NeuroDots: From Single-Target to Brain-Network Modulation: Why and What Is Needed?

OBJECTIVES: Current techniques in brain stimulation are still largely based on a phrenologic approach that a single brain target can treat a brain disorder. Nevertheless, meta-analyses of brain implants indicate an overall success rate of 50% improvement in 50% of patients, irrespective of the brain-related disorder. Thus, there is still a large margin for improvement. The goal of this manuscript is to 1) develop a general theoretical framework of brain functioning that is amenable to surgical neuromodulation, and 2) describe the engineering requirements of the next generation of implantable brain stimulators that follow from this theoretic model. MATERIALS AND METHODS: A neuroscience and engineering literature review was performed to develop a universal theoretical model of brain functioning and dysfunctioning amenable to surgical neuromodulation. RESULTS: Even though a single target can modulate an entire network, research in network science reveals that many brain disorders are the consequence of maladaptive interactions among multiple networks rather than a single network. Consequently, targeting the main connector hubs of those multiple interacting networks involved in a brain disorder is theoretically more beneficial. We, thus, envision next-generation network implants that will rely on distributed, multisite neuromodulation targeting correlated and anticorrelated interacting brain networks, juxtaposing alternative implant configurations, and finally providing solid recommendations for the realization of such implants. In doing so, this study pinpoints the potential shortcomings of other similar efforts in the field, which somehow fall short of the requirements. CONCLUSION: The concept of network stimulation holds great promise as a universal approach for treating neurologic and psychiatric disorders.

Disentangling cortical functional connectivity strength and topography reveals divergent roles of genes and environment.

The human brain varies across individuals in its morphology, function, and cognitive capacities. Variability is particularly high in phylogenetically modern regions associated with higher order cognitive abilities, but its relationship to the layout and strength of functional networks is poorly understood. In this study we disentangled the variability of two key aspects of functional connectivity: strength and topography. We then compared the genetic and environmental influences on these two features. Genetic contribution is heterogeneously distributed across the cortex and differs for strength and topography. In heteromodal areas genes predominantly affect the topography of networks, while their connectivity strength is shaped primarily by random environmental influence such as learning. We identified peak areas of genetic control of topography overlapping with parts of the processing stream from primary areas to network hubs in the default mode network, suggesting the coordination of spatial configurations across those processing pathways. These findings provide a detailed map of the diverse contribution of heritability and individual experience to the strength and topography of functional brain architecture.

Predicting neurosurgical outcomes in focal epilepsy patients using computational modelling.

SEE EISSA AND SCHEVON DOI101093/AWW332 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Surgery can be a last resort for patients with intractable, medically refractory epilepsy. For many of these patients, however, there is substantial risk that the surgery will be ineffective. The prediction of who is likely to benefit from a surgical approach is crucial for being able to inform patients better, conduct principled prospective clinical trials, and ultimately tailor therapeutic approaches to these patients more effectively. Dynamical computational models, informed with patient data, can be used to make predictions and give mechanistic insight. In this study, we develop patient-specific dynamical network models of epileptogenic cortex. We infer the network connectivity matrix from non-seizure electrographic recordings of patients and use these connectivity matrices as the network structure in our model. The model simulates the dynamics of a bi-stable switch at every node in this network, meaning that every node starts in a background state, but has the ability to transit to a co-existing seizure state. Whether a transition happens in a node is partly determined by the stochastic nature of the input to the node, but also by the input the node receives from other connected nodes in the network. By conducting simulations with such a model, we can detect the average transition time for nodes in a given network, and therefore define nodes with a short transition time as highly epileptogenic. In a retrospective study, we found that in some patients the regions with high epileptogenicity in the model overlap with those identified clinically as the seizure onset zone. Moreover, it was found that the resection of these regions in the model reduces the overall likelihood of a seizure. Following removal of these regions in the model, we predicted surgical outcomes and compared these to actual patient outcomes. Our predictions were found to be 81.3% accurate on a dataset of 16 patients with intractable epilepsy. Intriguingly, in patients with unsuccessful outcomes, the proposed computational approach is able to suggest alternative resection sites. The model presented here gives mechanistic insight as to why surgery may be unsuccessful in some patients. This may aid clinicians in presurgical evaluation by providing a tool to explore various surgical options, offering complementary information to existing clinical techniques.

Innovative diagnostic tools for early detection of Alzheimer's disease.

Current state-of-the-art diagnostic measures of Alzheimer's disease (AD) are invasive (cerebrospinal fluid analysis), expensive (neuroimaging) and time-consuming (neuropsychological assessment) and thus have limited accessibility as frontline screening and diagnostic tools for AD. Thus, there is an increasing need for additional noninvasive and/or cost-effective tools, allowing identification of subjects in the preclinical or early clinical stages of AD who could be suitable for further cognitive evaluation and dementia diagnostics. Implementation of such tests may facilitate early and potentially more effective therapeutic and preventative strategies for AD. Before applying them in clinical practice, these tools should be examined in ongoing large clinical trials. This review will summarize and highlight the most promising screening tools including neuropsychometric, clinical, blood, and neurophysiological tests.

Transport of Intensity phase imaging by intensity spectrum fitting of exponentially spaced defocus planes.

We propose an alternative method for solving the Transport of Intensity equation (TIE) from a stack of through-focus intensity images taken by a microscope or lensless imager. Our method enables quantitative phase and amplitude imaging with improved accuracy and reduced data capture, while also being computationally efficient and robust to noise. We use prior knowledge of how intensity varies with propagation in the spatial frequency domain in order to constrain a fitting algorithm [Gaussian process (GP) regression] for estimating the axial intensity derivative. Solving the problem in the frequency domain inspires an efficient measurement scheme which captures images at exponentially spaced focal steps, significantly reducing the number of images required. Low-frequency artifacts that plague traditional TIE methods can be suppressed without an excessive number of captured images. We validate our technique experimentally by recovering the phase of human cheek cells in a brightfield microscope.

Sparse ACEKF for phase reconstruction.

We propose a novel low-complexity recursive filter to efficiently recover quantitative phase from a series of noisy intensity images taken through focus. We first transform the wave propagation equation and nonlinear observation model (intensity measurement) into a complex augmented state space model. From the state space model, we derive a sparse augmented complex extended Kalman filter (ACEKF) to infer the complex optical field (amplitude and phase), and find that it converges under mild conditions. Our proposed method has a computational complexity of N(z)N logN and storage requirement of O(N), compared with the original ACEKF method, which has a computational complexity of O(NzN(3)) and storage requirement of O(N(2)), where Nz is the number of images and N is the number of pixels in each image. Thus, it is efficient, robust and recursive, and may be feasible for real-time phase recovery applications with high resolution images.

Efficient Variational Bayes Learning of Graphical Models With Smooth Structural Changes.

Estimating a sequence of dynamic undirected graphical models, in which adjacent graphs share similar structures, is of paramount importance in various social, financial, biological, and engineering systems, since the evolution of such networks can be utilized for example to spot trends, detect anomalies, predict vulnerability, and evaluate the impact of interventions. Existing methods for learning dynamic graphical models require the tuning parameters that control the graph sparsity and the temporal smoothness to be selected via brute-force grid search. Furthermore, these methods are computationally burdensome with time complexity O(NP3) for P variables and N time points. As a remedy, we propose a low-complexity tuning-free Bayesian approach, named BASS. Specifically, we impose temporally dependent spike and slab priors on the graphs such that they are sparse and varying smoothly across time. An efficient variational inference algorithm based on natural gradients is then derived to learn the graph structures from the data in an automatic manner. Owing to the pseudo-likelihood and the mean-field approximation, the time complexity of BASS is only O(NP2). To cope with the local maxima problem of variational inference, we resort to simulated annealing and propose a method based on bootstrapping of the observations to generate the annealing noise. We provide numerical evidence that BASS outperforms existing methods on synthetic data in terms of structure estimation, while being more efficient especially when the dimension P becomes high. We further apply the approach to the stock return data of 78 banks from 2005 to 2013 and find that the number of edges in the financial network as a function of time contains three peaks, in coincidence with the 2008 global financial crisis and the two subsequent European debt crisis. On the other hand, by identifying the frequency-domain resemblance to the time-varying graphical models, we show that BASS can be extended to learning frequency-varying inverse spectral density matrices, and further yields graphical models for multivariate stationary time series. As an illustration, we analyze scalp EEG signals of patients at the early stages of Alzheimer's disease (AD) and show that the brain networks extracted by BASS can better distinguish between the patients and the healthy controls.

Six-Center Assessment of CNN-Transformer with Belief Matching Loss for Patient-Independent Seizure Detection in EEG.

Neurologists typically identify epileptic seizures from electroencephalograms (EEGs) by visual inspection. This process is often time-consuming, especially for EEG recordings that last hours or days. To expedite the process, a reliable, automated, and patient-independent seizure detector is essential. However, developing a patient-independent seizure detector is challenging as seizures exhibit diverse characteristics across patients and recording devices. In this study, we propose a patient-independent seizure detector to automatically detect seizures in both scalp EEG and intracranial EEG (iEEG). First, we deploy a convolutional neural network with transformers and belief matching loss to detect seizures in single-channel EEG segments. Next, we extract regional features from the channel-level outputs to detect seizures in multi-channel EEG segments. At last, we apply post-processing filters to the segment-level outputs to determine seizures' start and end points in multi-channel EEGs. Finally, we introduce the minimum overlap evaluation scoring as an evaluation metric that accounts for minimum overlap between the detection and seizure, improving upon existing assessment metrics. We trained the seizure detector on the Temple University Hospital Seizure (TUH-SZ) dataset and evaluated it on five independent EEG datasets. We evaluate the systems with the following metrics: sensitivity (SEN), precision (PRE), and average and median false positive rate per hour (aFPR/h and mFPR/h). Across four adult scalp EEG and iEEG datasets, we obtained SEN of 0.617-1.00, PRE of 0.534-1.00, aFPR/h of 0.425-2.002, and mFPR/h of 0-1.003. The proposed seizure detector can detect seizures in adult EEGs and takes less than 15[Formula: see text]s for a 30[Formula: see text]min EEG. Hence, this system could aid clinicians in reliably identifying seizures expeditiously, allocating more time for devising proper treatment.

Evaluation of different classification methods using electronic nose data to diagnose sarcoidosis.

Electronic nose (eNose) technology is an emerging diagnostic application, using artificial intelligence to classify human breath patterns. These patterns can be used to diagnose medical conditions. Sarcoidosis is an often difficult to diagnose disease, as no standard procedure or conclusive test exists. An accurate diagnostic model based on eNose data could therefore be helpful in clinical decision-making. The aim of this paper is to evaluate the performance of various dimensionality reduction methods and classifiers in order to design an accurate diagnostic model for sarcoidosis. Various methods of dimensionality reduction and multiple hyperparameter optimised classifiers were tested and cross-validated on a dataset of patients with pulmonary sarcoidosis (n= 224) and other interstitial lung disease (n= 317). Best performing methods were selected to create a model to diagnose patients with sarcoidosis. Nested cross-validation was applied to calculate the overall diagnostic performance. A classification model with feature selection and random forest (RF) classifier showed the highest accuracy. The overall diagnostic performance resulted in an accuracy of 87.1% and area-under-the-curve of 91.2%. After comparing different dimensionality reduction methods and classifiers, a highly accurate model to diagnose a patient with sarcoidosis using eNose data was created. The RF classifier and feature selection showed the best performance. The presented systematic approach could also be applied to other eNose datasets to compare methods and select the optimal diagnostic model.

Computational synchronization of microarray data with application to Plasmodium falciparum.

BACKGROUND: Microarrays are widely used to investigate the blood stage of Plasmodium falciparum infection. Starting with synchronized cells, gene expression levels are continually measured over the 48-hour intra-erythrocytic cycle (IDC). However, the cell population gradually loses synchrony during the experiment. As a result, the microarray measurements are blurred. In this paper, we propose a generalized deconvolution approach to reconstruct the intrinsic expression pattern, and apply it to P. falciparum IDC microarray data. METHODS: We develop a statistical model for the decay of synchrony among cells, and reconstruct the expression pattern through statistical inference. The proposed method can handle microarray measurements with noise and missing data. The original gene expression patterns become more apparent in the reconstructed profiles, making it easier to analyze and interpret the data. We hypothesize that reconstructed gene expression patterns represent better temporally resolved expression profiles that can be probabilistically modeled to match changes in expression level to IDC transitions. In particular, we identify transcriptionally regulated protein kinases putatively involved in regulating the P. falciparum IDC. RESULTS: By analyzing publicly available microarray data sets for the P. falciparum IDC, protein kinases are ranked in terms of their likelihood to be involved in regulating transitions between the ring, trophozoite and schizont developmental stages of the P. falciparum IDC. In our theoretical framework, a few protein kinases have high probability rankings, and could potentially be involved in regulating these developmental transitions. CONCLUSIONS: This study proposes a new methodology for extracting intrinsic expression patterns from microarray data. By applying this method to P. falciparum microarray data, several protein kinases are predicted to play a significant role in the P. falciparum IDC. Earlier experiments have indeed confirmed that several of these kinases are involved in this process. Overall, these results indicate that further functional analysis of these additional putative protein kinases may reveal new insights into how the P. falciparum IDC is regulated.

Quantifying statistical interdependence, part III: N > 2 point processes.

Stochastic event synchrony (SES) is a recently proposed family of similarity measures. First, "events" are extracted from the given signals; next, one tries to align events across the different time series. The better the alignment, the more similar the N time series are considered to be. The similarity measures quantify the reliability of the events (the fraction of "nonaligned" events) and the timing precision. So far, SES has been developed for pairs of one-dimensional (Part I) and multidimensional (Part II) point processes. In this letter (Part III), SES is extended from pairs of signals to N > 2 signals. The alignment and SES parameters are again determined through statistical inference, more specifically, by alternating two steps: (1) estimating the SES parameters from a given alignment and (2), with the resulting estimates, refining the alignment. The SES parameters are computed by maximum a posteriori (MAP) estimation (step 1), in analogy to the pairwise case. The alignment (step 2) is solved by linear integer programming. In order to test the robustness and reliability of the proposed N-variate SES method, it is first applied to synthetic data. We show that N-variate SES results in more reliable estimates than bivariate SES. Next N-variate SES is applied to two problems in neuroscience: to quantify the firing reliability of Morris-Lecar neurons and to detect anomalies in EEG synchrony of patients with mild cognitive impairment. Those problems were also considered in Parts I and II, respectively. In both cases, the N-variate SES approach yields a more detailed analysis.

EAD-GAN: A Generative Adversarial Network for Disentangling Affine Transforms in Images.

This article proposes a generative adversarial network called explicit affine disentangled generative adversarial network (EAD-GAN), which explicitly disentangles affine transform in a self-supervised manner. We propose an affine transform regularizer to force the InfoGAN to have explicit properties of affine transform. To facilitate training an affine transform encoder, we decompose the affine matrix into two separate matrices and infer the explicit transform parameters by the least-squares method. Unlike the existing approaches, representations learned by the proposed EAD-GAN have clear physical meaning, where transforms, such as rotation, horizontal and vertical zooms, skews, and translations, are explicitly learned from training data. Thus, we set different values of each transform parameter individually to generate specifically affine transformed data by the learned network. We show that the proposed EAD-GAN successfully disentangles these attributes on the MNIST, CelebA, and dSprites datasets. EAD-GAN achieves higher disentanglement scores with a large margin compared to the state-of-the-art methods on the dSprites dataset. For example, on the dSprites dataset, EAD-GAN achieves the MIG and DCI score of 0.59 and 0.96 respectively, compared to 0.37 and 0.71, respectively, for the state-of-the-art methods.

Transformer Convolutional Neural Networks for Automated Artifact Detection in Scalp EEG.

It is well known that electroencephalograms (EEGs) often contain artifacts due to muscle activity, eye blinks, and various other causes. Detecting such artifacts is an essential first step toward a correct interpretation of EEGs. Although much effort has been devoted to semi-automated and automated artifact detection in EEG, the problem of artifact detection remains challenging. In this paper, we propose a convolutional neural network (CNN) enhanced by transformers using belief matching (BM) loss for automated detection of five types of artifacts: chewing, electrode pop, eye movement, muscle, and shiver. Specifically, we apply these five detectors at individual EEG channels to distinguish artifacts from background EEG. Next, for each of these five types of artifacts, we combine the output of these channel-wise detectors to detect artifacts in multi-channel EEG segments. These segment-level classifiers can detect specific artifacts with a balanced accuracy (BAC) of 0.947, 0.735, 0.826, 0.857, and 0.655 for chewing, electrode pop, eye movement, muscle, and shiver artifacts, respectively. Finally, we combine the outputs of the five segment-level detectors to perform a combined binary classification (any artifact vs. background). The resulting detector achieves a sensitivity (SEN) of 42.0%, 32.0%, and 13.3%, at a specificity (SPE) of 95%, 97%, and 99%, respectively. This artifact detection module can reject artifact segments while only removing a small fraction of the background EEG, leading to a cleaner EEG for further analysis.

Identifying psychiatric manifestations in schizophrenia and depression from audio-visual behavioural indicators through a machine-learning approach.

Schizophrenia (SCZ) and depression (MDD) are two chronic mental disorders that seriously affect the quality of life of millions of people worldwide. We aim to develop machine-learning methods with objective linguistic, speech, facial, and motor behavioral cues to reliably predict the severity of psychopathology or cognitive function, and distinguish diagnosis groups. We collected and analyzed the speech, facial expressions, and body movement recordings of 228 participants (103 SCZ, 50 MDD, and 75 healthy controls) from two separate studies. We created an ensemble machine-learning pipeline and achieved a balanced accuracy of 75.3% for classifying the total score of negative symptoms, 75.6% for the composite score of cognitive deficits, and 73.6% for the total score of general psychiatric symptoms in the mixed sample containing all three diagnostic groups. The proposed system is also able to differentiate between MDD and SCZ with a balanced accuracy of 84.7% and differentiate patients with SCZ or MDD from healthy controls with a balanced accuracy of 82.3%. These results suggest that machine-learning models leveraging audio-visual characteristics can help diagnose, assess, and monitor patients with schizophrenia and depression.

Improving automated diagnosis of epilepsy from EEGs beyond IEDs.

Objective.Clinical diagnosis of epilepsy relies partially on identifying interictal epileptiform discharges (IEDs) in scalp electroencephalograms (EEGs). This process is expert-biased, tedious, and can delay the diagnosis procedure. Beyond automatically detecting IEDs, there are far fewer studies on automated methods to differentiate epileptic EEGs (potentially without IEDs) from normal EEGs. In addition, the diagnosis of epilepsy based on a single EEG tends to be low. Consequently, there is a strong need for automated systems for EEG interpretation. Traditionally, epilepsy diagnosis relies heavily on IEDs. However, since not all epileptic EEGs exhibit IEDs, it is essential to explore IED-independent EEG measures for epilepsy diagnosis. The main objective is to develop an automated system for detecting epileptic EEGs, both with or without IEDs. In order to detect epileptic EEGs without IEDs, it is crucial to include EEG features in the algorithm that are not directly related to IEDs.Approach.In this study, we explore the background characteristics of interictal EEG for automated and more reliable diagnosis of epilepsy. Specifically, we investigate features based on univariate temporal measures (UTMs), spectral, wavelet, Stockwell, connectivity, and graph metrics of EEGs, besides patient-related information (age and vigilance state). The evaluation is performed on a sizeable cohort of routine scalp EEGs (685 epileptic EEGs and 1229 normal EEGs) from five centers across Singapore, USA, and India.Main results.In comparison with the current literature, we obtained an improved Leave-One-Subject-Out (LOSO) cross-validation (CV) area under the curve (AUC) of 0.871 (Balanced Accuracy (BAC) of 80.9%) with a combination of three features (IED rate, and Daubechies and Morlet wavelets) for the classification of EEGs with IEDs vs. normal EEGs. The IED-independent feature UTM achieved a LOSO CV AUC of 0.809 (BAC of 74.4%). The inclusion of IED-independent features also helps to improve the EEG-level classification of epileptic EEGs with and without IEDs vs. normal EEGs, achieving an AUC of 0.822 (BAC of 77.6%) compared to 0.688 (BAC of 59.6%) for classification only based on the IED rate. Specifically, the addition of IED-independent features improved the BAC by 21% in detecting epileptic EEGs that do not contain IEDs.Significance.These results pave the way towards automated detection of epilepsy. We are one of the first to analyze epileptic EEGs without IEDs, thereby opening up an underexplored option in epilepsy diagnosis.

The Impact of Negative Symptoms and Neurocognition on Functioning in MDD and Schizophrenia.

Introduction: Negative symptoms, neurocognitive deficits and functional impairment are prevalent in individuals with major depressive disorder (MDD) and schizophrenia (SCZ). However, unlike neurocognitive deficits, little is known about the role of negative symptoms toward functioning in individuals with MDD. On the other hand, both factors are well-studied in individuals with SCZ. Thus, this study aimed to examine the contributions of negative symptoms and neurocognitive impairments in functioning in individuals with MDD, compared to individuals with SCZ. Methods: Participants included 50 individuals with MDD, 49 individuals with SCZ and 49 healthy controls. The following measures were administered-Negative Symptom Assessment (NSA-16), Brief Assessment of Cognition in Schizophrenia (BACS), Patient Health Questionnaire (PHQ-9), and MIRECC-Global Assessment of Functioning (MIRECC-GAF) to evaluate negative symptoms, neurocognition, depressive symptoms, and functioning respectively. Results: Both MDD and SCZ groups had significantly more severe negative symptoms, depressive symptoms, and poorer functioning than healthy controls. Individuals with SCZ performed significantly poorer on the BACS than the other two groups. Both negative symptoms and neurocognition were significantly correlated with social and occupational functioning in SCZ. Motivation subdomain of the negative symptoms was significantly correlated with occupational functioning, while depressive symptoms correlated with functioning in MDD. Conclusion: Both negative symptoms and neurocognitive deficits appear to play differential roles on individual domains of functioning between MDD and SCZ. Future longitudinal studies with larger sample sizes should be done for a better understanding about the associations between the factors and functioning.

Comparative study of emotion recognition and theory of mind between major depressive disorder and schizophrenia.

BACKGROUND: Social cognition as a transdiagnostic construct between major depressive disorder (MDD) and schizophrenia (SCZ) is not well understood. This may be attributed to the variability of social cognitive measures indexing the same construct. This study aims to compare emotion recognition and theory of mind domains, known to be impaired in SCZ, between MDD and SCZ. METHODS: Three groups of participants (NTotal = 150) were enrolled in this study: MDD (n = 51), SCZ (n = 50) and healthy controls (HC; n = 49). Emotion recognition was assessed on the Bell Lysaker Emotion Recognition Task (BLERT) and Penn Emotion Recognition Task (ER40); theory of mind was measured on The Awareness of Social Inference Test (TASIT). Mixed ANCOVAs were utilised to compare social cognitive performance across the groups. RESULTS: SCZ performed poorer in all 3 social cognition tasks compared to both MDD and HC. No statistically significant difference in social cognitive performance was observed between MDD and HC. CONCLUSIONS: This study serves as an effort towards employing the same standardised social cognitive measures for direct comparison of performance patterns across diagnostic groups. Future work is needed to extend this in larger samples of different illness severity and diagnostic categories.

Rapid annotation of seizures and interictal-ictal-injury continuum EEG patterns.

BACKGROUND: Manual annotation of seizures and interictal-ictal-injury continuum (IIIC) patterns in continuous EEG (cEEG) recorded from critically ill patients is a time-intensive process for clinicians and researchers. In this study, we evaluated the accuracy and efficiency of an automated clustering method to accelerate expert annotation of cEEG. NEW METHOD: We learned a local dictionary from 97 ICU patients by applying k-medoids clustering to 592 features in the time and frequency domains. We utilized changepoint detection (CPD) to segment the cEEG recordings. We then computed a bag-of-words (BoW) representation for each segment. We further clustered the segments by affinity propagation. EEG experts scored the resulting clusters for each patient by labeling only the cluster medoids. We trained a random forest classifier to assess validity of the clusters. RESULTS: Mean pairwise agreement of 62.6% using this automated method was not significantly different from interrater agreements using manual labeling (63.8%), demonstrating the validity of the method. We also found that it takes experts using our method 5.31 ±â€¯4.44 min to label the 30.19 ±â€¯3.84 h of cEEG data, more than 45 times faster than unaided manual review, demonstrating efficiency. COMPARISON WITH EXISTING METHODS: Previous studies of EEG data labeling have generally yielded similar human expert interrater agreements, and lower agreements with automated methods. CONCLUSIONS: Our results suggest that long EEG recordings can be rapidly annotated by experts many times faster than unaided manual review through the use of an advanced clustering method.

Predicting Real-World Functioning in Schizophrenia: The Relative Contributions of Neurocognition, Functional Capacity, and Negative Symptoms.

Neurocognition and functional capacity are commonly reported predictors of real-world functioning in schizophrenia. However, the additional impact of negative symptoms, specifically its subdomains, i.e., diminished expression (DE) and avolition-apathy (AA), on real-world functioning remains unclear. The current study assessed 58 individuals with schizophrenia. Neurocognition was assessed with the Brief Assessment of Cognition in Schizophrenia, functional capacity with the UCSD Performance-based Skills Assessment (UPSA-B), and negative symptoms with the Negative Symptom Assessment-16. Real-world functioning was assessed with the Multnomah Community Ability Scale (MCAS) with employment status as an additional objective outcome. Hierarchical regressions and sequential logistic regressions were used to examine the associations between the variables of interest. The results show that global negative symptoms contribute substantial additional variance in predicting MCAS and employment status above and beyond the variance accounted for by neurocognition and functional capacity. In addition, both AA and DE predict the MCAS after controlling for cognition and functional capacity. Only AA accounts for additional variance in employment status beyond that by UPSA-B. In summary, negative symptoms contribute substantial additional variance in predicting both real-world functioning and employment outcomes after accounting for neurocognition and functional capacity. Our findings emphasize both DE and AA as important treatment targets in functional recovery for people with schizophrenia.