Graph Metrics of Structural Brain Networks in Individuals with Schizophrenia and Healthy Controls: Group Differences, Relationships with Intelligence, and Genetics.

OBJECTIVES: One of the most prominent features of schizophrenia is relatively lower general cognitive ability (GCA). An emerging approach to understanding the roots of variation in GCA relies on network properties of the brain. In this multi-center study, we determined global characteristics of brain networks using graph theory and related these to GCA in healthy controls and individuals with schizophrenia. METHODS: Participants (N=116 controls, 80 patients with schizophrenia) were recruited from four sites. GCA was represented by the first principal component of a large battery of neurocognitive tests. Graph metrics were derived from diffusion-weighted imaging. RESULTS: The global metrics of longer characteristic path length and reduced overall connectivity predicted lower GCA across groups, and group differences were noted for both variables. Measures of clustering, efficiency, and modularity did not differ across groups or predict GCA. Follow-up analyses investigated three topological types of connectivity--connections among high degree "rich club" nodes, "feeder" connections to these rich club nodes, and "local" connections not involving the rich club. Rich club and local connectivity predicted performance across groups. In a subsample (N=101 controls, 56 patients), a genetic measure reflecting mutation load, based on rare copy number deletions, was associated with longer characteristic path length. CONCLUSIONS: Results highlight the importance of characteristic path lengths and rich club connectivity for GCA and provide no evidence for group differences in the relationships between graph metrics and GCA.

Psychological and neuropsychological assessment of regular hoasca users.

BACKGROUND: Hoasca (also called ayahuasca) is a N,N-dimethyltryptamine (DMT) - containing psychedelic brew originally used for magico-religious purposes by Amerindian populations of the Amazon Basin. Recently, Brazilian syncretic churches have helped spread the ritual use of hoasca to Western societies. The aim of this study was to evaluate substance use, and neuropsychological and psychological functioning of regular hoasca users within a religious setting. METHODS: Assessment of socio-economic status, mood, personality traits, impulsiveness, drug use, quality of life, extrinsic and intrinsic religiosity, and neuropsychological function was performed on 30 volunteers from a U.S. branch of União do Vegetal (UDV), a Brazilian religion which uses hoasca ritually. We also assessed 27 non-hoasca-using control subjects matched by socio-demographic profile and church attendance. Mann-Whitney U, chi-squared and Fisher tests were used to analyze differences between groups. Spearman's association and simple logistic regression tests were used to analyze the impact of frequency of hoasca use on dependent variables. RESULTS: Relative to the control group, the UDV group demonstrated lower scores for depression (p=0.043, r=.27) and confusion (p=0.032, r=.29) as assessed by the Profile of Mood States (POMS); higher scores on the instrument Big Five Inventory (BFI) for the personality traits agreeableness (p=0.028, r=.29) and openness (p=0.037, r=.28); higher scores on the quality life domain role limitations due to physical health as determined by the instrument Medical Outcomes Study Short Form-36 - SF-36 (p=0.035, r=.28); less recent use of alcohol (p<0.001, φc=.57), greater past use of alcohol to intoxication (p=0.007, φc=.36) and past use of cannabis (p=0.001, φc=.45) as measured by the Addiction Severity Index (ASI), 5th edition; better score on a measure of memory vulnerability to proactive interference as measured by the California Verbal Learning Test - CVLT (p=0.040, r=.27). Lifetime use of hoasca was positively correlated with role limitations due to physical health (p=0.032, rs=.39) and negatively associated with lifetime heavy alcohol use (p=0.034, OR=0.979). CONCLUSIONS: The findings indicate that religious use of hoasca does not adversely affect neuropsychological functioning and may have positive effects on substance abuse and mood.

Three potential neurovascular pathways driving the benefits of mindfulness meditation for older adults.

Mindfulness meditation has been shown to be beneficial for a range of different health conditions, impacts brain function and structure relatively quickly, and has shown promise with aging samples. Functional magnetic resonance imaging metrics provide insight into neurovascular health which plays a key role in both normal and pathological aging processes. Experimental mindfulness meditation studies that included functional magnetic resonance metrics as an outcome measure may point to potential neurovascular mechanisms of action relevant for aging adults that have not yet been previously examined. We first review the resting-state magnetic resonance studies conducted in exclusively older adult age samples. Findings from older adult-only samples are then used to frame the findings of task magnetic resonance imaging studies conducted in both clinical and healthy adult samples. Based on the resting-state studies in older adults and the task magnetic resonance studies in adult samples, we propose three potential mechanisms by which mindfulness meditation may offer a neurovascular therapeutic benefit for older adults: (1) a direct neurovascular mechanism via increased resting-state cerebral blood flow; (2) an indirect anti-neuroinflammatory mechanism via increased functional connectivity within the default mode network, and (3) a top-down control mechanism that likely reflects both a direct and an indirect neurovascular pathway.

A graph theoretic approach to neurodegeneration: five data-driven neuropsychological subtypes in mild cognitive impairment.

Mild cognitive Impairment (MCI) is notoriously heterogenous in terms of clinical presentation, neuroimaging correlates, and subsequent progression. Predicting who will progress to dementia, which type of dementia, and over what timeframe is challenging. Previous work has attempted to identify MCI subtypes using neuropsychological measures in an effort to address this challenge; however, there is no consensus on approach, which may account for some of the variability. Using a hierarchical community detection approach, we examined cognitive subtypes within an MCI sample (from the Alzheimer's Disease Neuroimaging Initiative [ADNI] study). We then examined whether these subtypes were related to biomarkers (e.g., cortical volumes, fluorodeoxyglucose (FDG)-positron emission tomography (PET) hypometabolism) or clinical progression. We identified five communities (i.e., cognitive subtypes) within the MCI sample: 1) predominantly memory impairment, 2) predominantly language impairment, 3) cognitively normal, 4) multidomain, with notable executive dysfunction, 5) multidomain, with notable processing speed impairment. Community membership was significantly associated with 1) cortical volume in the hippocampus, entorhinal cortex, and fusiform cortex; 2) FDG PET hypometabolism in the posterior cingulate, angular gyrus, and inferior/middle temporal gyrus; and 3) conversion to dementia at follow up. Overall, community detection as an approach appears a viable method for identifying unique cognitive subtypes in a neurodegenerative sample that were linked to several meaningful biomarkers and modestly with progression at one year follow up.

Decreased Cerebrovascular Reactivity in Mild Cognitive Impairment Phenotypes.

BACKGROUND: Cerebrovascular health plays an important role in cognitive health in older adults. Cerebrovascular reactivity (CVR), a measure of cerebrovascular health, changes in both normal and pathological aging, and is increasingly being conceptualized as contributory to cognitive decline. Interrogation of this process will yield new insights into cerebrovascular correlates of cognition and neurodegeneration. OBJECTIVE: The current study examines CVR using advanced MRI in prodromal dementia states (amnestic and non-amnestic mild cognitive impairment phenotypes; aMCI and naMCI, respectively) and older adult controls. METHODS: CVR was assessed in 41 subjects (20 controls, 11 aMCI, 10 naMCI) using multiband multi-echo breath-holding task functional magnetic resonance imaging. Imaging data were preprocessed and analyzed using AFNI. All participants also completed a battery of neuropsychological tests. T-tests and ANOVA/ANCOVA analyses were conducted to compare controls to MCI groups on CVR and cognitive metrics. Partial correlation analyses between CVR derived from regions-of-interest (ROIs) and different cognitive functions were conducted. RESULTS: CVR was found to be significantly lower in aMCI and naMCI patients compared to controls. naMCI showed intermediate patterns between aMCI and controls (though aMCI and naMCI groups did not significantly differ). CVR of ROIs were positively correlated with neuropsychological measures of processing speed, executive functioning, and memory. CONCLUSION: The findings highlight regional CVR differences in MCI phenotypes compared to controls, where aMCI may have lower CVR than naMCI. Our results suggest possible cerebrovascular abnormalities associated with MCI phenotypes.

Detecting Primary Progressive Aphasia Atrophy Patterns: A Comparison of Visual Assessment and Quantitative Neuroimaging Techniques.

Background: There are now clinically available automated MRI analysis software programs that compare brain volumes of patients to a normative sample and provide z-score data for various brain regions. These programs have yet to be validated in primary progressive aphasia (PPA). Objective: To address this gap in the literature, we examined Neuroreader™ z-scores in PPA, relative to visual MRI assessment. We predicted that Neuroreader™ 1) would be more sensitive for detecting left > right atrophy in the cortical lobar regions in logopenic variant PPA clinical phenotype (lvPPA), and 2) would distinguish lvPPA (n = 11) from amnestic mild cognitive impairment (aMCI; n = 12). Methods: lvPPA or aMCI patients who underwent MRI with Neuroreader™ were included in this study. Two neuroradiologists rated 10 regions. Neuroreader™ lobar z-scores for those 10 regions, as well as a hippocampal asymmetry metric, were included in analyses. Results: Cohen's Kappa coefficients were significant in 10 of the 28 computations (k = 0.351 to 0.593, p≤0.029). Neuroradiologists agreed 0% of the time that left asymmetry was present across regions. No significant differences emerged between aMCI and lvPPA in Neuroreader™ z-scores across left or right frontal, temporal, or parietal regions (ps > 0.10). There were significantly lower z-scores in the left compared to right for the hippocampus, as well as parietal, occipital, and temporal cortices in lvPPA. Conclusion: Overall, our results indicated moderate to low interrater reliability, and raters never agreed that left asymmetry was present. While lower z-scores in the left hemisphere regions emerged in lvPPA, Neuroreader™ failed to differentiate lvPPA from aMCI.

Adolescent substance abuse: the effects of alcohol and marijuana on neuropsychological performance.

BACKGROUND: Adolescence is a period in which cognition and brain undergo dramatic parallel development. Whereas chronic use of alcohol and marijuana is known to cause cognitive impairments in adults, far less is known about the effect of these substances of abuse on adolescent cognition, including possible interactions with developmental processes. METHODS: Neuropsychological performance, alcohol use, and marijuana use were assessed in 48 adolescents (ages 12 to 18), recruited in 3 groups: a healthy control group (HC, n = 15), a group diagnosed with substance abuse or dependence (SUD, n = 19), and a group with a family history positive for alcohol use disorder (AUD) but no personal substance use disorder (FHP, n = 14). Age, drinks per drinking day (DPDD), percentage days drinking, and percentage days using marijuana were considered as covariates in a MANCOVA in which 6 neuropsychological composites (Verbal Reasoning, Visuospatial Ability, Executive Function, Memory, Attention, and Processing Speed) served as dependent variables. RESULTS: More DPDD predicted poorer performance on Attention and Executive Function composites, and more frequent use of marijuana was associated with poorer Memory performance. In separate analyses, adolescents in the SUD group had lower scores on Attention, Memory, and Processing Speed composites, and FHP adolescents had poorer Visuospatial Ability. CONCLUSIONS: In combination, these analyses suggest that heavy alcohol use in adolescence leads to reduction in attention and executive functioning and that marijuana use exerts an independent deleterious effect on memory. At the same time, premorbid deficits associated with family history of AUD appeared to be specific to visuospatial ability.

Convergent and discriminant validity of the ImPACT with traditional neuropsychological measures.

Neuropsychological assessment of cognitive sequelae secondary to sports concussion is limited by lengthy administration times and lack of readily available neuropsychologists. Brief computerized test batteries are now under development to address this, but the validity of these measures is not yet established. The validity of one such computerized test battery, the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT), was administered to 93 healthy NCAA Division I athletes, aged 18-24, along with a battery of traditional, well-described neuropsychological tests. Convergent and discriminant validity between the ImPACT and traditional measures was investigated using multitrait-multimethod matrix (MTMM) analysis. As an example, the ImPACT Visual Motor Speed composite demonstrated reasonably good convergent validity secondary to moderate correlations with traditional measures of processing speed, but it demonstrated relatively poor discriminant validity as it significantly correlated with the Reaction Time composite score. MTMM results were variable across ImPACT composites and data for each are presented. The ImPACT composite's validity was further investigated using exploratory factor analysis (EFA). Six principal components were termed processing speed, visual memory, verbal memory, attention & working memory, and verbal fluency, based upon traditional test loadings, and a sixth loaded only on the ImPACT Reaction Time composite. EFA indicated content validity of moderate strength for the Visual Motor Speed and Visual Memory composites, but revealed problems with specificity for the other composites. Based upon the present findings, validity problems render the interpretability of the ImPACT composites somewhat questionable, and more research is necessary prior to using the ImPACT for assessment of clinical populations.

Neural Circuitry of Impaired Emotion Regulation in Substance Use Disorders.

Impaired emotion regulation contributes to the development and severity of substance use disorders (substance disorders). This review summarizes the literature on alterations in emotion regulation neural circuitry in substance disorders, particularly in relation to disorders of negative affect (without substance disorder), and it presents promising areas of future research. Emotion regulation paradigms during functional magnetic resonance imaging are conceptualized into four dimensions: affect intensity and reactivity, affective modulation, cognitive modulation, and behavioral control. The neural circuitry associated with impaired emotion regulation is compared in individuals with and without substance disorders, with a focus on amygdala, insula, and prefrontal cortex activation and their functional and structural connectivity. Hypoactivation of the rostral anterior cingulate cortex/ventromedial prefrontal cortex (rACC/vmPFC) is the most consistent finding across studies, dimensions, and clinical populations (individuals with and without substance disorders). The same pattern is evident for regions in the cognitive control network (anterior cingulate and dorsal and ventrolateral prefrontal cortices) during cognitive modulation and behavioral control. These congruent findings are possibly related to attenuated functional and/or structural connectivity between the amygdala and insula and between the rACC/vmPFC and cognitive control network. Although increased amygdala and insula activation is associated with impaired emotion regulation in individuals without substance disorders, it is not consistently observed in substance disorders. Emotion regulation disturbances in substance disorders may therefore stem from impairments in prefrontal functioning, rather than excessive reactivity to emotional stimuli. Treatments for emotion regulation in individuals without substance disorders that normalize prefrontal functioning may offer greater efficacy for substance disorders than treatments that dampen reactivity.

1H-MRS glutamate level predicts auditory sensory gating in alcohol dependence: Preliminary results.

BACKGROUND: Impairment in auditory sensory gating (ASG) has been documented in alcohol dependence [1]. Likewise, it has been shown that ASG becomes abnormal during alcohol administration in otherwise healthy individuals [2]. Patterns of gating abnormality associated with alcohol use are likely associated with an alcohol responsive neurochemical like glutamate (Glu), particularly since it is well-established that alcohol affects NMDA receptors and that glutamatergic functioning is abnormal in both acute alcohol use and in alcohol dependence [3]. Hence, a link between Glu metabolite levels and ASG was hypothesized. It was first hypothesized that Glu and ASG abnormality would be found in groups with alcohol dependence. A second hypothesis was that across groups, greater Glu would predict reduced ASG. METHODS: Groups were comprised of healthy, non-drinking controls (Controls, N = 4), individuals with current alcohol dependence (AUD-current, N = 6), and with alcohol dependence in remission for at least 1 year (AUD-remission, N = 6). Participants underwent a diagnostic assessment for alcohol consumption, MRI, 1H-MRS for in vivo assessment of Glu and other metabolites, and MEG scanning during a paired click protocol. ASG was computed as the ratio of the source strength of the 50 ms component in the event related field (ERF) to the second click in the pair divided by the source strength of the 50 ms component to the first click in the pair. RESULTS: Univariate MANOVAs controlling for age and gender revealed a significant effect for group on Glu and ASG, such that ASG ratios were significantly elevated, implying weakened gating. Glu concentration was reduced in AUD-current relative to the other two groups. Further analysis revealed that when additionally controlling for the group effect, reduced Glu predicted increasing impairment in ASG. CONCLUSIONS: The overall results were consistent with the hypothesis that differences in Glu metabolite levels associated with alcohol dependence result in impaired ASG.

Psilocybin-assisted treatment for alcohol dependence: a proof-of-concept study.

UNLABELLED: Several lines of evidence suggest that classic (5HT2A agonist) hallucinogens have clinically relevant effects in alcohol and drug addiction. Although recent studies have investigated the effects of psilocybin in various populations, there have been no studies on the efficacy of psilocybin for alcohol dependence. We conducted a single-group proof-of-concept study to quantify acute effects of psilocybin in alcohol-dependent participants and to provide preliminary outcome and safety data. Ten volunteers with DSM-IV alcohol dependence received orally administered psilocybin in one or two supervised sessions in addition to Motivational Enhancement Therapy and therapy sessions devoted to preparation for and debriefing from the psilocybin sessions. Participants' responses to psilocybin were qualitatively similar to those described in other populations. Abstinence did not increase significantly in the first 4 weeks of treatment (when participants had not yet received psilocybin), but increased significantly following psilocybin administration (p < 0.05). Gains were largely maintained at follow-up to 36 weeks. The intensity of effects in the first psilocybin session (at week 4) strongly predicted change in drinking during weeks 5-8 (r = 0.76 to r = 0.89) and also predicted decreases in craving and increases in abstinence self-efficacy during week 5. There were no significant treatment-related adverse events. These preliminary findings provide a strong rationale for controlled trials with larger samples to investigate efficacy and mechanisms. TRIAL REGISTRATION: NCT02061293.

Genetic influences on cognitive endophenotypes in schizophrenia.

BACKGROUND: Cognitive deficits are prominent in schizophrenia and represent promising endophenotypes for genetic research. METHODS: The current study investigated the importance of two conceptually distinct genetic aggregates, one based on copy number variations (uncommon deletion burden), and one based on single nucleotide polymorphisms identified in recent risk studies (genetic risk score). The impact of these genetic factors, and their interaction, was examined on cognitive endophenotypes defined by principal component analysis (PCA) in a multi-center sample of 50 patients with schizophrenia and 86 controls. PCA was used to identify three different types of executive function (EF: planning, fluency, and inhibition), and in separate analyses, a measure general cognitive ability (GCA). RESULTS: Cognitive deficits were prominent among individuals with schizophrenia, but no group differences were evident for either genetic factor. Among patients the deletion burden measures predicted cognitive deficits across the three EF components and GCA. Further, an interaction was noted between the two genetic factors for both EF and GCA and the observed patterns of interaction suggested antagonistic epistasis. In general, the set of genetic interactions examined predicted a substantial portion of variance in these cognitive endophenotypes. LIMITATIONS: Though adequately powered, our sample size is small for a genetic study. CONCLUSIONS: These results draw attention to genetic interactions and the possibility that genetic influences on cognition differ in patients and controls.

The impact of copy number deletions on general cognitive ability and ventricle size in patients with schizophrenia and healthy control subjects.

BACKGROUND: General cognitive ability is usually lower in individuals with schizophrenia, partly due to genetic influences. However, the specific genetic features related to general cognitive ability are poorly understood. Individual variation in a specific type of mutation, uncommon genetic deletions, has recently been linked with both general cognitive ability and risk for schizophrenia. METHODS: We derived measures of the aggregate number of "uncommon" deletions (i.e., those occurring in 3% or less of our combined samples) and the total number of base pairs affected by these deletions in individuals with schizophrenia (n = 79) and healthy control subjects (n = 110) and related each measure to the first principal component of a large battery of cognitive tests, a common technique for characterizing general cognitive ability. These two measures of mutation load were also evaluated for relationships with total brain gray matter, white matter, and lateral ventricle volume. RESULTS: The groups did not differ on genetic variables. Multivariate general linear models revealed a group (control subjects vs. patients) × uncommon deletion number interaction, such that the latter variable was associated with lower general cognitive ability and larger ventricles in patients but not control subjects. CONCLUSIONS: These data suggest that aggregate uncommon deletion burden moderates central features of the schizophrenia phenotype.

Therapeutic mechanisms of classic hallucinogens in the treatment of addictions: from indirect evidence to testable hypotheses.

Alcohol and drug addiction are major public health problems, and existing treatments are only moderately effective. Although there has been interest for over half a century in the therapeutic use of classic hallucinogens to treat addictions, clinical research with these drugs was halted at an early stage in the early 1970s, leaving many fundamental questions unanswered. In the past two decades, clinical research on classic hallucinogens has resumed, although addiction treatment trials are only now beginning. The purpose of this paper is to provide a targeted review of the research most relevant to the therapeutic potential of hallucinogens, and to integrate this information with current thinking about addiction and recovery. On the basis of this information, we present a heuristic model which organizes a number of hypotheses that may be tested in future research. We conclude that existing evidence provides a convincing rationale for further research on the effects of classic hallucinogens in the treatment of addiction.