Top-down control of visual sensory processing during an ocular motor response inhibition task

The study addressed whether top-down control of visual cortex supports volitional behavioral control in a novel antisaccade task. The hypothesis was that anticipatory modulations of visual cortex activity would differentiate trials on which subjects knew an anti- versus a pro-saccade response was required. Trials consisted of flickering checkerboards in both peripheral visual fields, followed by brightening of one checkerboard (target) while both kept flickering. Neural activation related to checkerboards before target onset (bias signal) was assessed using electroencephalography. Pretarget visual cortex responses to checkerboards were strongly modulated by task demands (significantly lower on antisaccade trials), an effect that may reduce the predisposition to saccade generation instigated by visual capture. The results illustrate how top-down sensory regulation can complement motor preparation to facilitate adaptive voluntary behavioral control

Inflammation subtypes in psychosis and their relationships with genetic risk for psychiatric and cardiometabolic disorders

Cardiometabolic disorders have known inflammatory implications, and peripheral measures of inflammation and cardiometabolic disorders are common in persons with psychotic disorders. Inflammatory signatures are also related to neurobiological and behavioral changes in psychosis. Relationships between systemic inflammation and cardiometabolic genetic risk in persons with psychosis have not been examined. Thirteen peripheral inflammatory markers and genome-wide genotyping were assessed in 122 participants (n = 86 psychosis, n = 36 healthy controls) of European ancestry. Cluster analyses of inflammatory markers classified higher and lower inflammation subgroups. Single-trait genetic risk scores (GRS) were constructed for each participant using previously reported GWAS summary statistics for the following traits: schizophrenia, bipolar disorder, major depressive disorder, coronary artery disease, type-2 diabetes, low-density lipoprotein, high-density lipoprotein, triglycerides, and waist-to-hip ratio. Genetic correlations across traits were quantified. Principal component (PC) analysis of the cardiometabolic GRSs generated six PC loadings used in regression models to examine associations with inflammation markers. Functional module discovery explored biological mechanisms of the inflammation association of cardiometabolic GRS genes. A subgroup of 38% persons with psychotic disorders was characterized with higher inflammation status. These higher inflammation individuals had lower BACS scores (p = 0.038) compared to those with lower inflammation. The first PC of the cardiometabolic GRS matrix was related to higher inflammation status in persons with psychotic disorders (OR = 2.037, p = 0.001). Two of eight modules within the functional interaction network of cardiometabolic GRS genes were enriched for immune processes. Cardiometabolic genetic risk may predispose some individuals with psychosis to elevated inflammation which adversely impacts cognition associated with illness

Visuomotor brain network activation and functional connectivity among individuals with autism spectrum disorder

Sensorimotor abnormalities are common in autism spectrum disorder (ASD) and predictive of functional outcomes, though their neural underpinnings remain poorly understood. Using functional magnetic resonance imaging, we examined both brain activation and functional connectivity during visuomotor behavior in 27 individuals with ASD and 30 typically developing (TD) controls (ages 9–35 years). Participants maintained a constant grip force while receiving visual feedback at three different visual gain levels. Relative to controls, ASD participants showed increased force variability, especially at high gain, and reduced entropy. Brain activation was greater in individuals with ASD than controls in supplementary motor area, bilateral superior parietal lobules, and contralateral middle frontal gyrus at high gain. During motor action, functional connectivity was reduced between parietal-premotor and parietal-putamen in individuals with ASD compared to controls. Individuals with ASD also showed greater age-associated increases in functional connectivity between cerebellum and visual, motor, and prefrontal cortical areas relative to controls. These results indicate that visuomotor deficits in ASD are associated with atypical activation and functional connectivity of posterior parietal, premotor, and striatal circuits involved in translating sensory feedback information into precision motor behaviors, and that functional connectivity of cerebellar–cortical sensorimotor and nonsensorimotor networks show delayed maturation

Reduced Levels of Vasopressin and Reduced Behavioral Modulation of Oxytocin in Psychotic Disorders

Oxytocin (OT) and arginine vasopressin (AVP) exert robust influence on social affiliation and specific cognitive processes in healthy individuals. Abnormalities in these neuroendocrine systems have been observed in psychotic disorders, but their relation to impairments in behavioral domains that these endocrines modulate is not well understood. We compared abnormalities of OT and AVP serum concentrations in probands with schizophrenia (n = 57), schizoaffective disorder (n = 34), and psychotic bipolar disorder (n = 75); their first-degree relatives without a history of psychosis (n = 61, 43, 91, respectively); and healthy controls (n = 66) and examined their association with emotion processing and cognition. AVP levels were lower in schizophrenia (P = .002) and bipolar probands (P = .03) and in relatives of schizophrenia probands (P = .002) compared with controls. OT levels did not differ between groups. Familiality estimates were robust for OT (h 2 = 0.79, P = 3.97e−15) and AVP (h 2 = 0.78, P = 3.93e−11). Higher levels of OT were associated with better emotion recognition (β = 0.40, P < .001) and general neuropsychological function (β = 0.26, P = .04) in healthy controls as expected but not in any proband or relative group. In schizophrenia, higher OT levels were related to greater positive symptom severity. The dissociation of OT levels and behavioral function in all proband and relative groups suggests that risk and illness factors associated with psychotic disorders are not related to reduced OT levels but to a disruption in the ability of physiological levels of OT to modulate social cognition and neuropsychological function. Decreased AVP levels may be a marker of biological vulnerability in schizophrenia because alterations were seen in probands and relatives, and familiality was high

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Preliminary report on the effects of a low dose of LSD on resting state amygdalar functional connectivity

The practice of “microdosing”, or the use of repeated, very low doses of LSD to improve mood or cognition, has received considerable public attention, but empirical studies are lacking. Controlled studies are needed to investigate both the therapeutic potential and the neurobiological underpinnings of this pharmacologic treatment. Methods. The present study was designed to examine the effects of a single low dose of LSD (13 micrograms) vs placebo on resting-state functional connectivity and cerebral blood flow in healthy young adults. Twenty men and women, aged 18-35, participated in two fMRI scanning sessions in which they received placebo or LSD under double-blind conditions. During each session, the participants completed drug effect and mood questionnaires, and physiological measures were recorded. During expected peak drug effect, they underwent resting-state BOLD and ASL scans. Cerebral blood flow as well as amygdala and thalamic connectivity were analyzed. Results. LSD increased amygdala seed-based connectivity with the right angular gyrus, right middle frontal gyrus, and the cerebellum, and decreased amygdala connectivity with the left and right postcentral gyrus and the superior temporal gyrus. This low dose of LSD had weak and variable effects on mood, but its effects on positive mood were positively correlated with the increase in amygdala – middle frontal gyrus connectivity strength. Conclusions. These preliminary findings show that a very low dose of LSD, which produces negligible subjective changes, alters brain connectivity in limbic circuits. Additional studies, especially with repeated dosing, will reveal whether these neural changes are related to the drug’s purported antidepressant effect. NCT0379035

Action planning and predictive coding when speaking

Across the animal kingdom, sensations resulting from an animal's own actions are processed differently from sensations resulting from external sources, with self-generated sensations being suppressed. A forward model has been proposed to explain this process across sensorimotor domains. During vocalization, reduced processing of one's own speech is believed to result from a comparison of speech sounds to corollary discharges of intended speech production generated from efference copies of commands to speak. Until now, anatomical and functional evidence validating this model in humans has been indirect. Using EEG with anatomical MRI to facilitate source localization, we demonstrate that inferior frontal gyrus activity during the 300ms before speaking was associated with suppressed processing of speech sounds in auditory cortex around 100ms after speech onset (N1). These findings indicate that an efference copy from speech areas in prefrontal cortex is transmitted to auditory cortex, where it is used to suppress processing of anticipated speech sounds. About 100ms after N1, a subsequent auditory cortical component (P2) was not suppressed during talking. The combined N1 and P2 effects suggest that although sensory processing is suppressed as reflected in N1, perceptual gaps may be filled as reflected in the lack of P2 suppression, explaining the discrepancy between sensory suppression and preserved sensory experiences. These findings, coupled with the coherence between relevant brain regions before and during speech, provide new mechanistic understanding of the complex interactions between action planning and sensory processing that provide for differentiated tagging and monitoring of one's own speech, processes disrupted in neuropsychiatric disorders

Exploring the Intersections of Trauma, Structural Adversity, and Psychosis among a Primarily African-American Sample: A Mixed-Methods Analysis

Traumatic life events (TLEs) have been associated with multiple psychiatric diagnoses, including anxiety disorders, major depression, PTSD, and psychosis. To advance our understanding of the complex interactions between forms of adversity as they manifest across the lifespan, psychosis, and symptom content, we undertook a mixed-methods investigation of TLEs and psychosis. Our research explored the association between cumulative exposures, type of TLE, and proximity to the traumatic event and psychosis; the association between TLEs and clinical symptomology including specific types of delusions and/or hallucinations; and how qualitative data further inform understanding of complex relationships and patterns of past trauma and symptoms as they unfold over time. There were a total of 97 participants in the quantitative study sample, 51 participants with present state psychosis and 46 non-clinical. There were a total of 34 qualitative study participants, all of whom were experiencing psychosis. The quantitative analysis showed that when comparing persons with psychosis to the non-clinical group, there were no group differences in the overall total score of TLEs. However, there was a significant difference in cumulative TLEs that “Happened,” demonstrating that as the number of TLEs increased, the likelihood of clinical psychosis also increased. We also found a correlation between lifetime cumulative TLEs that “Happened” and PANSS five-factor analysis: positive, excitement, depression, thought disorder, activation, and paranoia scores. The qualitative analysis further built on these finding by providing rich narratives regarding the timing of trauma-related onset, relationships between trauma and both trauma-related and religious–spiritual content, and trauma and hallucinatory modality. Analysis of participant narratives suggests the central role of localized cultural and sociopolitical influences on onset, phenomenology, and coping and contributes to a growing literature calling for strengths-based, client-driven approaches to working with distressing voices and beliefs that centers the exploration of the personal and social meaning of such experiences including links to life narratives. Findings also underscore the clinical importance of trauma assessment and trauma-informed care

Neurophysiological Evidence of Corollary Discharge Function During Vocalization in Psychotic Patients and Their Nonpsychotic First-Degree Relatives

Predictions about sensations resulting from motor acts are instantiated through neural mechanisms such as the corollary discharge. With each action, the corollary discharge provides an unconscious comparison between predicted and actual sensations resulting from the action; closer matches result in greater suppression of sensation. This mechanism is disrupted in schizophrenia (SZ) and may contribute to, or reflect a failure to, distinguish self- from externally generated experiences, a hallmark of psychosis. We asked whether disruption is specific to SZ or is seen in other psychotic illnesses and in first-degree relatives of psychotic patients. Corollary discharge function was assessed in SZ patients (n = 30), schizoaffective (SA) patients (n = 19), bipolar patients with a history of psychosis (BPP; n = 39), nonpsychotic relatives of SZ (n = 30), SA (n = 23), and BPP (n = 50) patients, and healthy controls (n = 43). The N1 component of the event-related potential, reflecting auditory cortical responses to sounds, was elicited by speech sound onset as subjects talked and later when they listened to a recording of those sounds. N1 was suppressed during talking compared to N1 during listening, consistent with the suppressive action of the corollary discharge mechanism. Suppression was significantly reduced in SZ and BPP patients, with a similar trend in the smaller SA group. Patient groups did not differ, and unaffected relatives did not differ from controls or probands. The failure to monitor sensations resulting from self-generated actions, implicating corollary discharge dysfunction, may be a common feature across affective and nonaffective psychosis. Data from unaffected family members do not indicate that this is a marker of psychosis risk

A Pilot Study of Neural Correlates of Loss of Control Eating in Children With Overweight/Obesity: Probing Intermittent Access to Food as a Means of Eliciting Disinhibited Eating.

Objective:Neural substrates of loss of control (LOC) eating are undercharacterized. We aimed to model intermittent access to food to elicit disinhibited eating in youth undergoing neuroimaging, given evidence that restricted food access may increase subsequent food intake via enhancing reward value of food and diminishing eating-related self-control. Methods:Participants were 18 preadolescents (aged 9-12 years) who were overweight/obese with recent LOC eating (OW-LOC; n = 6); overweight/obese with no history of LOC eating (OW-CON; n = 5); or non-overweight with no history of LOC eating (NW-CON; n = 7). Participants underwent functional magnetic resonance imaging during a simulated food restriction paradigm in which they were alternately given restricted or unrestricted access to milkshake solutions. Results:There were no significant main effects of restricted versus unrestricted access to milkshake flavors. Group main effects revealed increased activation for OW-LOC relative to OW-CON in areas related to attentional processes (right middle frontal gyrus), inhibitory control/attentional shifts (right and left cuneus), and emotion regulation (left cingulate gyrus); and for OW-LOC relative to NW-CON in areas related to response inhibition (right inferior frontal gyrus). Significant block type × group interaction effects were found for the right middle frontal gyrus, left cingulate gyrus, and left cuneus, but these appeared to be accounted for primarily by group. Discussion:There were clear group differences in neural activity in brain regions related to self-regulation during a food restriction paradigm. Elevations in these regions among OW-LOC relative to OW-CON and NW-CON, respectively, may suggest that youth with LOC eating expended more cognitive effort to regulate ingestive behavior