Disrupted third visual pathway function in schizophrenia: Evidence from real and implied motion processing.

Impaired motion perception in schizophrenia has been associated with deficits in social-cognitive processes and with reduced activation of visual sensory regions, including the middle temporal area (MT+) and posterior superior temporal sulcus (pSTS). These findings are consistent with the recent proposal of the existence of a specific 'third visual pathway' specialized for social perception in which motion is a fundamental component. The third visual pathway transmits visual information from early sensory visual processing areas to the STS, with MT+ acting as a critical intermediary. We used functional magnetic resonance imaging to investigate functioning of this pathway during processing of naturalistic videos with explicit (real) motion and static images with implied motion cues. These measures were related to face emotion recognition and motion-perception, as measured behaviorally. Participants were 28 individuals with schizophrenia (Sz) and 20 neurotypical controls. Compared to controls, individuals with Sz showed reduced activation of third visual pathway regions (MT+, pSTS) in response to both real- and implied-motion stimuli. Dysfunction of early visual cortex and pulvinar were also associated with aberrant real-motion processing. Implied-motion stimuli additionally engaged a wide network of brain areas including parietal, motor and frontal nodes of the human mirror neuron system. The findings support concepts of MT+ as a mediator between visual sensory areas and higher-order brain and argue for greater focus on MT+ contributions to social-cognitive processing, in addition to its well-documented role in visual motion processing.

Bottom-up and top-down contributions to impaired motion processing in schizophrenia.

Background and Hypothesis: Motion processing deficits in schizophrenia have been linked to impairments in higher-order social-cognitive processes. The neural underpinnings are not fully understood but it has been hypothesized that middle temporal area (MT+) may serve as a bridge between purely sensory and more cognitive proceseses. We investigated the interrelationship between MT+ sensory processing deficits and impairments in higher-order processing using naturalistic videos with explicit motion and static images with implied-motion cues. Study Design: Functional magnetic resonance imaging was used to evaluate cortical and subcortical brain regions associated with real- and implied-motion processing in 28 individuals with schizophrenia and 20 neurotypical controls. These measures were related to face emotion recognition and motion-perception deficits, as measured behaviorally. Study Results: Activation of MT+ was abnormal in schizophrenia during both real- and implied-motion processing. Dysfunction of early visual cortex and pulvinar were also associated with impaired real-motion processing. During implied-motion-perception, MT+ participated in a wider network involving sensorimotor and prefrontal nodes of the human mirror neuron system, known to play a role in social-cognitive processes. Perception of both real- and implied-motion engaged the posterior superior temporal sulcus, a key node of the social brain network. Conclusions: The findings support concepts of MT+ as a bridge between visual sensory areas and higher-order brain regions especially in relationship to face emotion recognition and social cognition. Our data argue for greater focus on MT+ contributions to social-cognitive processing, in addition to its well-documented role in visual motion processing.

Disruption of early visual processing in amyloid-positive healthy individuals and mild cognitive impairment.

BACKGROUND: Amyloid deposition is a primary predictor of Alzheimer's disease (AD) and related neurodegenerative disorders. Retinal changes involving the structure and function of the ganglion cell layer are increasingly documented in both established and prodromal AD. Visual event-related potentials (vERP) are sensitive to dysfunction in the magno- and parvocellular visual systems, which originate within the retinal ganglion cell layer. The present study evaluates vERP as a function of amyloid deposition in aging, and in mild cognitive impairment (MCI). METHODS: vERP to stimulus-onset, motion-onset, and alpha-frequency steady-state (ssVEP) stimuli were obtained from 16 amyloid-positive and 41 amyloid-negative healthy elders and 15 MCI individuals and analyzed using time-frequency approaches. Social cognition was assessed in a subset of individuals using The Awareness of Social Inference Test (TASIT). RESULTS: Neurocognitively intact but amyloid-positive participants and MCI individuals showed significant deficits in stimulus-onset (theta) and motion-onset (delta) vERP generation relative to amyloid-negative participants (all p < .01). Across healthy elders, a composite index of these measures correlated highly (r = - .52, p < .001) with amyloid standardized uptake value ratios (SUVR) and TASIT performance. A composite index composed of vERP measures significant differentiated amyloid-positive and amyloid-negative groups with an overall classification accuracy of > 70%. DISCUSSION: vERP may assist in the early detection of amyloid deposition among older individuals without observable neurocognitive impairments and in linking previously documented retinal deficits in both prodromal AD and MCI to behavioral impairments in social cognition.

Disease-Specific Contribution of Pulvinar Dysfunction to Impaired Emotion Recognition in Schizophrenia.

One important aspect for managing social interactions is the ability to perceive and respond to facial expressions rapidly and accurately. This ability is highly dependent upon intact processing within both cortical and subcortical components of the early visual pathways. Social cognitive deficits, including face emotion recognition (FER) deficits, are characteristic of several neuropsychiatric disorders including schizophrenia (Sz) and autism spectrum disorders (ASD). Here, we investigated potential visual sensory contributions to FER deficits in Sz (n = 28, 8/20 female/male; age 21-54 years) and adult ASD (n = 20, 4/16 female/male; age 19-43 years) participants compared to neurotypical (n = 30, 8/22 female/male; age 19-54 years) controls using task-based fMRI during an implicit static/dynamic FER task. Compared to neurotypical controls, both Sz (d = 1.97) and ASD (d = 1.13) participants had significantly lower FER scores which interrelated with diminished activation of the superior temporal sulcus (STS). In Sz, STS deficits were predicted by reduced activation of early visual regions (d = 0.85, p = 0.002) and of the pulvinar nucleus of the thalamus (d = 0.44, p = 0.042), along with impaired cortico-pulvinar interaction. By contrast, ASD participants showed patterns of increased early visual cortical (d = 1.03, p = 0.001) and pulvinar (d = 0.71, p = 0.015) activation. Large effect-size structural and histological abnormalities of pulvinar have previously been documented in Sz. Moreover, we have recently demonstrated impaired pulvinar activation to simple visual stimuli in Sz. Here, we provide the first demonstration of a disease-specific contribution of impaired pulvinar activation to social cognitive impairment in Sz.

Grant Report on d-Serine Augmentation of Neuroplasticity-Based Auditory Learning in Schizophrenia †.

We report on the rationale and design of an ongoing NIMH sponsored R61-R33 project in schizophrenia/schizoaffective disorder. This project studies augmenting the efficacy of auditory neuroplasticity cognitive remediation (AudRem) with d-serine, an N-methyl-d-aspartate-type glutamate receptor (NMDAR) glycine-site agonist. We operationalize improved (smaller) thresholds in pitch (frequency) between successive auditory stimuli after AudRem as improved plasticity, and mismatch negativity (MMN) and auditory θ as measures of functional target engagement of both NMDAR agonism and plasticity. Previous studies showed that AudRem alone produces significant, but small cognitive improvements, while d-serine alone improves symptoms and MMN. However, the strongest results for plasticity outcomes (improved pitch thresholds, auditory MMN and θ) were found when combining d-serine and AudRem. AudRem improvements correlated with reading and other auditory cognitive tasks, suggesting plasticity improvements are predictive of functionally relevant outcomes. While d-serine appears to be efficacious for acute AudRem enhancement, the optimal dose remains an open question, as does the ability of combined d-serine + AudRem to produce sustained improvement. In the ongoing R61, 45 schizophrenia patients will be randomized to receive three placebo-controlled, double-blind d-serine + AudRem sessions across three separate 15 subject dose cohorts (80/100/120 mg/kg). Successful completion of the R61 is defined by ≥moderate effect size changes in target engagement and correlation with function, without safety issues. During the three-year R33, we will assess the sustained effects of d-serine + AudRem. In addition to testing a potentially viable treatment, this project will develop a methodology to assess the efficacy of novel NMDAR modulators, using d-serine as a "gold-standard".

Impact of image preprocessing on the scanner dependence of multi-parametric MRI radiomic features and covariate shift in multi-institutional glioblastoma datasets.

Recent advances in radiomics have enhanced the value of medical imaging in various aspects of clinical practice, but a crucial component that remains to be investigated further is the robustness of quantitative features to imaging variations and across multiple institutions. In the case of MRI, signal intensity values vary according to the acquisition parameters used, yet no consensus exists on which preprocessing techniques are favorable in reducing scanner-dependent variability of image-based features. Hence, the purpose of this study was to assess the impact of common image preprocessing methods on the scanner dependence of MRI radiomic features in multi-institutional glioblastoma multiforme (GBM) datasets. Two independent GBM cohorts were analyzed: 50 cases from the TCGA-GBM dataset and 111 cases acquired in our institution, and each case consisted of 3 MRI sequences viz. FLAIR, T1-weighted, and T1-weighted post-contrast. Five image preprocessing techniques were examined: 8-bit global rescaling, 8-bit local rescaling, bias field correction, histogram standardization, and isotropic resampling. A total of 420 features divided into eight categories representing texture, shape, edge, and intensity histogram were extracted. Two distinct imaging parameters were considered: scanner manufacturer and scanner magnetic field strength. Wilcoxon tests identified features robust to the considered acquisition parameters under the selected image preprocessing techniques. A machine learning-based strategy was implemented to measure the covariate shift between the analyzed datasets using features computed using the aforementioned preprocessing methods. Finally, radiomic scores (rad-scores) were constructed by identifying features relevant to patients' overall survival after eliminating those impacted by scanner variability. These were then evaluated for their prognostic significance through Kaplan-Meier and Cox hazards regression analyses. Our results demonstrate that overall, histogram standardization contributes the most in reducing radiomic feature variability as it is the technique to reduce the covariate shift for three feature categories and successfully discriminate patients into groups of different survival risks.

Preoperative MRI-radiomics features improve prediction of survival in glioblastoma patients over MGMT methylation status alone.

BACKGROUND: Glioblastoma (GBM) is the most common malignant central nervous system tumor, and MGMT promoter hypermethylation in this tumor has been shown to be associated with better prognosis. We evaluated the capacity of radiomics features to add complementary information to MGMT status, to improve the ability to predict prognosis. METHODS: 159 patients with untreated GBM were included in this study and divided into training and independent test sets. 286 radiomics features were extracted from the magnetic resonance images acquired prior to any treatments. A least absolute shrinkage selection operator (LASSO) selection followed by Kaplan-Meier analysis was used to determine the prognostic value of radiomics features to predict overall survival (OS). The combination of MGMT status with radiomics was also investigated and all results were validated on the independent test set. RESULTS: LASSO analysis identified 8 out of the 286 radiomic features to be relevant which were then used for determining association to OS. One feature (edge descriptor) remained significant on the external validation cohort after multiple testing (p=0.04) and the combination with MGMT identified a group of patients with the best prognosis with a survival probability of 0.61 after 43 months (p=0.0005). CONCLUSION: Our results suggest that combining radiomics with MGMT is more accurate in stratifying patients into groups of different survival risks when compared to with using these predictors in isolation. We identified two subgroups within patients who have methylated MGMT: one with a similar survival to unmethylated MGMT patients and the other with a significantly longer OS.