Toral Surti

NMDA receptor function in large-scale anticorrelated neural systems with implications for cognition and schizophrenia

Glutamatergic neurotransmission mediated by N-methyl-d-aspartate (NMDA) receptors is vital for the cortical computations underlying cognition and might be disrupted in severe neuropsychiatric illnesses such as schizophrenia. Studies on this topic have been limited to processes in local circuits; however, cognition involves large-scale brain systems with multiple interacting regions. A prominent feature of the human brain’s global architecture is the anticorrelation of default-mode vs. task-positive systems. Here, we show that administration of an NMDA glutamate receptor antagonist, ketamine, disrupted the reciprocal relationship between these systems in terms of task-dependent activation and connectivity during performance of delayed working memory. Furthermore, the degree of this disruption predicted task performance and transiently evoked symptoms characteristic of schizophrenia. We offer a parsimonious hypothesis for this disruption via biophysically realistic computational modeling, namely cortical disinhibition. Together, the present findings establish links between glutamate’s role in the organization of large-scale anticorrelated neural systems, cognition, and symptoms associated with schizophrenia in humans.

STRUCTURAL MODELS OF THE BOVINE PAPILLOMAVIRUS E5 PROTEIN

The bovine papillomavirus E5 protein is thought to be a type II integral membrane protein that exists as a disulfide‐linked homodimer in transformed cells. Polarized‐infrared measurements show that the E5 dimer in membrane bilayers is largely α‐helical and has a transmembrane orientation. Computational searches of helix‐helix conformations reveal two possible low‐energy dimer structures. Correlation of these results with previous mutagenesis studies on the E5 protein suggests how the E5 dimer may serve as a molecular scaffold for dimerization and ligand‐independent activation of the PDGF‐β receptor. We propose that on each face of the E5 dimer a PDGF‐β receptor molecule interacts directly with Gln17 from one E5 monomer and with Asp33 from the other E5 monomer. This model accounts for the requirement of Gln17 and Asp33 for complex formation and explains genetic results that dimerization of the E5 protein is essential for cell transformation. Proteins 33:601–612, 1998.

Successful computer-based visual training specifically predicts visual memory enhancement over verbal memory improvement in schizophrenia

We investigated whether improved early visual processing on cognitive remediation (CR) exercises generalizes to visual and auditory learning and information manipulation in schizophrenia. Fourteen participants received neuropsychological testing before and after CR consisting of visual, auditory and cognitive control training. Achievement on visual training exercises was strongly and significantly correlated with improved visual learning, but not improved verbal learning or increased ability to manipulate visual information. Improvement in training, not training time, predicted cognitive gain. Implications for improving cognitive outcomes from CR include ensuring the trained task is learned and providing exercises of multiple modalities.

A pilot and feasibility study of computer-based training for visual processing deficits in schizophrenia.

Fig. 1. VBM training is associated with improved VBM performance and improved visual memory. 1a) 9 participants completed 10 sessions of VBM training, and demonstrated improvement on all three tasks. The fraction correct at each ISI normalized by the fraction of unmasked trials correct is shown for T1, a VBM letter-identification task with a spatially overlapping mask. For T1, there was a significant time×ISI interaction (F(11,88)=2.8, p=0.004). Error bars represent standard error of the mean. Post-hoc t-tests were performed to determine at which ISIs there had been significant differences with time. * indicates pb0.05. 1b) 8 participants had MCCB assessments before and after the VBM training. The average preand post-training scores on the Brief Visuospatial Memory Test (BVMT) are shown, and the post-training Day 10 BVMT score is significantly higher than on Day 1. Error bars represent standard error of the mean. A pilot and feasibility study of computer-based training for visual processing deficits in schizophrenia

T73. NOVEL VISUAL TRAINING FOR COGNITIVE REMEDIATION IN SCHIZOPHRENIA

Abstract Background Though cognitive remediation has shown modest benefits for schizophrenia, relatively few training programs for have targeted the visual processing deficits common in the illness. Residual visual processing deficits following cognitive remediation may explain why cognitive remediation has had limited effects on visual learning and memory compared to auditory learning and memory. We sought to test whether training early visual processing would improve visual memory and facial affect recognition by targeting a well-characterized visual deficit in schizophrenia: visual backward masking (VBM). The deficit is so common in schizophrenia, and in non-affected family members to a lesser degree, that it is viewed as an endophenotype. The VBM deficit, however, can normalize as we have previously shown. In our prior open-label pilot study, individuals with schizophrenia (Surti and Wexler, 2012) made substantial gains in VBM performance with rudimentary computerized VBM training. The VBM improvements were also accompanied by improvements in visual memory. To test the hypothesis that improved early sensory training could lead to other cognitive gains in the same domain, we conducted a randomized control study with a new, more sophisticated computerized VBM training program, and compared it to an active control condition. We expected that visual memory and facial affect recognition would improve with the novel visual training (VT), and that VBM would improve with the VT as well. Methods 23 individuals with stable schizophrenia or schizoaffective disorder were randomized to receive 20 sessions of VT or an active control. The VT consisted of VBM training with multiple levels of difficulty, adaptive tracking, virtual rewards, and a variety of letters, numbers, and shapes to train different areas of the visual field. The active control condition was a commercially available computerized typing tutorial (TT) with animation, game narrative, and multiple typing activities. Participants were tested before and after training with: the Matrics Cognitive Consensus Battery (MCCB), including the Brief Visuospatial Memory Test-Revised (BVMT) as the study’s primary outcome; the Profile of Nonverbal Sensitivity (mini-PONS) to assess non-verbal social cues; standardized VBM tests; and typing assessments. Repeated measure ANOVAs were conducted in SPSS24 after checking for normality. Results 22 of 23 individuals completed the study, and by participants’ reports, both interventions were well tolerated, equally enjoyable and equally motivating, though the VT was slightly more frustrating for participants. Even when co-varying for education, which was higher in the VT group, there were no condition by time interactions for the BVMT, the mini-PONS, overall MCCB, or typing ability. There was a significant condition by time interactions for VBM performance (F = 5.8, p =0.028), with a substantial improvement in the VT group (Cohen’s d = 0.54; p=0.004). Discussion Patients with schizophrenia equally tolerated a computerized visual training designed in-house and an off-the shelf highly gamified control training, but only the visual training, specifically designed for individuals with schizophrenia, had effects on the trained task. The effects of the visual training did not generalize to visual memory, facial affect recognition, or global cognition, so further work is needed to facilitate generalization.

The dose-dependent psychomotor effects of intravenous delta-9-tetrahydrocannabinol (Δ9-THC) in humans

Background: Binding studies have demonstrated that levels of the cannabinoid receptor type-1 are highest in the basal ganglia and cerebellum, two areas critical for motor control. However, no studies have systematically examined the dose-related effects of intravenous delta-9-tetrahydrocannabinol, the primary cannabinoid receptor type-1 partial agonist in cannabis, on broad domains of psychomotor function in humans. Aims: Therefore, three domains of psychomotor function were assessed in former cannabis users (cannabis abstinent for a minimum of three months; n=23) in a three test-day, within-subject, double-blind, randomized, cross-over, and counterbalanced study during which they received intravenous delta-9-tetrahydrocannabinol (placebo, 0.015 mg/kg, and 0.03 mg/kg). Methods: Gross motor function was assessed via the Cambridge Neuropsychological Test Automated Battery Motor Screening Task, fine motor control via the Lafayette Instrument Grooved Pegboard task, and motor timing via a Paced Finger-Tapping Task. In addition, the Cambridge Neuropsychological Test Automated Battery Rapid Visual Processing Task was utilized to determine whether delta-9-tetrahydrocannabinol-induced motor deficits were confounded by disruptions in sustained attention. Results/outcomes: Delta-9-tetrahydrocannabinol resulted in robust dose-dependent deficits in fine motor control (Grooved Pegboard Task) and motor timing (Paced Finger-Tapping Task), while gross motor performance (Motor Screening Task) and sustained attention (Rapid Visual Processing Task) were unimpaired. Interestingly, despite the observed dose-dependent increases in motor impairment and blood levels of delta-9-tetrahydrocannabinol, subjects reported similar levels of intoxication in the two drug conditions. Conclusions/interpretation: These data suggest that while several domains of motor function are disrupted by delta-9-tetrahydrocannabinol, subjective feelings of intoxication are dissociable from cannabinoid-induced psychomotor effects. Results are discussed in terms of the potential neural mechanisms of delta-9-tetrahydrocannabinol in motor structures.