Ventral Prefrontal Cortex Research Articles

Cannabidiol attenuates methamphetamine-induced conditioned place preference in male rats and viability in PC12 cells through the Sigma1R/AKT/GSK3β/CREB signaling pathway

ABSTRACT Background: Methamphetamine use is associated with several negative consequences, including neurotoxicity and greater probability of exhibiting a substance use disorder. Sigma1 receptor is involved in the neurobiological basis of several drug use disorders. Cannabidiol has received attention in the treatment of drug use disorders and neurotoxicity. Objectives: To investigate the effects of cannabidiol on methamphetamine-induced conditioned place preference (CPP) and the viability of PC12 cells. Methods: Adult male rats (n = 70) underwent methamphetamine (2 mg/kg, IP) induced CPP, and were administered cannabidiol (10, 20, 40, or 80 mg/kg, IP) during the methamphetamine withdrawal period for five consecutive days. Methamphetamine (0.5 mg/kg) was then injected to reactivate CPP. Four brain regions (ventral tegmental area, nucleus accumbens, prefrontal cortex, and hippocampus) were extracted after the last test. PC12 cells were treated with cannabidiol, Sigma1R-siRNA, or BD1047 before methamphetamine exposure. Results: Administration of 20, 40, or 80 mg/kg cannabidiol facilitated CPP extinction (80 mg/kg, p < .001) and prevented CPP development (80 mg/kg, p < .0001). This was associated with changes in the expression of Sigma1R (ventral tegmental area, 80 mg/kg, p < .0001) in the four brain regions. Cannabidiol protected the PC12 cell’s viability (10 μM, p = .0008) and inhibited the methamphetamine-induced activation of the AKT/GSK3β/CREB signaling pathway by mediating Sigma1R (10 μM, p < .0001). Conclusions: Cannabidiol seems to inhibit the rewarding effects of methamphetamine and the effects of this drug on cell viability. Sigma1R should be given further consideration as a potential target for cannabidiol.

Dopamine-Mediated Major Depressive Disorder in the Neural Circuit of Ventral Tegmental Area-Nucleus Accumbens-Medial Prefrontal Cortex: From Biological Evidence to Computational Models.

Major depressive disorder (MDD) is a serious psychiatric disorder, with an increasing incidence in recent years. The abnormal dopaminergic pathways of the midbrain cortical and limbic system are the key pathological regions of MDD, particularly the ventral tegmental area- nucleus accumbens- medial prefrontal cortex (VTA-NAc-mPFC) neural circuit. MDD usually occurs with the dysfunction of dopaminergic neurons in VTA, which decreases the dopamine concentration and metabolic rate in NAc/mPFC brain regions. However, it has not been fully explained how abnormal dopamine concentration levels affect this neural circuit dynamically through the modulations of ion channels and synaptic activities. We used Hodgkin-Huxley and dynamical receptor binding model to establish this network, which can quantitatively explain neural activity patterns observed in MDD with different dopamine concentrations by changing the kinetics of some ion channels. The simulation replicated some important pathological patterns of MDD at the level of neurons and circuits with low dopamine concentration, such as the decreased action potential frequency in pyramidal neurons of mPFC with significantly reduced burst firing frequency. The calculation results also revealed that NaP and KS channels of mPFC pyramidal neurons played key roles in the functional regulation of this neural circuit. In addition, we analyzed the synaptic currents and local field potentials to explain the mechanism of MDD from the perspective of dysfunction of excitation-inhibition balance, especially the disinhibition effect in the network. The significance of this article is that we built the first computational model to illuminate the effect of dopamine concentrations for the NAc-mPFC-VTA circuit between MDD and normal groups, which can be used to quantitatively explain the results of existing physiological experiments, predict the results for unperformed experiments and screen possible drug targets.

The glucagon-like peptide-1 system is modulated by acute and chronic alcohol exposure: Findings from human laboratory experiments and a post-mortem brain study.

Growing evidence suggests that the glucagon-like peptide-1 (GLP-1) system modulates alcohol seeking and consumption, and GLP-1 analogues may represent novel pharmacotherapies for alcohol use disorder (AUD). Accordingly, it is important to understand the potential effects of alcohol on the endogenous GLP-1 system. In a series of secondary analyses of previous human laboratory experiments, we first examined the effects of alcohol administration, with different doses and routes of administration, on peripheral active GLP-1 concentrations in heavy-drinking individuals with AUD enrolled in placebo-controlled pharmacological studies (only placebo conditions were analysed here). Alcohol administration resulted in a significant reduction of GLP-1 levels across the four experiments (oral alcohol, variable dose: F3,28 = 6.52, p = 0.002; oral alcohol, fixed dose: F7,75.94 = 5.08, p < 0.001; intravenous alcohol, variable dose: F4,37.03 = 20.72, p < 0.001; intravenous alcohol, fixed dose: F4,13.92 = 10.44, p < 0.001). Next, central expression of the GLP-1 receptor (GLP-1R) in post-mortem brain tissues (amygdala, ventral tegmental area, nucleus accumbens, hippocampus and prefrontal cortex) was compared between individuals with AUD and controls. Fold change of GLP-1R mRNA in the hippocampus was significantly higher in individuals with AUD, compared to controls (F1,21 = 6.80, p = 0.01). A trend-level effect with the same direction was also found in the prefrontal cortex (F1,20 = 3.07, p = 0.09). Exploratory analyses showed that GLP-1R gene expression levels were correlated with behavioural measures of alcohol drinking (hippocampus) and cigarette smoking (hippocampus and prefrontal cortex). Collectively, these data provide novel information on the crosstalk between alcohol and GLP-1 in a clinically relevant sample. Further studies are needed to understand the underlying mechanisms of this link.

The incubation of cocaine craving is dissociated from changes in glial cell markers within prefrontal cortex and nucleus accumbens of rats

• Extended-access cocaine self-administration elicits an incubation of cocaine-seeking behavior during protracted withdrawal. • Extended-access cocaine self-administration lowers ventromedial prefrontal cortex expression of several glial cell markers in early withdrawal that persist into protracted withdrawal. • Extended-access cocaine self-administration produces few effects upon the expression of glial cell markers in the dorsomedial prefrontal cortex, or nucleus accumbens subregions. The majority of neurobiological research on cocaine addiction has centered on neuronal pathology, ignoring the fact that glial cells are critical contributors to brain function. The present study examined the expression of various glial cell subtype-specific proteins within forebrain regions that exhibit functional anomalies in addiction. For this, immunoblotting was conducted for a variety of markers of astrocytes and oligodendrocytes within prefrontal cortex (PFC) and nucleus accumbens (NAC) subregions of cocaine-abstinent rats (3 or 30 days). Cocaine-experienced rats exhibited a time-dependent increase in cocaine craving. Within ventral PFC, cocaine-experienced rats exhibited reduced expression of myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), and the NG2(+) proteoglycan that persisted into protracted withdrawal. Within the NAC core, a persistent reduction in Cx43 expression was also observed. No statistically significant protein changes were observed for the dPFC or the NAC shell. Thus, although a history of extended cocaine-access induced an incubation of cocaine craving, the observed changes in our glial-specific markers were time-independent during withdrawal. These data from rat are consistent with imagining and post-mortem findings from humans, indicating perturbations in oligodendrocyte function in those with cocaine use disorder. As myelin is critical for normal neuronal functioning and survival, the present data suggest a reduction in the functional integrity of oligodendrocytes as a potential mechanism underpinning the enduring PFC hypofunction reported in cocaine use disorder.

Alpha-beta decoupling relevant to inhibition deficits leads to suicide attempt in major depressive disorder

BackgroundOne devastating outcome of major depressive disorder (MDD) is high suicidality, especially for patients with suicide attempt (SA). Evidence indicated that SA may be strongly associated with inhibitory control deficits. We hypothesized that the inhibition function deficits of patient with SA might be underpinned by abnormal neuronal oscillations. MethodsOur study recruited 111 subjects including 74 patients and 37 controls, who performed a GO/NOGO task during magnetoencephalography recording. Time-frequency-representations and phase-amplitude-coupling were measured for the brain circuits involved in the inhibitory function. Phase-slope-indexes were calculated between regions to determine the direction of power flow. ResultsSignificant increased reaction time and decreased judgment accuracy were observed in SA group. During the perception stage of GO task (approximately 125 ms), SA group manifested elevated alpha power in ventral prefrontal cortex (VPFC) and attenuated beta power in dorsal anterior cingulate (dACC) compared with other groups (p < 0.01). In the processing stage of NOGO task (approximately 300 ms), they showed decreased beta power in VPFC and increased alpha power in dACC (p < 0.01). Alpha-beta decoupling during both tasks was observed in SA group. Furthermore, the decoupling from VPFC to dACC under NOGO tasks was significantly correlated with suicide risk level. LimitationsThe number of participants was relatively small, and psychological elements were not involved in current study. ConclusionDysregulated oscillatory activities of dACC and VPFC suggested deficits in execution and inhibition functions triggering high suicide risks. The alpha-beta decoupling from VPFC to dACC could be served as a neuro-electrophysiological biomarker for identifying potential suicide risk.

Value, Confidence, Deliberation: A Functional Partition of the Medial Prefrontal Cortex Demonstrated across Rating and Choice Tasks.

Deciding about courses of action involves minimizing costs and maximizing benefits. Decision neuroscience studies have implicated both the ventral and dorsal medial PFC (vmPFC and dmPFC) in signaling goal value and action cost, but the precise functional role of these regions is still a matter of debate. Here, we suggest a more general functional partition that applies not only to decisions but also to judgments about goal value (expected reward) and action cost (expected effort). In this conceptual framework, cognitive representations related to options (reward value and effort cost) are dissociated from metacognitive representations (confidence and deliberation) related to solving the task (providing a judgment or making a choice). We used an original approach aimed at identifying consistencies across several preference tasks, from likeability ratings to binary decisions involving both attribute integration and option comparison. fMRI results in human male and female participants confirmed the vmPFC as a generic valuation system, its activity increasing with reward value and decreasing with effort cost. In contrast, more dorsal regions were not concerned with the valuation of options but with metacognitive variables, confidence being reflected in mPFC activity and deliberation time in dmPFC activity. Thus, there was a dissociation between the effort attached to choice options (represented in the vmPFC) and the effort invested in deliberation (represented in the dmPFC), the latter being expressed in pupil dilation. More generally, assessing commonalities across preference tasks might help in reaching a unified view of the neural mechanisms underlying the cost/benefit tradeoffs that drive human behavior.SIGNIFICANCE STATEMENT Decision neuroscience studies have implicated the medial PFC in forming the cognitive representations that drive human choice behavior. However, different studies using different tasks have suggested somewhat inconsistent links between precise computational variables and specific brain regions. Here, we use fMRI to demonstrate a robust functional partition of the medial PFC that generalizes across tasks involving an estimation of goal value and/or action cost to provide a judgment or make a choice. This general functional partition makes a critical dissociation between neural representations of decisional factors (the expected costs and benefits attached to a given option) and metacognitive estimates (confidence in the judgment or choice, and effort invested in the deliberation process).

Effect of a brain-penetrant selective estrogen receptor degrader (SERD) on binge drinking in female mice.

BackgroundGreater circulating levels of the steroid hormone 17β‐estradiol (E2) are associated with higher levels of binge drinking in women. In female mice, estrogen receptors in the ventral tegmental area, a dopaminergic region of the brain involved in the motivation to consume ethanol, regulate binge‐like ethanol intake. We recently developed a brain‐penetrant selective estrogen receptor degrader (SERD), YL3‐122, that could be used to test the behavioral role of brain estrogen receptors. We hypothesized that treating female mice with this compound would reduce binge‐like ethanol drinking.MethodsFemale C57BL/6J mice were treated systemically with YL3‐122 and a related SERD with low brain penetrance, XR5‐27, and tested for binge‐like ethanol consumption in the drinking in the dark (DID) test. Mice were also tested for sucrose and water consumption and blood ethanol clearance after treatment with the SERDs. Finally, the effect of ethanol exposure on Esr1 gene expression was measured in the ventral tegmental area (VTA), prefrontal cortex (PFC), and ventral hippocampus (vHPC) of male and female mice by quantitative real‐time PCR after 4 DID sessions.ResultsYL3‐122 reduced ethanol consumption when mice were in diestrus but not estrus. YL3‐122 also decreased sucrose consumption but did not alter water intake or blood ethanol clearance. XR5‐27 did not affect any of these measures. Binge‐like ethanol drinking resulted in increased Esr1 transcript in the VTA of both sexes, male vHPC, and female PFC.ConclusionsThese results indicate that SERD treatment can decrease binge‐like ethanol drinking in female mice. Thus, it could be a novel strategy to reduce binge drinking in women, with the caveat that effectiveness may depend on menstrual cycle phase. In addition, Esr1 transcript is increased by binge ethanol exposure in both sexes but in a brain region‐specific manner.

SCH 23390 inhibits the acquisition of nitrous oxide-induced conditioned place preference and the changes in ERK phosphorylation expression in nucleus accumbens of mice

Nitrous oxide (N2O) has a long history of abuse, but its abuse mechanism has not been clear yet. This research aimed at the possibility of mesolimbic dopaminergic system (MLDS) involved in the rewarding effect of N2O. In this work, the rewarding behavior of N2O in mice was evaluated using a typical gas-administered conditioned place preference (CPP) procedure. SCH 23390, a Dopamine D1 receptor (D1R) antagonist, and Haloperidol, a Dopamine D2 receptor (D2R) antagonist were administered during CPP to evaluate the role of dopamine receptors in the N2O-induced CPP. The accompanying changes in phosphorylation of extracellular signal-regulated kinase (ERK) in MLDS related brain regions, including the ventral tegmental area (VTA), caudate putamen (CPu), prefrontal cortex (PFC), and nucleus accumbens (NAc) were measured to assess the neural plasticity changes in the CPP mice by Western blot analysis. Results revealed that 60% N2O induced CPP in the gas-administered mice and promoted the ERK phosphorylation (p-ERK) in the NAc and CPu during the test session of the CPP test. Pretreatment of SCH 23390 (0.5 mg/kg) inhibited the acquisition of N2O-induced CPP and the enhanced p-ERK in NAc. It suggested that Dopamine D1 receptor may play an important role in the acquisition of N2O-induced CPP and the accompanied ERK activation in the NAc, which provide insight into the molecular mechanism in the rewarding properties of nitrous oxide.

P240. Sex Differences in Neural Representation of Threat in Ventral Hippocampal and Prefrontal Cortical Projections to Nucleus Accumbens

Although fear is essential for survival, excessive fear characterizes many neuropsychiatric disorders. The nucleus accumbens (NAc) plays a role in encoding and responding to aversive stimuli by integrating input from several brain regions including the ventral hippocampus (vHIP) and prefrontal cortex (PFC). Here we investigate how neural activity in these projections is shaped by aversive experiences.

P7. Beta Oscillatory Activity Reflects Value Representation in Cortico-Striatal Reward Networks

Behavior is shaped by learning from and anticipating rewards. Past research has identified brain areas like ventral striatum, orbitofrontal cortex (OFC), and prefrontal cortex (PFC) with activity related to anticipation and outcome evaluation. We predict these areas act together dynamically at discrete oscillatory frequencies to build value representations.

P 13 Application of antipsychotic drugs in the treatment of schizophrenia according to single nucleotide polymorphisms of risk genes

Introduction: Schizophrenia is a chronic mental disease which has a genetic etiology in 80% of the cases. In the last years, about 260 risk genes with a predisposition to schizophrenia have been described, and correlations between single nucleotide polymorphisms (SNPs) of risk genes and the therapeutic efficacy of an antipsychotic treatment/pharmacotherapy resistance have been reported. Methods: In schizophrenia, important risk genes, such as catechol-O-methyl transferase (COMT), monoamine oxidase (MAO A/B), glutamic acid decarboxylase 67 (GAD 67), dysbindin-1 and neuregulin-1 are mentioned. To describe the function of these risk genes, neural networks in the ventral tegmental area, hippocampus and prefrontal cortex are developed. Results: An association between the SNPs of some risk genes and the efficacy of an antipsychotic treatment is reported: SNPs such as rs165599 ( COMT gene), rs1801028 ( D2 receptor gene) and rsSer9 Gly ( D3 receptor gene) are associated with a better antipsychotic treatment efficacy. In this case, a treatment of positive and negative schizophrenic symptoms with risperidone is secured. The rs4680 SNP ( COMT and D2 receptor genes) is associated with antipsychotic-induced dopamine hypersensitivity and pharmacotherapy resistance. The function of the COMT and MAO A/B risk genes is described. In schizophrenia, through a reduced activity in the corresponding enzymes, a decrease in dopamine degradation occurs and hence, via D2 receptors, and dopamine hyperactivity has been observed. The GAD 67 risk gene is linked with GABAergic dysfunction and consequently GABAergic neurons weakly presynaptically inhibit D2 dopaminergic neurons. The D-amino acid oxidase activator (DAOA) risk gene is connected with glutamatergic dysfunction via NMDA receptors. Glutamatergic neurons might exert a weak presynaptic inhibition upon 5-HT2A serotonergic neurons located in the ventral tegmental area and hippocampus. Conclusion: It is important to examine the SNPs of the risk genes involved in schizophrenia to establish a correlation between these SNPs and the efficacy of a determined antipsychotic drug. Thus, schizophrenic patients with a good response to a determined antipsychotic treatment and patients with resistance to this treatment could be well differentiated. The latter patients with pharmacoresistance might be treated with the antipsychotic drug clozapine and an additional treatment with cariprazine, a partial agonist at D2 and D3 receptors.

Sex Modulates the Pathological Aging Effect on Caudate Functional Connectivity in Mild Cognitive Impairment.

PurposeTo assess the pathological aging effect on caudate functional connectivity among mild cognitive impairment (MCI) participants and examine whether and how sex and amyloid contribute to this process.Materials and MethodsTwo hundred and seventy-seven functional magnetic resonance imaging (fMRI) sessions from 163 cognitive normal (CN) older adults and 309 sessions from 139 participants with MCI were included as the main sample in our analysis. Pearson's correlation was used to characterize the functional connectivity (FC) between caudate nuclei and each brain region, then caudate nodal strength was computed to quantify the overall caudate FC strength. Association analysis between caudate nodal strength and age was carried out in MCI and CN separately using linear mixed effect (LME) model with covariates (education, handedness, sex, Apolipoprotein E4, and intra-subject effect). Analysis of covariance was conducted to investigate sex, amyloid status, and their interaction effects on aging with the fMRI data subset having amyloid status available. LME model was applied to women and men separately within MCI group to evaluate aging effects on caudate nodal strength and each region's connectivity with caudate nuclei. We then evaluated the roles of sex and amyloid status in the associations of neuropsychological scores with age or caudate nodal strength. An independent cohort was used to validate the sex-dependent aging effects in MCI.ResultsThe MCI group had significantly stronger age-related increase of caudate nodal strength compared to the CN group. Analyzing women and men separately revealed that the aging effect on caudate nodal strength among MCI participants was significant only for women (left: P = 6.23 × 10−7, right: P = 3.37 × 10−8), but not for men (P > 0.3 for bilateral caudate nuclei). The aging effects on caudate nodal strength were not significantly mediated by brain amyloid burden. Caudate connectivity with ventral prefrontal cortex substantially contributed to the aging effect on caudate nodal strength in women with MCI. Higher caudate nodal strength is significantly related to worse cognitive performance in women but not in men with MCI.ConclusionSex modulates the pathological aging effects on caudate nodal strength in MCI regardless of amyloid status. Caudate nodal strength may be a sensitive biomarker of pathological aging in women with MCI.

Changes in mGlu5 Receptor Signaling Are Associated with Associative Learning and Memory Extinction in Mice.

Using an in vivo method for the assessment of polyphosphoinositide (PI) hydrolysis, we examine whether spatial learning and memory extinction cause changes in mGlu5 metabotropic glutamate receptor signaling in the hippocampus and prefrontal cortex. We use the following five groups of mice: (i) naive mice; (ii) control mice exposed to the same environment as learner mice; (iii) leaner mice, trained for four days in a water maze; (iv) mice in which memory extinction was induced by six trials without the platform; (v) mice that spontaneously lost memory. The mGlu5 receptor-mediated PI hydrolysis was significantly reduced in the dorsal hippocampus of learner mice as compared to naive and control mice. The mGlu5 receptor signaling was also reduced in the ventral hippocampus and prefrontal cortex of learner mice, but only with respect to naive mice. Memory extinction was associated with a large up-regulation of mGlu5 receptor-mediated PI hydrolysis in the three brain regions and with increases in mGlu5 receptor and phospholipase-Cβ protein levels in the ventral and dorsal hippocampus, respectively. These findings support a role for mGlu5 receptors in mechanisms underlying spatial learning and suggest that mGlu5 receptors are candidate drug targets for disorders in which cognitive functions are impaired or aversive memories are inappropriately retained.

Research on user experience of the video game difficulty based on flow theory and fNIRS

ABSTRACT Difficulty balance in the game level design is particularly important for user experience (UX). This study uses cognitive control and flow theory as a starting point, and based on the functional near-infrared spectroscopy technology, this research obtained oxygenated hemoglobin concentration (ΔHbO2) signals from three brain areas in the prefrontal cortex (PFC), namely the dorsolateral prefrontal cortex (DLPFC), the ventral prefrontal cortex (VLPFC), and the frontal area (FPA). Combined with the subjective flow state scale to explore the reaction difference between the video game players (VGPs) and the non-video game players (NVGPs) during the entire period of playing video games and the moment of game difficulty changes. The results show that VGPs and NVGPs have significant differences between flow state and HbO2 signals in different brain regions of the PFC. The players’ flow state is affected by the game difficulty. The HbO2 signals in the players’ DLPFC and FPA have a linear dependence relation with the flow state. This research proves that VGPs and NVGPs have different UX with game difficulty changes from the cognitive perspective. The results provide a reference for the future game level design about game difficulty balance to achieve a better UX in the game.

Guanosine boosts the fast, but not sustained, antidepressant-like and pro-synaptogenic effects of ketamine by stimulating mTORC1-driven signaling pathway

The mTORC1-dependent dendritic spines formation represents a key mechanism for fast and long-lasting antidepressant responses, but it remains to be determined whether this mechanism may account for the ability of guanosine in potentiating ketamine's actions. Here, we investigated the ability of ketamine plus guanosine to elicit fast and sustained antidepressant-like and pro-synaptogenic effects in mice and the role of mTORC1 signaling in these responses. The combined administration of subthreshold doses of ketamine (0.1 mg/kg, i.p.) and guanosine (0.01 mg/kg, p.o.) caused a fast (1 h – 24 h), but not long-lasting (7 days) reduction in the immobility time in the tail suspension test. This behavioral effect was paralleled by a rapid (started in 1 h) and transient (back to baseline in 24 h) increase on BDNF, p-Akt (Ser473), p-GSK-3β (Ser9), p-mTORC1 (Ser2448), p-p70S6K (Thr389) immunocontent in the hippocampus, but not in the prefrontal cortex. Conversely, ketamine plus guanosine increased PSD-95 and GluA1 immunocontent in the prefrontal cortex, but not the hippocampus after 1 h, whereas increased levels of these proteins in both brain structures were observed after 24 h, but these effects did not persist after 7 days. The combined administration of ketamine plus guanosine raised the dendritic spines density in the ventral hippocampal DG and prefrontal cortex after 24 h Rapamycin (0.2 nmol/site, i.c.v.) abrogated the antidepressant-like effect and pro-synaptogenic responses triggered by ketamine plus guanosine. These results indicate that guanosine may boost the antidepressant-like effect of ketamine for up to 24 h by a mTORC1-dependent mechanism.

Link between structural connectivity of the medial forebrain bundle, functional connectivity of the ventral tegmental area, and anhedonia in unipolar depression

The ventral tegmental area (VTA), nucleus accumbens (NAcc), and prefrontal cortex (PFC) are essential for experiencing pleasure and initiating motivated behaviour. The VTA, NAcc, and PFC are connected through the medial forebrain bundle (MFB). In humans, two branches have been described: an infero-medial branch (imMFB) and a supero-lateral branch (slMFB). This study aimed to explore the associations between structural connectivity of the MFB, functional connectivity (FC) of the VTA, anhedonia, and depression severity in patients with depression. Fifty-six patients with unipolar depression and 22 healthy controls matched for age, sex, and handedness were recruited at the University Hospital of Psychiatry and Psychotherapy in Bern, Switzerland. Diffusion-weighted imaging and resting-state functional magnetic resonance imaging scans were acquired. Using manual tractography, the imMFB and slMFB were reconstructed bilaterally for each participant. Seed-based resting-state FC was computed from the VTA to the PFC. Hedonic tone was assessed using the Fawcett-Clark Pleasure Scale. We identified reduced tract volume and reduced number of tracts in the left slMFB. There was an increase in FC between the VTA and right medial PFC in patients with depression. Depression severity was associated with reduced tract volume and fewer tracts in the left slMFB. Reduced hedonic tone was associated with reduced tract volume. Conversely, reduced hedonic tone was associated with increased FC between the VTA and the PFC. In conclusion, our results suggest reduced structural connectivity of the slMFB in patients with depression. Increases in FC between the VTA and PFC may be associated with anhedonia or compensatory hyperactivity.

Evaluation of sensory gating efficiency in adults with Down syndrome

AbstractBackgroundIn Down syndrome (DS), the amyloid precursor protein (APP) gene‐dosing effect drives a lifelong over‐production of amyloid‐beta (Aβ). The accumulation of Aβ begins to manifest as amyloid plaques as early as the teens and virtually in all by 40 years. The progression of Alzheimer’s Disease(AD)‐related neuropathology may underlie inhibitory disruption leading to over‐ or under‐sensitivity to auditory processing and cognitive deficits in DS. In positron electromagnetic tomography (PET) studies in DS, amyloid deposition has a defined temporal‐spatial profile that begins in the striatum and predictably progresses to the dorsolateral pre‐frontal cortex (DLPFC) and ventral pre‐frontal cortex (VPFC). Typically developing (TD) individuals with AD exhibit deficits of sensory gating, which can lead to sensory overload and disruption of higher cognitive processes. The auditory paired‐click paradigm has been used to evaluate sensory gating deficits in AD. We extend this inquiry to a cohort with DS to assess sensory gating in adults with DS by measuring the P50 and the N100 event‐related potential (ERP) components. The P50 component is elicited 50 ms post‐stimulus, involves the DLPFC and is sensitive to striatum‐dependent sensory gating. The N100 is elicited 100 ms post‐stimulus by auditory stimuli in absence of task demands.MethodIn this cross‐sectional study, data were collected using high‐density QEEG in 39 DS adults and 39 age‐matched TD controls. In this paradigm, two identical auditory stimuli (S1 and S2) were presented. For each stimuli, the response latency and amplitudes of the P50, and more salient N100 component were measured at the Cz and Fz electrode sites. General linear models examined the modulation of the ERP responses to S1 and S2 between the two groups.ResultWith P50 and N100 response amplitudes, an effect of stimulus was found. In the DS group, longer response latencies for the P50 and N100 corresponding to both S1 and S2 were observed.ConclusionIn DS, the ability to gate‐out irrelevant sensory information is intact when compared to TD; however, there is an overall slower processing of auditory stimuli, which may be attributed to amyloidopathy. The EEG‐based paired‐click paradigm offers functional insight into potential biomarkers for pre‐clinical AD in DS.

Executive Dysfunction and the Prefrontal Cortex.

This article summarizes the cognitive and behavioral functions of the prefrontal cortex with an emphasis on executive cognitive functions and the clinical consequences associated with executive dysfunction. The clinical manifestations of lesions to the lateral prefrontal, orbitofrontal, medial prefrontal, and frontopolar cortex are reviewed. Traditional lesion studies have emphasized the role of a brain region in controlling a cognitive function. With advances in neurology, neuropsychology, and neuroimaging, the participation of the prefrontal cortex in large-scale networks has been established with recognition that cognitive dysfunction can arise not only from a lesion within a network but also from degenerative disease targeting these large-scale, dynamic neural networks. Although executive dysfunction can result from frontal lobe injury, this article highlights the role of distributed processes subserving executive functions. An atypical phenotype of Alzheimer disease has been described that selectively targets parietal-temporal-frontal networks important for core executive functions. Executive function comprises working memory, cognitive flexibility, and inhibition and depends on top-down (ie, goal-driven) control of distributed processes occurring throughout the brain. The exact behavioral output (ie, function) depends on the content of the processes being controlled. Prefrontal cortex regions serve key cognitive functions related to social, emotional, and motivational aspects of behavior. The dorsal lateral prefrontal cortex plays a role in working memory, goal-driven attention, task switching, planning, problem-solving, and novelty-seeking. The ventral lateral prefrontal cortex plays a role in inhibition, response selection, and monitoring; the medial prefrontal cortex in self-knowledge, motivation, emotional regulation, and updating goal-directed behavior; the orbitofrontal cortex in personality, inhibition, and emotional and social reasoning. Although dysexecutive syndromes have been traditionally associated with dorsolateral prefrontal cortex injury, it is now recognized that they can also result from an impaired parietal-temporal-frontal system, which is targeted in a distinct form of atypical Alzheimer disease. This dysexecutive Alzheimer phenotype is characterized by impaired task performance on a wide battery of neuropsychological tests and simple daily tasks that require executive control. In contrast, dysexecutive syndromes more localized to the frontal lobe involve impaired executive control of social, emotional, and motivational aspects of behavior.

A graph theory-based whole brain approach to assess mood state differences in adolescents and young adults with bipolar disorder.

Identifying hubs of brain dysfunction in adolescents and young adults with Bipolar I Disorder (BDAYA ) could provide targets for early detection, prevention, and treatment. Previous neuroimaging studies across mood states of BDAYA are scarce and often examined limited brain regions potentially prohibiting detection of other important regions. We used a data-driven whole-brain Intrinsic Connectivity Distribution (ICD) approach to investigate dysconnectivity hubs across mood states in BDAYA . Functional magnetic resonance imaging whole-brain ICD data were investigated for differences across four groups: BDAYA -depressed (n=22), BDAYA -euthymic (n=45), BDAYA -elevated (n=24), and healthy controls (HC, n=111). Clusters of ICD differences were assessed for regional dysconnectivity and mood symptom relationships. Analyses were also performed for BDAYA overall (vs. HC) ICD differences persisting across mood states. ICD was higher in the BDAYA- depressed group than other groups in bilateral ventral/rostral/dorsal prefrontal cortex (PFC) and right lenticular nucleus (LN) (pcorrected <0.05). In BDAYA -depressed, functional connectivity (FC) was increased between these regions with their contralateral homologues and PFC-medial temporal FC was more negative (p<0.005). PFC-related findings correlated with depression scores (p<0.05). The overall BDAYA group showed ICD increases in more ventral left PFC and right cerebellum, present across euthymia and acute mood states. This ICD approach supports a PFC hub of inter- and intra-hemispheric frontotemporal dysconnectivity in BDAYA with potential trait features and disturbances of higher magnitude during depression. Hubs were also revealed in LN and cerebellum, less common foci of BD research. The hubs are potential targets for early interventions to detect, prevent, and treat BD.

CDH2 mutation affecting N-cadherin function causes attention-deficit hyperactivity disorder in humans and mice

Attention-deficit hyperactivity disorder (ADHD) is a common childhood-onset psychiatric disorder characterized by inattention, impulsivity and hyperactivity. ADHD exhibits substantial heritability, with rare monogenic variants contributing to its pathogenesis. Here we demonstrate familial ADHD caused by a missense mutation in CDH2, which encodes the adhesion protein N-cadherin, known to play a significant role in synaptogenesis; the mutation affects maturation of the protein. In line with the human phenotype, CRISPR/Cas9-mutated knock-in mice harboring the human mutation in the mouse ortholog recapitulated core behavioral features of hyperactivity. Symptoms were modified by methylphenidate, the most commonly prescribed therapeutic for ADHD. The mutated mice exhibited impaired presynaptic vesicle clustering, attenuated evoked transmitter release and decreased spontaneous release. Specific downstream molecular pathways were affected in both the ventral midbrain and prefrontal cortex, with reduced tyrosine hydroxylase expression and dopamine levels. We thus delineate roles for CDH2-related pathways in the pathophysiology of ADHD.