimulus disambiguation. Source reconstructions confirmed recruitment of right-sided analogues of language regions in SD: atrophy of anterior temporal lobes was associated with increased activity in right temporal pole, middle temporal gyrus, inferior frontal gyrus and supramarginal gyrus. Overall, the results indicate that anterior temporal lobes are necessary for normal and efficient lateralised processing of word identity by the language network.

Tourette syndrome (TS) is a neurological disorder of childhood onset that is characterised by the occurrence of motor and vocal tics. TS is associated with cortical-striatal-thalamic-cortical circuit [CSTC] dysfunction and hyper-excitability of cortical limbic and motor regions that are thought to lead to the occurrence of tics. Importantly, individuals with TS often report that their tics are preceded by ‘premonitory sensory/urge phenomena’ (PU) that are described as uncomfortable bodily sensations that precede the execution of a tic and are experienced as a strong urge for motor discharge. While the precise role played by PU in the occurrence of tics is largely unknown, they are nonetheless of considerable theoretical and clinical importance, not least because they form the core component in many behavioural therapies used in the treatment of tic disorders. Several lines of evidence indicate that the insular cortex may play a particularly important role in the generation of PU in TS and ‘urges-for-action’ more generally. In the current study we utilised voxel-based morphometry techniques together with ‘seed-to-voxel’ structural covariance network (SCN) mapping to investigate the putative role played by the right insular cortex in the generation of motor tics and the experience of PU in a relatively large group of young people TS. We demonstrate that clinical measures of motor tic severity and PU are uncorrelated with one another, that motor tic severity and PU scores are associated with separate regions of the insular cortex, and that the insula is associated with different structural covariance networks in individuals with TS compared to a matched group of typically developing individuals.

Tourette syndrome (TS) is a childhood-onset neurological disorder characterised by the occurrence of motor and vocal tics and the presence of premonitory sensory/urge phenomena. Functional neuroimaging studies in humans, and experimental investigations in animals, have shown that the genesis of tics in TS involve a complex interaction between cortical-striatal-thalamic-cortical brain circuits and additionally appears to involve the cerebellum. Furthermore, structural brain imaging studies have demonstrated alterations in grey matter (GM) volume in TS across a wide range of brain areas, including alterations in GM volume within the cerebellum. Until now, no study to our knowledge has yet investigated how GM structural covariance networks linked to the cerebellum may be altered in individuals with TS. In this study we employed voxel-based morphometry, and a ‘seed-to-voxel’ structural covariance network (SCN) mapping approach, to investigate alterations in GM cerebellar volume in people with TS, and alterations in cerebellar SCNs associated with TS. Data from 64 young participants was entered in the final analysis, of which 28 had TS while 36 were age-and sex-matched healthy volunteers. Using the spatially unbiased atlas template of the cerebellum and brainstem (SUIT) atlas, we found reduced GM volume in cerebellar lobule involved in higher-order cognitive functions and sensorimotor processing, in patients. In addition, we found that several areas located in frontal and cingulate cortices and sensorimotor network in addition to subcortical areas show altered structural covariance with our cerebellar seed compared to age-matched controls. These results add to the increasing evidence that cortico-basal ganglia-cerebellar interactions play an important role in tic symptomology.

Hemispheric asymmetries are a major organizational principle of the human brain. In different neurodevelopmental and psychiatric disorders, like schizophrenia, autism spectrum disorders, depression, dyslexia and posttraumatic stress disorder, functional and/or structural hemispheric asymmetries are altered compared to healthy controls. The question, why these disorders all share the common characteristic of altered hemispheric asymmetries despite vastly different etiologies and symptoms remains one of the unsolved mysteries of laterality research. This review is aimed at reviewing potential reasons for why atypical lateralization is so common in many neurodevelopmental and psychiatric disorders. To this end, we review the evidence for overlaps in the genetic and non-genetic factors involved in the ontogenesis of different disorders and hemispheric asymmetries. While there is evidence for genetic overlap between different disorders, only few asymmetry-related loci have also been linked to disorders and importantly, those effects are mostly specific to single disorders. However, there is evidence for shared non-genetic influences between disorders and hemispheric asymmetries. Most neurodevelopmental and psychiatric disorders show alterations in the hypothalamic-pituitary adrenocortical (HPA) axis and maternal as well as early life stress have been implicated in their etiology. Stress has also been suggested to affect hemispheric asymmetries. We propose a model in which early life stress as well as chronic stress not only increases the risk for psychiatric and neurodevelopmental disorders but also changes structural and functional hemispheric asymmetries leading to the aberrant lateralization patterns seen in these disorders. Thus, pathology-related changes in hemispheric asymmetries are not a factor causing disorders, but rather a different phenotype that is affected by partly overlapping ontogenetic factors, primarily stress.

Social group membership modulates the neural processing of emotional facial expressions, which, in turn, recruits part of the neural production system. However, little is known about how mixed – and potential conflicting – social identity cues affect this mechanism. In this study, we tested the hypothesis that incongruent cues of two group memberships (ethnic and experimentally created minimal groups) elicit conflict processing for neutral and, in particular, angry facial expressions. We further expected this interaction of ethnic group, minimal group and emotion to also modulate activation in an emotional production-perception network. Twenty-two healthy German subjects saw dynamic angry and neutral facial expressions, presented in short video clips during functional MRI scanning. All depicted actors belonged to an ethnic in- or outgroup (German or Turkish descent) as well as an ad hoc experimentally created minimal in- or outgroup. Additionally, subjects produced angry or neutral expressions themselves. The whole-brain interaction of ethnic group, minimal group and emotion revealed activity in the right parietal lobule and left cerebellum. Both showed strongest activation for angry faces with conflicting group memberships (e.g., ‘ethnic outgroup/minimal ingroup’). In addition, a sub-region of the left cerebellum cluster was also activated for both perceiving and producing angry vs. neutral expressions. These results suggest that incongruent group members displaying angry facial expressions elicit conflict processing. Group interaction effects in an emotional production-perception network further indicate stronger neural resonance for incongruent group members.

Why do the left and right sides of the brain have different functions? Having a lateralized brain, in which each hemisphere processes sensory inputs differently and carries out different functions, is common in vertebrates, and it has now been reported for invertebrates too. Experiments with several animal species have shown that having a lateralized brain can enhance the capacity to perform two tasks at the same time. Thus, the different specializations of the left and right sides of the brain seem to increase brain efficiency. Other advantages may involve control of action that, in Bilateria, may be confounded by separate and independent sensory processing and motor outputs on the left and right sides. Also, the opportunity for increased perceptual training associated with preferential use of only one sensory or motoric organ may result in a time advantage for the dominant side. Although brain efficiency of individuals can be achieved without the need for alignment of lateralization in the population, lateral biases (such as preferences in the use of a laterally-placed eye) usually occur at the population level, with most individuals showing a similar direction of bias. Why is this the case? Not only humans, but also most non-human animals, show a similar pattern of population bias (i.e., directional asymmetry). For instance, in several vertebrate species (from fish to mammals) most individuals react faster when a predator approaches from their left side, although some individuals (a minority usually ranging from 10 to 35%) escape faster from predators arriving from their right side. Invoking individual efficiency (lateralization may increase fitness), evolutionary chance or simply genetic inheritance cannot explain this widespread pattern. Using mathematical theory of games, it has been argued that the population structure of lateralization (with either antisymmetry or directional asymmetry) may result from the type of interactions asymmetric organisms face with each other.

Depression is one of the most common psychiatric diseases and the prevalence of depressive symptoms in women is almost twice compared to men, although the reasons of this gender difference are not fully understood yet. Recently, soluble amyloid beta (Aβ)1-42 peptide has been receiving great importance in the development of depression, also considering that depression is highly comorbid with Alzheimer’s disease and other neurodegenerative illnesses. The central role played by Aβ in the development of depressive-like symptoms in rodents has been evidenced in environmental rodent model of depression. Indeed, we have previously found that lifelong exposure to n-3 polyunsaturated fatty acids (PUFA) deficient diet in female rats at 8 weeks of life leads to depressive like- symptoms and higher susceptibility to stress associated with increased Aβ levels. In order to understand if such effects were maintained over time, rats were exposed to the same diet regimen until 6 or 21 weeks of life. We found that both timepoints of exposure to n-3 PUFA deficient diet lead to depressive-like phenotype. Furthermore, a significant alteration in brain neurochemistry was retrieved. In particular, in hippocampal area a significant reduction in serotonin (5-HT) and noradrenaline (NA) content was evidenced. Considering the prominent role of NA in counterbalancing neuroinflammatory state, we quantified in the same brain area kynurenine levels, a metabolite of tryptophan implicated in inflammatory state and brought to the fore for its implication in depression. Interestingly, kynurenine levels were significantly increased in hippocampus (HIPP) of female rats exposed to such diet. In addition, lifelong deficiency in n-3 PUFA dietary intake led to systemic increase of corticosterone, hence hypothalamic pituitary adrenal (HPA) axis hyperactivation, and higher proinflammatory cytokine production. Increased production of kynurenine, along with HPA axis hyperactivation, have been associated with immune system modulation, particularly through Toll-like receptor type 2 (TLR2) and Toll-like receptor type 4 (TLR4) involvement. In addition, it has been shown that soluble forms of Aβ1-42 can induced depressive like-phenotype in consequence to a crosstalk between TLR4 and 5-HTergic system. Thus, considering that in this model we have previously reported increased plasma Aβ1-42 level, we quantified TRL2 and 4 expression in HIPP of treated rats. We found that chronic exposure to a diet characterized by very low n-3 PUFA content led to higher expression of TLR2 and TLR4 in HIPP of female treated rats, indicating an activation of the immune system and was accompanied by increased expression of oligomeric Aβ. Taken together, our data indicate that the pro-depressive effects induced by a diet poor in n-3 PUFA can be attributable to a shift of hippocampal tryptophan metabolism toward inflammatory metabolite ultimately corresponding to altered immune response and increased Aβ oligomerization.

Recently, the (GGC)n repeat expansion in the NOTCH2NLC gene has been identified to be associated with neuronal intranuclear inclusion disease (NIID). Given the clinical overlap of dementia-dominant NIID with neurodegenerative dementia, we therefore hypothesized that the NOTCH2NLC repeat expansion might also contribute to these diseases. In the present study, repeat primed polymerase chain reaction (RP-PCR) and GC-rich PCR were conducted to detect the repeats of NOTCH2NLC in a cohort of 1004 patients with neurodegenerative dementias from mainland China. As a result, four sporadic patients were found to carry the NOTCH2NLC repeats expansion, totally accounting for 0.4% of all dementia individuals, and the accurate repeated sizes were 110, 133 120 and 76 respectively. Of four mutation carriers, three and one were clinically diagnosed Alzheimer’s disease (AD) and frontotemporal dementia (FTD) respectively. In addition, three out of them revealed leukoencephalopathy in T2-Flair imaging. This study revealed that although rare, the NOTCH2NLC repeat expansions may be associated with AD or FTD-like phenotype as well as leukoencephalopathy.

Beta amyloid (Aβ) accumulation is the earliest pathological marker of Alzheimer’s disease (AD), but early AD pathology also affects white matter (WM) integrity. We performed a cross-sectional study including 44 subjects (23 healthy controls and 21 MCI or early AD) that underwent simultaneous MR-PET using 18F-Florbetapir, and were categorized into three groups based on Aβ burden: Aβ- [mean mSUVr ≤ 1.00], Aβi [1.00 < mSUVr < 1.17], Aβ+ [mSUVr ≥ 1.17]. Inter-group comparisons of diffusion MRI metrics revealed significant differences across multiple WM tracts. Aβi group displayed more restricted diffusion (higher fractional anisotropy, radial kurtosis, axonal water fraction and lower radial diffusivity) than both Aβ- and Aβ+ groups. This non-monotonic trend was confirmed by significant continuous correlations between mSUVr and diffusion metrics going in opposite direction for two cohorts: pooled Aβ-/Aβi and pooled Aβi/Aβ+. The transient period of increased diffusion restriction may be due to inflammation that accompanies rising Aβ burden. In the later stages of Aβ accumulation, neurodegeneration is the predominant factor affecting diffusion.

Behavioral and cognitive tests in individuals who were malnourished as children have revealed malnutrition-related deficits that persist throughout the lifespan. These findings have motivated recent neuroimaging investigations that use highly portable functional near-infrared spectroscopy (fNIRS) instruments to meet the demands of brain imaging experiments in low-resource environments and enable longitudinal investigations of brain function in the context of long-term malnutrition. However, recent studies in healthy subjects have demonstrated that high-density diffuse optical tomography (HD-DOT) can significantly improve image quality over that obtained with sparse fNIRS imaging arrays. In studies of both task activations and resting state functional connectivity, HD-DOT is beginning to approach the data quality of fMRI for superficial cortical regions. In this work, we developed a customized HD-DOT system for use in malnutrition studies in Cali, Colombia. Our results evaluate the performance of the HD-DOT instrument for assessing brain function in a cohort of malnourished children. In addition to demonstrating portability and wearability, we show the HD-DOT instrument's sensitivity to distributed brain responses using a sensory processing task and measurements of homotopic functional connectivity. Task-evoked responses to the passive word listening task produce activations localized to bilateral superior temporal gyrus, replicating previously published work using this paradigm. Evaluating this localization performance across sparse and dense reconstruction schemes indicates that greater localization consistency is associated with a dense array of overlapping optical measurements. These results provide a foundation for additional avenues of investigation, including identifying and characterizing a child's individual malnutrition burden and eventually contributing to intervention development.

Microvascular blood volume pulsations due to the cardiac and respiratory cycles induce brain tissue deformation and, as such, are considered to drive the brain's waste clearance system. We have developed a high-field magnetic resonance imaging (MRI) technique to quantify both cardiac and respiration-induced tissue deformations, which could not be assessed noninvasively before. The technique acquires motion encoded snapshot images in which various forms of motion and confounders are entangled. First, we optimized the motion sensitivity for application in the human brain. Next, we isolated the heartbeat and respiration-related deformations, by introducing a linear model that fits the snapshot series to the recorded physiological information. As a result, we obtained maps of the physiological tissue deformation with 3 mm isotropic spatial resolution. Heartbeat- and respiration induced volumetric strain were significantly different from zero in the basal ganglia (median (25–75% interquartile range): 0.85·10−3 (0.39·10−3–1.05·10−3), p = 0.0008 and −0.28·10−3 (−0.41·10−3–0.06·10−3), p = 0.047, respectively). Smaller volumetric strains were observed in the white matter of the centrum semi ovale (0.28·10−3 (0–0.59·10−3) and −0.06·10−3 (−0.17·10−3–0.20·10−3)), which was only significant for the heart beat (p = 0.02 and p = 0.7, respectively). Furthermore, heartbeat induced volumetric strain was about three times larger than respiration induced volumetric strain. This technique opens a window on the driving forces of the human brain clearance system.

Visceral hypersensitivity and pain result, at least in part, from increased excitability of primary afferents that innervate the colon. In addition to intrinsic changes in these neurons, emerging evidence indicates that changes in lining epithelial cells may also contribute to increased excitability. Here we review recent studies on how colon epithelial cells communicate directly with colon afferents. Specifically, anatomical studies revealed specialized synaptic connections between epithelial cells and nerve fibers and studies using optogenetic activation of the epithelium showed initiation of pain-like responses. We review the possible mechanisms of epithelial–neuronal communication and provide an overview of the possible neurotransmitters and receptors involved. Understanding the biology of this interface and how it changes in pathological conditions may provide new treatments for visceral pain conditions.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Stability of microtubule protein (MTP) network required for its physiological functions is disrupted in the course of neurodegenerative disorders. Thus, design of novel therapeutic approaches for microtubule stabilization is a focus of intensive study. Dynamin-related protein-1 (Drp1) is a guanosine triphosphatase (GTPase), which plays a prevailing role in mitochondrial fission. Several isoforms of Drp1 have been identified that one of these isoforms (Drp1-x01) has been previously described with MTP stabilizing activity. Here, we synthesized peptide LIQ, an 11-amino acid peptide derived from Drp1-x01 isoform, and reported that LIQ could induce tubulin assembly in vitro. Using Stern-Volmer plot and continuous variation method, we proposed one binding site on tubulin for this peptide. Interestingly, FRET experiment and docking studies showed that LIQ binds taxol-binding site on β-tubulin. Furthermore, circular dichroism (CD) spectroscopy and 8-anilino-1-naphthalenesulfonic acid (ANS) assay provided data on tubulin structural changes upon LIQ binding that result in forming more stable tubulin dimers. Flow cytometry analysis and fluorescence microscopy displayed that cellular internalization of 5-FAM-labeled LIQ is attributed to a mechanism that mostly involves endocytosis. In addition, LIQ promoted polymerization of tubulin and stabilized MTP in primary astroglia cells and also protected these cells against zinc toxicity. This excellent feature of cellular neuroprotection by LIQ provides a promising therapeutic approach for neurodegenerative diseases.

Glycyrrhizin (Glycyrrhizic Acid), a bioactive triterpenoid saponin found in Glycyrrhiza glabra, has been used for a long time in traditional medicine. Glycyrrhizin possesses a plethora of pharmacological activities including anti-inflammatory, antioxidant, anti-microbial and anti-ageing potential. It is a well-established pharmacological inhibitor of high mobility group box 1 (HMGB1), a ubiquitous protein with pro-inflammatory cytokine-like activity. HMGB1 contributes to an array of inflammatory diseases when released extracellularly, primarily via the activation of cell signaling upon binding to receptor for advanced glycation end products (RAGE) and toll-like receptor 4 (TLR4). HMGB1 neutralization strategies have demonstrated disease-modifying outcomes against several pre-clinical models of neurological disorders, mainly through inhibition of HMGB1 expression and release. In this review, we aim to enlighten the therapeutic potential of glycyrrhizin against different neurological disorders. Current research studies demonstrate the therapeutic potential of glycyrrhizin against several HMGB1-mediated pathological conditions including Traumatic brain injury, Neuroinflammation and associated conditions, Epileptic seizures, Alzheimer’s disease and related pathology, Parkinson’s disease and Multiple sclerosis. Glycyrrhizin’s effects in neurological disorders are mainly attributed to attenuation of neuronal damage by inhibiting HMGB1 expression and translocation as well as by downregulating expression of inflammatory cytokines. Current scientific evidence indicates that glycyrrhizin might be a promising therapeutic alternative that could overcome the limitations of current treatment strategy against these neurological disorders discussed herein mainly via halting disease progression. However, future research is warranted for deeper exploration of the precise underlying molecular mechanism as well as for clinical translation

Gabapentinoids, which are the common analgesics, are also thought to be an effective treatment for anxiety disorder, which is one of several psychiatric disorders triggered and exacerbated by stress. The aim of the present study was to investigate whether mirogabalin, a recently launched gabapentinoid, protects multiple brain functions against repeated restraint stress. Adult male ddY mice were restrained for 7 days (repeated restraint stress: 2 h/day) or for 30 min (single restraint stress). Mirogabalin (intraperitoneal, intracerebroventricular or intrahippocampal injection) was administered prior to the restraint stress. Y-maze, elevated-plus maze and c-Fos immunohistochemistry were performed to evaluate learning function, anxiety levels and hippocampal neuronal activities, respectively, after the 7th day of the repeated restraint stress. Intestinal function was evaluated in terms of defecation, which was scored after the 5th day of repeated restraint stress and by the number of fecal pellets excreted after a single session of restraint stress. Repeated restraint stress induced memory dysfunction, anxiety-like behavior, an abnormal defecation score and increased hippocampal c-Fos expression. These changes were prevented by systemic administration of mirogabalin. Abnormal defecation was also induced by single restraint stress, and was inhibited by both systemic and central administration of mirogabalin, suggesting that the effect on the intestinal function was also mediated via the central nervous system. Enhancement of c-Fos expression by repeated stress was decreased by intrahippocampal injection of mirogabalin. Together, these observations suggest that mirogabalin protects multiple brain functions from repeated stress, which may be mediated by inhibition of hippocampal neuron hyperactivation.

Contrast sensitivity (CS) is one of the primary fundamental factors determining how well we can see, and it directly influences object recognition. Whether bisphenol-A (BPA, an environmental xenoestrogen) can perturb contrast detection in the visual system has yet to be elucidated. In the present study, we analyzed CS of single neurons in the primary visual cortex (area 17, A17) of cats before and after BPA exposure using a multiple-channel recording technique. The results showed that CS of A17 neurons was markedly depressed with an increased contrast threshold after two hour of intravenous BPA administration, which had a positive correlation with decreased firing rates of A17 neurons. Additionally, responses of these neurons presented an overt increase in the trial-to-trail response variability (a kind of neuronal noise), which could disturb the information-filtering function of single neurons. We also found that neuronal CS in the visual relay station was not disturbed after BPA administration, which rules out the contribution of CS alteration in the optical pathway. Importantly, acute BPA treatment obviously increased the inhibitory innervation to the visual pyramidal neurons. This implies that alteration of intracortical inhibitory regulation contributes to the compromised contrast detection in the visual system after BPA treatment.

Objectives To determine if auditory function is associated with current long chain polyunsaturated fatty acids (LCPUFA) concentrations in a cohort of young adults who consume oceanic fish with naturally acquired methylmercury (MeHg). We measured participants plasma LCPUFA concentrations (total n-3, total n-6 and the n-6:n-3 ratio) and looked for an association with Auditory Brain Response (ABR) latencies and Otoacoustic Emissions (OAE) amplitudes. Design Auditory function of 534 participants from the Seychelles Child Development Study (SCDS) main cohort was examined at 19 years of age. Tests included standard pure-tone audiometry, tympanometry, ABR and both Click-Evoked OAE (CEOAE) and Distortion-Product OAE (DPOAE). Associations of LCPUFA status, measured at the time of examination, and auditory outcomes were examined using covariate-adjusted linear regression models. All models were adjusted for sex, prenatal and current MeHg exposure and hearing status. Results LCPUFA concentrations were similar for both sexes and when comparing participants with normal hearing (90.4%) to those who had a sensorineural hearing loss in one or both ears (9.6%). When looking at a subset of only hearing impaired participants, LCPUFA concentrations were similar in those participants who had a mild sensorineural hearing loss as compared with participants that had a moderate sensorineural hearing loss. LCPUFA concentrations were not correlated with current hair MeHg. LCPUFA concentrations were statistically significantly associated with only 6 of 174 ABR and OAE endpoints examined. Four of the 6 significant associations were present in only one sex. In female participants as n-6 concentrations increased, the ABR wave I absolute latency increased for a 60 dBnHL 19 click/sec stimulus. For male participants the interwave I-III latencies for a 60 dBnHL 69 clicks/sec stimulus increased as the n-6:n-3 LCPUFA ratio increased and the interwave I-V interval decreased for a 60 dBnHL 39 clicks/sec stimulus as the n-6 concentration increased. For both sexes interwave latencies were prolonged for the III-V interwave interval for an 80 dBnHL 39 clicks/sec as n-3 LCPUFA concentration increased. As the n-3 LCPUFA concentrations increased, the amplitude of the 6000 Hz DPOAE in the right ear increased for both sexes. As the n-6:n-3 ratio increased, the amplitude of the 1500 Hz DPOAE in the left ear decreased for females. The amplitude of the CEOAE was not associated with n-3, n-6 LCPUFA concentrations or the n-6:n-3 ratio. Conclusion There was no evidence to suggest LCPUFA status was associated with hearing acuity, ABR latencies or OAE amplitudes, even though our participants tended to have higher LCPUFA concentrations as compared to individuals consuming a more western diet. No association was observed between LCPUFA status and a participants hearing status (normal hearing or hearing loss). Although we found a few associations between current plasma LCPUFA status and ABR and OAE auditory endpoints examined, no clear pattern exists. Some of these associations would be considered detrimental resulting in prolonged ABR latencies or smaller OAE amplitudes, while others would be considered beneficial resulting in shortened ABR latencies or larger OAE amplitudes.

While it is generally accepted that structural and functional brain deficits underlie the behavioral deficits associated with fetal alcohol spectrum disorders (FASD), the degree to which these problems are expressed in sensory pathology is unknown. Electrophysiological measures indicate that neural processing is delayed in visual and auditory domains. Furthermore, multiple reports of white matter deficits due to prenatal alcohol exposure indicate altered cortical connectivity in individuals with FASD. Multisensory integration requires close coordination between disparate cortical areas leading us to hypothesize that individuals with FASD will have impaired multisensory integration relative to healthy control participants. Participants’ neurophysiological responses were recorded using magnetoencephalography (MEG) during passive unisensory or simultaneous, spatially congruent or incongruent multisensory auditory and somatosensory stimuli. Source timecourses from evoked responses were estimated using multi-dipole spatiotemporal modeling. Auditory M100 response latency was faster for the multisensory relative to the unisensory condition but no group differences were observed. M200 auditory latency to congruent stimuli was earlier and congruent amplitude was larger in participants with FASD relative to controls. Somatosensory M100 response latency was faster in right hemisphere for multisensory relative to unisensory stimulation in both groups. FASD participants’ somatosensory M200 responses were delayed by 13 ms, but only for the unisensory presentation of the somatosensory stimulus. M200 results indicate that unisensory and multisensory processing is altered in FASD; it remains to be seen if the multisensory response represents a normalization of the unisensory deficits.

Large scale unbiased quantification of immunohistochemistry is time consuming, expensive, and/or limited in scope. Heterogeneous tissue types such as brain tissue have presented a further challenge to the development of automated analysis, as differing cellular morphologies result in either limited applicability or require large amounts of training tissue for machine-learning methods. Here we present the use of QuPath, a free and open source software, to quantify whole-brain sections stained with the immunohistochemical markers IBA1 and AT8, for microglia and phosphorylated tau respectively. The pixel-based method of analysis herein allows for statistical comparison of global protein expression between brains and generates heat-maps of stain intensity, visualizing stain signal across whole sections and permitting more specific investigation of regions of interest. This method is fast, automated, unbiased, and easily replicable. We compared swine brains that had undergone a closed head traumatic brain injury with brains of sham animals, and found a global increase in both microglial signal expression and phosphorylated tau. We discuss the immunohistochemistry methods necessary to utilize this analysis and provide detailed instruction on the use of QuPath in the pixel-based analysis of whole-slide images.

Brain ischaemia, which can cause severe nerve injury, is a global health challenge. Long non-coding RNA (lncRNA) growth-arrest specific 5 (Gas5) has been documented to exert tumour suppressive effects in several cancers. However, its role in cerebrovascular disease still requires further investigation. Therefore, in this study, we focused on the role of lncRNA regulatory signalling related to lncRNA Gas5 in ischaemic brain injury. Middle cerebral artery occlusion (MCAO) was employed as a model of ischaemic brain injury in rats. The expression of lncRNA Gas5 and microRNA-21 (miR-21) was altered in neurons to elucidate their effects in ischaemic brain injury and to identify the interactions among lncRNA Gas5, miR-21 and Pten. The neuronal survival rate, apoptosis and the expression of phosphatidyl inositol 3-kinase (PI3K)/Akt signalling pathway-related genes were also evaluated in vitro to determine the effects of lncRNA Gas5. In the brains of rats subjected to MCAO, the expression of lncRNA Gas5 and Pten was upregulated, while miR-21 was downregulated. LncRNA Gas5 inhibited miR-21 expression, leading to elevated levels of Pten. In vitro experiments revealed that lncRNA Gas5 depletion and miR-21 elevation resulted in the suppression of neuronal apoptosis, thus promoting neuronal survival via the PI3K/Akt signalling pathway. These findings demonstrate that lncRNA Gas5 increases miR-21 and activates Pten, contributing to the development of ischaemic brain injury, supporting the silencing of lncRNA Gas5 as a possible therapeutic target for the treatment of ischaemic brain injury.

Clinical and animal studies show maternal alcohol consumption during pregnancy causes in offspring persistent alterations in neuroimmune and neurochemical systems known to increase alcohol drinking and related behaviors. Studies in lateral hypothalamus (LH) demonstrate in adolescent offspring that maternal oral administration of ethanol stimulates the neuropeptide, melanin-concentrating hormone (MCH), together with the inflammatory chemokine C-C motif ligand 2 (CCL2) and its receptor CCR2 which are increased in most MCH neurons. These effects, consistently stronger in females than males, are detected in embryos, not only in LH but hypothalamic neuroepithelium (NEP) along the third ventricle where neurons are born and CCL2 is stimulated within radial glia progenitor cells and their laterally projecting processes that facilitate MCH neuronal migration toward LH. With ethanol’s effects similarly produced by maternal peripheral CCL2 administration and blocked by CCR2 antagonist, we tested here using in utero intracerebroventricular (ICV) injections whether CCL2 acts locally within the embryonic NEP. After ICV injection of CCL2 (0.1 µg/µl) on embryonic day 14 (E14) when neurogenesis peaks, we observed in embryos just before birth (E19) a significant increase in endogenous CCL2 within radial glia cells and their processes in NEP. These auto-regulatory effects, evident only in female embryos, were accompanied by increased density of CCL2 and MCH neurons in LH, more strongly in females than males. These results support involvement of embryonic CCL2/CCR2 neuroimmune system in radial glia progenitor cells in mediating sexually dimorphic effects of maternal challenges such as ethanol on LH MCH neurons that colocalize CCL2 and CCR2.

Calcium acts as a second messenger that mediates physiologic functions, such as metabolism, cell proliferation, and apoptosis. Hippocalcin is a neuronal calcium sensor protein that regulates intracellular calcium concentration. Moreover, it prevents neuronal cell death from oxidative stress. Quercetin has excellent antioxidant properties and preventative effects. We studied modulation of hippocalcin expression by quercetin treatment in cerebral ischemic injury and glutamate-induced neuronal cell damage. Focal cerebral ischemia was induced by permanent middle cerebral artery occlusion (pMCAO). Male Sprague-Dawley rats were injected with vehicle or quercetin (10 mg/kg) 1 h prior to pMCAO, and cerebral cortical tissues were isolated 24 h after pMCAO. Quercetin improved pMCAO-induced neuronal movement deficit and infarction. pMCAO induced a decrease in hippocalcin expression in the cerebral cortex. However, quercetin treatment attenuated this pMCAO-induced decrease. In cultured hippocampal cells, glutamate excitotoxicity dramatically increased the intracellular calcium concentration, whereas quercetin alleviated intracellular calcium overload. Moreover, Western blot and immunocytochemical studies showed reduction of hippocalcin expression in glutamate-exposed cells. Quercetin prevented this glutamate-induced decrease. Furthermore, caspase-3 expression in hippocalcin siRNA transfection conditions is higher than caspase-3 expression in un-transfection conditions. Quercetin treatment attenuated the increase of caspase-3. Taken together, these results suggest that quercetin exerts a preventative effect through attenuation of intracellular calcium overload and restoration of down-regulated hippocalcin expression during ischemic injury.

Objectives The objective of this study was to examine the interactive effects of exercise and low-level inhibition of GABAA receptors on the recovery of motor function and BDNF expression in the primary motor cortex (M1) of a stroke rat model. Methods Male Sprague-Dawley rats were divided into 5 groups: sham (SHAM), control (CON), exercise (EX), bicuculline (BIC), and bicuculline plus exercise (BICEX) groups. All rats, except those in the SHAM group, underwent middle cerebral artery occlusion (MCAO) surgery to induce an ischemic stroke. GABAA receptor antagonist, bicuculline (0.25 mg/kg, i.p.), was administered to the BIC and BICEX groups. The EX and BICEX groups exercised on a treadmill (11 m/min for 30 min). Each intervention started 3 days after the MCAO surgery and was carried out every day for 2 weeks. Following the intervention, bilateral M1 BDNF mRNA and protein expression levels were assessed using qRT-PCR and ELISA. Results Marginal recovery was found in the EX and BIC groups, whereas motor function recovery was enhanced with exercise in the presence of bicuculline administration specifically in the BICEX group. Furthermore, BDNF protein level in the ipsilateral M1 was significantly higher in the BICEX group than in other groups. Conclusions This study indicated that exercise combined with low-level inhibition of GABAA receptors after stroke could facilitate the recovery of motor function accompanied by BDNF upregulation in the ipsilateral M1. Therefore, this study provides a novel insight of pharmacological neuromodulation into stroke rehabilitation.

The etiology of neurological impairments associated with prematurity and other perinatal complications often involves an infectious or pro-inflammatory component. The use of antioxidant molecules have proved useful to protect the neonatal brain from injury. The choroid plexuses-CSF system shapes the central nervous system response to inflammation at the adult stage, but little is known on the neuroimmune interactions that take place at the choroidal blood-CSF barrier during development. We previously described that peripheral administration to neonatal mice of the TLR2 ligand PAM3CSK4 (P3C), a prototypic Gram-positive bacterial lipopeptide, induces the migration of innate immune cells to the CSF. Here we showed in neonatal rats exposed to P3C that the migration of neutrophils into the CSF, which occurred through the choroid plexuses, is abolished following administration of the antioxidant drug N-acetylcysteine. Combining light sheet microscopy imaging of choroid plexus, a differentiated model of the blood-CSF barrier, and multiplex cytokine assays, we showed that the choroidal epithelium responds to the bacterial insult by a specific pattern of cytokine secretion, leading to a selective accumulation of neutrophils in the choroid plexus and to their trafficking into CSF. N-acetylcysteine acted by blocking neutrophil migration across both the endothelium of choroidal stromal vessels and the epithelium forming the blood-CSF barrier, without interfering with neutrophil blood count, neutrophil tropism for choroid plexus, and choroidal chemokine-driven chemotaxis. N-acetylcysteine reduced the injury induced by hypoxia-ischemia in P3C-sensitized neonatal rats. Overall, the data show that a double endothelial and epithelial check point controls the transchoroidal migration of neutrophils into the developing brain. They also point to the efficacy of N-acetylcysteine in reducing the deleterious effects of inflammation-associated perinatal injuries by a previously undescribed mechanism, i.e. the inhibition of innate immune cell migration across the choroid plexuses, without interfering with the systemic inflammatory response to infection.

Multiple visual attention mechanisms are active already in infancy, most notably one supporting orienting towards stimuli and another, maintaining appropriate levels of alertness, when exploring the environment. They are thought to depend on separate brain networks, but their effects are difficult to isolate in existing behavioural paradigms. Better understanding of the contribution of each network to individual differences in visual orienting may help to explain their role in attention development. Here, we tested whether alerting and spatial cues differentially modulate pupil dilation in 8-month-old infants in a visual orienting paradigm. We found differential effects in the time course of these responses depending on the cue type. Moreover, using Principal Component Analysis (PCA) we identified two main components of pupillary response, which may reflect the alerting and orienting network activity. In a regression analysis, these components together explained nearly 40% of variance in saccadic latencies in the spatial cueing condition of the task. These results likely demonstrate that both networks work together in 8-month-old infants and that their activity can be indexed with pupil dilation combined with PCA, but not with raw changes in pupil diameter.

The molecular mechanism mediating degeneration of nigrostriatal dopaminergic neurons in Parkinson’s disease (PD) is not yet fully understood. Previously, we have shown the contribution of glia maturation factor (GMF), a proinflammatory protein in dopaminergic neurodegeneration mediated by activation of mast cells (MCs). In this study, methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced nigrostriatal neurodegeneration and astro-glial activations were determined by western blot and immunofluorescence techniques in wild type (WT) mice, MC-deficient (MC-KO) mice and GMF-deficient (GMF-KO) mice, with or without MC reconstitution before MPTP administration. We show that GMF-KO in the MCs reduces the synergistic effects of MC and Calpain1 (calcium-activated cysteine protease enzyme)-dependent dopaminergic neuronal loss that reduces motor behavioral impairments in MPTP-treated mouse. Administration of MPTP increase in calpain-mediated proteolysis in nigral dopaminergic neurons further resulting in motor decline in mice. We found that MPTP administered WT mice exhibits oxidative stress due to significant increases in the levels of malondialdehyde, superoxide dismutase and reduction in the levels of reduced glutathione and glutathione peroxidase activity as compared with both MC-KO and GMF-KO mice. The number of TH-positive neurons in the ventral tegmental area, substantia nigra and the fibers in the striatum were significantly reduced while granulocyte macrophage colony-stimulating factor (GM-CSF), MC-Tryptase, GFAP, IBA1, Calpain1 and intracellular adhesion molecule 1 expression were significantly increased in WT mice. Similarly, tyrosine hydroxylase, dopamine transporters and vesicular monoamine transporters 2 proteins expression were significantly reduced in the SN of MPTP treated WT mice. The motor behavior as analyzed by rotarod and hang test was significantly reduced in WT mice as compared with both the MC-KO and GMF-KO mice. We conclude that GMF-dependent MC activation enhances the detrimental effect of astro-glial activation-mediated oxidative stress and neuroinflammation in the midbrain, and its inhibition may slowdown the progression of PD.

In this paper, we present an effective deep prediction framework based on robust recurrent neural networks (RNNs) to predict the likely therapeutic classes of medications a patient is taking, given a sequence of diagnostic billing codes in their record. Accurately capturing the list of medications currently taken by a given patient is extremely challenging due to undefined errors and omissions. We present a general robust framework that explicitly models the possible contamination through overtime decay mechanism on the input billing codes and noise injection into the recurrent hidden states, respectively. By doing this, billing codes are reformulated into its temporal patterns with decay rates on each medical variable, and the hidden states of RNNs are regularised by random noises which serve as dropout to improved RNNs robustness towards data variability in terms of missing values and multiple errors. The proposed method is extensively evaluated on real health care data to demonstrate its effectiveness in suggesting medication orders from contaminated values.

In this paper, the l2-l∞ state estimation problem is addressed for a class of delayed artificial neural networks under high-rate communication channels with Round-Robin (RR) protocol. To estimate the state of the artificial neural networks, numerous sensors are deployed to measure the artificial neural networks. The sensors communicate with the remote state estimator through a shared high-rate communication channel. In the high-rate communication channel, the RR protocol is utilized to schedule the transmission sequence of the numerous sensors. The aim of this paper is to design an estimator such that, under the high-rate communication channel and the RR protocol, the exponential stability of the estimation error dynamics as well as the l2-l∞ performance constraint are ensured. First, sufficient conditions are given which guarantee the existence of the desired l2-l∞ state estimator. Then, the estimator gains are obtained by solving two sets of matrix inequalities. Finally, numerical examples are provided to verify the effectiveness of the developed l2-l∞ state estimation scheme.

Recent studies have provided insight into inter-individual differences in creative thinking, focusing on characterizations of distributed large-scale brain networks both at the local level of regions and their pairwise interactions and at the global level of the brain as a whole. However, it remains unclear how creative thinking relates to mesoscale network features, e.g. community and hub organization. We applied a data-driven approach to examine community and hub structure in resting-state functional imaging data from a large sample of participants, and how they relate to individual differences in creative thinking. First, we computed for every participant the co-assignment probability of brain regions to the same community. We found that greater capacity for creative thinking was related to increased and decreased co-assignment of medial-temporal and subcortical regions to the same community, respectively, suggesting that creative capacity may be reflected in inter-individual differences in the meso-scale organization of brain networks. We then used participant-specific communities to identify network hubs—nodes whose connections form bridges across the boundaries of different communities—quantified based on their participation coefficients. We found that increased hubness of DMN and medial-temporal regions were positively and negatively related with creative ability, respectively. These findings suggest that creative capacity may be reflected in inter-individual differences in community interactions of DMN and medial-temporal structures. Collectively, these results demonstrate the fruitfulness of investigating mesoscale brain network features in relation to creative thinking.

Kremer, L., S.E.J. Klein Holkenborg, I.S. Reimert, J.E. Bolhuis, L.E. Webb. The nut and bolts of animal emotion. NEUROSCI BIOBEHAV REV X, XXX-XXX, 2019. - The study of animal emotion, as with its human equivalent, can be confusing due to the complicated and inconsistent use of terminology, and the number of interlinked fields and topics it encompasses. With this review, we aim to provide an up-to-date and, to the best of our knowledge, complete overview of the field of animal emotion, especially intended for new-comers to the field who wish to get a grasp of this field. We start by tackling the terminology and proposing definitions of commonly used terms, and present the different frameworks used for the study of animal emotion. Here, we heavily draw from human literature, as the definitions of animal emotion are derived originally from human research. We follow-up with an overview of current methodologies for the study of animal emotion, in particular the valence dimension of emotion, and including some of the associated limitations linked to these methodologies. We end by pointing out key areas for future research.

Research in social neuroscience has primarily focused on carving up cognition into distinct pieces, as a function of mental process, neural network or social behaviour, while the need for unifying models that span multiple social phenomena has been relatively neglected. Here we present a novel framework that treats social cognition as a case of semantic cognition, which provides a neurobiologically constrained and generalizable framework, with clear, testable predictions regarding sociocognitive processing in the context of both health and disease. According to this framework, social cognition relies on two principal systems of representation and control. These systems are neuroanatomically and functionally distinct, but interact to (1) enable development of foundational, conceptual-level knowledge and (2) regulate access to this information in order to generate flexible and context-appropriate social behaviour. The Social Semantics framework shines new light on the mechanisms of social information processing by maintaining as much explanatory power as prior models of social cognition, whilst remaining simpler, by virtue of relying on fewer components that are “tuned” towards social interactions.

Objectives Clozapine (CLZ) is prescribed to (relatively) treatment-resistant patients with schizophrenia spectrum disorders. Currently, it is unknown what factors predict response to CLZ. Therefore, we performed meta-analyses to identify predictors of CLZ response, hence aiming to facilitate timely and efficient prescribing of CLZ. Methods A systematic search was performed in ‘Pubmed’ and ‘Embase’ until 1 January 2019. Articles were eligible if they provided data on predictors of CLZ response measured demographic and clinical factors at baseline or biochemical factors at follow-up in schizophrenia spectrum disorder patients. Results A total of 34 articles (total number of participants = 9,386; N unique = 2,094) were eligible. Factors significantly associated with better CLZ response were: lower age, lower PANSS negative score and paranoid schizophrenia subtype. Conclusion The results of our meta-analyses suggest that three baseline demographic and clinical features are associated with better clozapine response, i.e. relatively young age, few negative symptoms and paranoid schizophrenia subtype. These variables may be taken into account by clinicians who consider treating a specific patient with CLZ. Keywords: Clozapine, response, schizophrenia spectrum disorders, prediction

The interplay between viral infection and Alzheimer’s disease (AD) has long been an area of interest, but proving causality has been elusive. Several recent studies have renewed the debate concerning the role of herpesviruses, and human herpesvirus 6 (HHV-6) in particular, in AD. We screened for HHV-6 detection across three independent AD brain repositories using (1) RNA sequencing (RNA-seq) datasets and (2) DNA samples extracted from AD and non-AD control brains. The RNA-seq data were screened for pathogens against taxon references from over 25,000 microbes, including 118 human viruses, whereas DNA samples were probed for PCR reactivity to HHV-6A and HHV-6B. HHV-6 demonstrated little specificity to AD brains over controls by either method, whereas other viruses, such as Epstein-Barr virus (EBV) and cytomegalovirus (CMV), were detected at comparable levels. These direct methods of viral detection do not suggest an association between HHV-6 and AD.