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While the process of teaching student perfusionists has been in development since the 1950s, the publication of the processes to improve perfusion clinical education has been largely lacking. Publications regarding education from other allied health and medical fields have shown the value of student-centered learning. The use of reflective practice to move perfusion students from thinking about actions after cardiopulmonary bypass (CPB) to reflecting and reacting on actions during CPB is better encouraged by moving from a teacher-centered to a student-centered clinical model. Our institution’s teaching process has developed into a multi-point procedure to make our students into reflective practicing clinicians. Student preceptor evaluations were reversed to allow the students to evaluate themselves first, with feedback from the preceptor given subsequently. Additionally, a biweekly student educational session, where the student chooses a topic and reviews current evidence-based practice, was instituted. The clinical program director serves as the moderator and clinical expert to facilitate problem-based learning during the sessions. Students were also given three skill/experience levels with goals to reach and move through during the rotation. These student levels were also helpful to our preceptors in knowing what each student’s skill level was throughout their rotation. Overall, moving from a teacher-centered to a student-centered clinical rotation has helped make students familiar with reflective practice, self-evaluation, evidence-based practice, and problem-based learning. The incorporation of these processes will hopefully lead students to become lifelong reflective perfusionists.

Purpose: Recognizing the negative impact that antipsychotic-induced movement disorders have on the quality of life and treatment outcomes in bipolar disorder (BD), this study aimed to assess clinical correlates and antipsychotic use patterns of tardive dyskinesia (TD+) in BD., Materials and Methods: Participants with and without TD were included. Clinical variables were compared using t-test and χ2 test. Antipsychotic use patterns in TD+, including number of trials, mean doses, and estimated cumulative exposure, were assessed in a case-only analysis., Results: The prevalence rate of TD was 5.1%. In comparison to the TD- group (n = 1074), TD+ participants (n = 58) were older, more likely to be female and have type I bipolar illness. There were 60.3% of the TD+ group that continued using antipsychotics at study entry and had a mean cumulative exposure to antipsychotics of 18.2 ± 15.6 years. Average dose, in haloperidol equivalents, was 5.9 ± 3.5 mg and 77.7% of the trials were second-generation antipsychotics., Conclusions: This study confirms previously identified TD risk factors, such as age, sex, and bipolar subtype in a large BD cohort. Limitations included a cross-sectional design and the lack of tardive illness severity assessment. As atypical antipsychotics continue to be primary mood stabilization treatment, attempting to harmonize large data sets to identify additional biomarkers of tardive risk will optimize individualized care for patients with BD., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: To evaluate the prevalence and clinical correlates of lifetime migraine among patients with bipolar disorder (BD)., Methods: In a cross-sectional study, we evaluated 721 adults with BD from the Mayo Clinic Bipolar Disorder Biobank and compared clinical correlates of those with and without a lifetime history of migraine. A structured clinical interview (DSM-IV) and a clinician-assessed questionnaire were utilized to establish a BD diagnosis, lifetime history of migraine, and clinical correlates., Results: Two hundred and seven (29%) BD patients had a lifetime history of migraine. BD patients with migraine were younger and more likely to be female as compared to those without migraine (p values <0.01). In a multivariate logistic regression model, younger age (OR=0.98, p<0.01), female sex (OR=2.02, p<0.01), higher shape/weight concern (OR=1.04, p=0.02), greater anxiety disorder comorbidities (OR=1.24, p<0.01), and evening chronotype (OR=1.65, p=0.03) were associated with migraine. In separate regression models for each general medical comorbidity (controlled for age, sex, and site), migraines were significantly associated with fibromyalgia (OR=3.17, p<0.01), psoriasis (OR=2.65, p=0.03), and asthma (OR=2.0, p<0.01). Participants with migraine were receiving ADHD medication (OR=1.53, p=0.05) or compounds associated with weight loss (OR=1.53, p=0.02) at higher rates compared to those without migraine., Limitations: Study design precludes determination of causality. Migraine subtypes and features were not assessed., Conclusions: Migraine prevalence is high in BD and is associated with a more severe clinical burden that includes increased comorbidity with pain and inflammatory conditions. Further study of the BD-migraine phenotype may provide insight into common underlying neurobiological mechanisms., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Aims: Long-term lithium therapy (LTLT) has been associated with kidney insufficiency in bipolar disorder (BD). We aimed to investigate the risk factors of chronic kidney disease (CKD) development and progression among BD patients receiving LTLT., Methods: We included adult patients with BD on LTLT (≥1 year) who were enrolled in the Mayo Clinic Bipolar Biobank, Rochester, Minnesota. We reviewed electronic medical records to extract information related to lithium therapy and kidney-related data to assess changes in the estimated glomerular filtration rate (eGFR). CKD severity was assessed based on eGFR., Results: Among 154 patients who received LTLT, 41 patients (27%) developed CKD, of whom 20 (49%) patients continued lithium (continuers) and 19 (46%) discontinued it (discontinuers). The median time to stage 3 CKD development was 21.7 years from the start of Li treatment. Type-2 diabetes mellitus and benzodiazepine use were independent predictors for CKD development in the survival analysis, after controlling for age. The subsequent CKD progression rate did not differ between continuers and discontinuers (mean GFR 48.6 vs. 44.1, p = 0.13) at the end of follow-up duration (mean duration: 3.5 ± 4.4 years for continuers and 4.9 ± 5.3 years for discontinuers)., Conclusion: CKD was observed in one fourth of patients with BD receiving LTLT. There was no significant difference in the progression of CKD among Li continuers versus discontinuers, at the mean follow-up duration of 4.2 years, after the CKD diagnosis. Progression of CKD could be influenced by existing comorbidities and may not necessarily be due to lithium alone., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Several antiepileptic drugs (AEDs) have US Food and Drug Administration (FDA) approval for use as mood stabilizers in bipolar disorder (BD), but not all BD patients respond to these AED mood stabilizers (AED-MSs). To identify genetic polymorphisms that contribute to the variability in AED-MS response, we performed a discovery genome-wide association study (GWAS) of 199 BD patients from the Mayo Clinic Bipolar Disorder Biobank. Most of these patients had been treated with the AED-MS valproate/divalproex and/or lamotrigine. AED-MS response was assessed using the Alda scale, which quantifies clinical improvement while accounting for potential confounding factors. We identified two genome-wide significant single-nucleotide polymorphism (SNP) signals that mapped to the THSD7A (rs78835388, P = 7.1E-09) and SLC35F3 (rs114872993, P = 3.2E-08) genes. We also identified two genes with statistically significant gene-level associations: ABCC1 (P = 6.7E-07; top SNP rs875740, P = 2.0E-6), and DISP1 (P = 8.9E-07; top SNP rs34701716, P = 8.9E-07). THSD7A SNPs were previously found to be associated with risk for several psychiatric disorders, including BD. Both THSD7A and SLC35F3 are expressed in excitatory/glutamatergic and inhibitory/γ-aminobutyric acidergic (GABAergic) neurons, which are targets of AED-MSs. ABCC1 is involved in the transport of valproate and lamotrigine metabolites, and the SNPs in ABCC1 and DISP1 with the strongest evidence of association in our GWAS are strong splicing quantitative trait loci in the human gut, suggesting a possible influence on drug absorption. In conclusion, our pharmacogenomic study identified novel genetic loci that appear to contribute to AED-MS treatment response, and may facilitate precision medicine in BD., (© 2020 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Objective: Our aim was to investigate evening chronotype, a proxy marker of circadian system dysfunction, as a clinical subphenotype in bipolar disorder (BD)., Methods: In this cross-sectional study, 773 BD participants and 146 control subjects were evaluated using the Structured Clinical Interview for DSM-IV and a set of questionnaires. Chronotype was determined using item-5 from the reduced Morningness-Eveningness Questionnaire. Univariate analyses and regression models were used to compare evening and non-evening chronotype in BD and chronotype association with clinical variables., Results: Overall, 205 (27%) of BD patients reported an evening chronotype. Evening chronotype was higher in a matched sub-sample of BD patients (n = 150) than in controls (24% and 5% respectively, OR=5.4, p<0.01). Compared to those with non-evening chronotypes, BD patients with an evening chronotype were younger, had an earlier age of onset of BD, and had more prior depressive and manic episodes, higher rates of rapid cycling, past suicide attempts, more comorbid anxiety and substance use disorders. Multivariate regression showed age, prior suicide attempts, and co-occurring substance use disorder were associated with evening chronotype (OR range of 0.97 to1.59). Hypertension, migraine, asthma, and obstructive sleep apnea were significantly associated with evening chronotype (OR range of 1.56 to 2.0)., Limitation: Limitations include a cross-sectional study design that precludes establishing causality. Analyses did not control for medication use. Younger participant age may prevent evaluation of associations with late-life illnesses., Conclusions: Evening chronotype may be a discrete clinical subphenotype in BD and circadian dysfunction a shared pathophysiological mechanism between psychopathology and medical morbidity., Competing Interests: Declaration of Competing Interest Dr. Romo-Nava reports support from the Brain & Behavior Research Foundation NARSAD Young Investigator Award; receiving nonfinancial support from Soterix Medical outside the submitted work; and having patent 62 581 968 pending. dr. McElroy reported receiving grants and personal fees from Allergan, Avanir, Myriad, Shire, and Sunovion; receiving grants from Brainsway, Marriott Foundation, Medibio, Neurocrine, and Novo Nordisk; receiving personal fees from Bracket, F. Hoffmann-LaRoche Limited, Mitsubishi Tanabe Pharma America, and Opiant; being a consultant to or member of the scientific advisory boards of Bracket, MedAvante, Naurex, Shire, and Sunovion; being a principal or co-investigator on studies sponsored by the Agency for Healthcare Research & Quality, AstraZeneca, Cephalon, Forest, Marriott Foundation, the National Institute of Mental Health, Orexigen Therapeutics Inc, Shire, and Takeda Pharmaceutical Company Ltd; being an inventor on US Patent 6 323 236 B2; and receiving payments from Johnson & Johnson, which has exclusive patent rights. dr.. Frye reported receiving grants from the Marriott Foundation during the conduct of the study; receiving grants from the National Institute of Alcohol Abuse and Alcoholism and National Institute of Mental Health, National Institutes of Health, Assurex Health, Myriad, and Pfizer; being a consultant to Janssen Global Services LLC; receiving other support from Mitsubishi Tanabe Pharma Corporation, Myriad, Sunovion, and Teva Pharmaceuticals; receiving travel and hotel honoraria from CME Outfitters to give a lecture for continuing medical education credit and receiving support for a presentation from Sunovion. No other disclosures are reported., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Bipolar disorder (BD) affects both sexes, but important sex differences exist with respect to its symptoms and comorbidities. For example, rapid cycling (RC) is more prevalent in females, and alcohol use disorder (AUD) is more prevalent in males. We hypothesize that X chromosome variants may be associated with sex-specific characteristics of BD. Few studies have explored the role of the X chromosome in BD, which is complicated by X chromosome inactivation (XCI). This process achieves "dosage compensation" for many X chromosome genes by silencing one of the two copies in females, and most statistical methods either ignore that XCI occurs or falsely assume that one copy is inactivated at all loci. We introduce new statistical methods that do not make these assumptions., Methods: We investigated this hypothesis in 1001 BD patients from the Genetic Association Information Network (GAIN) and 957 BD patients from the Mayo Clinic Bipolar Disorder Biobank. We examined the association of over 14,000 X chromosome single nucleotide polymorphisms (SNPs) with sex-associated BD traits using two statistical approaches that account for whether a SNP may be undergoing or escaping XCI. In the "XCI-informed approach," we fit a sex-adjusted logistic regression model assuming additive genetic effects where we coded the SNP either assuming one copy is expressed or two copies are expressed based on prior knowledge about which regions are inactivated. In the "XCI-robust approach," we fit a logistic regression model with sex, SNP, and SNP-sex interaction effects that is flexible to whether the region is inactivated or escaping XCI., Results: Using the "XCI-informed approach," which considers only the main effect of SNP and does not allow the SNP effect to differ by sex, no significant associations were identified for any of the phenotypes. Using the "XCI-robust approach," intergenic SNP rs5932307 was associated with BD (P = 8.3 × 10 -8 ), with a stronger effect in females (odds ratio in males (OR M ) = 1.13, odds ratio in females for a change of two allele copies (OR W2 ) = 3.86)., Conclusion: X chromosome association studies should employ methods which account for its unique biology. Future work is needed to validate the identified associations with BD, to formally assess the performance of both approaches under different true genetic architectures, and to apply these approaches to study sex differences in other conditions.

Bipolar disorder (BD) is highly heterogeneous in symptomatology. Narrowing the clinical phenotype may increase the power to identify risk genes that contribute to particular BD subtypes. This study was designed to test the hypothesis that genetic overlap between schizophrenia (SZ) and BD is higher for BD with a history of manic psychosis. Analyses were conducted using a Mayo Clinic Bipolar Biobank cohort of 957 bipolar cases (including 333 with history of psychosis during mania, 64 with history of psychosis only during depression, 547 with no history of psychosis, and 13 with unknown history of psychosis) and 778 controls. Polygenic risk score (PRS) analysis was performed by calculating a SZ-PRS for the BD cases and controls, and comparing the calculated SZ risk between different psychosis subgroups and bipolar types. The SZ-PRS was significantly higher for BD-I cases with manic psychosis than BD-I cases with depressive psychosis (Nagelkerke's R 2  = 0.021; p = 0.045), BD-I cases without psychosis (R 2  = 0.015; p = 0.007), BD-II cases without psychosis (R 2  = 0.014; p = 0.017), and controls (R 2  = 0.065; p = 2 × 10 -13 ). No other significant differences were found. Our results show that BD-I with manic psychosis is genetically more similar to SZ than any other tested BD subgroup. Further investigations on genetics of distinct clinical phenotypes composing major psychoses may help refine the current diagnostic classification system.

Bipolar disorder (BD) is associated with binge eating behavior (BE), and both conditions are heritable. Previously, using data from the Genetic Association Information Network (GAIN) study of BD, we performed genome-wide association (GWA) analyses of BD with BE comorbidity. Here, utilizing data from the Mayo Clinic BD Biobank (969 BD cases, 777 controls), we performed a GWA analysis of a BD subtype defined by BE, and case-only analysis comparing BD subjects with and without BE. We then performed a meta-analysis of the Mayo and GAIN results. The meta-analysis provided genome-wide significant evidence of association between single nucleotide polymorphisms (SNPs) in PRR5-ARHGAP8 and BE in BD cases (rs726170 OR = 1.91, P = 3.05E-08). In the meta-analysis comparing cases with BD with comorbid BE vs. non-BD controls, a genome-wide significant association was observed at SNP rs111940429 in an intergenic region near PPP1R2P5 (p = 1.21E-08). PRR5-ARHGAP8 is a read-through transcript resulting in a fusion protein of PRR5 and ARHGAP8. PRR5 encodes a subunit of mTORC2, a serine/threonine kinase that participates in food intake regulation, while ARHGAP8 encodes a member of the RhoGAP family of proteins that mediate cross-talk between Rho GTPases and other signaling pathways. Without BE information in controls, it is not possible to determine whether the observed association reflects a risk factor for BE in general, risk for BE in individuals with BD, or risk of a subtype of BD with BE. The effect of PRR5-ARHGAP8 on BE risk thus warrants further investigation.

Background: Although multiple genes have been implicated in bipolar disorder (BD), they explain only a small proportion of its heritability. Identifying additional BD risk variants may be impaired by phenotypic heterogeneity, which is usually not taken into account in genome-wide association studies (GWAS). BD with early age at onset is a more homogeneous familial form of the disorder associated with greater symptom severity., Methods: We conducted a GWAS of early-onset BD (onset of mania/hypomania ≤19 years old) in a discovery sample of 419 cases and 1034 controls and a replication sample of 181 cases and 777 controls. These two samples were meta-analyzed, followed by replication of one signal in a third independent sample of 141 cases and 746 controls., Results: No single nucleotide polymorphism (SNP) associations were genome-wide significant in the discovery sample. Of the top 15 SNPs in the discovery analysis, rs114034759 in the muskelin (MKLN1) gene was nominally significant in the replication analysis, and was among the top associations in the meta-analysis (p=2.63E-06, OR=1.9). In the third sample, this SNP was again associated with early-onset BD (p=0.036, OR=1.6). Gene expression analysis showed that the rs114034759 risk allele is associated with decreased hippocampal MKLN1 expression., Limitations: The sample sizes of the early-onset BD subgroups were relatively small., Conclusions: Our results suggest MKLN1 is associated with early-onset BD. MKLN1 regulates cellular trafficking of GABA-A receptors, which is involved in synaptic transmission and plasticity, and is implicated in the mechanism of action of a group of antiepileptic mood stabilizers. These results therefore indicate that GABAergic neurotransmission may be implicated in early-onset BD. We propose that an increase in GABA-A receptors in the hippocampus in BD patients due to lower MKLN1 expression might increase the excitability during the GABA-excited early phase of young neurons, leading to an increased risk of developing a manic/hypomanic episode. Further studies are needed to test this model., (Copyright © 2016 Elsevier B.V. All rights reserved.)

A key structure for directing saccadic eye movements is the superior colliculus (SC). The visual pathways that project to the SC have been reported to carry only luminance information and not color information. Short-wavelength-sensitive cones (S-cones) in the retina make little or no contribution to luminance signals, leading to the conclusion that S-cone stimuli should be invisible to SC neurons. The premise that S-cone stimuli are invisible to the SC has been used in numerous clinical and human psychophysical studies. The assumption that the SC cannot use S-cone stimuli to guide behavior has never been tested. We show here that express saccades, which depend on the SC, can be driven by S-cone input. Further, express saccade reaction times and changes in SC activity depend on the amount of S-cone contrast. These results demonstrate that the SC can use S-cone stimuli to guide behavior. We conclude that the use of S-cone stimuli is insufficient to isolate SC function in psychophysical and clinical studies of human subjects.

Objectives: Bipolar disorder (BD) is a complex disease associated with various hereditary traits, including a higher body mass index (BMI). In a prior genome-wide association study, we found that BMI modified the association of rs12772424 - a common variant in the gene encoding transcription factor 7-like 2 (TCF7L2) - with risk for BD. TCF7L2 is a transcription factor in the canonical Wnt pathway, involved in multiple disorders, including diabetes, cancer and psychiatric conditions. Here, using an independent sample, we evaluated 26 TCF7L2 single nucleotide polymorphisms (SNPs) to explore further the association of BD with the TCF7L2-BMI interaction., Methods: Using a sample of 662 BD cases and 616 controls, we conducted SNP-level and gene-level tests to assess the evidence for an association between BD and the interaction of BMI and genetic variation in TCF7L2. We also explored the potential mechanism behind the detected associations using human brain expression quantitative trait loci (eQTL) analysis., Results: The analysis provided independent evidence of an rs12772424-BMI interaction (p = 0.011). Furthermore, while overall there was no evidence for SNP marginal effects on BD, the TCF7L2-BMI interaction was significant at the gene level (p = 0.042), with seven of the 26 SNPs showing SNP-BMI interaction effects with p < 0.05. The strongest evidence of interaction was observed for rs7895307 (p = 0.006). TCF7L2 expression showed a significant enrichment of association with the expression of other genes in the Wnt canonical pathway., Conclusions: The current study provides further evidence suggesting that TCF7L2 involvement in BD risk may be regulated by BMI. Detailed, prospective assessment of BMI, comorbidity, and other possible contributing factors is necessary to explain fully the mechanisms underlying this association., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: To determine whether clinical features of bipolar disorder, such as history of psychosis, and cardiovascular disease (CVD) risk factors contribute to a higher risk of CVD among patients with bipolar disorder., Methods: This cross-sectional study included a sample of 988 patients with bipolar I or bipolar II disorder or schizoaffective bipolar type confirmed by the Structured Clinical Interview for DSM-IV-TR disorders (SCID). Medical comorbidity burden was quantified utilizing the Cumulative Illness Severity Rating Scale (CIRS). This 13-item organ-based scale includes cardiac disease severity quantification. Confirmed by medical record review, patients who scored 1 (current mild or past significant problem) or higher in the cardiac item were compared by logistic regression to patients who scored 0 (no impairment), adjusting for CVD risk factors that were selected using a backwards stepwise approach or were obtained from the literature., Results: In a multivariate model, age [odds ratio (OR) = 3.03, 95% confidence interval (CI): 1.66-5.54, p < 0.0001], hypertension (OR = 2.43, 95% CI: 1.69-3.55, p < 0.0001), and history of psychosis (OR = 1.48, 95% CI: 1.03-2.13, p = 0.03) were associated with CVD. When CVD risk factors from the literature were added to the analysis, age (OR = 3.19, 95% CI: 1.67-6.10, p = 0.0005) and hypertension (OR = 2.46, 95% CI: 1.61-3.76, p < 0.01) remained significant, with psychosis being at the trend level (OR = 1.43, 95% CI: 0.96-2.13, p = 0.08)., Conclusions: The phenotype of psychotic bipolar disorder may reflect higher illness severity with associated cardiac comorbidity. Further studies are encouraged to clarify the effect of the disease burden (i.e., depression), lifestyle, and treatment interventions (i.e., atypical antipsychotics) on this risk association., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Bipolar disorder (BD) is a highly heritable disease. While genome-wide association (GWA) studies have identified several genetic risk factors for BD, few of these studies have investigated the genetic etiology of specific disease subtypes. In particular, BD is positively associated with eating dysregulation traits such as binge eating behavior (BE), yet the genetic risk factors underlying BD with comorbid BE have not been investigated., Methods: Utilizing data from the Genetic Association Information Network study of BD, which included 729,454 single nucleotide polymorphisms (SNPs) genotyped in 1001 European American bipolar cases and 1034 controls, we performed GWA analyses of bipolar subtypes defined by the presence or absence of BE history, and performed a case-only analysis comparing BD subjects with and without BE history. Association signals were refined using imputation, and network analysis was performed with Ingenuity Pathway Analysis software. Based on these results, candidate SNPs were selected for replication in an independent sample of 855 cases and 857 controls., Results: Top ranking SNPs in the discovery set included rs6006893 in PRR5, rs17045162 in ANK2, rs13233490 near PER4, rs4665788 and rs10198175 downstream of APOB, rs2367911 in CACNA2D1, and rs7249968 near ZNF536. Rs10198175 in APOB also demonstrated evidence of association in the replication sample and a meta-analysis of the two samples., Limitations: Without information of BE history in controls, it is not possible to determine whether the observed association with APOB reflects a risk factor for BE behavior in general or a risk factor for a subtype of BD with BE. Further longitudinal and functional studies are needed to determine the causal pathways underlying the observed associations., Conclusions: This study identified new potential BD-susceptibility genes, highlighting the advantages of phenotypic sub-classification in genetic research and clinical practice., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Objective: To examine the effectiveness and tolerability of triple therapy with pegylated interferon (p-IFN), ribavirin (RBV), and telaprevir in patients with chronic hepatitis C receiving treatment in an academic practice setting and in a more clinically diverse population compared with patients receiving treatment in phase 3 trials., Patients and Methods: A prospective database of all patients with viral hepatitis undergoing antiviral therapy from January 1, 2006, to July 1, 2012, was queried to identify treatment-naive and -experienced patients with chronic hepatitis C receiving dual and triple therapies. On-treatment response categories included rapid virologic response, extended rapid virologic response, early virologic response, and sustained virologic response. These patients were compared with matched controls, namely, patients who underwent dual therapy with p-IFN and RBV. Matching was performed for age, cirrhosis status, and prior treatment., Results: There were 55 patients who received triple therapy and met the eligibility criteria, consisting of treatment-naive (n=35) and -experienced patients (n=20: those with relapse, 9; those with nonresponse, 9; and those who terminated the treatment early, 2). Rapid virologic response was achieved in 41% of the patients, extended rapid virologic response in 41%, and early virologic response in 75%. Sustained virologic response was observed in 51% (18/35) of treatment-naive patients, 67% (6/9) of the patients with prior nonresponse, and 56% (5/9) of those with prior relapse. Corresponding results after dual therapy were 37% (23/62), 11% (2/18), and 27% (3/11), respectively. The mean decrease in the hemoglobin level at weeks 4, 8, and 24 of triple therapy was 2.8, 3.8, and 3.2 mg/dL compared with 2.4, 2.6, and 2.4 mg/dL with dual therapy (to convert mg/dL to mmol/L, multiply values by 0.0259)., Conclusion: Telaprevir-based triple therapy in clinical practice is considerably more effective than dual therapy with p-IFN and RBV despite the significant degree of anemia that complicated therapy, requiring RBV dose reduction and erythropoietin support., (Copyright © 2014 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

To further explore reports of association of alcohol dependence and response to acamprosate treatment with the GATA4 rs13273672 single nucleotide polymorphism (SNP), we genotyped this and 10 other GATA4 SNPs in 816 alcohol-dependent cases and 1248 controls. We tested for association of alcohol dependence with the 11 SNPs individually and performed a global test for association using a principle components analysis. Our analyses demonstrate significant association between GATA4 and alcohol dependence at the gene level (P = 0.009) but no association with rs13273672. Further studies are needed to identify potential causal GATA4 variation(s) and the functional mechanism(s) contributing to this association., (© 2012 The Authors, Addiction Biology © 2012 Society for the Study of Addiction.)

We explore the visual world by making rapid eye movements (saccades) to focus on objects and locations of interest. Despite abrupt retinal image shifts, we see the world as stable. Remapping contributes to visual stability by updating the internal image with every saccade. Neurons in macaque lateral intraparietal cortex (LIP) and other brain areas update information about salient locations around the time of a saccade. The depth of information transfer remains to be thoroughly investigated. Area LIP, as part of the dorsal visual stream, is regarded as a spatially selective area, yet there is evidence that LIP neurons also encode object features. We sought to determine whether LIP remaps shape information. This knowledge is important for understanding what information is retained from each glance. We identified 82 remapping neurons. First, we presented shapes within the receptive field and tested for shape selectivity in a fixation task. Among the remapping neurons, 28 neurons (34%) were selective for shape. Second, we presented the same shapes in the future location of the receptive field around the time of the saccade and tested for shape selectivity during remapping. Thirty-one (38%) neurons were selective for shape. Of 11 neurons that were shape selective in both tasks, 5 showed significant correlation between shape selectivity in the two tasks. Across the population, there was a weak but significant correlation between responses to shape in the two tasks. Our results provide neurophysiological evidence that remapped responses in area LIP can encode shape information as well as spatial information.

Synthetic κ-opioid receptor (KOR) agonists induce dysphoric and pro-depressive effects and variations in the KOR (OPRK1) and prodynorphin (PDYN) genes have been shown to be associated with alcohol dependence. We genotyped 23 single nucleotide polymorphisms (SNPs) in the PDYN and OPRK1 genes in 816 alcohol-dependent subjects and investigated their association with: (1) negative craving measured by a subscale of the Inventory of Drug Taking Situations; (2) a self-reported history of depression; (3) the intensity of depressive symptoms measured by the Beck Depression Inventory-II. In addition, 13 of the 23 PDYN and OPRK1 SNPs, which were previously genotyped in a set of 1248 controls, were used to evaluate association with alcohol dependence. SNP and haplotype tests of association were performed. Analysis of a haplotype spanning the PDYN gene (rs6045784, rs910080, rs2235751, rs2281285) revealed significant association with alcohol dependence (p = 0.00079) and with negative craving (p = 0.0499). A candidate haplotype containing the PDYN rs2281285-rs1997794 SNPs that was previously associated with alcohol dependence was also associated with negative craving (p = 0.024) and alcohol dependence (p = 0.0008) in this study. A trend for association between depression severity and PDYN variation was detected. No associations of OPRK1 gene variation with alcohol dependence or other studied phenotypes were found. These findings support the hypothesis that sequence variation in the PDYN gene contributes to both alcohol dependence and the induction of negative craving in alcohol-dependent subjects.

We hypothesized that the suppression of uninvolved immunoglobulin in monoclonal gammopathy of undetermined significance (MGUS) as detected by suppression of the isotype-specific heavy and light chain (HLC-pair suppression) increases the risk of progression to malignancy. This approach required quantitation of individual heavy/light chains (for example, IgGλ in IgGκ MGUS patients). Of 1384 MGUS patients from Southeastern Minnesota seen at the Mayo Clinic from 1960 to 1994, baseline serum samples obtained within 30 days of diagnosis were available in 999 persons. We identified HLC-pair suppression in 27% of MGUS patient samples compared with 11% of patients with suppression of uninvolved IgG, IgA or IgM. HLC-pair suppression was a significant risk factor for progression (hazard ratio (HR), 2.3; 95% confidence interval (CI) 1.5-3.7; P<0.001). On multivariate analysis, HLC-pair suppression was an independent risk factor for progression to malignancy in combination with serum M-spike size, heavy chain isotype and free light chain ratio (HR, 1.8; 95% CI, 1.1-3.00; P=0.018). The finding that HLC-pair suppression predicts progression in MGUS and occurs several years before malignant transformation has implications for myeloma biology.

Genome-wide association studies (GWAS) have revealed many single nucleotide polymorphisms (SNPs) associated with complex traits. Although these studies frequently fail to identify statistically significant associations, the top association signals from GWAS may be enriched for true associations. We therefore investigated the association of alcohol dependence with 43 SNPs selected from association signals in the first two published GWAS of alcoholism. Our analysis of 808 alcohol-dependent cases and 1,248 controls provided evidence of association of alcohol dependence with SNP rs1614972 in the ADH1C gene (unadjusted p = 0.0017). Because the GWAS study that originally reported association of alcohol dependence with this SNP [1] included only men, we also performed analyses in sex-specific strata. The results suggest that this SNP has a similar effect in both sexes (men: OR (95%CI) = 0.80 (0.66, 0.95); women: OR (95%CI) = 0.83 (0.66, 1.03)). We also observed marginal evidence of association of the rs1614972 minor allele with lower alcohol consumption in the non-alcoholic controls (p = 0.081), and independently in the alcohol-dependent cases (p = 0.046). Despite a number of potential differences between the samples investigated by the prior GWAS and the current study, data presented here provide additional support for the association of SNP rs1614972 in ADH1C with alcohol dependence and extend this finding by demonstrating association with consumption levels in both non-alcoholic and alcohol-dependent populations. Further studies should investigate the association of other polymorphisms in this gene with alcohol dependence and related alcohol-use phenotypes.

Objectives: To determine the incidence of monoclonal gammopathy of undetermined significance (MGUS) in the general population and to estimate the duration of occult MGUS before first diagnosis., Methods: To estimate incidence we used innovative methods to exploit the Olmsted County, Minnesota, MGUS prevalence data, along with follow-up from a large cohort of patients with clinically detected MGUS. The prevalence cohort consisted of 21,463 persons systematically screened for the presence or absence of MGUS. The clinical cohort consisted of 7472 patients with MGUS diagnosed at Mayo Clinic from January 1, 1990, to May 13, 2010. The incidence of MGUS was estimated using the prevalence estimates, the rate of MGUS progression, and the death rates from MGUS using Markov chain methods., Results: We estimate that the annual incidence of MGUS in men is 120 per 100,000 population at the age of 50 years and increases to 530 per 100,000 population at the age of 90 years. The rates for women are 60 per 100,000 population at the age of 50 years and 370 per 100,000 population at the age of 90 years. We estimate that 56% of women 70 years of age diagnosed as having MGUS have had the condition for more than 10 years, including 28% for more than 20 years. Corresponding values for men are 55% and 31%, respectively. At 60 years of age, the proportion of prevalent cases that are clinically recognized is 13%. This rate increases to 33% at the age of 80 years., Conclusion: In addition to an accumulation of cases, the age-related increase in prevalence of MGUS is related to a true increase in incidence with age. When first clinically recognized, MGUS has likely been present in an undetected state for a median duration of more than 10 years., (Copyright © 2012 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Background: Identifying variants associated with complex human traits in high-dimensional data is a central goal of genome-wide association studies. However, complicated etiologies such as gene-gene interactions are ignored by the univariate analysis usually applied in these studies. Random Forests (RF) are a popular data-mining technique that can accommodate a large number of predictor variables and allow for complex models with interactions. RF analysis produces measures of variable importance that can be used to rank the predictor variables. Thus, single nucleotide polymorphism (SNP) analysis using RFs is gaining popularity as a potential filter approach that considers interactions in high-dimensional data. However, the impact of data dimensionality on the power of RF to identify interactions has not been thoroughly explored. We investigate the ability of rankings from variable importance measures to detect gene-gene interaction effects and their potential effectiveness as filters compared to p-values from univariate logistic regression, particularly as the data becomes increasingly high-dimensional., Results: RF effectively identifies interactions in low dimensional data. As the total number of predictor variables increases, probability of detection declines more rapidly for interacting SNPs than for non-interacting SNPs, indicating that in high-dimensional data the RF variable importance measures are capturing marginal effects rather than capturing the effects of interactions., Conclusions: While RF remains a promising data-mining technique that extends univariate methods to condition on multiple variables simultaneously, RF variable importance measures fail to detect interaction effects in high-dimensional data in the absence of a strong marginal component, and therefore may not be useful as a filter technique that allows for interaction effects in genome-wide data.

Model studies in mice indicate that the severity of alcohol withdrawal is associated with polymorphic variation and expression of the MPDZ gene. Current knowledge about variation in the human MPDZ gene is limited; however, our data indicate its potential association with alcohol dependence. The multi-PDZ protein is an important part of the N-methyl-D-aspartate (NMDA)-dependent α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor trafficking cascade that controls glutamate-related excitatory neurotransmission. To investigate association of variation in the NMDA-dependent AMPA trafficking cascade with alcohol dependence, we performed a gene-set (pathway) analysis using single nucleotide polymorphism (SNP) data from the Study of Addiction: Genetic and Environment. Rather than testing for association with each SNP individually, which typically has low power to detect small effects of multiple SNPs, gene-set analysis applies a single statistical test to evaluate whether variation in a set of genes is associated with the phenotype of interest. Gene-set analysis of 988 SNPs in 13 genes in the pathway demonstrated a significant association with alcohol dependence, with P < 0.01 for the global effect of variation in this pathway. The statistically significant association of alcohol dependence with genetic variation in the NMDA-dependent AMPA receptor trafficking cascade indicates a need for further investigation of the role of this pathway in alcohol dependence., (© 2011 The Authors, Addiction Biology © 2011 Society for the Study of Addiction.)

Objective: To determine whether the free light chain (FLC) assay provides prognostic information relevant to the general population., Methods: After excluding persons with a known plasma cell disorder, we studied 15,859 Olmsted County, Minnesota, residents 50 years or older in whom unmasked data and samples for FLC testing were available. Baseline information was obtained between March 13, 1995, and November 21, 2003, and follow-up status and cause of death were identified through June 30, 2009. The κ and λ FLC sum (Σ FLC) was evaluated for its ability to predict overall survival. Specific causes of death were also investigated., Results: In 158,003 person-years of follow-up, 4348 individuals died. A high Σ FLC was significantly predictive of worse overall survival; the risk ratio for death for those with the highest decile of Σ FLC (ie, ≥ 4.72 mg/dL) was 4.4 (95% confidence interval, 4.1-4.7) relative to the remaining study participants. Multivariate analyses demonstrated that this excess risk of death was independent of age, sex, and renal insufficiency, with a corrected risk ratio of 2.1 (95% confidence interval, 1.9-2.2). The increased mortality was not restricted to any particular cause of death because the observed-to-expected risk of death from most causes was significantly higher among those individuals with an antecedent Σ FLC of 4.72 mg/dL or higher, which is near the upper limit of normal for the test., Conclusion: A nonclonal elevation of Σ FLC is a significant predictor of worse overall survival in the general population of persons without plasma cell disorders., (Copyright © 2012 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Previously, we reported increased risk of heavy-chain (HC) monoclonal gammopathy of undetermined significance (MGUS) among first-degree (1°) relatives of multiple myeloma (MM) or HC-MGUS probands. This study investigated whether there was comparable risk for light-chain (LC) MGUS among 911 relatives of the same HC-MGUS/MM probands versus a reference population of 21 463. Seventeen 1° relatives had LC-MGUS (adjusted prevalence = 1·7%, 95% CI = 0·9–2·6%). There was increased risk of LC-MGUS in relatives of MM probands (RR = 3·4, 95% CI = 2·0–5·5). We saw no increased risk in relatives of HC-MGUS probands. We conclude that the prevalence of LC-MGUS is significantly higher among 1° relatives of MM probands compared to the reference population.

Visual perception is based on both incoming sensory signals and information about ongoing actions. Recordings from single neurons have shown that corollary discharge signals can influence visual representations in parietal, frontal and extrastriate visual cortex, as well as the superior colliculus (SC). In each of these areas, visual representations are remapped in conjunction with eye movements. Remapping provides a mechanism for creating a stable, eye-centred map of salient locations. Temporal and spatial aspects of remapping are highly variable from cell to cell and area to area. Most neurons in the lateral intraparietal area remap stimulus traces, as do many neurons in closely allied areas such as the frontal eye fields the SC and extrastriate area V3A. Remapping is not purely a cortical phenomenon. Stimulus traces are remapped from one hemifield to the other even when direct cortico-cortical connections are removed. The neural circuitry that produces remapping is distinguished by significant plasticity, suggesting that updating of salient stimuli is fundamental for spatial stability and visuospatial behaviour. These findings provide new evidence that a unified and stable representation of visual space is constructed by redundant circuitry, comprising cortical and subcortical pathways, with a remarkable capacity for reorganization.

Immunoglobulin free light chains (FLCs) are the precursors of amyloid fibrils in primary amyloidosis (AL). We studied the relationship between FLC levels and clinical features in 730 patients with newly diagnosed AL. The plasma cell clone was λ in 72% patients, and κ in 28% patients. κ-AL had more GI tract and liver involvement, where as renal involvement was more with λ-AL. While the overall survival (OS) was similar for κ and λ-AL, the median OS for those without an identifiable serum heavy chain was significantly shorter (12.6 vs 29.9 months; P = .02). The OS was shorter among those with a higher dFLC (involved FLC-uninvolved FLC; κ > 29.4 mg/dL or λ > 18.2 mg/dL using median for cutoff); 10.9 vs 37.1 months; P < .001. In multivariate analysis, dFLC was independent of other prognostic factors. The type of light chain impacts the spectrum of organ involvement and the FLC burden correlates with survival in AL.

Our eyes are constantly moving, allowing us to attend to different visual objects in the environment. With each eye movement, a given object activates an entirely new set of visual neurons, yet we perceive a stable scene. One neural mechanism that may contribute to visual stability is remapping. Neurons in several brain regions respond to visual stimuli presented outside the receptive field when an eye movement brings the stimulated location into the receptive field. The stored representation of a visual stimulus is remapped, or updated, in conjunction with the saccade. Remapping depends on neurons being able to receive visual information from outside the classic receptive field. In previous studies, we asked whether remapping across hemifields depends on the forebrain commissures. We found that, when the forebrain commissures are transected, behavior dependent on accurate spatial updating is initially impaired but recovers over time. Moreover, neurons in lateral intraparietal cortex (LIP) continue to remap information across hemifields in the absence of the forebrain commissures. One possible explanation for the preserved across-hemifield remapping in split-brain animals is that neurons in a single hemisphere could represent visual information from both visual fields. In the present study, we measured receptive fields of LIP neurons in split-brain monkeys and compared them with receptive fields in intact monkeys. We found a small number of neurons with bilateral receptive fields in the intact monkeys. In contrast, we found no such neurons in the split-brain animals. We conclude that bilateral representations in area LIP following forebrain commissures transection cannot account for remapping across hemifields.

Monoclonal gammopathy of undetermined significance (MGUS) is associated with a long-term risk of progression to multiple myeloma (MM) or related malignancy. To prevent serious myeloma-related complications, lifelong annual follow-up has been recommended, but its value is unknown. We reviewed all patients from southeastern Minnesota seen at Mayo Clinic between 1973 and 2004 with MGUS who subsequently progressed to MM. Of 116 patients, 69% had optimal follow-up of MGUS. Among these, abnormalities on serial follow-up laboratory testing led to the diagnosis of MM in 16%, whereas MM was diagnosed only after serious MM-related complications in 45%. In the remaining, workup of less serious symptoms (25%), incidental finding during workup of unrelated medical conditions (11%), and unknown (3%) were the mechanisms leading to MM diagnosis. High-risk MGUS patients (≥ 1.5 g/dL and/or non-IgG MGUS) were more likely to be optimally followed (81% vs 64%), and be diagnosed with MM secondary to serial follow-up testing (21% vs 7%). This retrospective study suggests that routine annual follow-up of MGUS may not be required in low-risk MGUS. Future studies are needed to replicate and expand our findings and to determine the optimal frequency of monitoring in higher-risk MGUS patients.

In previous studies, we demonstrated that the forebrain commissures are the primary pathway for remapping from one hemifield to the other. Nonetheless, remapping in lateral intraparietal cortex (LIP) across hemifield is still present in split brain monkeys. This finding indicates that a subcortical structure must contribute to remapping. The primary goal of the current study was to characterize remapping activity in the superior colliculus in intact and split brain monkeys. We recorded neurons in both the superficial and intermediate layers of the SC. We found that across-hemifield remapping was reduced in magnitude and delayed compared with within-hemifield remapping in the intermediate layers of the SC in split brain monkeys. These results mirror our previous findings in area LIP. In contrast, we found no difference in the magnitude or latency for within- compared with across-hemifield remapping in the superficial layers. At the behavioral level, we compared the performance of the monkeys on two conditions of a double-step task. When the second target remained within a single hemifield, performance remained accurate. When the second target had to be updated across hemifields, the split brain monkeys' performance was impaired. Remapping activity in the intermediate layers was correlated with the accuracy and latency of the second saccade during the across-hemifield trials. Remapping in the superficial layers was correlated with latency of the second saccade during the within- and across-hemifield trials. The differences between the layers suggest that different circuits underlie remapping in the superficial and intermediate layers of the superior colliculus.

Background: Monoclonal gammopathy of undetermined significance (MGUS) is defined by expression of heavy-chain immunoglobulin (IgH) and is the precursor lesion for 80% of cases of multiple myeloma. The remaining 20% are characterised by absence of IgH expression; we aimed to assess prevalence of a corresponding precursor entity, light-chain MGUS., Methods: We used a population-based cohort, previously assembled to estimate MGUS prevalence, of 21,463 residents of Olmsted County, MN, USA, aged 50 years and older. We did a serum free light-chain assay on all samples with sufficient serum remaining, and immunofixation electrophoresis was done for all samples with an abnormal free light-chain ratio or abnormal protein electrophoresis results from the original study. Light-chain MGUS was defined as an abnormal free light-chain ratio with no IgH expression, plus increased concentration of the involved light chain. We calculated age-specific and sex-specific prevalence and rates of progression to lymphoproliferative disorders for light-chain and conventional MGUS and assessed incidence of renal disorders in patients with light-chain MGUS., Findings: 610 (3.3%) of 18,357 people tested had an abnormal free light-chain ratio, of whom 213 had IgH expression that was diagnostic of conventional MGUS. 146 of the remaining 397 individuals had an increase of at least one free light chain and met criteria for light-chain MGUS. Prevalence of light-chain MGUS was 0.8% (95% CI 0.7-0.9), contributing to an overall MGUS prevalence of 4.2% (3.9-4.5). Risk of progression to multiple myeloma in patients with light-chain MGUS was 0.3% (0.1-0.8) per 100 person-years. 30 (23%) of 129 patients with light-chain MGUS were diagnosed with renal disease., Interpretation: We define a clinical entity representing the light-chain equivalent of conventional MGUS and posing a risk of progression to light-chain multiple myeloma and related disorders., Funding: US National Cancer Institute., (Copyright 2010 Elsevier Ltd. All rights reserved.)

The current definition of complete response in multiple myeloma includes a requirement for a bone marrow (BM) examination showing less than 5% plasma cells in addition to negative serum and urine immunofixation. There have been suggestions to eliminate the need for BM examinations when defining complete response. We evaluated 92 patients with multiple myeloma who achieved negative immunofixation in the serum and urine after therapy and found that 14% had BM plasma cells more than or equal to 5%. Adding a requirement for normalization of the serum-free light chain ratio to negative immunofixation studies did not negate the need for BM studies; 10% with a normal serum-free light chain ratio had BM plasma cells more than or equal to 5%. We also found that, on achieving immunofixation-negative status, patients with less than 5% plasma cells in the BM had improved overall survival compared with those with 5% or more BM plasma cells (6.2 years vs 2.3 years, respectively; P = .01).

We examined whether monoclonal gammopathy of undetermined significance (MGUS) is increased in first-degree relatives of multiple myeloma (MM) or MGUS patients. Probands were recruited from a population-based prevalence study (MGUS) and the Mayo Clinic (MM). Serum samples were collected from first-degree relatives older than 40 years and subjected to electrophoresis and immunofixation. The prevalence of MGUS in relatives was compared with population-based rates. Nine-hundred eleven relatives of 232 MM and 97 MGUS probands were studied. By electrophoresis, MGUS was detected in 55 (6%) relatives, and immunofixation identified 28 additional relatives for an age- and sex-adjusted prevalence of 8.1% (95% CI, 6.3 to 9.8). The prevalence of MGUS in relatives increased with age (1.9%, 6.9%, 11.6%, 14.6%, 21.0% for ages 40-49, 50-59, 60-69, 70-79, >/= 80 years, respectively; P < .001). Using similar MGUS detection methods, there was a higher risk of MGUS in relatives (age-adjusted risk ratio [RR], 2.6; 95% CI, 1.9 to 3.4) compared with the reference population. The increased risk was seen among relatives of MM (RR, 2.0; 95% CI, 1.4 to 2.8) and MGUS probands (RR, 3.3; 95% CI, 2.1 to 4.8). The increased risk of MGUS in first-degree relatives of MGUS or MM patients implies shared environment and/or genetics.

A basic question in cognition is how visual information obtained in separate glances can produce a stable, continuous percept. Previous explanations have included theories such as integration in a trans-saccadic buffer or storage in visual memory, or even that perception begins anew with each fixation. Converging evidence from primate neurophysiology, human psychophysics and neuroimaging indicate an additional explanation: the intention to make a saccadic eye movement leads to a fundamental alteration in visual processing itself before and after the saccadic eye movement. We outline five principles of 'trans-saccadic perception' that could help to explain how it is possible - despite discrete sensory input and limited memory - that conscious perception across saccades seems smooth and predictable.

Each time the eyes move, the visual system must adjust internal representations to account for the accompanying shift in the retinal image. In the lateral intraparietal cortex (LIP), neurons update the spatial representations of salient stimuli when the eyes move. In previous experiments, we found that split-brain monkeys were impaired on double-step saccade sequences that required updating across visual hemifields, as compared to within hemifield. Here we describe a subsequent experiment to characterize the relationship between behavioral performance and neural activity in LIP in the split-brain monkey. We recorded from single LIP neurons while split-brain and intact monkeys performed two conditions of the double-step saccade task: one required across-hemifield updating and the other required within-hemifield updating. We found that, despite extensive experience with the task, the split-brain monkeys were significantly more accurate for within-hemifield than for across-hemifield sequences. In parallel, we found that population activity in LIP of the split-brain monkeys was significantly stronger for the within-hemifield than for the across-hemifield condition of the double-step task. In contrast, in the normal monkey, both the average behavioral performance and population activity showed no bias toward the within-hemifield condition. Finally, we found that the difference between within-hemifield and across-hemifield performance in the split-brain monkeys was reflected at the level of single-neuron activity in LIP. These findings indicate that remapping activity in area LIP is present in the split-brain monkey for the double-step task and covaries with spatial behavior on within-hemifield compared to across-hemifield sequences.

With each eye movement, stationary objects in the world change position on the retina, yet we perceive the world as stable. Spatial updating, or remapping, is one neural mechanism by which the brain compensates for shifts in the retinal image caused by voluntary eye movements. Remapping of a visual representation is believed to arise from a widespread neural circuit including parietal and frontal cortex. The current experiment tests the hypothesis that extrastriate visual areas in human cortex have access to remapped spatial information. We tested this hypothesis using functional magnetic resonance imaging (fMRI). We first identified the borders of several occipital lobe visual areas using standard retinotopic techniques. We then tested subjects while they performed a single-step saccade task analogous to the task used in neurophysiological studies in monkeys, and two conditions that control for visual and motor effects. We analyzed the fMRI time series data with a nonlinear, fully Bayesian hierarchical statistical model. We identified remapping as activity in the single-step task that could not be attributed to purely visual or oculomotor effects. The strength of remapping was roughly monotonic with position in the visual hierarchy: remapped responses were largest in areas V3A and hV4 and smallest in V1 and V2. These results demonstrate that updated visual representations are present in cortical areas that are directly linked to visual perception.

We explore the world around us by making rapid eye movements to objects of interest. Remarkably, these eye movements go unnoticed, and we perceive the world as stable. Spatial updating is one of the neural mechanisms that contributes to this perception of spatial constancy. Previous studies in macaque lateral intraparietal cortex (area LIP) have shown that individual neurons update, or "remap," the locations of salient visual stimuli at the time of an eye movement. The existence of remapping implies that neurons have access to visual information from regions far beyond the classically defined receptive field. We hypothesized that neurons have access to information located anywhere in the visual field. We tested this by recording the activity of LIP neurons while systematically varying the direction in which a stimulus location must be updated. Our primary finding is that individual neurons remap stimulus traces in multiple directions, indicating that LIP neurons have access to information throughout the visual field. At the population level, stimulus traces are updated in conjunction with all saccade directions, even when we consider direction as a function of receptive field location. These results show that spatial updating in LIP is effectively independent of saccade direction. Our findings support the hypothesis that the activity of LIP neurons contributes to the maintenance of spatial constancy throughout the visual field.

With each eye movement, a new image impinges on the retina, yet we do not notice any shift in visual perception. This perceptual stability indicates that the brain must be able to update visual representations to take our eye movements into account. Neurons in the lateral intraparietal area (LIP) update visual representations when the eyes move. The circuitry that supports these updated representations remains unknown, however. In this experiment, we asked whether the forebrain commissures are necessary for updating in area LIP when stimulus representations must be updated from one visual hemifield to the other. We addressed this question by recording from LIP neurons in split-brain monkeys during two conditions: stimulus traces were updated either across or within hemifields. Our expectation was that across-hemifield updating activity in LIP would be reduced or abolished after transection of the forebrain commissures. Our principal finding is that LIP neurons can update stimulus traces from one hemifield to the other even in the absence of the forebrain commissures. This finding provides the first evidence that representations in parietal cortex can be updated without the use of direct cortico-cortical links. The second main finding is that updating activity in LIP is modified in the split-brain monkey: across-hemifield signals are reduced in magnitude and delayed in onset compared with within-hemifield signals, which indicates that the pathways for across-hemifield updating are less effective in the absence of the forebrain commissures. Together these findings reveal a dynamic circuit that contributes to updating spatial representations.

Internal representations of the sensory world must be constantly adjusted to take movements into account. In the visual system, spatial updating provides a mechanism for maintaining a coherent map of salient locations as the eyes move. Little is known, however, about the pathways that produce updated spatial representations. In the present study, we asked whether direct cortico-cortical links are required for spatial updating. We addressed this question by investigating whether the forebrain commissures-the direct path between the two cortical hemispheres-are necessary for updating visual representations from one hemifield to the other. We assessed spatial updating in two split-brain monkeys using the double-step task, which involves saccades to two sequentially appearing targets. Accurate performance requires that the representation of the second target be updated to take the first saccade into account. We made two central discoveries regarding the pathways that underlie spatial updating. First, we found that split-brain monkeys exhibited a selective initial impairment on double-step sequences that required updating across visual hemifields. Second, and most surprisingly, these impairments were neither universal nor permanent: the monkeys were ultimately able to perform the across-hemifield sequences and, in some cases, this ability emerged rapidly. These findings indicate that direct cortical links provide the main substrate for updating visual representations, but they are not the sole substrate. Rather, a unified and stable representation of visual space is supported by a redundant cortico-subcortical network with a striking capacity for reorganization.

Vision is an active process. We do not see the world directly; rather, we construct a representation of it from sensory inputs in combination with internal, nonvisual signals. In the case of spatial perception, our representation of the visual scene must take into account our own movements. This allows us to perceive the world as stationary despite the constant eye movements that produce new images on the retina. How is this perceptual stability achieved? Our central hypothesis is that a corollary discharge of the eye movement command updates, or remaps, an internal representation when the eyes move. In support of this hypothesis, the authors review evidence that parietal cortex and extrastriate visual areas in both monkeys and humans participate in spatial updating. These findings shed new light on the neural circuitry involved in producing a stable and coherent perception of visual space.

How does the brain keep track of salient locations in the visual world when the eyes move? In parietal, frontal and extrastriate cortex, and in the superior colliculus, neurons update or 'remap' stimulus representations in conjunction with eye movements. This updating reflects a transfer of visual information, from neurons that encode a salient location before the saccade, to neurons that encode the location after the saccade. Copies of the oculomotor command - corollary discharge signals - must initiate this transfer. We investigated the circuitry that supports spacial updating in the primate brain. Our central hypothesis was that the forebrain commissures provide the primary route for remapping spatial locations across visual hemifields, from one cortical hemisphere to the other. Further, we hypothesized that these commissures provide the primary route for communicating corollary discharge signals from one hemisphere to the other. We tested these hypotheses using the double-step task and subsequent physiological recording in two split-brain monkeys. In the double-step task, monkeys made sequential saccades to two briefly presented targets, T1 and T2. In the visual version of the task, the representation of T2 was updated either within the same hemifield ("visual-within"), or across hemifields ("visual-across"). In the motor version, updating of the visual stimulus was always within-hemifield. The corollary discharge signal that initiated the updating, however, was generated either within the same hemisphere ("motor-within") or in the opposite hemisphere ("motor-across"). We expected that, in the absence of the forebrain commissures, both visual-across and motor-across conditions would be impaired relative to their "within" controls. In behavioral experiments, we observed striking initial impairments in the monkeys' ability to update stimuli across visual hemifields. Surprisingly, however, both animals were ultimately capable of performing the visual-across sequences of the double-step task. In subsequent physiological experiments, we found that neurons in lateral intraparietal cortex (LIP) can remap stimuli across visual hemifields, albeit with a reduction in the strength of remapping activity. These behavioral and neural findings indicate that the transfer of visual information is compromised, but by no means abolished, in the absence of the forebrain commissures. We found minimal evidence of impairment of the motor-across condition. Both monkeys readily performed the motor-across sequences of the double-step task, and LIP neurons were robustly active when within-hemifield updating was initiated by a saccade into the opposite hemifield. These results indicate that corollary discharge signals are available bilaterally. Altogether, our findings show that both visual and corollary discharge signals from opposite hemispheres can converge to update spatial representations in the absence of the forebrain commissures. These investigations provide new evidence that a unified and stable representation of visual space is supported by a redundant circuit, comprised of cortical as well as subcortical pathways, with a remarkable capacity for reorganization.

Single neurons in monkey parietal cortex update visual information in conjunction with eye movements. This remapping of stimulus representations is thought to contribute to spatial constancy. We hypothesized that a similar process occurs in human parietal cortex and that we could visualize it with functional MRI. We scanned subjects during a task that involved remapping of visual signals across hemifields. We observed an initial response in the hemisphere contralateral to the visual stimulus, followed by a remapped response in the hemisphere ipsilateral to the stimulus. We ruled out the possibility that this remapped response resulted from either eye movements or visual stimuli alone. Our results demonstrate that updating of visual information occurs in human parietal cortex.

The performance of spatial working memory tasks is known to evoke activity in a set of higher-order association areas, including the prefrontal cortex, posterior parietal cortex and the frontal and supplementary eye fields. Recent physiological studies in monkey have shown that memory-related activity also is found in extrastriate cortex [J. Neurophysiol. 84 (2000) 677]. We conducted functional magnetic resonance imaging studies to determine whether human extrastriate cortex contributes to the on-line maintenance of spatial information in an eye movement task. We found that performance of memory-guided saccades, as compared to visually guided saccades, elicited significant activation in two areas of extrastriate cortex: the posterior superior temporal sulcus (PST) and lateral occipitotemporal cortex (LOT). Both areas also were activated during the basic sensorimotor task of visually guided saccades as compared to fixation. We further determined that area LOT is close to but distinct from motion-sensitive area MT+. These findings demonstrate that areas PST and LOT, along with higher-level association cortex, help to encode and maintain spatial representations.

Behavioral and physiological studies have established that visual attention to a given feature or location can modulate early visual processing. In the present experiment, we asked whether auditory attention can likewise influence visual processing. We used a visual illusion, the motion aftereffect (MAE), to assess the effects of visual and auditory attention on motion processing in human area MT+. We acquired psychophysical and functional magnetic resonance imaging (fMRI) data while subjects fixated and viewed moving and stationary stimuli in alternating blocks. For each of four motion conditions, we measured the duration of the subsequent MAE, the time for activity in MT+ to return to baseline after motion adaptation (decay time), and the magnitude of MT+ activity during motion adaptation. For each subject, we first obtained measures of motion processing in the absence of attentional demands, by comparing reversing and expanding motion conditions. Subjects perceived the MAE following adaptation to expanding but not reversing motion, as observed previously, and decay times in MT+ were selectively prolonged after expanding motion. We then assessed the effects of performing either a visual or an auditory attentional task during expanding motion adaptation. Performance of the attentional task, whether visual or auditory, produced a significant reduction of subsequent MAE perception and associated decay times in MT+, as compared to expanding motion with fixation only. Both attentional tasks also reduced the magnitude of activation during motion adaptation. These data show that auditory attention, like visual attention, can modify sensory processing at a remarkably early stage of the visual hierarchy.

Neurons in the lateral intraparietal area, frontal eye field, and superior colliculus exhibit a pattern of activity known as remapping. When a salient visual stimulus is presented shortly before a saccade, the representation of that stimulus is updated, or remapped, at the time of the eye movement. This updating is presumably based on a corollary discharge of the eye movement command. To investigate whether visual areas also exhibit remapping, we recorded from single neurons in extrastriate and striate cortex while monkeys performed a saccade task. Around the time of the saccade, a visual stimulus was flashed either at the location occupied by the neuron's receptive field (RF) before the saccade (old RF) or at the location occupied by it after the saccade (new RF). More than half (52%) of V3A neurons responded to a stimulus flashed in the new RF even though the stimulus had already disappeared before the saccade. These neurons responded to a trace of the flashed stimulus brought into the RF by the saccade. In 16% of V3A neurons, remapped activity began even before saccade onset. Remapping also was observed at earlier stages of the visual hierarchy, including in areas V3 and V2. At these earlier stages, the proportion of neurons that exhibited remapping decreased, and the latency of remapped activity increased relative to saccade onset. Remapping was very rare in striate cortex. These results indicate that extrastriate visual areas are involved in the process of remapping.

Delay-related sustained activity in the prefrontal cortex of primates, a neurological analogue of working memory, has been proposed to arise from synaptic interactions in local cortical circuits. The implication is that memories are coded by spatially localized foci of sustained activity. We investigate the mechanisms by which sustained foci are initiated, maintained, and extinguished by excitation in networks of Hodgkin-Huxley neurons coupled with biophysical spatially structured synaptic connections. For networks with a balance between excitation and inhibition, a localized transient stimulus robustly initiates a localized focus of activity. The activity is then maintained by recurrent excitatory AMPA-like synapses. We find that to maintain the focus, the firing must be asynchronous. Consequently, inducing transient synchrony through an excitatory stimulus extinguishes the sustained activity. Such a monosynaptic excitatory turn-off mechanism is compatible with the working memory being wiped clean by an efferent copy of the motor command. The activity that codes working memories may be structured so that the motor command is both the read-out and a direct clearing signal. We show examples of data that is compatible with our theory.

We used functional magnetic resonance imaging (fMRI) to investigate cortical activation during the performance of three oculomotor tasks that impose increasing levels of cognitive demand. (1) In a visually guided saccade (VGS) task, subjects made saccades to flashed targets. (2) In a compatible task, subjects made leftward and rightward saccades in response to foveal presentation of the uppercase words "LEFT" or "RIGHT." (3) In a mixed task, subjects made rightward saccades in response to the lowercase word "left" and leftward saccades in response to the lowercase word "right" on incompatible trials (60%). The remaining 40% of trials required compatible responses to uppercase words. The VGS and compatible tasks, when compared to fixation, activated the three cortical eye fields: the supplementary eye field (SEF), the frontal eye field (FEF), and the parietal eye field (PEF). The mixed task, when compared to the compatible task, activated three additional cortical regions proximate to the three eye fields: (1) rostral to the SEF in medial frontal cortex; (2) rostral to the FEF in dorsolateral prefrontal cortex (DLPFC); (3) rostral and lateral to the PEF in posterior parietal cortex. These areas may contribute to the suppression of prepotent responses and in holding novel visuomotor associations in working memory., (Copyright 2001 Academic Press.)

Area V3A is an extrastriate visual area that provides a major input to parietal cortex. To identify the sensory, saccade-related, and cognitive signals carried by V3A neurons, we recorded from single units in alert monkeys during performance of fixation and memory guided saccade tasks. We found that visual responses to stationary stimuli in area V3A were affected by the behavioral relevance of the stimulus. The amplitude of the visual response differed between the memory-guided saccade task, in which the monkey had to use the information provided by the stimulus to guide its behavior, and the fixation task. For 18% (29/163) of V3A neurons, the response was significantly enhanced in the memory-guided saccade task as compared with that in the fixation task. For 8% (13/163) of V3A neurons, the amplitude of response in the memory-guided saccade task was significantly suppressed. We also observed task-related modulation of activity prior to stimulus onset. Among the V3A neurons (37/163) that showed significant differences between tasks in prestimulus activity, the majority (89%; 33/37) showed greater prestimulus activity in the memory-guided saccade task. Task-related increases in prestimulus activity in the memory-guided saccade task were not always matched by increases in the sensory response, indicating that visual responses and prestimulus activity can be modulated independently. Activity in the memory period was suppressed compared with prestimulus activity for 83% (49/59) of the V3A neurons that showed a significant difference in activity (59/197) between these two epochs. For some neurons, memory-period activity dropped even below the baseline level in the fixation task, indicating that there may be an active suppression mechanism. Many V3A neurons (75%, 148/197) also had activity in the saccade epoch. This activity was most prominent immediately after the saccade. Postsaccadic activity was observed even when testing was carried out in total darkness, indicating that this activity reflects, at least in part, extraretinal signals and is not simply a response to visual reafference. These results indicate that several kinds of signals are carried by single neurons in extrastriate area V3A. Moreover, activity in V3A is subject to modulation by extraretinal factors, including attention, anticipation, memory, and saccadic eye movements.

The space around us is represented not once but many times in parietal cortex. These multiple representations encode locations and objects of interest in several egocentric reference frames. Stimulus representations are transformed from the coordinates of receptor surfaces, such as the retina or the cochlea, into the coordinates of effectors, such as the eye, head, or hand. The transformation is accomplished by dynamic updating of spatial representations in conjunction with voluntary movements. This direct sensory-to-motor coordinate transformation obviates the need for a single representation of space in environmental coordinates. In addition to representing object locations in motoric coordinates, parietal neurons exhibit strong modulation by attention. Both top-down and bottom-up mechanisms of attention contribute to the enhancement of visual responses. The saliance of a stimulus is the primary factor in determining the neural response to it. Although parietal neurons represent objects in motor coordinates, visual responses are independent of the intention to perform specific motor acts.