Donald C. Rojas

The role of glutamate and its receptors in autism and the use of glutamate receptor antagonists in treatment

Glutamate is the major excitatory neurotransmitter in the brain and may be a key neurotransmitter involved in autism. Literature pertaining to glutamate and autism or related disorders (e.g., Fragile X syndrome) is reviewed in this article. Interest in glutamatergic dysfunction in autism is high due to increasing convergent evidence implicating the system in the disorder from peripheral biomarkers, neuroimaging, protein expression, genetics and animal models. Currently, there are no pharmaceutical interventions approved for autism that address glutamate deficits in the disorder. New treatments related to glutamatergic neurotransmission, however, are emerging. In addition, older glutamate-modulating medications with approved indications for use in other disorders are being investigated for re-tasking as treatments for autism. This review presents evidence in support of glutamate abnormalities in autism and the potential for translation into new treatments for the disorder.

Adverse effects of dextromethorphan on the spatial learning of rats in the Morris water maze

The effects of the non-competitive NMDA receptor antagonist dextromethorphan on spatial learning were assessed using the Morris water maze. Dextromethorphan was administered to 4 groups of rats in 10, 20, 30, and 40 mg/kg doses. An additional group of rats was administered saline to serve as a vehicle control group. Dextromethorphan impaired learning dose dependently in the initial training phase of the experiment. During the probe trial, dose-dependent performance deficits were noted in the first 15 s of the trial only. Search strategy differences between the lowest and highest dose groups were also observed during the probe trial. During the reversal training phase, when the platform was moved to a new location, the dose-dependent impairment was seen again, but the 40 mg/kg group perseverated to the former location longer than the other groups. A cued control trial indicated that in addition to the learning impairment produced, the highest dose of dextromethorphan may also impair sensory-motor coordination.

Schizoaffective disorder - a possible MEG auditory evoked field biomarker.

We recorded magnetoencephalographic auditory steady state responses (SSR) from eight schizoaffective (SAD) subjects and compared the resulting data with previously published findings in persons with schizophrenia (SZ) and controls. SAD subjects exhibited SSR responses similar to controls in the left hemisphere and greater than controls in the right hemisphere, whereas SZ subjects exhibited deficits in both amplitude and phase control in both hemispheres. Our findings suggest preservation of GABAergic inhibitory interneuronal control of layer 3 pyramidal cell activity in primary auditory cortex in SAD.

Magnetic Resonance Spectroscopy Studies of Glutamate and GABA in Autism: Implications for Excitation-Inhibition Imbalance Theory

One popular major theory of neurotransmitter dysfunction is an imbalance in excitation and inhibition (EI theory).The EI imbalance theory is thought to impact widely across neural circuits mediating language, social, and cognitive functions, and could potentially explain some aspects of the autism phenotype. Evidence from genetic and molecular studies provide support for abnormal suppression of γ-aminobutyric acid (GABA) function and an overabundance of glutamatergic transmission as potential mechanisms of this hyperexcitability. Proton magnetic resonance spectroscopy (1H-MRS) is a potentially exciting neuroimaging tool allowing in vivo estimation of glutamate and GABA neurotransmitters in people with autism spectrum disorder (ASD). We reviewed all available published studies of ASD reporting 1H-MRS measurement of glutamate, GABA, or both neurotransmitters. Glutamate results across studies are equivocal, with nearly equal numbers of studies reporting increases or decreases in autism. However, the age of the individuals studied appears to relate to the direction of the findings, suggesting that future longitudinal studies of glutamate should be conducted. Although fewer GABA-specific studies have been published, all have reported decreases in autism. Overall, from 1H-MRS studies alone, support for the glutamate side of the EI imbalance theory is tenuous, but this is an indication of serious limitations in the 1H-MRS literature. For GABA dysfunction, the GABA findings to date are consistent for reduced concentration in autism; however, there are only a few published 1H-MRS studies of GABA in autism, all from studies with a small number of subjects. More studies, particularly longitudinal developmental studies across both child and adult development, are needed.

Neuronal effects of nicotine during auditory selective attention in schizophrenia

Although nicotine has been shown to improve attention deficits in schizophrenia, the neurobiological mechanisms underlying this effect are poorly understood. We hypothesized that nicotine would modulate attention‐associated neuronal response in schizophrenia patients in the ventral parietal cortex (VPC), hippocampus, and anterior cingulate based on previous findings in control subjects. To test this hypothesis, the present study examined response in these regions in a cohort of nonsmoking patients and healthy control subjects using an auditory selective attention task with environmental noise distractors during placebo and nicotine administration. In agreement with our hypothesis, significant diagnosis (Control vs. Patient) X drug (Placebo vs. Nicotine) interactions were observed in the VPC and hippocampus. The interaction was driven by task‐associated hyperactivity in patients (relative to healthy controls) during placebo administration, and decreased hyperactivity in patients after nicotine administration (relative to placebo). No significant interaction was observed in the anterior cingulate. Task‐associated hyperactivity of the VPC predicted poor task performance in patients during placebo. Poor task performance also predicted symptoms in patients as measured by the Brief Psychiatric Rating Scale. These results are the first to suggest that nicotine may modulate brain activity in a selective attention‐dependent manner in schizophrenia. Hum Brain Mapp 37:410–421, 2016.

MEG and EEG demonstrate similar test-retest reliability of the 40 Hz auditory steady-state response

The auditory steady-state response (ASSR) is increasingly being used as a biomarker in neuropsychiatric disorders, but research investigating the test-retest reliability of this measure is needed. We previously reported ASSR reliability, measured by electroencephalography (EEG), to 40Hz amplitude-modulated white noise and click train stimuli. The purpose of the current study was to (a) assess the reliability of the MEG-measured ASSR to 40Hz amplitude-modulated white noise and click train stimuli, and (b) compare test-retest reliability between MEG and EEG measures of ASSR, which has not previously been investigated. Additionally, impact of stimulus parameter choice on reliability was assessed, by comparing responses to white noise and click train stimuli. Test-retest reliability, across sessions approximately one week apart, was assessed in 17 healthy adults. On each study day, participants completed two passive listening tasks (white noise and click train stimuli) during separate MEG and EEG recordings. Between-session correlations for evoked power and inter-trial phase coherence (ITPC) were assessed following source-space projection. Overall, the MEG-measured ASSR was significantly correlated between sessions (p<0.05, FDR corrected), suggesting acceptable test-retest reliability. Results suggest greater response reproducibility for ITPC compared to evoked responses and for click train compared to white noise stimuli, although further study is warranted. No significant differences in reliability were observed between MEG and EEG measures, suggesting they are similarly reliable. This work supports use of the ASSR as a biomarker in clinical interventions with repeated measures.

Harnessing the power of disgust: a randomized trial to reduce high-calorie food appeal through implicit priming

BACKGROUND In our increasingly obesogenic environment, in which high-calorie convenience foods are readily available, food choices can drastically affect weight and overall health. Learned food preferences, which are developed through repeated pairings with positively and negatively valenced stimuli, can contribute to obesity susceptibility if positive attitudes toward high-calorie foods are developed. Thus, the modification of automatic associations with food may be a viable strategy to promote healthier eating behaviors. OBJECTIVE In this study, we investigated the ability of an implicit priming (IP) intervention to alter responses to visual food cues by using an evaluative conditioning approach. The main objective was to implicitly (i.e., below conscious perception) associate disgust with high-calorie foods with the aim of reducing liking of these foods. DESIGN Participants were randomly assigned to active or control IP. In active IP (n = 22), high-calorie food images were implicitly primed with negatively valenced images, and low-calorie food images were implicitly primed with positively valenced images. In control IP (n = 20), all food images were primed with neutral images of fixation crosses. Food images were rated on the desire to eat immediately before and after IP. RESULTS A significant main effect of calorie (high compared with low; P < 0.001) and a significant calorie-by-group (active compared with control) interaction (P = 0.025) were observed. Post hoc tests identified a significantly greater high-calorie rating decline after active IP than after control IP (P = 0.036). Furthermore, there was significantly greater change in high-calorie ratings than in low-calorie ratings in the active group (P = 0.001). Active IP effects extended to high-calorie foods not specifically included in the intervention, which suggested an effect generalization. Moreover, a greater change in high-calorie ratings than in low-calorie ratings persisted 3-5 d after active IP (P < 0.007), which suggested lasting effects. CONCLUSION This study provides initial evidence that IP can be used to alter high-calorie food preferences, which could promote healthier eating habits.

Imaging decision about whether to benefit self by harming others: Adolescents with conduct and substance problems, with or without callous-unemotionality, or developing typically ☆

We sought to identify brain activation differences in conduct-problem youth with limited prosocial emotions (LPE) compared to conduct-problem youth without LPE and community adolescents, and to test associations between brain activation and severity of callous-unemotional traits. We utilized a novel task, which asks subjects to repeatedly decide whether to accept offers where they will benefit but a beneficent other will be harmed. Behavior on this task has been previously associated with levels of prosocial emotions and severity of callous-unemotional traits, and is related to empathic concern. During fMRI acquisition, 66 male adolescents (21 conduct-problem patients with LPE, 21 without, and 24 typically-developing controls) played this novel game. Within typically-developing controls, we identified a network engaged during decision involving bilateral insula, and inferior parietal and medial frontal cortices, among other regions. Group comparisons using non-parametric (distribution-free) permutation tests demonstrated LPE patients had lower activation estimates than typically-developing adolescents in right anterior insula. Additional significant group differences emerged with our a priori parametric cluster-wise inference threshold. These results suggest measurable functional brain activation differences in conduct-problem adolescents with LPE compared to typically-developing adolescents. Such differences may underscore differential treatment needs for conduct-problem males with and without LPE.

Predicting academic career outcomes by predoctoral publication record

Background For students entering a science PhD program, a tenure-track faculty research position is often perceived as the ideal long-term goal. A relatively small percentage of individuals ultimately achieve this goal, however, with the vast majority of PhD recipients ultimately finding employment in industry or government positions. Given the disparity between academic career ambitions and outcomes, it is useful to understand factors that may predict those outcomes. Toward this goal, the current study examined employment status of PhD graduates from biomedical sciences programs at the University of Colorado Anschutz Medical Campus (CU AMC) and related this to metrics of predoctoral publication records, as well as to other potentially important factors, such as sex and time-since-degree, to determine if these measures could predict career outcomes. Methods Demographic information (name, PhD program, graduation date, sex) of CU AMC biomedical sciences PhD graduates between 2000 and 2015 was obtained from University records. Career outcomes (academic faculty vs. non-faculty) and predoctoral publication records (number and impact factors of first-author and non-first-author publications) were obtained via publicly available information. Relationships between predoctoral publication record and career outcomes were investigated by (a) comparing faculty vs. non-faculty publication metrics, using t-tests, and (b) investigating the ability of predoctoral publication record, sex, and time-since-degree to predict career outcomes, using logistic regression. Results Significant faculty vs. non-faculty differences were observed in months since graduation (p < 0.001), first-author publication number (p = 0.001), average first-author impact factor (p = 0.006), and highest first-author impact factor (p = 0.004). With sex and months since graduation as predictors of career outcome, the logistic regression model was significant (p < 0.001), with both being male and having more months since graduation predicting career status. First-author related publication metrics (number of publications, average impact factor, highest impact factor) all significantly improved model fit (χ2 < 0.05 for all) and were all significant predictors of faculty status (p < 0.05 for all). Non-first-author publication metrics did not significantly improve model fit or predict faculty status. Discussion Results suggest that while sex and months since graduation also predict career outcomes, a strong predoctoral first-author publication record may increase likelihood of obtaining an academic faculty research position. Compared to non-faculty, individuals employed in faculty positions produced more predoctoral first-author publications, with these being in journals with higher impact factors. Furthermore, first-author publication record, sex, and months since graduation were significant predictors of faculty status.

Residual effects of cannabis use on attentional bias towards fearful faces

ABSTRACT Cannabis use has increased since legalization in various states within the United States of America. Although much of the research on the neurological and psychological effects of cannabis has been on non‐human animals, the current research suggests that it can have anxiolytic effects and also decrease some cognitive functioning (e.g. memory, emotional processing, etc.). Individuals with high anxiety have been suggested to have increased attentional bias towards threat‐related stimuli. The current study measured event‐related potential (ERP) during a dot‐probe task with fearful and neutral facial expression to examine the residual effects of cannabis use on attentional bias. The results indicated that there was reduced attentional bias, as measured by the P1 component in cannabis users, which is similar to low anxious individuals. Additionally, there was no difference between users and non‐users in N170, indicating that the residual effects of cannabis did not interfere with face processing. However, an exploratory correlation indicated that higher cannabis use was associated with reduced N170 towards fearful faces. Cannabis use was associated with enhanced N2pc, which would indicate greater spatial orientation of attention. These results suggest that cannabis use did have an effect on attentional bias towards fearful faces. HighlightsCannabis has been suggested to decrease anxiety.Anxiety is related with greater attentional bias towards fearful faces.Cannabis users had reduced attentional bias.Attentional bias may be an anxiety mechanism that cannabis affects.