Faculty Bibliography

Epilepsy is a neurologic condition which often occurs with other neurologic and psychiatric disorders. The relation between epilepsy and these conditions is complex. Some population-based studies have identified a bidirectional relation, whereby not only patients with epilepsy are at increased risk of suffering from some of these neurologic and psychiatric disorders (migraine, stroke, dementia, autism, depression, anxiety disorders, Attention deficit hyperactivity disorder (ADHD), and psychosis), but also patients with these conditions are at increased risk of suffering from epilepsy. The existence of common pathogenic mechanisms has been postulated as a potential explanation of this phenomenon. To reassess the relationships between neurological and psychiatric conditions in general, and specifically autism, depression, Alzheimer's disease, schizophrenia, and epilepsy, a recent meeting brought together basic researchers and clinician scientists entitled "Epilepsy as a Network Disorder." This was the fourth in a series of conferences, the "Fourth International Halifax Conference and Retreat". This manuscript summarizes the proceedings on potential relations between Epilepsy on the one hand and autism and depression on the other. A companion manuscript provides a summary of the proceedings about the relation between epilepsy and Alzheimer's disease and schizophrenia, closed by the role of translational research in clarifying these relationships. The review of the topics in these two manuscripts will provide a better understanding of the mechanisms operant in some of the common neurologic and psychiatric comorbidities of epilepsy.

OBJECTIVE:Neural hypo-sensitivity to cues predicting positive reinforcement has been observed in ADHD using the Monetary Incentive Delay (MID) task. Here we report the first study using an electrophysiological analogue of this task to distinguish between (i) cue related anticipation of reinforcement and downstream effects on (ii) target engagement and (iii) performance in a clinical sample of adolescents with ADHD and controls. METHODS:Thirty-one controls and 32 adolescents with ADHD aged 10-16 years performed the electrophysiological (e)-MID task - in which preparatory cues signal whether a response to an upcoming target will be reinforced or not - under three conditions; positive reinforcement, negative reinforcement (response cost) and no consequence (neutral). We extracted values for both cue-related potentials known to be, both, associated with response preparation and modulated by reinforcement (Cue P3 and Cue CNV) and target-related potentials (target P3) and compared these between ADHD and controls. RESULTS:ADHD and controls did not differ on cue-related components on neutral trials. Against expectation, adolescents with ADHD displayed Cue P3 and Cue CNV reinforcement-related enhancement (versus neutral trials) compared to controls. ADHD individuals displayed smaller target P3 amplitudes and slower and more variable performance - but effects were not modulated by reinforcement contingencies. When age, IQ and conduct problems were controlled effects were marginally significant but the pattern of results did not change. DISCUSSION/CONCLUSIONS:ADHD was associated with hypersensitivity to positive (and marginally negative) reinforcement reflected on components often thought to be associated with response preparation - however these did not translate into improved attention to targets. In the case of ADHD, upregulated CNV may be a specific marker of hyper-arousal rather than an enhancement of anticipatory attention to upcoming targets. Future studies should examine the effects of age, IQ and conduct problems on reinforcement sensitivity in ADHD.

Disgust is a core emotion evolved to detect and avoid the ingestion of poisonous food as well as the contact with pathogens and other harmful agents. Previous research has shown that multisensory presentation of olfactory and visual information may strengthen the processing of disgust-relevant information. However, it is not known whether these findings extend to dynamic facial stimuli that changes from neutral to emotionally expressive, or if individual differences in trait body odor disgust may influence the processing of disgust-related information. In this preregistered study, we tested whether a classification of dynamic facial expressions as happy or disgusted, and an emotional evaluation of these facial expressions, would be affected by individual differences in body odor disgust sensitivity, and by exposure to a sweat-like, negatively valenced odor (valeric acid), as compared with a soap-like, positively valenced odor (lilac essence) or a no-odor control. Using Bayesian hypothesis testing, we found evidence that odors do not affect recognition of emotion in dynamic faces even when body odor disgust sensitivity was used as moderator. However, an exploratory analysis suggested that an unpleasant odor context may cause faster RTs for faces, independent of their emotional expression. Our results further our understanding of the scope and limits of odor effects on facial perception affect and suggest further studies should focus on reproducibility, specifying experimental circumstances where odor effects on facial expressions may be present versus absent.

BACKGROUND:The Affordable Care Act of 2010 advanced the economic model of bundled payments for total joint arthroplasty (TJA), in which hospitals will be financially responsible for readmissions, typically at 90 days after surgery. However, little is known about the financial burden of readmissions and what patient, clinical, and hospital factors drive readmission costs. QUESTIONS/PURPOSES/OBJECTIVE:(1) What is the incidence, payer mix, and demographics of THA and TKA readmissions in the United States? (2) What patient, clinical, and hospital factors are associated with the cost of 30- and 90-day readmissions after primary THA and TKA? (3) Are there any differences in the economic burden of THA and TKA readmissions between payers? (4) What types of THA and TKA readmissions are most costly to the US hospital system? METHODS:The recently developed Nationwide Readmissions Database from the Healthcare Cost and Utilization Project (2006 hospitals from 21 states) was used to identify 719,394 primary TJAs and 62,493 90-day readmissions in the first 9 months of 2013 based on International Classification of Diseases, 9th Revision, Clinical Modification codes. We classified the reasons for readmissions as either procedure- or medical-related. Cost-to-charge ratios supplied with the Nationwide Readmissions Database were used to compute the individual per-patient cost of 90-day readmissions as a continuous variable in separate general linear models for THA and TKA. Payer, patient, clinical, and hospital factors were treated as covariates. We estimated the national burden of readmissions by payer and by the reason for readmission. RESULTS:The national rates of 30- and 90-day readmissions after THA were 4% (95% confidence interval [CI], 4.2%-4.5%) and 8% (95% CI, 7.5%-8.1%), respectively. The national rates of 30- and 90-day readmissions after primary TKA were 4% (95% CI, 3.8%-4.0%) and 7% (95% CI, 6.8%-7.2%), respectively. The five most important variables responsible for the cost of 90-day THA readmissions (in rank order, based on the Type III F-statistic, p < 0.001) were length of stay (LOS), all patient-refined diagnosis-related group (APR DRG) severity, type of readmission (that is, medical- versus procedure-related), hospital ownership, and age. Likewise, the five most important variables responsible for the cost of 90-day TKA readmissions were LOS, APR DRG severity, gender, hospital procedure volume, and hospital ownership. After adjusting for covariates, mean 90-day readmission costs reimbursed by private insurance were, on average, USD 1324 and USD 1372 greater than Medicare (p < 0.001) for THA and TKA, respectively. In the 90 days after TJA, two-thirds of the total annual readmission costs were covered by Medicare. In 90 days after THA, more readmissions were still associated with procedure-related complications, including infections, dislocations, and periprosthetic fractures, which in aggregate account for 59% (95% CI, 59.1%-59.6%) of the total readmission costs to the US healthcare system. For TKA, 49% of the total readmission cost (95% CI, 48.8%-49.6%) in 90 days for the United States was associated with procedure issues, most notably including infections. CONCLUSIONS:Hospital readmissions up to 90 days after TJA represent a massive economic burden on the US healthcare system. Approximately half of the total annual economic burden for readmissions in the United States is medical and unrelated to the joint replacement procedure and half is related to procedural complications. CLINICAL RELEVANCE/CONCLUSIONS:This national study underscores LOS during readmission as a primary cost driver, suggesting that hospitals and doctors further optimize, to the extent possible, the clinical pathways for the hospitalization of readmitted patients. Because patients readmitted as a result of infection, dislocation, and periprosthetic fractures are the most costly types of readmissions, efforts to reduce the LOS for these types of readmissions will have the greatest impact on their economic burden. Additional clinical research is needed to determine the extent to which, if any, the LOS during readmissions can be reduced without sacrificing quality or access of care.

Cat-scratch disease-associated vertebral osteomyelitis and epidural involvement are rare and may manifest with nonspecific chronic symptoms in children, such as fever or torticollis. We present only the fourth case in the literature describing epidural involvement in an immunocompetent boy presenting with fever, torticollis, and indiscriminate left upper back tenderness. Bartonella henselae serologies are important to consider because such atypical complications often are responsive to conservative management with antibiotics.

What do infants learn when they learn to sit upright? We tested behavioral flexibility in learning to sit-the ability to adapt posture to changes in the environment-in 6- to 9-month-old infants sitting on forward and backward slopes. Infants began with slant at 0°; then slant increased in 2° increments until infants lost balance. Infants kept balance on impressively steep slopes, especially in the forward direction, despite the unexpected movements of the apparatus. Between slant adjustments while the slope was stationary, infants adapted posture to the direction and degree of slant by leaning backward on forward slopes and forward on backward slopes. Postural adaptations were nearly optimal for backward slopes. Sitting experience predicted greater postural adaptations and increased ability to keep balance on steeper changes of slant, but only for forward slopes. We suggest that behavioral flexibility is integral to learning to sit and increases with sitting experience.

People consistently show preferences and behaviors that benefit others at a cost to themselves, a phenomenon termed altruism. We investigated if perception of one's body signals - interoception - may be underlying such behaviors. We tested if participants' sensitivity to their own heartbeat predicted their decision on a choice between self-interest and altruism, and if improving this sensitivity through training would make participants more altruistic. Across these two experiments, interoceptive sensitivity predicted altruism measured through monetary generosity. Improving interoceptive sensitivity did, however, not lead to more altruistic behaviour. We conclude that there is a unique link between interoception and altruistic behaviour, likely established over an individual's history of altruistic acts, and the body responses they elicit. The findings suggest that humans might literally 'listen to their heart' to guide their altruistic behavior.

Cerebral lateralization is expressed at both the structural and functional levels, and can exist as either a stable characteristic or as a dynamic feature during behavior and development. The anatomically relatively simple olfactory system demonstrates lateralization in both human and non-human animals. Here, we explored functional lateralization in both primary olfactory cortex - a region critical for odor memory and perception- and orbitofrontal cortex (OFC) - a region involved in reversal learning- in rats performing an odor learning and reversal task. We find significant asymmetry in both olfactory and orbitofrontal cortical odor-evoked activity, which is expressed in a performance- and task-dependent manner. The emergence of learning-dependent asymmetry during reversal learning was associated with decreased functional connectivity both between the bilateral OFC and between the OFC-olfactory cortex. The results suggest an inter-hemispheric asymmetry and olfactory cortical functional separation that may allow multiple, specialized processing circuits to emerge during a reversal task requiring behavioral flexibility.

BACKGROUND:Attention-deficit/hyperactivity disorder (ADHD) and bipolar disorder (BPD) are frequently co-occurring and highly heritable mental health conditions. We hypothesized that BPD cases with an early age of onset (≤21 years old) would be particularly likely to show genetic covariation with ADHD. METHODS:Genome-wide association study data were available for 4609 individuals with ADHD, 9650 individuals with BPD (5167 thereof with early-onset BPD), and 21,363 typically developing controls. We conducted a cross-disorder genome-wide association study meta-analysis to identify whether the observed comorbidity between ADHD and BPD could be due to shared genetic risks. RESULTS:) on chromosome 5 in the ADCY2 gene. Additional nominally significant regions identified contained known expression quantitative trait loci with putative functional consequences for NT5DC1, NT5DC2, and CACNB3 expression, whereas functional predictions implicated ABLIM1 as an allele-specific expressed gene in neuronal tissue. CONCLUSIONS:The single nucleotide polymorphism-based genetic correlation between ADHD and BPD is substantial, significant, and consistent with the existence of genetic overlap between ADHD and BPD, with potential differential genetic mechanisms involved in early and later BPD onset.

Importance: Clinical overlap between autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) is increasingly appreciated, but the underlying brain mechanisms remain unknown to date. Objective: To examine associations between white matter organization and 2 commonly co-occurring neurodevelopmental conditions, ASD and ADHD, through both categorical and dimensional approaches. Design, Setting, and Participants: This investigation was a cross-sectional diffusion tensor imaging (DTI) study at an outpatient academic clinical and research center, the Department of Child and Adolescent Psychiatry at New York University Langone Medical Center. Participants were children with ASD, children with ADHD, or typically developing children. Data collection was ongoing from December 2008 to October 2015. Main Outcomes and Measures: The primary measure was voxelwise fractional anisotropy (FA) analyzed via tract-based spatial statistics. Additional voxelwise DTI metrics included radial diffusivity (RD), mean diffusivity (MD), axial diffusivity (AD), and mode of anisotropy (MA). Results: This cross-sectional DTI study analyzed data from 174 children (age range, 6.0-12.9 years), selected from a larger sample after quality assurance to be group matched on age and sex. After quality control, the study analyzed data from 69 children with ASD (mean [SD] age, 8.9 [1.7] years; 62 male), 55 children with ADHD (mean [SD] age, 9.5 [1.5] years; 41 male), and 50 typically developing children (mean [SD] age, 9.4 [1.5] years; 38 male). Categorical analyses revealed a significant influence of ASD diagnosis on several DTI metrics (FA, MD, RD, and AD), primarily in the corpus callosum. For example, FA analyses identified a cluster of 4179 voxels (TFCE FEW corrected P < .05) in posterior portions of the corpus callosum. Dimensional analyses revealed associations between ASD severity and FA, RD, and MD in more extended portions of the corpus callosum and beyond (eg, corona radiata and inferior longitudinal fasciculus) across all individuals, regardless of diagnosis. For example, FA analyses revealed clusters overall encompassing 12121 voxels (TFCE FWE corrected P < .05) with a significant association with parent ratings in the social responsiveness scale. Similar results were evident using an independent measure of ASD traits (ie, children communication checklist, second edition). Total severity of ADHD-traits was not significantly related to DTI metrics but inattention scores were related to AD in corpus callosum in a cluster sized 716 voxels. All these findings were robust to algorithmic correction of motion artifacts with the DTIPrep software. Conclusions and Relevance: Dimensional analyses provided a more complete picture of associations between ASD traits and inattention and indexes of white matter organization, particularly in the corpus callosum. This transdiagnostic approach can reveal dimensional relationships linking white matter structure to neurodevelopmental symptoms.