Predicting drug-resistant epilepsy - A machine learning approach based on administrative claims data.

Patients with drug-resistant epilepsy (DRE) are at high risk of morbidity and mortality, yet their referral to specialist care is frequently delayed. The ability to identify patients at high risk of DRE at the time of treatment initiation, and to subsequently steer their treatment pathway toward more personalized interventions, has high clinical utility. Here, we aim to demonstrate the feasibility of developing algorithms for predicting DRE using machine learning methods. Longitudinal, intersected data sourced from US pharmacy, medical, and adjudicated hospital claims from 1,376,756 patients from 2006 to 2015 were analyzed; 292,892 met inclusion criteria for epilepsy, and 38,382 were classified as having DRE using a proxy measure for drug resistance. Patients were characterized using 1270 features reflecting demographics, comorbidities, medications, procedures, epilepsy status, and payer status. Data from 175,735 randomly selected patients were used to train three algorithms and from the remainder to assess the trained models' predictive power. A model with only age and sex was used as a benchmark. The best model, random forest, achieved an area under the receiver operating characteristic curve (95% confidence interval [CI]) of 0.764 (0.759, 0.770), compared with 0.657 (0.651, 0.663) for the benchmark model. Moreover, predicted probabilities for DRE were well-calibrated with the observed frequencies in the data. The model predicted drug resistance approximately 2 years before patients in the test dataset had failed two antiepileptic drugs (AEDs). Machine learning models constructed using claims data predicted which patients are likely to fail ≥3 AEDs and are at risk of developing DRE at the time of the first AED prescription. The use of such models can ensure that patients with predicted DRE receive specialist care with potentially more aggressive therapeutic interventions from diagnosis, to help reduce the serious sequelae of DRE.

Baby schema modulates the brain reward system in nulliparous women.

Ethologist Konrad Lorenz defined the baby schema ("Kindchenschema") as a set of infantile physical features, such as round face and big eyes, that is perceived as cute and motivates caretaking behavior in the human, with the evolutionary function of enhancing offspring survival. The neural basis of this fundamental altruistic instinct is not well understood. Prior studies reported a pattern of brain response to pictures of children, but did not dissociate the brain response to baby schema from the response to children. Using functional magnetic resonance imaging and controlled manipulation of the baby schema in infant faces, we found that baby schema activates the nucleus accumbens, a key structure of the mesocorticolimbic system mediating reward processing and appetitive motivation, in nulliparous women. Our findings suggest that engagement of the mesocorticolimbic system is the neurophysiologic mechanism by which baby schema promotes human caregiving, regardless of kinship.

Opposing amygdala and ventral striatum connectivity during emotion identification.

Lesion and electrophysiological studies in animals provide evidence of opposing functions for subcortical nuclei such as the amygdala and ventral striatum, but the implications of these findings for emotion identification in humans remain poorly described. Here we report a high-resolution fMRI study in a sample of 39 healthy subjects who performed a well-characterized emotion identification task. As expected, the amygdala responded to THREAT (angry or fearful) faces more than NON-THREAT (sad or happy) faces. A functional connectivity analysis of the time series from an anatomically defined amygdala seed revealed a strong anticorrelation between the amygdala and the ventral striatum/ventral pallidum, consistent with an opposing role for these regions in during emotion identification. A second functional connectivity analysis (psychophysiological interaction) investigating relative connectivity on THREAT vs. NON-THREAT trials demonstrated that the amygdala had increased connectivity with the orbitofrontal cortex during THREAT trials, whereas the ventral striatum demonstrated increased connectivity with the posterior hippocampus on NON-THREAT trials. These results indicate that activity in the amygdala and ventral striatum may be inversely related, and that both regions may provide opposing affective bias signals during emotion identification.

Frontolimbic responses to emotional face memory: the neural correlates of first impressions.

First impressions, especially of emotional faces, may critically impact later evaluation of social interactions. Activity in limbic regions, including the amygdala and ventral striatum, has previously been shown to correlate with identification of emotional content in faces; however, little work has been done describing how these signals may influence emotional face memory. We report an event-related functional magnetic resonance imaging study in 21 healthy adults where subjects attempted to recognize a neutral face that was previously viewed with a threatening (angry or fearful) or nonthreatening (happy or sad) affect. In a hypothesis-driven region of interest analysis, we found that neutral faces previously presented with a threatening affect recruited the left amygdala. In contrast, faces previously presented with a nonthreatening affect activated the left ventral striatum. A whole-brain analysis revealed increased response in the right orbitofrontal cortex to faces previously seen with threatening affect. These effects of prior emotion were independent of task performance, with differences being seen in the amygdala and ventral striatum even if only incorrect trials were considered. The results indicate that a network of frontolimbic regions may provide emotional bias signals during facial recognition.

Assessing Predictors of Early and Late Hospital Readmission After Kidney Transplantation.

BACKGROUND: A better understanding of the risk factors of posttransplant hospital readmission is needed to develop accurate predictive models. METHODS: We included 40 461 kidney transplant recipients from United States renal data system (USRDS) between 2005 and 2014. We used Prentice, Williams and Peterson Total time model to compare the importance of various risk factors in predicting posttransplant readmission based on the number of the readmissions (first vs subsequent) and a random forest model to compare risk factors based on the timing of readmission (early vs late). RESULTS: Twelve thousand nine hundred eighty-five (31.8%) and 25 444 (62.9%) were readmitted within 30 days and 1 year postdischarge, respectively. Fifteen thousand eight hundred (39.0%) had multiple readmissions. Predictive accuracies of our models ranged from 0.61 to 0.63. Transplant factors remained the main predictors for early and late readmission but decreased with time. Although recipients' demographics and socioeconomic factors only accounted for 2.5% and 11% of the prediction at 30 days, respectively, their contribution to the prediction of later readmission increased to 7% and 14%, respectively. Donor characteristics remained poor predictors at all times. The association between recipient characteristics and posttransplant readmission was consistent between the first and subsequent readmissions. Donor and transplant characteristics presented a stronger association with the first readmission compared with subsequent readmissions. CONCLUSIONS: These results may inform the development of future predictive models of hospital readmission that could be used to identify kidney transplant recipients at high risk for posttransplant hospitalization and design interventions to prevent readmission.

Alterations of fronto-temporal connectivity during word encoding in schizophrenia.

Cognitive deficits, including impaired verbal memory, are prominent in schizophrenia and lead to increased disability. Functional neuroimaging of patients with schizophrenia performing memory tasks has revealed abnormal activation patterns in prefrontal cortex and temporo-limbic regions. Aberrant fronto-temporal interactions thus represent a potential pathophysiological mechanism underlying verbal memory deficits, yet this hypothesis of disturbed connectivity is not tested directly with standard activation studies. We performed within-subject correlations of frontal and temporal timeseries to measure functional connectivity during verbal encoding. Our results confirm earlier findings of aberrant fronto-temporal connectivity in schizophrenia, and extend them by identifying distinct alterations within dorsal and ventral prefrontal cortex. Relative to healthy controls, patients with schizophrenia had reduced connectivity between the dorsolateral prefrontal cortex (DLPFC) and temporal lobe areas including parahippocampus and superior temporal gyrus. In contrast, patients showed increased connectivity between a region of ventrolateral prefrontal cortex (VLPFC) and these same temporal lobe regions. Higher temporal-DLPFC connectivity during encoding was associated with better subsequent recognition accuracy in controls, but not patients. Temporal-VLPFC connectivity was uncorrelated with recognition accuracy in either group. The results suggest that reduced temporal-DLPFC connectivity in schizophrenia could underlie encoding deficits, and increased temporal-VLPFC connectivity may represent an ineffective compensatory effort.

Functional magnetic resonance imaging of internal source monitoring in schizophrenia: recognition with and without recollection.

Patients with schizophrenia tend to have impaired source monitoring and intact item recognition, suggesting an over-reliance of familiarity effects. We previously demonstrated that providing patients with a levels-of-processing (LOP) semantic encoding strategy normalized source monitoring. The current blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) study tests the hypothesis that patients will have abnormally increased fronto-temporal activation despite intact performance. fMRI was measured in 13 patients and 13 demographically matched healthy controls during a LOP source monitoring paradigm. SPM2 was used for standard pre-processing and statistical analyses, with a corrected significance threshold of p<.05. Examination of accuracy and speed measures did not reveal any group differences in task performance. Regardless of source retrieval success both groups activated expected prefrontal and parietal regions, with no areas of relatively greater control versus patient activation. In support of the hypothesis, patients showed abnormally increased activation in temporolimbic areas including middle and superior temporal gyrus, thalamus, and parahippocampal gyrus. Activation in these areas was associated with worse positive and negative symptoms, but did not correlate with performance, suggesting inefficient rather than compensatory activation.

Levels-of-processing effect on frontotemporal function in schizophrenia during word encoding and recognition.

OBJECTIVE: Patients with schizophrenia improve episodic memory accuracy when given organizational strategies through levels-of-processing paradigms. This study tested if improvement is accompanied by normalized frontotemporal function. METHOD: Event-related blood-oxygen-level-dependent functional magnetic resonance imaging (fMRI) was used to measure activation during shallow (perceptual) and deep (semantic) word encoding and recognition in 14 patients with schizophrenia and 14 healthy comparison subjects. RESULTS: Despite slower and less accurate overall word classification, the patients showed normal levels-of-processing effects, with faster and more accurate recognition of deeply processed words. These effects were accompanied by left ventrolateral prefrontal activation during encoding in both groups, although the thalamus, hippocampus, and lingual gyrus were overactivated in the patients. During word recognition, the patients showed overactivation in the left frontal pole and had a less robust right prefrontal response. CONCLUSIONS: Evidence of normal levels-of-processing effects and left prefrontal activation suggests that patients with schizophrenia can form and maintain semantic representations when they are provided with organizational cues and can improve their word encoding and retrieval. Areas of overactivation suggest residual inefficiencies. Nevertheless, the effect of teaching organizational strategies on episodic memory and brain function is a worthwhile topic for future interventional studies.

Subsequent memory effects in schizophrenia.

Differential neural activation at encoding can predict which stimuli will be subsequently remembered or forgotten, and memory deficits are pronounced in schizophrenia. We used event-related functional magnetic resonance imaging (fMRI) to investigate subsequent memory (SM) effects for visual fractals in patients with schizophrenia (n=26) and healthy controls (n=28). Participants incidentally encoded the fractals during an oddball task and 10 min later they made old/new recognition memory judgments on 30 target fractals and 30 foil fractals. We found evidence for subsequent memory (SM, subsequently remembered>subsequently forgotten) effects on regional brain activation in both groups but with distinct patterns. Region of interest (ROI) analyses in controls demonstrated SM activation in both medial temporal lobe (MTL) and fusiform cortex (FF), whereas patients showed SM effects only in the FF. There were no significant between group differences in MTL activation; however, patients demonstrated greater FF activation than controls. Notably, greater FF activation during successful encoding was associated with more severe negative symptoms. Exploratory whole brain analyses in patients demonstrated SM activation in the occipital pole, lateral occipital cortex, left inferior temporal gyrus, and fusiform cortex; whereas in controls there was no significant activation that survived correction for multiple comparisons. Our findings suggest that patients, particularly those with prominent negative symptoms, may activate FF as a compensatory strategy to promote successful encoding, with relatively less reliance on MTL recruitment.

Comparison of auditory and visual oddball fMRI in schizophrenia.

Individuals with schizophrenia often suffer from attentional deficits, both in focusing on task-relevant targets and in inhibiting responses to distractors. Schizophrenia also has a differential impact on attention depending on modality: auditory or visual. However, it remains unclear how abnormal activation of attentional circuitry differs between auditory and visual modalities, as these two modalities have not been directly compared in the same individuals with schizophrenia. We utilized event-related functional magnetic resonance imaging (fMRI) to compare patterns of brain activation during an auditory and visual oddball task in order to identify modality-specific attentional impairment. Healthy controls (n=22) and patients with schizophrenia (n=20) completed auditory and visual oddball tasks in separate sessions. For responses to targets, the auditory modality yielded greater activation than the visual modality (A-V) in auditory cortex, insula, and parietal operculum, but visual activation was greater than auditory (V-A) in visual cortex. For responses to novels, A-V differences were found in auditory cortex, insula, and supramarginal gyrus; and V-A differences in the visual cortex, inferior temporal gyrus, and superior parietal lobule. Group differences in modality-specific activation were found only for novel stimuli; controls showed larger A-V differences than patients in prefrontal cortex and the putamen. Furthermore, for patients, greater severity of negative symptoms was associated with greater divergence of A-V novel activation in the visual cortex. Our results demonstrate that patients have more pronounced activation abnormalities in auditory compared to visual attention, and link modality specific abnormalities to negative symptom severity.

Association of abstinence-induced alterations in working memory function and COMT genotype in smokers.

RATIONALE: The common methionine (met) for valine (val) at codon 158 (val(158)met) polymorphism in the catechol-O-methyltransferase (COMT) gene has been associated with nicotine dependence, alterations in executive cognitive function, and abstinence-induced working memory deficits in smokers. OBJECTIVES: We sought to replicate the association of the COMT val allele with abstinence-induced alterations in working memory-related activity in task-positive (executive control) and task-negative (default mode network) regions. METHODS: Forty smokers (20 val/val and 20 met/met) performed an N-back task while undergoing blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) on two separate occasions: following 72 h of confirmed abstinence and during smoking as usual. An independent sample of 48 smokers who completed the identical N-back task during fMRI in smoking vs. abstinence for another study was used as a validation sample. RESULTS: Contrary to expectations, genotype by session interactions on BOLD signal in executive control regions (dorsolateral prefrontal cortex and dorsal cingulate/medial prefrontal cortex) revealed significant abstinence-induced reductions in the met/met group, but not the val/val group. Results also revealed that val/val smokers may exhibit less suppression of activation in task-negative regions such as the posterior cingulate cortex during abstinence (vs. smoking). These patterns were confirmed in the validation sample and in the whole-brain analysis, though the regions differed from the a priori regions of interest (ROIs) (e.g., precuneus, insula). CONCLUSIONS: The COMT val(158)met polymorphism was associated with abstinence-related working memory deficits in two independent samples of smokers. However, inconsistencies compared to prior findings and across methods (ROI vs. whole-brain analysis) highlight the challenges inherent in reproducing results of imaging genetic studies in addiction.

Effects of tolcapone on working memory and brain activity in abstinent smokers: a proof-of-concept study.

BACKGROUND: Dopamine levels in the prefrontal cortex (PFC) are thought to play an important role in cognitive function and nicotine dependence. The catechol-O-methyltransferase (COMT) inhibitor tolcapone, an FDA-approved treatment for Parkinson's disease, increases prefrontal dopamine levels, with cognitive benefits that may vary by COMT genotype. We tested whether tolcapone alters working memory-related brain activity and performance in abstinent smokers. METHODS: In this double-blind crossover study, 20 smokers completed 8 days of treatment with tolcapone and placebo. In both medication periods, smokers completed blood oxygen level-dependent (BOLD) fMRI scans while performing a working memory N-back task after 24h of abstinence. Smokers were genotyped prospectively for the COMT val(158)met polymorphism for exploratory analysis. RESULTS: Compared to placebo, tolcapone modestly improved accuracy (p=0.017) and enhanced suppression of activation in the ventromedial prefrontal cortex (vmPFC) (p=0.002). There were no effects of medication in other a priori regions of interest (dorsolateral PFC, dorsal cingulate/medial prefrontal cortex, or posterior cingulate cortex). Exploratory analyses suggested that tolcapone led to a decrease in BOLD signal in several regions among smokers with val/val genotypes, but increased or remained unchanged among met allele carriers. Tolcapone did not attenuate craving, mood, or withdrawal symptoms compared to placebo. CONCLUSIONS: Data from this proof-of-concept study do not provide strong support for further evaluation of COMT inhibitors as smoking cessation aids.

Not pitch perfect: sensory contributions to affective communication impairment in schizophrenia.

BACKGROUND: Schizophrenia patients have vocal affect (prosody) deficits that are treatment resistant and associated with negative symptoms and poor outcome. The neural correlates of this dysfunction are unclear. Prior study has suggested that schizophrenia vocal affect perception deficits stem from an inability to use acoustic cues, notably pitch, in decoding emotion. METHODS: Functional magnetic resonance imaging was performed in 24 schizophrenia patients and 28 healthy control subjects, during the performance of a four-choice (happiness, fear, anger, neutral) vocal affect identification task in which items for each emotion varied parametrically in affective salient acoustic cue levels. RESULTS: We observed that parametric increases in cue levels in schizophrenia failed to produce the same identification rate increases as in control subjects. These deficits correlated with diminished reciprocal activation changes in superior temporal and inferior frontal gyri and reduced temporo-frontal connectivity. Task activation also correlated with independent measures of pitch perception and negative symptom severity. CONCLUSIONS: These findings illustrate the interplay between sensory and higher-order cognitive dysfunction in schizophrenia. Sensory contributions to vocal affect deficits also suggest that this neurobehavioral marker could be targeted by pharmacological or behavioral remediation of acoustic feature discrimination.

Ventrolateral prefrontal cortex and the effects of task demand context on facial affect appraisal in schizophrenia.

Schizophrenia patients display impaired performance and brain activity during facial affect recognition. These impairments may reflect stimulus-driven perceptual decrements and evaluative processing abnormalities. We differentiated these two processes by contrasting responses to identical stimuli presented under different contexts. Seventeen healthy controls and 16 schizophrenia patients performed an fMRI facial affect detection task. Subjects identified an affective target presented amongst foils of differing emotions. We hypothesized that targeting affiliative emotions (happiness, sadness) would create a task demand context distinct from that generated when targeting threat emotions (anger, fear). We compared affiliative foil stimuli within a congruent affiliative context with identical stimuli presented in an incongruent threat context. Threat foils were analysed in the same manner. Controls activated right orbitofrontal cortex (OFC)/ventrolateral prefrontal cortex (VLPFC) more to affiliative foils in threat contexts than to identical stimuli within affiliative contexts. Patients displayed reduced OFC/VLPFC activation to all foils, and no activation modulation by context. This lack of context modulation coincided with a 2-fold decrement in foil detection efficiency. Task demands produce contextual effects during facial affective processing in regions activated during affect evaluation. In schizophrenia, reduced modulation of OFC/VLPFC by context coupled with reduced behavioural efficiency suggests impaired ventral prefrontal control mechanisms that optimize affective appraisal.

Association of enhanced limbic response to threat with decreased cortical facial recognition memory response in schizophrenia.

OBJECTIVE: Recognition memory of faces is impaired in patients with schizophrenia, as is the neural processing of threat-related signals, but how these deficits interact to produce symptoms is unclear. The authors used an affective face recognition paradigm to examine possible interactions between cognitive and affective neural systems in schizophrenia. METHOD: Blood-oxygen-level-dependent response was examined by means of functional magnetic resonance imaging (3 Tesla) in healthy comparison subjects (N=21) and in patients with schizophrenia (N=12) or schizoaffective disorder, depressed type (N=4), during a two-choice recognition task that used images of human faces. Each target face, previously displayed with a threatening or nonthreatening affect, was displayed with neutral affect. Responses to successful recognition and responses to the effect of previously threatening versus nonthreatening affect were evaluated, and correlations with symptom severity (total Brief Psychiatric Rating Scale score) were examined. Functional connectivity analyses examined the relationship between activation in the amygdala and cortical regions involved in recognition memory. RESULTS: Patients performed the task more slowly than healthy comparison subjects. Comparison subjects recruited the expected cortical regions to a greater degree than patients, and patients with more severe symptoms demonstrated proportionally less recruitment. Increased symptoms were also correlated with augmented amygdala and orbitofrontal cortex response to threatening faces. Comparison subjects exhibited a negative correlation between activity in the amygdala and cortical regions involved in cognition, while patients showed weakening of this relationship. CONCLUSION: Increased symptoms were related to an enhanced threat response in limbic regions and a diminished recognition memory response in cortical regions, supporting a link between these two brain systems that are often examined in isolation. This finding suggests that abnormal processing of threat-related signals in the environment may exacerbate cognitive impairment in schizophrenia.

"It's Not What You Say, But How You Say it": A Reciprocal Temporo-frontal Network for Affective Prosody.

Humans communicate emotion vocally by modulating acoustic cues such as pitch, intensity and voice quality. Research has documented how the relative presence or absence of such cues alters the likelihood of perceiving an emotion, but the neural underpinnings of acoustic cue-dependent emotion perception remain obscure. Using functional magnetic resonance imaging in 20 subjects we examined a reciprocal circuit consisting of superior temporal cortex, amygdala and inferior frontal gyrus that may underlie affective prosodic comprehension. Results showed that increased saliency of emotion-specific acoustic cues was associated with increased activation in superior temporal cortex [planum temporale (PT), posterior superior temporal gyrus (pSTG), and posterior superior middle gyrus (pMTG)] and amygdala, whereas decreased saliency of acoustic cues was associated with increased inferior frontal activity and temporo-frontal connectivity. These results suggest that sensory-integrative processing is facilitated when the acoustic signal is rich in affective information, yielding increased activation in temporal cortex and amygdala. Conversely, when the acoustic signal is ambiguous, greater evaluative processes are recruited, increasing activation in inferior frontal gyrus (IFG) and IFG STG connectivity. Auditory regions may thus integrate acoustic information with amygdala input to form emotion-specific representations, which are evaluated within inferior frontal regions.