Partitioning heritability analysis reveals a shared genetic basis of brain anatomy and schizophrenia.

This corrects the article DOI: 10.1038/mp.2017.42.

Association between polygenic risk for schizophrenia, neurocognition and social cognition across development.

Breakthroughs in genomics have begun to unravel the genetic architecture of schizophrenia risk, providing methods for quantifying schizophrenia polygenic risk based on common genetic variants. Our objective in the current study was to understand the relationship between schizophrenia genetic risk variants and neurocognitive development in healthy individuals. We first used combined genomic and neurocognitive data from the Philadelphia Neurodevelopmental Cohort (4303 participants ages 8-21 years) to screen 26 neurocognitive phenotypes for their association with schizophrenia polygenic risk. Schizophrenia polygenic risk was estimated for each participant based on summary statistics from the most recent schizophrenia genome-wide association analysis (Psychiatric Genomics Consortium 2014). After correction for multiple comparisons, greater schizophrenia polygenic risk was significantly associated with reduced speed of emotion identification and verbal reasoning. These associations were significant by age 9 years and there was no evidence of interaction between schizophrenia polygenic risk and age on neurocognitive performance. We then looked at the association between schizophrenia polygenic risk and emotion identification speed in the Harvard/MGH Brain Genomics Superstruct Project sample (695 participants ages 18-35 years), where we replicated the association between schizophrenia polygenic risk and emotion identification speed. These analyses provide evidence for a replicable association between polygenic risk for schizophrenia and a specific aspect of social cognition. Our findings indicate that individual differences in genetic risk for schizophrenia are linked with the development of aspects of social cognition and potentially verbal reasoning, and that these associations emerge relatively early in development.

Partitioning heritability analysis reveals a shared genetic basis of brain anatomy and schizophrenia.

Schizophrenia is a devastating neurodevelopmental disorder with a complex genetic etiology. Widespread cortical gray matter loss has been observed in patients and prodromal samples. However, it remains unresolved whether schizophrenia-associated cortical structure variations arise due to disease etiology or secondary to the illness. Here we address this question using a partitioning-based heritability analysis of genome-wide single-nucleotide polymorphism (SNP) and neuroimaging data from 1750 healthy individuals. We find that schizophrenia-associated genetic variants explain a significantly enriched proportion of trait heritability in eight brain phenotypes (false discovery rate=10%). In particular, intracranial volume and left superior frontal gyrus thickness exhibit significant and robust associations with schizophrenia genetic risk under varying SNP selection conditions. Cross-disorder comparison suggests that the neurogenetic architecture of schizophrenia-associated brain regions is, at least in part, shared with other psychiatric disorders. Our study highlights key neuroanatomical correlates of schizophrenia genetic risk in the general population. These may provide fundamental insights into the complex pathophysiology of the illness, and a potential link to neurocognitive deficits shaping the disorder.

Relationship between M100 Auditory Evoked Response and Auditory Radiation Microstructure in 16p11.2 Deletion and Duplication Carriers.

BACKGROUND AND PURPOSE: Deletion and duplication of chromosome 16p11.2 (BP4-BP5) have been associated with developmental disorders such as autism spectrum disorders, and deletion subjects exhibit a large (20-ms) delay of the auditory evoked cortical response as measured by magnetoencephalography (M100 latency). The purpose of this study was to use a multimodal approach to test whether changes in white matter microstructure are associated with delayed M100 latency. MATERIALS AND METHODS: Thirty pediatric deletion carriers, 9 duplication carriers, and 39 control children were studied with both magnetoencephalography and diffusion MR imaging. The M100 latency and auditory system DTI measures were compared between groups and tested for correlation. RESULTS: In controls, white matter diffusivity significantly correlated with the speed of the M100 response. However, the relationship between structure and function appeared uncoupled in 16p11.2 copy number variation carriers. The alterations to auditory system white matter microstructure in the 16p11.2 deletion only partially accounted for the 20-ms M100 delay. Although both duplication and deletion groups exhibit abnormal white matter microstructure, only the deletion group has delayed M100 latency. CONCLUSIONS: These results indicate that gene dosage impacts factors other than white matter microstructure, which modulate conduction velocity.

Comparison of the Vidas C. difficile GDH Automated Enzyme-Linked Fluorescence Immunoassay (ELFA) with Another Commercial Enzyme Immunoassay (EIA) (Quik Chek-60), Two Selective Media, and a PCR Assay for gluD for Detection of Clostridium difficile in Fecal Samples.

Prevention and management of Clostridium difficile infection (CDI) can be improved by rapid and reliable diagnostics. The Vidas C. difficile glutamate dehydrogenase assay had performance comparable to that of the Quik Chek-60 assay (overall agreement, 95%) and a sensitivity of >93%; thus, it is suitable as the first test in two-stage algorithms for a CDI diagnosis.

An international, prospective, multicenter evaluation of the combination of AdvanDx Staphylococcus QuickFISH BC with mecA XpressFISH for detection of methicillin-resistant Staphylococcus aureus isolates from positive blood cultures.

Sepsis caused by Staphylococcus aureus is a major health problem worldwide. Better outcomes are achieved when rapid diagnosis and determination of methicillin susceptibility enable early optimization of antimicrobial therapy. Eight large clinical laboratories, seven from the United States and one from Scotland, evaluated the combination of the Staphylococcus QuickFISH BC and the new mecA XpressFISH assay (both AdvanDx, Woburn, MA, USA) for the detection of methicillin-resistant S. aureus in positive blood cultures. Blood cultures flagged as positive by automated blood culture instruments and demonstrating only Gram-positive cocci in clusters on Gram stain were tested by QuickFISH, a 20-min assay. If only S. aureus was detected, mecA XpressFISH testing followed. The recovered S. aureus isolates were tested by cefoxitin disk diffusion as the reference method. The QuickFISH assay results were concordant with the routine phenotypic testing methods of the testing laboratories in 1,211/1,221 (99.1%) samples and detected 488/491 S. aureus organisms (sensitivity, 99.4%; specificity, 99.6%). Approximately 60% of the samples (730) contained coagulase-negative staphylococci or nonstaphylococci as assessed by the QuickFISH assay and were not tested further. The 458 compliant samples positive exclusively for S. aureus by the QuickFISH assay were tested by the mecA XpressFISH assay, which detected 209 of 211 methicillin-resistant S. aureus organisms (sensitivity, 99.1%; specificity, 99.6%). The mecA XpressFISH assay also showed high reproducibility, with 534/540 tests performed by 6 operators over 5 days achieving reproducible results (98.9% agreement). The combination of the Staphylococcus QuickFISH BC and mecA XpressFISH assays is sensitive, specific, and reproducible for the detection of methicillin-resistant S. aureus and yields complete results in 2 h after the blood culture turns positive.

Optogenetic drive of neocortical pyramidal neurons generates fMRI signals that are correlated with spiking activity.

Local fluctuations in the blood oxygenation level-dependent (BOLD) signal serve as the basis of functional magnetic resonance imaging (fMRI). Understanding the correlation between distinct aspects of neural activity and the BOLD response is fundamental to the interpretation of this widely used mapping signal. Analysis of this question requires the ability to precisely manipulate the activity of defined neurons. To achieve such control, we combined optogenetic drive of neocortical neurons with high-resolution (9.4 T) rodent fMRI and detailed analysis of neurophysiological data. Light-driven activation of pyramidal neurons resulted in a positive BOLD response at the stimulated site. To help differentiate the neurophysiological correlate(s) of the BOLD response, we employed light trains of the same average frequency, but with periodic and Poisson distributed pulse times. These different types of pulse trains generated dissociable patterns of single-unit, multi-unit and local field potential (LFP) activity, and of BOLD signals. The BOLD activity exhibited the strongest correlation to spiking activity with increasing rates of stimulation, and, to a first approximation, was linear with pulse delivery rate, while LFP activity showed a weaker correlation. These data provide an example of a strong correlation between spike rate and the BOLD response. This article is part of a Special Issue entitled Optogenetics (7th BRES).

Mapping brain networks in awake mice using combined optical neural control and fMRI.

Behaviors and brain disorders involve neural circuits that are widely distributed in the brain. The ability to map the functional connectivity of distributed circuits, and to assess how this connectivity evolves over time, will be facilitated by methods for characterizing the network impact of activating a specific subcircuit, cell type, or projection pathway. We describe here an approach using high-resolution blood oxygenation level-dependent (BOLD) functional MRI (fMRI) of the awake mouse brain-to measure the distributed BOLD response evoked by optical activation of a local, defined cell class expressing the light-gated ion channel channelrhodopsin-2 (ChR2). The utility of this opto-fMRI approach was explored by identifying known cortical and subcortical targets of pyramidal cells of the primary somatosensory cortex (SI) and by analyzing how the set of regions recruited by optogenetically driven SI activity differs between the awake and anesthetized states. Results showed positive BOLD responses in a distributed network that included secondary somatosensory cortex (SII), primary motor cortex (MI), caudoputamen (CP), and contralateral SI (c-SI). Measures in awake compared with anesthetized mice (0.7% isoflurane) showed significantly increased BOLD response in the local region (SI) and indirectly stimulated regions (SII, MI, CP, and c-SI), as well as increased BOLD signal temporal correlations between pairs of regions. These collective results suggest opto-fMRI can provide a controlled means for characterizing the distributed network downstream of a defined cell class in the awake brain. Opto-fMRI may find use in examining causal links between defined circuit elements in diverse behaviors and pathologies.

Evaluating functional MRI procedures for assessing hemispheric language dominance in neurosurgical patients.

Two methods of quantifying hemispheric language dominance (HLD) in neurosurgical patients are compared: (1) an average magnitudes (AM) method, which is a calculation of the average signal intensity variation in regions of interest for each patient that were predefined in a group analysis for each task, and (2) a lateralization indices (LI) method, which is based on the number of activated pixels in regions of interest predefined in each individual patient. Four language tasks [a living/nonliving (LNL) judgment, word stem completion (WSC), semantic associate (SA) and a phonological associate (PA) task] were compared with "gold standard" measures such as the Wada test or electrocortical stimulation. Results showed that the LI method was more accurate (73% agreement with gold standard methods) than the AM method (only 40% agreement) across tasks and subjects. Furthermore, by varying the threshold used for determining laterality, the ability of functional magnetic resonance imaging (fMRI) to predict HLD was influenced for the AM method, whereas the LI method was relatively unaffected by changing the threshold. Using the LI method, the SA task was the most accurate for quantifying HLD (100% agreement with gold standard methods) with respect to the other three language tasks (80% accuracy for WSC, 65% for the LNL and 63% for phonological task). Depending on the method and the task, fMRI may be a promising tool for assessing HLD in neurosurgical patients.

Normative estimates of cross-sectional and longitudinal brain volume decline in aging and AD.

OBJECTIVE: To test the hypotheses 1) that whole-brain volume decline begins in early adulthood, 2) that cross-sectional and longitudinal atrophy estimates agree in older, nondemented individuals, and 3) that longitudinal atrophy accelerates in the earliest stages of Alzheimer disease (AD). METHODS: High-resolution, high-contrast structural MRIs were obtained from 370 adults (age 18 to 97). Participants over 65 (n = 192) were characterized using the Clinical Dementia Rating (CDR) as either nondemented (CDR 0, n = 94) or with very mild to mild dementia of the Alzheimer type (DAT, CDR 0.5 and 1, n = 98). Of these older participants, 79 belonged to a longitudinal cohort and were imaged again a mean 1.8 years after baseline. Estimates of gray matter (nGM), white matter (nWM), and whole-brain volume (nWBV) normalized for head sizes were generated based on atlas registration and image segmentation. RESULTS: Hierarchical regression of nWBV estimates from nondemented individuals across the adult lifespan revealed a strong linear, moderate quadratic pattern of decline beginning in early adulthood, with later onset of nWM than nGM loss. Whole-brain volume differences were detected by age 30. The cross-sectional atrophy model overlapped with the rates measured longitudinally in older, nondemented individuals (mean decline of -0.45% per year). In those individuals with very mild DAT, atrophy rate more than doubled (-0.98% per year). CONCLUSIONS: Nondemented individuals exhibit a slow rate of whole-brain atrophy from early in adulthood with white-matter loss beginning in middle age; in older adults, the onset of dementia of the Alzheimer type is associated with a markedly accelerated atrophy rate.

Rapid self-paced event-related functional MRI: feasibility and implications of stimulus- versus response-locked timing.

Many cognitive paradigms require self-paced responses or examine events that occur at unpredictable times. To explore whether functional MRI (fMRI) can accommodate such paradigms, a method allowing rapid, unpredictable trial pacing was developed and tested on 17 subjects using activation of the motor network as a model. Trial onset was determined solely by the subjects' self-paced responses and trials occurred, on average, less than 2 s apart. The hemodynamic response was estimated both in relation to stimulus onset (stimulus-locked) and in relation to behavioral response time (response-locked). Results yielded robust activation maps and hemodynamic response estimates. Specifically, significant activation in motor cortex, supplementary motor area (SMA), and cerebellum was observed both at the group and at the individual-subject level, confirming predicted patterns of brain activity. Moreover, the self-paced design resulted in even temporal sampling of the hemodynamic response across the image acquisition, allowing estimation of response parameters. Stimulus-locked analysis demonstrated strong correlation between hemodynamic- and behavioral-response timing both within and across subjects. Conversely, response-locked analysis showed minimal correlation with behavioral timing, suggesting effective resynchronization of the timing parameters. These results demonstrate fMRI procedures that can accommodate rapid, arbitrarily timed events and, in doing so, provide precise temporal estimates of the hemodynamic response.

Dissociating memory retrieval processes using fMRI: evidence that priming does not support recognition memory.

We employed event-related fMRI to constrain cognitive accounts of memory retrieval. Studies of explicit retrieval reveal that lateral and medial parietal, dorsal middle frontal gyrus, and anterior prefrontal cortex respond more for studied than new words, reflecting a correlate of "retrieval success." Studies of implicit memory suggest left temporal cortex, ventral and dorsal inferior frontal gyrus respond less for studied than new words, reflecting a correlate of "conceptual priming." In the present study, responses for old and new items were compared during performance on explicit recognition (old/new judgement) and semantic (abstract/concrete judgement) tasks. Regions associated with priming were only modulated during the semantic task, whereas regions associated with retrieval success were modulated during both tasks. These findings constrain functional-anatomic accounts of the networks, suggesting that processes associated with priming do not support explicit recognition judgments.

An event-related fMRI study of overt and covert word stem completion.

In fMRI studies of language processing, it would be extremely useful to obtain high-quality images during tasks requiring spoken output. Recent studies have suggested that this may be possible, particularly if event-related fMRI methods are used. This study assesses the feasibility of acquiring interpretable images during speech by applying event-related methods to visual word stem completion, a task that has been studied extensively. On each trial, a different three-letter word stem (e.g., COU) was presented visually and subjects were required to generate a word beginning with that stem (e.g., COUSIN). In covert runs, subjects were instructed to say the word once to themselves, without moving their lips. In overt runs, subjects were instructed to say the word once aloud. Ten subjects were scanned during six overt runs and six covert runs at three presentation rates. Data were analyzed using an implementation of the general linear model making no assumptions about response shape. Images were relatively free of artifacts, and regions demonstrating task-related activation were similar to those reported in previous imaging studies. Regions active during overt task performance were similar to those active during covert task performance, with the addition of several regions commonly associated with motor aspects of speech production. Consistent with other studies, magnitude of activation was greater in the overt condition than in the covert condition, and there was a modest decrease in magnitude at the fastest presentation rate. Together, these results help to validate the use of event-related fMRI during tasks that require spoken output. Press

Direct comparison of prefrontal cortex regions engaged by working and long-term memory tasks.

Neuroimaging studies have suggested the involvement of ventrolateral, dorsolateral, and frontopolar prefrontal cortex (PFC) regions in both working (WM) and long-term memory (LTM). The current study used functional magnetic resonance imaging (fMRI) to directly compare whether these PFC regions show selective activation associated with one memory domain. In a within-subjects design, subjects performed the n-back WM task (two-back condition) as well as LTM encoding (intentional memorization) and retrieval (yes-no recognition) tasks. Additionally, each task was performed with two different types of stimulus materials (familiar words, unfamiliar faces) in order to determine the influence of material-type vs task-type. A bilateral region of dorsolateral PFC (DL-PFC; BA 46/9) was found to be selectively activated during the two-back condition, consistent with a hypothesized role for this region in active maintenance and/or manipulation of information in WM. Left frontopolar PFC (FP-PFC) was also found to be selectively engaged during the two-back. Although FP-PFC activity has been previously associated with retrieval from LTM, no frontopolar regions were found to be selectively engaged by retrieval. Finally, lateralized ventrolateral PFC (VL-PFC) regions were found to be selectively engaged by material-type, but uninfluenced by task-type. These results highlight the importance of examining PFC activity across multiple memory domains, both for functionally differentiating PFC regions (e.g., task-selectivity vs material-selectivity in DL-PFC and VL-PFC) and for testing the applicability of memory domain-specific theories (e.g., FP-PFC in LTM retrieval).

Neural correlates of verbal memory encoding during semantic and structural processing tasks.

Eighteen participants were imaged using fMRI to explore whether brain regions predicting successful verbal memory encoding during semantic decisions would continue to predict encoding during structural (non-semantic) decisions. Consistent with prior studies, left inferior frontal and fusiform regions were more active during semantic than structural decisions, and activity was greater for remembered than forgotten words during semantic decisions. Critically, structural decisions yielded significantly greater activity for remembered than forgotten words in these regions providing evidence that a common frontal-temporal network supports verbal memory encoding irrespective of orienting task. Further analysis revealed activity associated with successful encoding in the right precentral gyrus, suggesting other regions may also play a role in verbal encoding during non-semantic processing.

Encoding processes during retrieval tasks.

Episodic memory encoding is pervasive across many kinds of task and often arises as a secondary processing effect in tasks that do not require intentional memorization. To illustrate the pervasive nature of information processing that leads to episodic encoding, a form of incidental encoding was explored based on the "Testing" phenomenon: The incidental-encoding task was an episodic memory retrieval task. Behavioral data showed that performing a memory retrieval task was as effective as intentional instructions at promoting episodic encoding. During fMRI imaging, subjects viewed old and new words and indicated whether they remembered them. Relevant to encoding, the fate of the new words was examined using a second, surprise test of recognition after the imaging session. fMRI analysis of those new words that were later remembered revealed greater activity in left frontal regions than those that were later forgotten - the same pattern of results as previously observed for traditional incidental and intentional episodic encoding tasks. This finding may offer a partial explanation for why repeated testing improves memory performance. Furthermore, the observation of correlates of episodic memory encoding during retrieval tasks challenges some interpretations that arise from direct comparisons between "encoding tasks" and "retrieval tasks" in imaging data. Encoding processes and their neural correlates may arise in many tasks, even those nominally labeled as retrieval tasks by the experimenter.

Human brain activity time-locked to perceptual event boundaries.

Temporal structure has a major role in human understanding of everyday events. Observers are able to segment ongoing activity into temporal parts and sub-parts that are reliable, meaningful and correlated with ecologically relevant features of the action. Here we present evidence that a network of brain regions is tuned to perceptually salient event boundaries, both during intentional event segmentation and during naive passive viewing of events. Activity within this network may provide a basis for parsing the temporally evolving environment into meaningful units.

Spatiotemporal maps of brain activity underlying word generation and their modification during repetition priming.

Spatiotemporal maps of brain activity based on magnetoencephalography were used to observe sequential stages in language processing and their modification during repetition priming. Subjects performed word-stem completion and produced either novel or repeated (primed) words across trials. Activation passes from primary visual cortex (activated at approximately 100 msec after word presentation), to left anteroventral occipital ( approximately 180 msec), to cortex in and near Wernicke's ( approximately 210 msec) and then Broca's ( approximately 370 msec) areas. In addition, a posteroventral temporal area is activated simultaneously with posterosuperior temporal cortex. This area shows an early ( approximately 200-245 msec) increase in activation to repeated word stems. In contrast, prefrontal and anterior temporal regions showed activity reductions to repeated word stems late ( approximately 365-500 msec) in processing. These results tend to support classical models of language and suggest that an effect of direct item repetition is to allow word-form processing to increase its contribution to task performance while concurrently allowing reductions in time-consuming frontal temporal processing.

Perceptual specificity in visual object priming: functional magnetic resonance imaging evidence for a laterality difference in fusiform cortex.

Seeing an object on one occasion may facilitate or prime processing of the same object if it is later again encountered. Such priming may also be found -- but at a reduced level -- for different but perceptually similar objects that are alternative exemplars or 'tokens' of the initially presented object. We explored the neural correlates of this perceptual specificity using event-related functional magnetic resonance imaging (fMRI) procedures, contrasting neural activity when participants made object classification decisions (size judgments) regarding previously presented objects (repeated same), alternative exemplars of previously presented objects (repeated different), or entirely new objects (novel). Many frontal regions (including bilateral frontal operculum, bilateral posterior inferior frontal/precentral, left anterior inferior frontal, and superior frontal cortices) and multiple late visual and posterior regions (including middle occipital, fusiform, fusiform-parahippocampal, precuneus, and posterior cingulate, all bilaterally), demonstrated reduced neural activity for repeated compared to novel objects. Greater repetition-induced reductions were observed for same than for different exemplars in several of these regions (bilateral posterior inferior frontal, right precuneus, bilateral middle occipital, bilateral fusiform, bilateral parahippocampal and bilateral superior parietal). Additionally, right fusiform (occipitotemporal) cortex showed significantly less priming for different versus same exemplars than did left fusiform. These findings converge with behavioral evidence from divided visual field studies and with neuropsychological evidence underscoring the key role of right occipitotemporal cortex in processing specific visual form information; possible differences in the representational-functional role of left fusiform are discussed.