At home adaptive dual target deep brain stimulation in Parkinson's disease with proportional control.

Continuous deep brain stimulation (cDBS) of the subthalamic nucleus (STN) or globus pallidus is an effective treatment for the motor symptoms of Parkinson's disease. The relative benefit of one region over the other is of great interest but cannot usually be compared in the same patient. Simultaneous DBS of both regions may synergistically increase the therapeutic benefit. Continuous DBS is limited by a lack of responsiveness to dynamic, fluctuating symptoms intrinsic to the disease. Adaptive DBS (aDBS) adjusts stimulation in response to biomarkers to improve efficacy, side effects, and efficiency. We combined bilateral DBS of both STN and globus pallidus (dual target DBS) in a prospective within-participant, clinical trial in six patients with Parkinson's disease (n = 6, 55-65 years, n = 2 females). Dual target cDBS was tested for Parkinson's disease symptom control annually over 2 years, measured by motor rating scales, on time without dyskinesia, and medication reduction. Random amplitude experiments probed system dynamics to estimate parameters for aDBS. We then implemented proportional-plus-integral aDBS using a novel distributed (off-implant) architecture. In the home setting, we collected tremor and dyskinesia scores as well as individualized ß and DBS amplitudes. Dual target cDBS reduced motor symptoms as measured by Unified Parkinson's Disease Rating Scale (UPDRS) to a greater degree than either region alone (P < 0.05, linear mixed model) in the cohort. The amplitude of ß-oscillations in the STN correlated to the speed of hand grasp movements for five of six participants (P < 0.05, Pearson correlation). Random amplitude experiments provided insight into temporal windowing to avoid stimulation artefacts and demonstrated a correlation between STN ß amplitude and DBS amplitude. Proportional plus integral control of aDBS reduced average power, while preserving UPDRS III scores in the clinic (P = 0.28, Wilcoxon signed rank), and tremor and dyskinesia scores during blinded testing at home (n = 3, P > 0.05, Wilcoxon ranked sum). In the home setting, DBS power reductions were slight but significant. Dual target cDBS may offer an improvement in treatment of motor symptoms of Parkinson's disease over DBS of either the STN or globus pallidus alone. When combined with proportional plus integral aDBS, stimulation power may be reduced, while preserving the increased benefit of dual target DBS.

Signet ring cells and conditional survival after trimodality therapy for esophageal adenocarcinoma.

BACKGROUND AND METHODS: Although signet ring cell (SRC) histology is associated with resistance to neoadjuvant chemoradiotherapy and worse overall survival (OS) in esophageal adenocarcinoma (EAC), its prognostic relationship among patients who survive the early period following resection is unknown. EAC patients who underwent trimodality therapy at a single institution (2006-2018) were identified. Bayesian multivariable regression (BMR) analyses of OS and additional OS from a 3-year landmark were performed. RESULTS: Of 631 patients, SRCs were present in 16.0% (N = 101). SRC was associated with shorter median OS (45.8 [95% confidence interval: 31.0-96.7] vs. 79.8 [63.0-107.2] months; p = 0.014). In BMR analysis, the absence of an SRC component was moderately associated with improved OS (probability of beneficial effect, PBE = 0.879). Three-year conditional BMR analysis of additional OS (N = 357) showed that SRC status no longer had a prognostic effect (PBE = 0.546); higher pathological stage was strongly associated with worse additional OS (PBE < 0.001). CONCLUSIONS: The presence of SRC portends worse OS following trimodality therapy for EAC. However, this prognostic impact is dynamic and abates by 3 years postoperatively. In contrast, a higher pathological stage is strongly associated with poor overall and 3-year conditional survival. DISCUSSION: These findings may inform postoperative patient counseling and surveillance protocols.

CD73 expression defines immune, molecular, and clinicopathological subgroups of lung adenocarcinoma.

INTRODUCTION: CD73 is a membrane-bound enzyme crucial in adenosine generation. The adenosinergic pathway plays a critical role in immunosuppression and in anti-tumor effects of immune checkpoint inhibitors (ICI). Here, we interrogated CD73 expression in a richly annotated cohort of human lung adenocarcinoma (LUAD) and its association with clinicopathological, immune, and molecular features to better understand the role of this immune marker in LUAD pathobiology. MATERIALS AND METHODS: Protein expression of CD73 was evaluated by immunohistochemistry in 106 archived LUADs from patients that underwent surgical treatment without neoadjuvant therapy. Total CD73 (T +) was calculated as the average of luminal (L +) and basolateral (BL +) percentage membrane expression scores for each LUAD and was used to classify tumors into three groups based on the extent of T CD73 expression (high, low, and negative). RESULTS: CD73 expression was significantly and progressively increased across normal-appearing lung tissue, adenomatous atypical hyperplasia, adenocarcinoma in situ, minimally invasive adenocarcinoma, and LUAD. In LUAD, BL CD73 expression was associated with an increase in PD-L1 expression in tumor cells and increase of tumor-associated immune cells. Stratification of LUADs based on T CD73 extent also revealed that tumors with high expression of this enzyme overall exhibited significantly elevated immune infiltration and PD-L1 protein expression. Immune profiling demonstrated that T-cell inflammation and adenosine signatures were significantly higher in CD73-expressing lung adenocarcinomas relative to those lacking CD73. CONCLUSION: Our study suggests that higher CD73 expression is associated with an overall augmented host immune response, suggesting potential implications in the immune pathobiology of early stage lung adenocarcinoma. Our findings warrant further studies to explore the role of CD73 in immunotherapeutic response of LUAD.

Pulmonary resection for tissue harvest in adoptive tumor-infiltrating lymphocyte therapy: Safety and feasibility.

BACKGROUND AND OBJECTIVES: Adoptive T-cell therapies (ACTs) using expansion of tumor-infiltrating lymphocyte (TIL) populations are of great interest for advanced malignancies, with promising response rates in trial settings. However, postoperative outcomes following pulmonary TIL harvest have not been widely documented, and surgeons may be hesitant to operate in the setting of widespread disease. METHODS: Patients who underwent pulmonary TIL harvest were identified, and postoperative outcomes were studied, including pulmonary, cardiovascular, infectious, and wound complications. RESULTS: 83 patients met inclusion criteria. Pulmonary TIL harvest was undertaken primarily via a thoracoscopy with a median operative blood loss and duration of 30 ml and 65 min, respectively. The median length of stay was 2 days. Postoperative events were rare, occurring in only five (6%) patients, including two discharged with a chest tube, one discharged with oxygen, one episode of urinary retention, and one blood transfusion. No reoperations occurred. The median time from TIL harvest to ACT infusion was 37 days. CONCLUSIONS: Pulmonary TIL harvest is safe and feasible, without major postoperative events in our cohort. All patients were able to receive intended ACT infusion without delays. Therefore, thoracic surgeons should actively participate in ongoing ACT trials and aggressively seek to enroll patients on these protocols.

18F-fluorodeoxyglucose positron emission tomography correlates with tumor immunometabolic phenotypes in resected lung cancer.

Enhanced tumor glycolytic activity is a mechanism by which tumors induce an immunosuppressive environment to resist adoptive T cell therapy; therefore, methods of assessing intratumoral glycolytic activity are of considerable clinical interest. In this study, we characterized the relationships among tumor 18F-fluorodeoxyglucose (FDG) retention, tumor metabolic and immune phenotypes, and survival in patients with resected non-small cell lung cancer (NSCLC). We retrospectively analyzed tumor preoperative positron emission tomography (PET) 18F-FDG uptake in 59 resected NSCLCs and investigated correlations between PET parameters (SUVMax, SUVTotal, SUVMean, TLG), tumor expression of glycolysis- and immune-related genes, and tumor-associated immune cell densities that were quantified by immunohistochemistry. Tumor glycolysis-associated immune gene signatures were analyzed for associations with survival outcomes. We found that each 18F-FDG PET parameter was positively correlated with tumor expression of glycolysis-related genes. Elevated 18F-FDG SUVMax was more discriminatory of glycolysis-associated changes in tumor immune phenotypes than other 18F-FDG PET parameters. Increased SUVMax was associated with multiple immune factors characteristic of an immunosuppressive and poorly immune infiltrated tumor microenvironment, including elevated PD-L1 expression, reduced CD57+ cell density, and increased T cell exhaustion gene signature. Elevated SUVMax identified immune-related transcriptomic signatures that were associated with enhanced tumor glycolytic gene expression and poor clinical outcomes. Our results suggest that 18F-FDG SUVMax has potential value as a noninvasive, clinical indicator of tumor immunometabolic phenotypes in patients with resectable NSCLC and warrants investigation as a potential predictor of therapeutic response to immune-based treatment strategies.

Importance of resection for locoregional disease control in Masaoka stage IVA thymic neoplasms.

BACKGROUND AND OBJECTIVES: It is unclear if a specific strategy for simultaneous treatment of primary thymic neoplasms and pleural metastases confers benefit for Masaoka stage IVA disease. We reviewed our experience with thymic neoplasms with concurrent pleural metastases to identify factors influencing outcomes. METHODS: Records of patients who presented with stage IVA thymic neoplasms from 2000 to 2018 were assessed. Multivariate Cox proportional hazards analyses were completed to determine predictors of progression-free and overall survival. RESULTS: Forty-eight patients were identified, including 34 (71%) who underwent surgery. Median overall and progression-free survival were 123 and 21 months, respectively. The extent of resection varied, and was most commonly thymectomy plus partial pleurectomy (22, 65%). Median progression-free survival for patients who underwent surgical resection versus those who had not was 24 versus 12 months (P = .018). Following surgical resection, mediastinal recurrence was uncommon (2, 6%, vs 7, 50% nonoperatively). Five-year survival rates in these groups were suggestive of possible benefit to surgery (87% vs 68%). CONCLUSIONS: Thymic neoplasms with pleural dissemination represents a treatment challenge. As part of a multidisciplinary approach, surgery appears to be associated with more favorable long-term results, although selection bias may account for some of the survival differences observed.

High mutational concordance between primary colorectal tumors and associated pulmonary metastases.

BACKGROUND AND OBJECTIVES: Precision medicine has altered the management of colorectal cancer (CRC). However, the concordance of mutational findings between primary CRC tumors and associated pulmonary metastases (PM) is not well-described. This study aims to determine the concordance of genomic profiles between primary CRC and PM. METHODS: Patients treated for colorectal PM at a single institution from 2000 to 2017 were identified. Mutational concordance was defined as either both wild-type or both mutant alleles in lung and colorectal lesion; genes with opposing mutational profiles were reported as discordant. RESULTS: Thirty-eight patients met inclusion criteria, among whom KRAS, BRAF, NRAS, MET, RET, and PIK3CA were examined for concordance. High concordance was demonstrated among all evaluated genes, ranging from 86% (KRAS) to 100% concordance (NRAS, RET, and MET). De novo KRAS mutations were detected in the PM of 4 from 35 (11%) patients, 3 of whom had previously received anti-epidermal growth factor receptor (EGFR) therapy. Evaluation of Cohen's κ statistic demonstrated moderate to perfect correlation among evaluated genes. CONCLUSIONS: Because high intertumoral genomic homogeneity exists, it may be reasonable to use primary CRC mutational profiles to guide prognostication and targeted therapy for PM. However, the possibility of de novo KRAS-mutant PM should be considered, particularly among patients previously treated with anti-EGFR therapy.

Frontal alpha asymmetry in schizotypy: electrophysiological evidence for motivational dysfunction.

Introduction: Schizotypy is defined as personality traits reflecting an underlying risk for schizophrenia-spectrum disorders. As yet, there is a dearth of suitable objective markers for measuring schizotypy. Frontal alpha asymmetry, characterised by reduced left versus right frontal region activity, reflects trait-like diminished approach-related systems and has been found in schizophrenia. Methods: The present study used electroencephalography (EEG) recorded on a consumer-grade mobile headset to examine asymmetric resting-state frontal alpha, beta, and gamma power within the multidimensional schizotypy (e.g. positive, negative, disorganised) during a three-minute "eyes closed" resting period in college undergraduates (n=49). Results: Findings suggest that schizotypy was exclusively related to reduced left versus right-lateralised power in the alpha frequency (8.1-12.9 Hz., R2= .16). Follow-up analysis suggested that positive schizotypy was uniquely associated with increased right alpha activity, indicating increased withdrawal motivation. Conclusions: Frontal asymmetry is a possible ecologically valid objective marker for schizotypy that may be detectable using easily accessible, consumer-grade technology.

Colorectal cancer mutations are associated with survival and recurrence after pulmonary metastasectomy.

BACKGROUND AND OBJECTIVES: While knowledge has grown extensively regarding the impact of mutations on colorectal cancer prognosis, their role in outcomes after pulmonary metastasectomy (PM) remains minimally understood. We sought to determine the prognostic role of mutant disease on survival and recurrence after metastasectomy. METHODS: Patients with available tumor sequencing profiles who underwent PM for colorectal cancer at a single institution from 2011 to 2017 were reviewed. Various demographic and clinicopathologic factors, as well as mutational status, were tested in the Cox regression analyses to identify predictors of survival and disease-free survival (DFS). RESULTS: A total of 130 patients met inclusion criteria, among whom 78 (60%) were male and the mean age was 57 years. The median survival time and 5-year survival rate were 58.2 months and 47%, respectively. A single pulmonary nodule was present in 54%. Disease recurrence occurred for 87 (67%) patients, including 75 (58%) who had at least one lung recurrence after metastasectomy at a median time to recurrence of 19.4 months. Upon multivariable analysis, RAS and TP53 mutations were associated with shorter survival DFS, while APC is associated with prolonged survival. CONCLUSIONS: After metastasectomy for colorectal cancer, mutations in RAS, TP53, and APC play an important role in survival and recurrence.

Patient Experience with Rechargeable Implantable Pulse Generator Deep Brain Stimulation for Movement Disorders.

BACKGROUND/AIMS: Nonrechargeable deep brain stimulation implantable pulse generators (IPGs) for movement disorders require surgical replacement every few years due to battery depletion. Rechargeable IPGs reduce frequency of replacement surgeries and inherent risks of complications but require frequent recharging. Here, we evaluate patient experience with rechargeable IPGs and define predictive characteristics for higher satisfaction. METHODS: We contacted all patients implanted with rechargeable IPGs at a single center in a survey-based study. We analyzed patient satisfaction with respect to age, diagnosis, target, charging duration, and body mass index. We tabulated hardware-related adverse events. RESULTS: Dystonia patients had significantly higher satisfaction than Parkinson's disease patients in recharging, display, programmer, and training domains. Common positive responses were "fewer surgeries" and "small size." Common negative responses were "difficulty finding the right position to recharge" and "need to recharge every day." Hardware-related adverse events occurred in 21 of 59 participants. CONCLUSION: Patient experience with rechargeable IPGs was largely positive; however, frustrations with recharging and adverse events were common. Dystonia diagnosis was most predictive of high satisfaction across multiple categories, potentially related to expected long disease duration with need for numerous IPG replacements.

Should endoscopic mucosal resection be attempted for cT2N0 esophageal cancer?

Endoscopic mucosal resection (EMR) can be an effective therapy for superficial esophageal cancer. Many patients with cT2 invasion by endoscopic ultrasound (EUS) receive surgery but are subsequently found to have superficial disease. The purpose of this study was to investigate the safety profile and the added value of attempting EMR for EUS-staged cT2N0 esophageal cancer. A retrospective review was performed at a single institution from 2008 to 2017. Patients who were staged cT2N0 by EUS were identified from a prospectively maintained surgical database. Among 75 patients identified for analysis, 30 underwent an attempt at EMR. No perforations or other immediate complications occurred. EMR was more likely to be attempted among older patients (P = 0.001) with smaller tumor size (P < 0.001) and diminished SUVmax (P = 0.001). At the time of treatment, EMR was successful in clearing all known disease among 17/30 patients, with 12 representing pT1a or less and 5 representing pT1b with negative margins. Among the 17 patients for whom EMR was able to clear all known disease, there were no recurrences or cancer-related deaths. Although all the patients were staged as cT2N0 by EUS, many patients were identified by EMR to have superficial disease. There were no perforations or other adverse events related to EMR. Furthermore, EMR cleared all known disease among 17 patients with no known recurrences or cancer-related deaths. The results indicate that EMR for cT2N0 esophageal cancer is a safe diagnostic option that is therapeutic for some.

Predictors of the response of operating room personnel to surgeon behaviors.

PURPOSE: Several studies have assessed the physician-nurse relationship, particularly between females working together. While the surgeon workforce is increasingly represented by females, gendered relationships and biases in the operating room remain largely unstudied. METHODS: We performed a prospective randomized study in which operative support staff, including nurses, surgical technologists, and surgical assistants, assessed scenarios describing questionable surgeon behaviors. Respondents were randomized to a survey that either discussed a female or male surgeon. For each scenario, one of the four standardized responses was selected. The respondents' assessments of surgeon behaviors were analyzed. RESULTS: The response rate was 4.4% (3128/71143). Females were more likely than males to deem the surgeon's behavior inappropriate regardless of surgeon sex (p = 0.001). The likelihood of writing up the surgeon was predicted by role, with technologists, nurses, and assistants reporting surgeons at frequencies of 65.5%, 53.2%, and 48.8%, respectively (p = 0.008). While the overall respondents did not show a propensity to write-up either sex differentially (p = 0.070), technologists were significantly more likely to report female surgeons than male surgeons (p = 0.006). CONCLUSION: Characteristics of operative personnel were correlated with varying tolerance of surgeon behaviors, with specific subgroups more critical of female surgeons than males. Further exploration of these perceptions will serve to improve interactions in a diverse workplace.

Predictors of survival after resection of primary sarcomas of the chest wall-A large, single-institution series.

BACKGROUND AND OBJECTIVES: Chest wall sarcomas are rare and may demonstrate heterogeneous features. Surgery remains the mainstay of treatment with chemotherapy and radiotherapy used as adjuncts. Herein, we report outcomes of a large cohort of patients with primary chest wall sarcoma who underwent resection. METHODS: Records of 121 patients who underwent resection for primary chest wall sarcoma between 1998 and 2013 were reviewed. A thoracic pathologist reexamined all tumors and categorized them according to grade. Univariable and multivariable Cox analyses were conducted to identify predictors of overall survival (OS). RESULTS: The median age was 45.0 (range, 11-81) years, and most tumors (63.6%, 77) were high grade. The median tumor size was 7 cm (range, 1-21 cm). Fifty-nine (48.8%) patients received neoadjuvant chemotherapy and 12 (9.9%) received neoadjuvant radiotherapy. A complete resection was achieved in 103 (85.1%) patients. Neoadjuvant chemotherapy (P = 0.532) and radiation ( P = 1.000) were not associated with a complete resection. Five-year OS among patients undergoing R0 and R1 resections was 61.9% and 27.8%, respectively. Multivariable analysis identified high grade (HR, 15.21; CI, 3.57-64.87; P < 0.001), R1 (HR, 3.10; CI, 1.40-6.86; P = 0.005), R2 resection (HR, 5.18; CI, 1.91-14.01; P = 0.001), and age (HR, 1.02; CI, 1.01-1.03; P = 0.002) as predictors of OS. CONCLUSIONS: In this series of resected chest wall sarcomas, complete resection and tumor grade remain the most important survival predictors. Individual decisions are required for the utilization of neoadjuvant therapy.

Blunted vocal affect and expression is not associated with schizophrenia: A computerized acoustic analysis of speech under ambiguous conditions.

INTRODUCTION: Patients with schizophrenia are consistently rated by clinicians as having high levels of blunted vocal affect and alogia. However, objective technologies have often failed to substantiate these abnormalities. It could be the case that negative symptoms are context-dependent. OBJECTIVES: The present study examined speech elicited under conditions demonstrated to exacerbate thought disorder. METHODS: The Rorschach Test was administered to 36 outpatients with schizophrenia and 25 nonpatient controls. Replies to separate "perceptual" and "memory" phases were analyzed using validated acoustic analytic methods. RESULTS: Compared to nonpatient controls, schizophrenia patients did not display abnormal speech expression on objective measure of blunted vocal affect or alogia. Moreover, clinical ratings of negative symptoms were not significantly correlated with objective measures. CONCLUSIONS: These findings suggest that in patients with schizophrenia, vocal affect/alogia is generally unremarkable under ambiguous conditions. Clarifying the nature of blunted vocal affect and alogia, and how objective measures correspond to what clinicians attend to when making clinical ratings are important directions for future research.

Cognitive functioning in schizotypy through the lens of the accessibility model.

INTRODUCTION: Individuals with schizotypy self-report subjective cognitive complaints commensurate with deficits reported by individuals with schizophrenia. In contrast to schizophrenia, objective deficits in memory are modest in individuals with schizotypy, as compared to their self-reported cognitive complaints. It has been proposed that abnormalities in semantic memory systems may underlie this dysjunction. METHODS: This study employed a modified verbal memory paradigm in a sample of 87 individuals with psychometrically defined schizotypy. Appraisals of memory performance were evaluated across global (i.e. drawing on semantic memory systems and assessing perceived typical performance) and situation-specific (i.e. drawing on episodic memory systems) epochs. Objective memory performance was assessed using a verbal recall paradigm. RESULTS: Individuals with schizotypy did not differ in situation-specific appraisals or in objective memory performance. Global appraisals of memory performance predicted negative and disorganised schizotypy scores. No other measure of memory performance predicted any facet of schizotypy. Individuals with schizotypy appraised their global memory performance higher than controls at a medium effect. CONCLUSIONS: Higher order global appraisals of cognitive performance, subsumed within semantic networks, may be important in the subjective-objective paradox in schizotypy, suggesting the importance of considering demand characteristics when assessing measures of neurocognitive performance in individuals with schizotypy.

A psychometric investigation of "macroscopic" speech measures for clinical and psychological science.

The analysis of vocal expression is a critical endeavor for psychological and clinical sciences and is an increasingly popular application for computer-human interfaces. Despite this, and despite advances in the efficiency, affordability, and sophistication of vocal analytic technologies, there is considerable variability across studies regarding what aspects of vocal expression are studied. Vocal signals can be quantified in a myriad of ways, and their underlying structure, at least with respect to "macroscopic" measures from extended speech, is presently unclear. To address this issue, we evaluated the psychometric properties-notably, the structural and construct validity-of a systematically defined set of global vocal features. Our analytic strategy focused on (a) identifying redundant variables among this set, (b) employing principal components analysis (PCA) to identify nonoverlapping domains of vocal expression, (c) examining the degrees to which the vocal variables are modulated as a function of changes in speech task, and (d) evaluating the relationship between the vocal variables and cognitive (i.e., verbal fluency) and clinical (i.e., depression, anxiety, and hostility) variables. Spontaneous speech samples from 11 independent studies of young adults (>60 s in length), employing one of three different speaking tasks, were examined (N = 1,350). Confounding variables (i.e., sex, ethnicity) were statistically controlled for. The PCA identified six distinct domains of vocal expression. Collectively, vocal expression (defined in terms of these domains) was modulated as a function of speech task and was related to the cognitive and clinical variables. These findings provide empirically grounded implications for the study of vocal expression in psychological and clinical sciences.

In vitro comparison of two different mechanical circulatory support devices installed in series and in parallel.

This study investigates the novel approach of placing a ventricular assist pump in the descending aorta in series configuration with the heart and compares it with the two traditional approaches of left-ventricle-to-ascending-aorta (LV-AA) and left-ventricle-to-descending-aorta (LV-DA) placement in parallel with the heart. Experiments were conducted by using the in-house simulator of the cardiovascular blood-flow loop (SCVL). The results indicate that the use of the LV-AA in-parallel configuration leads to a significant improvement in the systemic and pulmonic flow as the level of continuous flow is increased; however, this approach is considered highly invasive. The use of the LV-DA in-parallel configuration leads to an improvement in the systemic and pulmonic flow at lower levels of continuous flow but at higher levels of pump support leads to retrograde flow. In both in-parallel configurations, increasing the level of pump continuous flow leads to a decrease in pulsatility to a certain extent. The results of placing the pump in the descending aorta in series configuration show that the pressure drop upstream of the pump facilitates cardiac output as a result of afterload reduction. In addition, the pressure rise downstream of the pump may assist with renal perfusion. However, at the same time, the pressure drop generated at the proximal part of the descending aorta induces a slight drop in carotid perfusion, which would be autoregulated by the brain in a native cardiovascular system. The pulse wave analysis shows that placing the pump in the descending aorta leads to improved pulsatility in comparison with the traditional in-parallel configurations.

Pupillary responses as a biomarker of cognitive effort and the impact of task difficulty on reward processing in schizophrenia.

Negative symptoms of schizophrenia robustly predict functional outcomes but remain relatively resistant to available treatments. Better measures of negative symptoms, especially motivational deficits, are needed to better understand these symptoms and improve treatment development. Recent research shows promise in linking behavioral effort tasks to motivational negative symptoms, reward processing deficits, and defeatist attitudes, but few studies account for individual or group (patient v. control) differences in cognitive ability to perform the tasks. Individuals with poorer abilities might be less motivated to perform tasks because they find them more difficult to perform. This study used a personalized digit span task to control task difficulty while measuring task effort via pupillary responses (greater dilation indicates greater cognitive effort) at varying monetary rewards ($1 & $2). Participants with schizophrenia (N = 34) and healthy controls (N = 41) performed a digit span task with personalized max span lengths and easy (max- 2 digits) and overload (max+ 2 digits) conditions. Consistent with many studies, pupillary responses (cognitive effort) increased with greater difficulty until exceeding capacity. A similar pattern of reward responsivity was seen in both groups, such that greater reward increased dilation (effort) comparably for both groups when difficulty was within capacity. Neither patients nor controls exerted increased effort for greater reward when difficulty exceeded capacity. In patients, positive relationships were found between pupil dilation and defeatist performance beliefs if task difficulty was within capacity; a relationship that reversed if the task was too difficult. The findings demonstrate the importance of accounting for cognitive capacity and task difficulty when evaluating motivation and reward sensitivity and illustrate the utility of pupillary responses as an objective measure of effort in schizophrenia.