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1. Identifying canonical and replicable multi‐scale intrinsic connectivity networks in 100k+ resting‐state fMRI datasets

Author

Iraji, A, Fu, Z, Faghiri, A, Duda, M, Chen, J, Rachakonda, S, DeRamus, T, Kochunov, P, Adhikari, BM, Belger, A, Ford, JM, Mathalon, DH, Pearlson, GD, Potkin, SG, Preda, A, Turner, JA, van Erp, TGM, Bustillo, JR, Yang, K, Ishizuka, K, Faria, A, Sawa, A, Hutchison, K, Osuch, EA, Theberge, J, Abbott, C, Mueller, BA, Zhi, D, Zhuo, C, Liu, S, Xu, Y, Salman, M, Liu, J, Du, Y, Sui, J, Adali, T, and Calhoun, VD

Subjects
Biomedical and Clinical Sciences, Biological Psychology, Cognitive and Computational Psychology, Neurosciences, Psychology, Bioengineering, Clinical Research, Neurological, Humans, Brain Mapping, Magnetic Resonance Imaging, Reproducibility of Results, Nerve Net, Brain, functional connectivity, functional templates, independent component analysis, intrinsic connectivity networks, Cognitive Sciences, Experimental Psychology, Biological psychology, Cognitive and computational psychology
Abstract

Despite the known benefits of data-driven approaches, the lack of approaches for identifying functional neuroimaging patterns that capture both individual variations and inter-subject correspondence limits the clinical utility of rsfMRI and its application to single-subject analyses. Here, using rsfMRI data from over 100k individuals across private and public datasets, we identify replicable multi-spatial-scale canonical intrinsic connectivity network (ICN) templates via the use of multi-model-order independent component analysis (ICA). We also study the feasibility of estimating subject-specific ICNs via spatially constrained ICA. The results show that the subject-level ICN estimations vary as a function of the ICN itself, the data length, and the spatial resolution. In general, large-scale ICNs require less data to achieve specific levels of (within- and between-subject) spatial similarity with their templates. Importantly, increasing data length can reduce an ICN's subject-level specificity, suggesting longer scans may not always be desirable. We also find a positive linear relationship between data length and spatial smoothness (possibly due to averaging over intrinsic dynamics), suggesting studies examining optimized data length should consider spatial smoothness. Finally, consistency in spatial similarity between ICNs estimated using the full data and subsets across different data lengths suggests lower within-subject spatial similarity in shorter data is not wholly defined by lower reliability in ICN estimates, but may be an indication of meaningful brain dynamics which average out as data length increases.

Published
2023

2. Moving beyond the 'CAP' of the Iceberg: Intrinsic connectivity networks in fMRI are continuously engaging and overlapping.

Author

Iraji, A, Faghiri, A, Fu, Z, Kochunov, P, Adhikari, BM, Belger, A, Ford, JM, McEwen, S, Mathalon, DH, Pearlson, GD, Potkin, SG, Preda, A, Turner, JA, Van Erp, TGM, Chang, C, and Calhoun, VD

Subjects
Brain, Nerve Net, Humans, Magnetic Resonance Imaging, Brain Mapping, Functional Neuroimaging, Activation spatial map, Co-activation patterns, Event absent time points, Event present time points, Functional connectivity, Independent component analysis, Intrinsic connectivity networks, Brain Disorders, Neurosciences, Biomedical Imaging, 1.1 Normal biological development and functioning, Underpinning research, Mental health, Neurological, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery
Abstract

Resting-state functional magnetic resonance imaging is currently the mainstay of functional neuroimaging and has allowed researchers to identify intrinsic connectivity networks (aka functional networks) at different spatial scales. However, little is known about the temporal profiles of these networks and whether it is best to model them as continuous phenomena in both space and time or, rather, as a set of temporally discrete events. Both categories have been supported by series of studies with promising findings. However, a critical question is whether focusing only on time points presumed to contain isolated neural events and disregarding the rest of the data is missing important information, potentially leading to misleading conclusions. In this work, we argue that brain networks identified within the spontaneous blood oxygenation level-dependent (BOLD) signal are not limited to temporally sparse burst moments and that these event present time points (EPTs) contain valuable but incomplete information about the underlying functional patterns. We focus on the default mode and show evidence that is consistent with its continuous presence in the BOLD signal, including during the event absent time points (EATs), i.e., time points that exhibit minimum activity and are the least likely to contain an event. Moreover, our findings suggest that EPTs may not contain all the available information about their corresponding networks. We observe distinct default mode connectivity patterns obtained from all time points (AllTPs), EPTs, and EATs. We show evidence of robust relationships with schizophrenia symptoms that are both common and unique to each of the sets of time points (AllTPs, EPTs, EATs), likely related to transient patterns of connectivity. Together, these findings indicate the importance of leveraging the full temporal data in functional studies, including those using event-detection approaches.

Published
2022

3. Decreased hemispheric connectivity and decreased intra- and inter- hemisphere asymmetry of resting state functional network connectivity in schizophrenia

Author

Agcaoglu, O, Miller, R, Damaraju, E, Rashid, B, Bustillo, J, Cetin, MS, Van Erp, TGM, McEwen, S, Preda, A, Ford, JM, Lim, KO, Manoach, DS, Mathalon, DH, Potkin, SG, and Calhoun, VD

Subjects
Schizophrenia, Mental Health, Clinical Research, Neurosciences, Brain Disorders, Mental health, Adolescent, Adult, Brain, Brain Mapping, Female, Functional Laterality, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Neural Pathways, Rest, Young Adult, Functional network connectivity, Laterality, Hemisphere, Lateral connectivity, Heterotopic connectivity, Homotopic connectivity, Medical and Health Sciences, Psychology and Cognitive Sciences, Experimental Psychology
Abstract

Many studies have shown that schizophrenia patients have aberrant functional network connectivity (FNC) among brain regions, suggesting schizophrenia manifests with significantly diminished (in majority of the cases) connectivity. Schizophrenia is also associated with a lack of hemispheric lateralization. Hoptman et al. (2012) reported lower inter-hemispheric connectivity in schizophrenia patients compared to controls using voxel-mirrored homotopic connectivity. In this study, we merge these two points of views together using a group independent component analysis (gICA)-based approach to generate hemisphere-specific timecourses and calculate intra-hemisphere and inter-hemisphere FNC on a resting state fMRI dataset consisting of age- and gender-balanced 151 schizophrenia patients and 163 healthy controls. We analyzed the group differences between patients and healthy controls in each type of FNC measures along with age and gender effects. The results reveal that FNC in schizophrenia patients shows less hemispheric asymmetry compared to that of the healthy controls. We also found a decrease in connectivity in all FNC types such as intra-left (L_FNC), intra-right (R_FNC) and inter-hemisphere (Inter_FNC) in the schizophrenia patients relative to healthy controls, but general patterns of connectivity were preserved in patients. Analyses of age and gender effects yielded results similar to those reported in whole brain FNC studies.

Published
2018

4. Widespread white matter microstructural differences in schizophrenia across 4322 individuals: results from the ENIGMA Schizophrenia DTI Working Group

Author

Kelly, S, Jahanshad, N, Zalesky, A, Kochunov, P, Agartz, I, Alloza, C, Andreassen, OA, Arango, C, Banaj, N, Bouix, S, Bousman, CA, Brouwer, RM, Bruggemann, J, Bustillo, J, Cahn, W, Calhoun, V, Cannon, D, Carr, V, Catts, S, Chen, J, Chen, J-X, Chen, X, Chiapponi, C, Cho, Kl K, Ciullo, V, Corvin, AS, Crespo-Facorro, B, Cropley, V, De Rossi, P, Diaz-Caneja, CM, Dickie, EW, Ehrlich, S, Fan, F-M, Faskowitz, J, Fatouros-Bergman, H, Flyckt, L, Ford, JM, Fouche, J-P, Fukunaga, M, Gill, M, Glahn, DC, Gollub, R, Goudzwaard, ED, Guo, H, Gur, RE, Gur, RC, Gurholt, TP, Hashimoto, R, Hatton, SN, Henskens, FA, Hibar, DP, Hickie, IB, Hong, LE, Horacek, J, Howells, FM, Hulshoff Pol, HE, Hyde, CL, Isaev, D, Jablensky, A, Jansen, PR, Janssen, J, Jönsson, EG, Jung, LA, Kahn, RS, Kikinis, Z, Liu, K, Klauser, P, Knöchel, C, Kubicki, M, Lagopoulos, J, Langen, C, Lawrie, S, Lenroot, RK, Lim, KO, Lopez-Jaramillo, C, Lyall, A, Magnotta, V, Mandl, RCW, Mathalon, DH, McCarley, RW, McCarthy-Jones, S, McDonald, C, McEwen, S, McIntosh, A, Melicher, T, Mesholam-Gately, RI, Michie, PT, Mowry, B, Mueller, BA, Newell, DT, O'Donnell, P, Oertel-Knöchel, V, Oestreich, L, Paciga, SA, Pantelis, C, Pasternak, O, Pearlson, G, Pellicano, GR, Pereira, A, and Pineda Zapata, J

Subjects
Neurosciences, Brain Disorders, Mental Health, Serious Mental Illness, Biomedical Imaging, Schizophrenia, Clinical Research, Mental health, Adult, Aged, Aged, 80 and over, Brain, Cohort Studies, Corpus Callosum, Diffusion Magnetic Resonance Imaging, Diffusion Tensor Imaging, Female, Humans, Image Processing, Computer-Assisted, Male, Middle Aged, White Matter, Young Adult, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

The regional distribution of white matter (WM) abnormalities in schizophrenia remains poorly understood, and reported disease effects on the brain vary widely between studies. In an effort to identify commonalities across studies, we perform what we believe is the first ever large-scale coordinated study of WM microstructural differences in schizophrenia. Our analysis consisted of 2359 healthy controls and 1963 schizophrenia patients from 29 independent international studies; we harmonized the processing and statistical analyses of diffusion tensor imaging (DTI) data across sites and meta-analyzed effects across studies. Significant reductions in fractional anisotropy (FA) in schizophrenia patients were widespread, and detected in 20 of 25 regions of interest within a WM skeleton representing all major WM fasciculi. Effect sizes varied by region, peaking at (d=0.42) for the entire WM skeleton, driven more by peripheral areas as opposed to the core WM where regions of interest were defined. The anterior corona radiata (d=0.40) and corpus callosum (d=0.39), specifically its body (d=0.39) and genu (d=0.37), showed greatest effects. Significant decreases, to lesser degrees, were observed in almost all regions analyzed. Larger effect sizes were observed for FA than diffusivity measures; significantly higher mean and radial diffusivity was observed for schizophrenia patients compared with controls. No significant effects of age at onset of schizophrenia or medication dosage were detected. As the largest coordinated analysis of WM differences in a psychiatric disorder to date, the present study provides a robust profile of widespread WM abnormalities in schizophrenia patients worldwide. Interactive three-dimensional visualization of the results is available at www.enigma-viewer.org.

Published
2018

9. EEG findings of reduced neural synchronization during visual integration in schizophrenia

Author

Wynn, JK, Roach, BJ, Lee, J, Horan, WP, Ford, JM, Jimenez, AM, and Green, MF

Subjects
schizophrenia, event-related potentials, visual integration, Electroencephalography, Electroencephalography Phase Synchronization, Evoked Potentials, Humans, Photic Stimulation, Schizophrenia, Visual Perception, General Science & Technology
Abstract

Schizophrenia patients exhibit well-documented visual processing deficits. One area of disruption is visual integration, the ability to form global objects from local elements. However, most studies of visual integration in schizophrenia have been conducted in the context of an active attention task, which may influence the findings. In this study we examined visual integration using electroencephalography (EEG) in a passive task to elucidate neural mechanisms associated with poor visual integration. Forty-six schizophrenia patients and 30 healthy controls had EEG recorded while passively viewing figures comprised of real, illusory, or no contours. We examined visual P100, N100, and P200 event-related potential (ERP) components, as well as neural synchronization in the gamma (30-60 Hz) band assessed by the EEG phase locking factor (PLF). The N100 was significantly larger to illusory vs. no contour, and illusory vs. real contour stimuli while the P200 was larger only to real vs. illusory stimuli; there were no significant interactions with group. Compared to controls, patients failed to show increased phase locking to illusory versus no contours between 40-60 Hz. Also, controls, but not patients, had larger PLF between 30-40 Hz when viewing real vs. illusory contours. Finally, the positive symptom factor of the BPRS was negatively correlated with PLF values between 40-60 Hz to illusory stimuli, and with PLF between 30-40 Hz to real contour stimuli. These results suggest that the pattern of results across visual processing conditions is similar in patients and controls. However, patients have deficits in neural synchronization in the gamma range during basic processing of illusory contours when attentional demand is limited.

Published
2015

10. Oxytocin administration selectively improves olfactory detection thresholds for lyral in patients with schizophrenia.

Author

Woolley, JD, Lam, O, Chuang, B, Ford, JM, Mathalon, DH, and Vinogradov, S

Subjects
Humans, Olfaction Disorders, Aldehydes, Oxytocin, Oxytocics, Cyclic AMP, Administration, Intranasal, Case-Control Studies, Cross-Over Studies, Double-Blind Method, Sensory Thresholds, Smell, Schizophrenia, Signal Transduction, Adult, Middle Aged, Female, Male, Cyclohexenes, Young Adult, Olfaction, Brain Disorders, Clinical Research, Serious Mental Illness, Mental Health, Neurosciences, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Mental health, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

BackgroundOlfaction plays an important role in mammalian social behavior. Olfactory deficits are common in schizophrenia and correlate with negative symptoms and low social drive. Despite their prominence and possible clinical relevance, little is understood about the pathological mechanisms underlying olfactory deficits in schizophrenia and there are currently no effective treatments for these deficits. The prosocial neuropeptide oxytocin may affect the olfactory system when administered intranasally to humans and there is growing interest in its therapeutic potential in schizophrenia.MethodsTo examine this model, we administered 40IU of oxytocin and placebo intranasally to 31 patients with a schizophrenia spectrum illness and 34 age-matched healthy control participants in a randomized, double-blind, placebo-controlled, cross-over study. On each test day, participants completed an olfactory detection threshold test for two different odors: (1) lyral, a synthetic fragrance compound for which patients with schizophrenia have specific olfactory detection threshold deficits, possibly related to decreased cyclic adenosine 3',5'-monophosphate (cAMP) signaling; and (2) anise, a compound for which olfactory detection thresholds change with menstrual cycle phase in women.ResultsOn the placebo test day, patients with schizophrenia did not significantly differ from healthy controls in detection of either odor. We found that oxytocin administration significantly and selectively improved olfactory detection thresholds for lyral but not for anise in patients with schizophrenia. In contrast, oxytocin had no effect on detection of either odor in healthy controls.DiscussionOur data indicate that oxytocin administration may ameliorate olfactory deficits in schizophrenia and suggest the effects of intranasal oxytocin may extend to influencing the olfactory system. Given that oxytocin has been found to increase cAMP signaling in vitro a possible mechanism for these effects is discussed.

Published
2015

11. Effects of nicotine on the neurophysiological and behavioral effects of ketamine in humans

Author

Mathalon, Daniel, Mathalon, DH, Ahn, KH, Perry, EB, Cho, HS, Roach, BJ, Blais, RK, Bhakta, S, Ranganathan, M, Ford, JM, and D'Souza, DC

Abstract

Background: N-methyl-d-aspartate (NMDA) receptor hypofunction has been implicated in the pathophysiology of schizophrenia and its associated neurocognitive impairments. The high rate of cigarette smoking in schizophrenia raises questions about how nicotine

Published
2014

12. Dynamic functional connectivity analysis reveals transient states of dysconnectivity in schizophrenia

Author

Damaraju, E, Allen, EA, Belger, A, Ford, JM, McEwen, S, Mathalon, DH, Mueller, BA, Pearlson, GD, Potkin, SG, Preda, A, Turner, JA, Vaidya, JG, van Erp, TG, and Calhoun, VD

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Psychology, Brain Disorders, Serious Mental Illness, Schizophrenia, Mental Health, Neurosciences, Clinical Research, Underpinning research, 1.1 Normal biological development and functioning, Mental health, Adult, Brain, Brain Mapping, Female, Humans, Image Interpretation, Computer-Assisted, Magnetic Resonance Imaging, Male, Neural Pathways, Biological psychology, Clinical and health psychology
Abstract

Schizophrenia is a psychotic disorder characterized by functional dysconnectivity or abnormal integration between distant brain regions. Recent functional imaging studies have implicated large-scale thalamo-cortical connectivity as being disrupted in patients. However, observed connectivity differences in schizophrenia have been inconsistent between studies, with reports of hyperconnectivity and hypoconnectivity between the same brain regions. Using resting state eyes-closed functional imaging and independent component analysis on a multi-site data that included 151 schizophrenia patients and 163 age- and gender matched healthy controls, we decomposed the functional brain data into 100 components and identified 47 as functionally relevant intrinsic connectivity networks. We subsequently evaluated group differences in functional network connectivity, both in a static sense, computed as the pairwise Pearson correlations between the full network time courses (5.4 minutes in length), and a dynamic sense, computed using sliding windows (44 s in length) and k-means clustering to characterize five discrete functional connectivity states. Static connectivity analysis revealed that compared to healthy controls, patients show significantly stronger connectivity, i.e., hyperconnectivity, between the thalamus and sensory networks (auditory, motor and visual), as well as reduced connectivity (hypoconnectivity) between sensory networks from all modalities. Dynamic analysis suggests that (1), on average, schizophrenia patients spend much less time than healthy controls in states typified by strong, large-scale connectivity, and (2), that abnormal connectivity patterns are more pronounced during these connectivity states. In particular, states exhibiting cortical-subcortical antagonism (anti-correlations) and strong positive connectivity between sensory networks are those that show the group differences of thalamic hyperconnectivity and sensory hypoconnectivity. Group differences are weak or absent during other connectivity states. Dynamic analysis also revealed hypoconnectivity between the putamen and sensory networks during the same states of thalamic hyperconnectivity; notably, this finding cannot be observed in the static connectivity analysis. Finally, in post-hoc analyses we observed that the relationships between sub-cortical low frequency power and connectivity with sensory networks is altered in patients, suggesting different functional interactions between sub-cortical nuclei and sensorimotor cortex during specific connectivity states. While important differences between patients with schizophrenia and healthy controls have been identified, one should interpret the results with caution given the history of medication in patients. Taken together, our results support and expand current knowledge regarding dysconnectivity in schizophrenia, and strongly advocate the use of dynamic analyses to better account for and understand functional connectivity differences.

Published
2014

13. Studying hallucinations within the NIMH RDoC framework

Author

Ford, Judith, Ford, JM, Morris, SE, Hoffman, RE, Sommer, I, Waters, F, McCarthy-Jones, S, Thoma, RJ, Turner, JA, Keedy, SK, and Badcock, JC

Abstract

We explore how hallucinations might be studied within the National Institute of Mental Health (NIMH) Research Domain Criteria (RDoC) framework, which asks investigators to step back from diagnoses based on symptoms and focus on basic dimensions of function

Published
2014

14. Auditory cortex processes variation in our own speech

Author

Mathalon, Daniel, Ford, Judith, Houde, John, Sitek, KR, Mathalon, DH, Roach, BJ, Houde, JF, Niziolek, CA, and Ford, JM

Abstract

As we talk, we unconsciously adjust our speech to ensure it sounds the way we intend it to sound. However, because speech production involves complex motor planning and execution, no two utterances of the same sound will be exactly the same. Here, we show

Published
2013

15. Deficient suppression of default mode regions during working memory in individuals with early psychosis and at clinical high-risk for psychosis

Author

Mathalon, Daniel, Fryer, SL, Woods, SW, Kiehl, KA, Calhoun, VD, Pearlson, GD, Roach, BJ, Ford, JM, Srihari, VH, McGlashan, TH, and Mathalon, DH

Abstract

Background: The default mode network (DMN) is a set of brain regions typically activated at rest and suppressed during extrinsic cognition. Schizophrenia has been associated with deficient DMN suppression, though the extent to which DMN dysfunction predate

Published
2013

16. Chapter 11 Converging evidence for gamma synchrony deficits in schizophrenia

Author

Roach, BJ, Ford, JM, Hoffman, RE, and Mathalon, DH

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Psychology, Schizophrenia, Brain Disorders, Serious Mental Illness, Mental Health, Mental health, Acoustic Stimulation, Adult, Analysis of Variance, Auditory Perceptual Disorders, Brain Mapping, Brain Waves, Case-Control Studies, Electroencephalography, Evoked Potentials, Auditory, Female, Humans, Male, Middle Aged, Psychiatric Status Rating Scales, Psychoacoustics, Reaction Time, Time Factors, Young Adult
Abstract

BackgroundIn electroencephalogram (EEG) studies of auditory steady-state responses (ASSRs), patients with schizophrenia show a deficit in power and/or phase-locking, particularly at the 40 Hz frequency where these responses resonate. In addition, studies of the transient gamma-band response (GBR) elicited by single tones have revealed deficits in gamma power and phase-locking in schizophrenia. We examined the degree to which the 40 Hz ASSR and the transient GBR to single tones are correlated and whether they assess overlapping or distinct gamma-band abnormalities in schizophrenia.MethodsEEG was recorded during 40 Hz ASSR and auditory oddball paradigms from 28 patients with schizophrenia or schizoaffective disorder (SZ) and 25 age- and gender-matched healthy controls (HC). The ASSR was elicited by 500 ms click trains, and the transient GBR was elicited by the standard tones from the oddball paradigm. Gamma phase and magnitude values, calculated using Morlet wavelet transformations, were used to derive total power and phase-locking measures.ResultsRelative to HC, SZ patients had significant deficits in total gamma power and phase-locking for both ASSR- and GBR-based measures. Within both groups, the 40 Hz ASSR and GBR phase-locking measures were significantly correlated, with a similar trend evident for the total power measures. Moreover, co-varying for GBR substantially reduced 40 Hz ASSR power and phase-locking differences between the groups.Conclusions40 Hz ASSR and transient GBR measures provide very similar information about auditory gamma abnormalities in schizophrenia, despite the overall enhancement of 40 Hz ASSR total power and phase-locking values relative to the corresponding GBR values.

Published
2013

17. Neurobiology of schizophrenia: Search for the elusive correlation with symptoms

Author

Mathalon, Daniel, Mathalon, DH, and Ford, JM

Abstract

In the last half-century, human neuroscience methods provided a way to study schizophrenia in vivo, and established that it is associated with subtle abnormalities in brain structure and function. However, efforts to understand the neurobiological bases of

Published
2012

18. Neurobiology of schizophrenia: Search for the elusive correlation with symptoms

Author

Mathalon, DH and Ford, JM

Subjects
Experimental Psychology, Neurosciences, Psychology, Cognitive Sciences
Abstract

In the last half-century, human neuroscience methods provided a way to study schizophrenia in vivo, and established that it is associated with subtle abnormalities in brain structure and function. However, efforts to understand the neurobiological bases of the clinical symptoms that the diagnosis is based on have been largely unsuccessful. In this paper, we provide an overview of the conceptual and methodological obstacles that undermine efforts to link the severity of specific symptoms to specific neurobiological measures. These obstacles include small samples, questionable reliability and validity of measurements, medication confounds, failure to distinguish state and trait effects, correlation-causation ambiguity, and the absence of compelling animal models of specific symptoms to test mechanistic hypotheses derived from brain-symptom correlations. We conclude with recommendations to promote progress in establishing brain-symptom relationships. © 2012 Mathalon and Ford.

Published
2012

19. Advanced brain age correlates with greater rumination and less mindfulness in schizophrenia

Author

Abram, S, Roach, BJ, Hua, JPY, Han, LKM, Mathalon, DH, Ford, JM, Fryer, SL, Abram, S, Roach, BJ, Hua, JPY, Han, LKM, Mathalon, DH, Ford, JM, and Fryer, SL

Abstract

BACKGROUND: Individual variation in brain aging trajectories is linked with several physical and mental health outcomes. Greater stress levels, worry, and rumination correspond with advanced brain age, while other individual characteristics, like mindfulness, may be protective of brain health. Multiple lines of evidence point to advanced brain aging in schizophrenia (i.e., neural age estimate > chronological age). Whether psychological dimensions such as mindfulness, rumination, and perceived stress contribute to brain aging in schizophrenia is unknown. METHODS: We estimated brain age from high-resolution anatomical scans in 54 healthy controls (HC) and 52 individuals with schizophrenia (SZ) and computed the brain predicted age difference (BrainAGE-diff), i.e., the delta between estimated brain age and chronological age. Emotional well-being summary scores were empirically derived to reflect individual differences in trait mindfulness, rumination, and perceived stress. Core analyses evaluated relationships between BrainAGE-diff and emotional well-being, testing for slopes differences across groups. RESULTS: HC showed higher emotional well-being (greater mindfulness and less rumination/stress), relative to SZ. We observed a significant group difference in the relationship between BrainAge-diff and emotional well-being, explained by BrainAGE-diff negatively correlating with emotional well-being scores in SZ, and not in HC. That is, SZ with younger appearing brains (predicted age < chronological age) had emotional summary scores that were more like HC, a relationship that endured after accounting for several demographic and clinical variables. CONCLUSIONS: These data reveal clinically relevant aspects of brain age heterogeneity among SZ and point to case-control differences in the relationship between advanced brain aging and emotional well-being.

Published
2023

20. Large- scale analysis of structural brain asymmetries in schizophrenia via the ENIGMA consortium

Author

Schijven, D, Postema, MC, Fukunaga, M, Matsumoto, J, Miura, K, de Zwarte, SMC, van Haren, NEM, Cahn, W, Pol, HEH, Kahn, RS, Ayesa-Arriola, R, de la Foz, VO-G, Tordesillas-Gutierrez, D, Vazquez-Bourgon, J, Crespo-Facorro, B, Alnaes, D, Dahl, A, Westlye, LT, Agartz, I, Andreassen, OA, Jonsson, EG, Kochunov, P, Bruggemann, JM, Catts, SV, Michie, PT, Mowry, BJ, Quide, Y, Rasser, PE, Schall, U, Scott, RJ, Carr, VJ, Green, MJ, Henskens, FA, Loughland, CM, Pantelis, C, Weickert, CS, Weickert, TW, De Haan, L, Brosch, K, Pfarr, J-K, Ringwald, KG, Stein, F, Jansen, A, Kircher, TTJ, Nenadic, I, Kramer, B, Gruber, O, Satterthwaite, TD, Bustillo, J, Mathalon, DH, Preda, A, Calhoun, VD, Ford, JM, Potkin, SG, Chen, J, Tan, Y, Wang, Z, Xiang, H, Fan, F, Bernardoni, F, Ehrlich, S, Fuentes-Claramonte, P, Garcia-Leon, MA, Guerrero-Pedraza, A, Salvador, R, Sarro, S, Pomarol-Clotet, E, Ciullo, V, Piras, F, Vecchio, D, Banaj, N, Spalletta, G, Michielse, S, van Amelsvoort, T, Dickie, EW, Voineskos, AN, Sim, K, Ciufolini, S, Dazzan, P, Murray, RM, Kim, W-S, Chung, Y-C, Andreou, C, Schmidt, A, Borgwardt, S, McIntosh, AM, Whalley, HC, Lawrie, SM, Du Plessis, S, Luckhoff, HK, Scheffler, F, Emsley, R, Grotegerd, D, Lencer, R, Dannlowski, U, Edmond, JT, Rootes-Murdy, K, Stephen, JM, Mayer, AR, Antonucci, LA, Fazio, L, Pergola, G, Bertolino, A, Diaz-Caneja, CM, Janssen, J, Lois, NG, Arango, C, Tomyshev, AS, Lebedeva, I, Cervenkav, S, Sellgrenv, CM, Georgiadis, F, Kirschner, M, Kaiser, S, Hajek, T, Skoch, A, Spaniel, F, Kim, M, Bin Kwak, Y, Oh, S, Kwon, JS, James, A, Bakker, G, Knochel, C, Stablein, M, Oertel, V, Uhlmann, A, Howells, FM, Stein, DJ, Temmingh, HS, Diaz-Zuluaga, AM, Pineda-Zapata, JA, Lopez-Jaramillo, C, Homan, S, Ji, E, Surbeck, W, Homan, P, Fishera, SE, Franke, B, Glahn, DC, Gur, RC, Hashimoto, R, Jahanshad, N, Luders, E, Medland, SE, Thompson, PM, Turner, JA, van Erp, TGM, Francks, C, Schijven, D, Postema, MC, Fukunaga, M, Matsumoto, J, Miura, K, de Zwarte, SMC, van Haren, NEM, Cahn, W, Pol, HEH, Kahn, RS, Ayesa-Arriola, R, de la Foz, VO-G, Tordesillas-Gutierrez, D, Vazquez-Bourgon, J, Crespo-Facorro, B, Alnaes, D, Dahl, A, Westlye, LT, Agartz, I, Andreassen, OA, Jonsson, EG, Kochunov, P, Bruggemann, JM, Catts, SV, Michie, PT, Mowry, BJ, Quide, Y, Rasser, PE, Schall, U, Scott, RJ, Carr, VJ, Green, MJ, Henskens, FA, Loughland, CM, Pantelis, C, Weickert, CS, Weickert, TW, De Haan, L, Brosch, K, Pfarr, J-K, Ringwald, KG, Stein, F, Jansen, A, Kircher, TTJ, Nenadic, I, Kramer, B, Gruber, O, Satterthwaite, TD, Bustillo, J, Mathalon, DH, Preda, A, Calhoun, VD, Ford, JM, Potkin, SG, Chen, J, Tan, Y, Wang, Z, Xiang, H, Fan, F, Bernardoni, F, Ehrlich, S, Fuentes-Claramonte, P, Garcia-Leon, MA, Guerrero-Pedraza, A, Salvador, R, Sarro, S, Pomarol-Clotet, E, Ciullo, V, Piras, F, Vecchio, D, Banaj, N, Spalletta, G, Michielse, S, van Amelsvoort, T, Dickie, EW, Voineskos, AN, Sim, K, Ciufolini, S, Dazzan, P, Murray, RM, Kim, W-S, Chung, Y-C, Andreou, C, Schmidt, A, Borgwardt, S, McIntosh, AM, Whalley, HC, Lawrie, SM, Du Plessis, S, Luckhoff, HK, Scheffler, F, Emsley, R, Grotegerd, D, Lencer, R, Dannlowski, U, Edmond, JT, Rootes-Murdy, K, Stephen, JM, Mayer, AR, Antonucci, LA, Fazio, L, Pergola, G, Bertolino, A, Diaz-Caneja, CM, Janssen, J, Lois, NG, Arango, C, Tomyshev, AS, Lebedeva, I, Cervenkav, S, Sellgrenv, CM, Georgiadis, F, Kirschner, M, Kaiser, S, Hajek, T, Skoch, A, Spaniel, F, Kim, M, Bin Kwak, Y, Oh, S, Kwon, JS, James, A, Bakker, G, Knochel, C, Stablein, M, Oertel, V, Uhlmann, A, Howells, FM, Stein, DJ, Temmingh, HS, Diaz-Zuluaga, AM, Pineda-Zapata, JA, Lopez-Jaramillo, C, Homan, S, Ji, E, Surbeck, W, Homan, P, Fishera, SE, Franke, B, Glahn, DC, Gur, RC, Hashimoto, R, Jahanshad, N, Luders, E, Medland, SE, Thompson, PM, Turner, JA, van Erp, TGM, and Francks, C

Abstract

Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, with MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case-control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case-control status. Subtle case-control differences of brain macrostructural asymmetry may reflect differences at the molecular, cytoarchitectonic, or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.

Published
2023

21. Virtual Ontogeny of Cortical Growth Preceding Mental Illness

Author

Patel, Y, Shin, J, Abe, C, Agartz, I, Alloza, C, Alnaes, D, Ambrogi, S, Antonucci, LA, Arango, C, Arolt, V, Auzias, G, Ayesa-Arriola, R, Banaj, N, Banaschewski, T, Bandeira, C, Basgoze, Z, Cupertino, RB, Bau, CHD, Bauer, J, Baumeister, S, Bernardoni, F, Bertolino, A, del Mar Bonnin, C, Brandeis, D, Brem, S, Bruggemann, J, Bulow, R, Bustillo, JR, Calderoni, S, Calvo, R, Canales-Rodriguez, EJ, Cannon, DM, Carmona, S, Carr, VJ, Catts, SV, Chenji, S, Chew, QH, Coghill, D, Connolly, CG, Conzelmann, A, Craven, AR, Crespo-Facorro, B, Cullen, K, Dahl, A, Dannlowski, U, Davey, CG, Deruelle, C, Diaz-Caneja, CM, Dohm, K, Ehrlich, S, Epstein, J, Erwin-Grabner, T, Eyler, LT, Fedor, J, Fitzgerald, J, Foran, W, Ford, JM, Fortea, L, Fuentes-Claramonte, P, Fullerton, J, Furlong, L, Gallagher, L, Gao, B, Gao, S, Goikolea, JM, Gotlib, I, Goya-Maldonado, R, Grabe, HJ, Green, M, Grevet, EH, Groenewold, NA, Grotegerd, D, Gruber, O, Haavik, J, Hahn, T, Harrison, BJ, Heindel, W, Henskens, F, Heslenfeld, DJ, Hilland, E, Hoekstra, PJ, Hohmann, S, Holz, N, Howells, FM, Ipser, JC, Jahanshad, N, Jakobi, B, Jansen, A, Janssen, J, Jonassen, R, Kaiser, A, Kaleda, V, Karantonis, J, King, JA, Kircher, T, Kochunov, P, Koopowitz, S-M, Landen, M, Landro, NI, Lawrie, S, Lebedeva, I, Luna, B, Lundervold, AJ, MacMaster, FP, Maglanoc, LA, Mathalon, DH, McDonald, C, McIntosh, A, Meinert, S, Michie, PT, Mitchell, P, Moreno-Alcazar, A, Mowry, B, Muratori, F, Nabulsi, L, Nenadic, I, Tuura, RO, Oosterlaan, J, Overs, B, Pantelis, C, Parellada, M, Pariente, JC, Pauli, P, Pergola, G, Piarulli, FM, Picon, F, Piras, F, Pomarol-Clotet, E, Pretus, C, Quide, Y, Radua, J, Ramos-Quiroga, JA, Rasser, PE, Reif, A, Retico, A, Roberts, G, Rossell, S, Rovaris, DL, Rubia, K, Sacchet, M, Salavert, J, Salvador, R, Sarro, S, Sawa, A, Schall, U, Scott, R, Selvaggi, P, Silk, T, Sim, K, Skoch, A, Spalletta, G, Spaniel, F, Stein, DJ, Steinstrater, O, Stolicyn, A, Takayanagi, Y, Tamm, L, Tavares, M, Teumer, A, Thiel, K, Thomopoulos, SI, Tomecek, D, Tomyshev, AS, Tordesillas-Gutierrez, D, Tosetti, M, Uhlmann, A, Van Rheenen, T, Vazquez-Bourgon, J, Vernooij, MW, Vieta, E, Vilarroya, O, Weickert, C, Weickert, T, Westlye, LT, Whalley, H, Willinger, D, Winter, A, Wittfeld, K, Yang, TT, Yoncheva, Y, Zijlmans, JL, Hoogman, M, Franke, B, van Rooij, D, Buitelaar, J, Ching, CRK, Andreassen, OA, Pozzi, E, Veltman, D, Schmaal, L, van Erp, TGM, Turner, J, Castellanos, FX, Pausova, Z, Thompson, P, Paus, T, Patel, Y, Shin, J, Abe, C, Agartz, I, Alloza, C, Alnaes, D, Ambrogi, S, Antonucci, LA, Arango, C, Arolt, V, Auzias, G, Ayesa-Arriola, R, Banaj, N, Banaschewski, T, Bandeira, C, Basgoze, Z, Cupertino, RB, Bau, CHD, Bauer, J, Baumeister, S, Bernardoni, F, Bertolino, A, del Mar Bonnin, C, Brandeis, D, Brem, S, Bruggemann, J, Bulow, R, Bustillo, JR, Calderoni, S, Calvo, R, Canales-Rodriguez, EJ, Cannon, DM, Carmona, S, Carr, VJ, Catts, SV, Chenji, S, Chew, QH, Coghill, D, Connolly, CG, Conzelmann, A, Craven, AR, Crespo-Facorro, B, Cullen, K, Dahl, A, Dannlowski, U, Davey, CG, Deruelle, C, Diaz-Caneja, CM, Dohm, K, Ehrlich, S, Epstein, J, Erwin-Grabner, T, Eyler, LT, Fedor, J, Fitzgerald, J, Foran, W, Ford, JM, Fortea, L, Fuentes-Claramonte, P, Fullerton, J, Furlong, L, Gallagher, L, Gao, B, Gao, S, Goikolea, JM, Gotlib, I, Goya-Maldonado, R, Grabe, HJ, Green, M, Grevet, EH, Groenewold, NA, Grotegerd, D, Gruber, O, Haavik, J, Hahn, T, Harrison, BJ, Heindel, W, Henskens, F, Heslenfeld, DJ, Hilland, E, Hoekstra, PJ, Hohmann, S, Holz, N, Howells, FM, Ipser, JC, Jahanshad, N, Jakobi, B, Jansen, A, Janssen, J, Jonassen, R, Kaiser, A, Kaleda, V, Karantonis, J, King, JA, Kircher, T, Kochunov, P, Koopowitz, S-M, Landen, M, Landro, NI, Lawrie, S, Lebedeva, I, Luna, B, Lundervold, AJ, MacMaster, FP, Maglanoc, LA, Mathalon, DH, McDonald, C, McIntosh, A, Meinert, S, Michie, PT, Mitchell, P, Moreno-Alcazar, A, Mowry, B, Muratori, F, Nabulsi, L, Nenadic, I, Tuura, RO, Oosterlaan, J, Overs, B, Pantelis, C, Parellada, M, Pariente, JC, Pauli, P, Pergola, G, Piarulli, FM, Picon, F, Piras, F, Pomarol-Clotet, E, Pretus, C, Quide, Y, Radua, J, Ramos-Quiroga, JA, Rasser, PE, Reif, A, Retico, A, Roberts, G, Rossell, S, Rovaris, DL, Rubia, K, Sacchet, M, Salavert, J, Salvador, R, Sarro, S, Sawa, A, Schall, U, Scott, R, Selvaggi, P, Silk, T, Sim, K, Skoch, A, Spalletta, G, Spaniel, F, Stein, DJ, Steinstrater, O, Stolicyn, A, Takayanagi, Y, Tamm, L, Tavares, M, Teumer, A, Thiel, K, Thomopoulos, SI, Tomecek, D, Tomyshev, AS, Tordesillas-Gutierrez, D, Tosetti, M, Uhlmann, A, Van Rheenen, T, Vazquez-Bourgon, J, Vernooij, MW, Vieta, E, Vilarroya, O, Weickert, C, Weickert, T, Westlye, LT, Whalley, H, Willinger, D, Winter, A, Wittfeld, K, Yang, TT, Yoncheva, Y, Zijlmans, JL, Hoogman, M, Franke, B, van Rooij, D, Buitelaar, J, Ching, CRK, Andreassen, OA, Pozzi, E, Veltman, D, Schmaal, L, van Erp, TGM, Turner, J, Castellanos, FX, Pausova, Z, Thompson, P, and Paus, T

Abstract

BACKGROUND: Morphology of the human cerebral cortex differs across psychiatric disorders, with neurobiology and developmental origins mostly undetermined. Deviations in the tangential growth of the cerebral cortex during pre/perinatal periods may be reflected in individual variations in cortical surface area later in life. METHODS: Interregional profiles of group differences in surface area between cases and controls were generated using T1-weighted magnetic resonance imaging from 27,359 individuals including those with attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depressive disorder, schizophrenia, and high general psychopathology (through the Child Behavior Checklist). Similarity of interregional profiles of group differences in surface area and prenatal cell-specific gene expression was assessed. RESULTS: Across the 11 cortical regions, group differences in cortical area for attention-deficit/hyperactivity disorder, schizophrenia, and Child Behavior Checklist were dominant in multimodal association cortices. The same interregional profiles were also associated with interregional profiles of (prenatal) gene expression specific to proliferative cells, namely radial glia and intermediate progenitor cells (greater expression, larger difference), as well as differentiated cells, namely excitatory neurons and endothelial and mural cells (greater expression, smaller difference). Finally, these cell types were implicated in known pre/perinatal risk factors for psychosis. Genes coexpressed with radial glia were enriched with genes implicated in congenital abnormalities, birth weight, hypoxia, and starvation. Genes coexpressed with endothelial and mural genes were enriched with genes associated with maternal hypertension and preterm birth. CONCLUSIONS: Our findings support a neurodevelopmental model of vulnerability to mental illness whereby prenatal risk factors acting through cell-specific processes lead to deviations from t

Published
2022

22. Virtual histology of cortical thickness and shared neurobiology in 6 psychiatric disorders

Author

Patel, Y, Parker, N, Shin, J, Howard, D, French, L, Thomopoulos, SI, Pozzi, E, Abe, Y, Abé, C, Anticevic, A, Alda, M, Aleman, A, Alloza, C, Alonso-Lana, S, Ameis, SH, Anagnostou, E, McIntosh, AA, Arango, C, Arnold, PD, Asherson, P, Assogna, F, Auzias, G, Ayesa-Arriola, R, Bakker, G, Banaj, N, Banaschewski, T, Bandeira, CE, Baranov, A, Bargalló, N, Bau, CHD, Baumeister, S, Baune, BT, Bellgrove, MA, Benedetti, F, Bertolino, A, Boedhoe, PSW, Boks, M, Bollettini, I, Del Mar Bonnin, C, Borgers, T, Borgwardt, S, Brandeis, D, Brennan, BP, Bruggemann, JM, Bülow, R, Busatto, GF, Calderoni, S, Calhoun, VD, Calvo, R, Canales-Rodríguez, EJ, Cannon, DM, Carr, VJ, Cascella, N, Cercignani, M, Chaim-Avancini, TM, Christakou, A, Coghill, D, Conzelmann, A, Crespo-Facorro, B, Cubillo, AI, Cullen, KR, Cupertino, RB, Daly, E, Dannlowski, U, Davey, CG, Denys, D, Deruelle, C, Di Giorgio, A, Dickie, EW, Dima, D, Dohm, K, Ehrlich, S, Ely, BA, Erwin-Grabner, T, Ethofer, T, Fair, DA, Fallgatter, AJ, Faraone, SV, Fatjó-Vilas, M, Fedor, JM, Fitzgerald, KD, Ford, JM, Frodl, T, Fu, CHY, Fullerton, JM, Gabel, MC, Glahn, DC, Roberts, G, Gogberashvili, T, Goikolea, JM, Gotlib, IH, Goya-Maldonado, R, Grabe, HJ, Green, MJ, Grevet, EH, Groenewold, NA, Grotegerd, D, Gruber, O, Gruner, P, Guerrero-Pedraza, A, Silk, Timothy, Patel, Y, Parker, N, Shin, J, Howard, D, French, L, Thomopoulos, SI, Pozzi, E, Abe, Y, Abé, C, Anticevic, A, Alda, M, Aleman, A, Alloza, C, Alonso-Lana, S, Ameis, SH, Anagnostou, E, McIntosh, AA, Arango, C, Arnold, PD, Asherson, P, Assogna, F, Auzias, G, Ayesa-Arriola, R, Bakker, G, Banaj, N, Banaschewski, T, Bandeira, CE, Baranov, A, Bargalló, N, Bau, CHD, Baumeister, S, Baune, BT, Bellgrove, MA, Benedetti, F, Bertolino, A, Boedhoe, PSW, Boks, M, Bollettini, I, Del Mar Bonnin, C, Borgers, T, Borgwardt, S, Brandeis, D, Brennan, BP, Bruggemann, JM, Bülow, R, Busatto, GF, Calderoni, S, Calhoun, VD, Calvo, R, Canales-Rodríguez, EJ, Cannon, DM, Carr, VJ, Cascella, N, Cercignani, M, Chaim-Avancini, TM, Christakou, A, Coghill, D, Conzelmann, A, Crespo-Facorro, B, Cubillo, AI, Cullen, KR, Cupertino, RB, Daly, E, Dannlowski, U, Davey, CG, Denys, D, Deruelle, C, Di Giorgio, A, Dickie, EW, Dima, D, Dohm, K, Ehrlich, S, Ely, BA, Erwin-Grabner, T, Ethofer, T, Fair, DA, Fallgatter, AJ, Faraone, SV, Fatjó-Vilas, M, Fedor, JM, Fitzgerald, KD, Ford, JM, Frodl, T, Fu, CHY, Fullerton, JM, Gabel, MC, Glahn, DC, Roberts, G, Gogberashvili, T, Goikolea, JM, Gotlib, IH, Goya-Maldonado, R, Grabe, HJ, Green, MJ, Grevet, EH, Groenewold, NA, Grotegerd, D, Gruber, O, Gruner, P, Guerrero-Pedraza, A, and Silk, Timothy

Published
2021

23. The genetic architecture of the human cerebral cortex

Author

Grasby, KL, Jahanshad, N, Painter, JN, Colodro-Conde, L, Bralten, J, Hibar, DP, Lind, PA, Pizzagalli, F, Ching, CRK, McMahon, MAB, Shatokhina, N, Zsembik, LCP, Thomopoulos, SI, Zhu, AH, Strike, LT, Agartz, I, Alhusaini, S, Almeida, MAA, Alnæs, D, Amlien, IK, Andersson, M, Ard, T, Armstrong, NJ, Ashley-Koch, A, Atkins, JR, Bernard, M, Brouwer, RM, Buimer, EEL, Bülow, R, Bürger, C, Cannon, DM, Chakravarty, M, Chen, Q, Cheung, JW, Couvy-Duchesne, B, Dale, AM, Dalvie, S, de Araujo, TK, de Zubicaray, GI, de Zwarte, SMC, den Braber, A, Doan, NT, Dohm, K, Ehrlich, S, Engelbrecht, HR, Erk, S, Fan, CC, Fedko, IO, Foley, SF, Ford, JM, Fukunaga, M, Garrett, ME, Ge, T, Giddaluru, S, Goldman, AL, Green, MJ, Groenewold, NA, Grotegerd, D, Gurholt, TP, Gutman, BA, Hansell, NK, Harris, MA, Harrison, MB, Haswell, CC, Hauser, M, Herms, S, Heslenfeld, DJ, Ho, NF, Hoehn, D, Hoffmann, P, Holleran, L, Hoogman, M, Hottenga, JJ, Ikeda, M, Janowitz, D, Jansen, IE, Jia, T, Jockwitz, C, Kanai, R, Karama, S, Kasperaviciute, D, Kaufmann, T, Kelly, S, Kikuchi, M, Klein, M, Knapp, M, Knodt, AR, Krämer, B, Lam, M, Lancaster, TM, Lee, PH, Lett, TA, Lewis, LB, Lopes-Cendes, I, Luciano, M, Macciardi, F, Marquand, AF, Mathias, SR, Melzer, TR, Milaneschi, Y, Grasby, KL, Jahanshad, N, Painter, JN, Colodro-Conde, L, Bralten, J, Hibar, DP, Lind, PA, Pizzagalli, F, Ching, CRK, McMahon, MAB, Shatokhina, N, Zsembik, LCP, Thomopoulos, SI, Zhu, AH, Strike, LT, Agartz, I, Alhusaini, S, Almeida, MAA, Alnæs, D, Amlien, IK, Andersson, M, Ard, T, Armstrong, NJ, Ashley-Koch, A, Atkins, JR, Bernard, M, Brouwer, RM, Buimer, EEL, Bülow, R, Bürger, C, Cannon, DM, Chakravarty, M, Chen, Q, Cheung, JW, Couvy-Duchesne, B, Dale, AM, Dalvie, S, de Araujo, TK, de Zubicaray, GI, de Zwarte, SMC, den Braber, A, Doan, NT, Dohm, K, Ehrlich, S, Engelbrecht, HR, Erk, S, Fan, CC, Fedko, IO, Foley, SF, Ford, JM, Fukunaga, M, Garrett, ME, Ge, T, Giddaluru, S, Goldman, AL, Green, MJ, Groenewold, NA, Grotegerd, D, Gurholt, TP, Gutman, BA, Hansell, NK, Harris, MA, Harrison, MB, Haswell, CC, Hauser, M, Herms, S, Heslenfeld, DJ, Ho, NF, Hoehn, D, Hoffmann, P, Holleran, L, Hoogman, M, Hottenga, JJ, Ikeda, M, Janowitz, D, Jansen, IE, Jia, T, Jockwitz, C, Kanai, R, Karama, S, Kasperaviciute, D, Kaufmann, T, Kelly, S, Kikuchi, M, Klein, M, Knapp, M, Knodt, AR, Krämer, B, Lam, M, Lancaster, TM, Lee, PH, Lett, TA, Lewis, LB, Lopes-Cendes, I, Luciano, M, Macciardi, F, Marquand, AF, Mathias, SR, Melzer, TR, and Milaneschi, Y

Abstract

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.

Published
2020

24. You just had to get on with it’: Exploring the persistence of gender inequality through women’s career histories

Author

Ford, JM, Atkinson, Carol, Harding, NH, Collinson, D, Ford, JM, Atkinson, Carol, Harding, NH, and Collinson, D

Abstract

This article examines the career histories of the first generation of UK women to enter professional employment in the 1970s and 1980s in comparatively large numbers. In so doing, it contributes to the sparse literature on older women’s working life histories. Presenting empirical research on women’s experiences in the legal and HR sectors, it reveals how women pioneers were often silenced by requirements to conform with male-dominated norms, values and practices governing masculine career pathways. They learned to speak a predominantly masculine language that in turn constituted a significant barrier to effective resistance and disallowed new ways of speaking about careers. The article argues that these earlier conditions of entry into careers continue to influence the barriers women face at work today. Through this analysis of older women’s working lives, the article also contributes to contemporary debates about intersectionality by illustrating how gender and age interact in ways that reinforce earlier patterns of career disadvantage.

Published
2020

25. Hereditary diffuse gastric cancer: updated clinical practice guidelines

Author

Blair, VR, McLeod, M, Carneiro, F, Coit, DG, D'Addario, JL, van Dieren, JM, Harris, KL, Hoogerbrugge, N, Oliveira, C, van der Post, RS, Arnold, J, Benusiglio, PR, Bisseling, TM, Boussioutas, A, Cats, A, Charlton, A, Schreiber, KEC, Davis, JL, di Pietro, M, Fitzgerald, RC, Ford, JM, Gamet, K, Gullo, I, Hardwick, RH, Huntsman, DG, Kaurah, P, Kupfer, SS, Latchford, A, Mansfield, PF, Nakajima, T, Parry, S, Rossaak, J, Sugimura, H, Svrcek, M, Tischkowitz, M, Ushijima, T, Yamada, H, Yang, H-K, Claydon, A, Figueiredo, J, Paringatai, K, Seruca, R, Bougen-Zhukov, N, Brew, T, Busija, S, Carneiro, P, DeGregorio, L, Fisher, H, Gardner, E, Godwin, TD, Holm, KN, Humar, B, Lintott, CJ, Monroe, EC, Muller, MD, Norero, E, Nouri, Y, Paredes, J, Sanches, JM, Schulpen, E, Ribeiro, AS, Sporle, A, Whitworth, J, Zhang, L, Reeve, AE, Guilford, P, Blair, VR, McLeod, M, Carneiro, F, Coit, DG, D'Addario, JL, van Dieren, JM, Harris, KL, Hoogerbrugge, N, Oliveira, C, van der Post, RS, Arnold, J, Benusiglio, PR, Bisseling, TM, Boussioutas, A, Cats, A, Charlton, A, Schreiber, KEC, Davis, JL, di Pietro, M, Fitzgerald, RC, Ford, JM, Gamet, K, Gullo, I, Hardwick, RH, Huntsman, DG, Kaurah, P, Kupfer, SS, Latchford, A, Mansfield, PF, Nakajima, T, Parry, S, Rossaak, J, Sugimura, H, Svrcek, M, Tischkowitz, M, Ushijima, T, Yamada, H, Yang, H-K, Claydon, A, Figueiredo, J, Paringatai, K, Seruca, R, Bougen-Zhukov, N, Brew, T, Busija, S, Carneiro, P, DeGregorio, L, Fisher, H, Gardner, E, Godwin, TD, Holm, KN, Humar, B, Lintott, CJ, Monroe, EC, Muller, MD, Norero, E, Nouri, Y, Paredes, J, Sanches, JM, Schulpen, E, Ribeiro, AS, Sporle, A, Whitworth, J, Zhang, L, Reeve, AE, and Guilford, P

Abstract

Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer syndrome that is characterised by a high prevalence of diffuse gastric cancer and lobular breast cancer. It is largely caused by inactivating germline mutations in the tumour suppressor gene CDH1, although pathogenic variants in CTNNA1 occur in a minority of families with HDGC. In this Policy Review, we present updated clinical practice guidelines for HDGC from the International Gastric Cancer Linkage Consortium (IGCLC), which recognise the emerging evidence of variability in gastric cancer risk between families with HDGC, the growing capability of endoscopic and histological surveillance in HDGC, and increased experience of managing long-term sequelae of total gastrectomy in young patients. To redress the balance between the accessibility, cost, and acceptance of genetic testing and the increased identification of pathogenic variant carriers, the HDGC genetic testing criteria have been relaxed, mainly through less restrictive age limits. Prophylactic total gastrectomy remains the recommended option for gastric cancer risk management in pathogenic CDH1 variant carriers. However, there is increasing confidence from the IGCLC that endoscopic surveillance in expert centres can be safely offered to patients who wish to postpone surgery, or to those whose risk of developing gastric cancer is not well defined.

Published
2020

27. Reply to: New Meta- and Mega-analyses of Magnetic Resonance Imaging Findings in Schizophrenia: Do They Really Increase Our Knowledge About the Nature of the Disease Process?

Author

van Erp, TGM, Walton, E, Hibar, DP, Schmaal, L, Jiang, W, Glahn, DC, Pearlson, GD, Yao, N, Fukunaga, M, Hashimoto, R, Okada, N, Yamamori, H, Clark, VP, Mueller, BA, de Zwarte, SMC, Ophoff, RA, van Haren, NEM, Andreassen, OA, Gurholt, TP, Gruber, O, Kraemer, B, Richter, A, Calhoun, VD, Crespo-Facorro, B, Roiz-Santiañez, R, Tordesillas-Gutiérrez, D, Loughland, C, Catts, S, Fullerton, JM, Green, MJ, Henskens, F, Jablensky, A, Mowry, BJ, Pantelis, C, Quidé, Y, Schall, U, Scott, RJ, Cairns, MJ, Seal, M, Tooney, PA, Rasser, PE, Cooper, G, Shannon Weickert, C, Weickert, TW, Hong, E, Kochunov, P, Gur, RE, Gur, RC, Ford, JM, Macciardi, F, Mathalon, DH, Potkin, SG, Preda, A, Fan, F, Ehrlich, S, King, MD, De Haan, L, Veltman, DJ, Assogna, F, Banaj, N, de Rossi, P, Iorio, M, Piras, F, Spalletta, G, Pomarol-Clotet, E, Kelly, S, Ciufolini, S, Radua, J, Murray, R, Marques, TR, Simmons, A, Borgwardt, S, Schönborn-Harrisberger, F, Riecher-Rössler, A, Smieskova, R, Alpert, KI, Bertolino, A, Bonvino, A, Di Giorgio, A, Neilson, E, Mayer, AR, Yun, JY, Cannon, DM, Lebedeva, I, Tomyshev, AS, Akhadov, T, Kaleda, V, Fatouros-Bergman, H, Flyckt, L, Farde, L, Cervenka, S, Agartz, I, Collste, K, Victorsson, P, Engberg, G, Erhardt, S, Schwieler, L, Malmqvist, A, Hedberg, M, Orhan, F, van Erp, TGM, Walton, E, Hibar, DP, Schmaal, L, Jiang, W, Glahn, DC, Pearlson, GD, Yao, N, Fukunaga, M, Hashimoto, R, Okada, N, Yamamori, H, Clark, VP, Mueller, BA, de Zwarte, SMC, Ophoff, RA, van Haren, NEM, Andreassen, OA, Gurholt, TP, Gruber, O, Kraemer, B, Richter, A, Calhoun, VD, Crespo-Facorro, B, Roiz-Santiañez, R, Tordesillas-Gutiérrez, D, Loughland, C, Catts, S, Fullerton, JM, Green, MJ, Henskens, F, Jablensky, A, Mowry, BJ, Pantelis, C, Quidé, Y, Schall, U, Scott, RJ, Cairns, MJ, Seal, M, Tooney, PA, Rasser, PE, Cooper, G, Shannon Weickert, C, Weickert, TW, Hong, E, Kochunov, P, Gur, RE, Gur, RC, Ford, JM, Macciardi, F, Mathalon, DH, Potkin, SG, Preda, A, Fan, F, Ehrlich, S, King, MD, De Haan, L, Veltman, DJ, Assogna, F, Banaj, N, de Rossi, P, Iorio, M, Piras, F, Spalletta, G, Pomarol-Clotet, E, Kelly, S, Ciufolini, S, Radua, J, Murray, R, Marques, TR, Simmons, A, Borgwardt, S, Schönborn-Harrisberger, F, Riecher-Rössler, A, Smieskova, R, Alpert, KI, Bertolino, A, Bonvino, A, Di Giorgio, A, Neilson, E, Mayer, AR, Yun, JY, Cannon, DM, Lebedeva, I, Tomyshev, AS, Akhadov, T, Kaleda, V, Fatouros-Bergman, H, Flyckt, L, Farde, L, Cervenka, S, Agartz, I, Collste, K, Victorsson, P, Engberg, G, Erhardt, S, Schwieler, L, Malmqvist, A, Hedberg, M, and Orhan, F

Published
2019

28. Efference copy/corollary discharge function and targeted cognitive training in patients with schizophrenia

Author

Roach, B, Ford, J, Biagianti, B, Hamilton, H, Ramsay, I, Fisher, M, Loewy, R, Vinogradov, S, Mathalon, D, Roach BJ, Ford JM, Biagianti B, Hamilton HK, Ramsay IS, Fisher M, Loewy R, Vinogradov S, Mathalon DH, Roach, B, Ford, J, Biagianti, B, Hamilton, H, Ramsay, I, Fisher, M, Loewy, R, Vinogradov, S, Mathalon, D, Roach BJ, Ford JM, Biagianti B, Hamilton HK, Ramsay IS, Fisher M, Loewy R, Vinogradov S, and Mathalon DH

Abstract

Introduction: During vocalization, efference copy/corollary discharge mechanisms suppress the auditory cortical response to self-generated sounds as reflected in the N1 component of the auditory event-related potential (ERP). N1 suppression during talking is reduced in patients with schizophrenia. We hypothesized that these deficits would recover with auditory training that targets the speech processing system. Methods: Forty-nine individuals early in the course of a schizophrenia-spectrum illness (ESZ) were randomly assigned to 40 h of Targeted Auditory Training (TAT; n = 23) or Computer Games (CG; n = 26). The N1 ERP component was elicited during production (Talk) and playback (Listen) of vocalization. Effects of Treatment on Global Cognition, N1 suppression (Talk-Listen), N1 during Talking and Listening were assessed. Simple effects of the passage of time were also assessed in the HC after 28 weeks. Results: There was a Treatment × Time interaction revealing that N1 suppression was improved with TAT, but not with CG. TAT, but not CG, also improved Global Cognition. However, TAT and CG groups differed in their pre-treatment N1 suppression, and greater N1-suppression abnormalities were strongly associated with greater improvement in N1 suppression. Conclusions: In this sample of ESZ individuals, targeted auditory training appeared to improve the function of the efference copy/corollary discharge mechanism which tended to deteriorate with computer games. It remains to be determined if baseline N1 suppression abnormalities are necessary for TAT treatment to have a positive effect on efference copy/corollary discharge function or if improvements observed in this study represent a regression to the mean N1 suppression in ESZ.

Published
2019

29. From the Past to the Present: Insurer Coverage Frameworks for Next-Generation Tumor Sequencing

Author

Trosman, JR, Weldon, CB, Gradishar, WJ, III, BAB, Cristofanilli, M, Kurian, AW, Ford, JM, Balch, A, Watkins, J, and Phillips, KA

Subjects
tumor sequencing, History, precision medicine, Decision Making, Human Genome, Insurance Carriers, High-Throughput Nucleotide Sequencing, insurance coverage, 21st Century, reimbursement, Basic Behavioral and Social Science, Good Health and Well Being, Clinical Research, Neoplasms, precision oncology, Applied Economics, Behavioral and Social Science, Genetics, Public Health and Health Services, Health Policy & Services, Humans, next-generation sequencing, Generic health relevance, Cancer
Abstract

Next-generation sequencing promises major advancements in precision medicine but faces considerable challenges with insurance coverage. These challenges are especially important to address in oncology in which next-generation tumor sequencing (NGTS) holds a particular promise, guiding the use of life-saving or life-prolonging therapies. Payers' coverage decision making on NGTS is challenging because this revolutionary technology pushes the very boundaries of the underlying framework used in coverage decisions. Some experts have called for the adaptation of the coverage framework to make it better equipped for assessing NGTS. Medicare's recent decision to cover NGTS makes this topic particularly urgent to examine. In this article, we discussed the previously proposed approaches for adaptation of the NGTS coverage framework, highlighted their innovations, and outlined remaining gaps in their ability to assess the features of NGTS. We then compared the three approaches with Medicare's national coverage determination for NGTS and discussed its implications for US private payers as well as for other technologies and clinical areas. We focused on US payers because analyses of coverage approaches and policies in the large and complex US health care system may inform similar efforts in other countries. We concluded that further adaptation of the coverage framework will facilitate a better suited assessment of NGTS and future genomics innovations.

Published
2018

31. Cortical Brain Abnormalities in 4474 Individuals With Schizophrenia and 5098 Control Subjects via the Enhancing Neuro Imaging Genetics Through Meta Analysis (ENIGMA) Consortium

Author

van Erp, TGM, Walton, E, Hibar, DP, Schmaal, L, Jiang, W, Glahn, DC, Pearlson, GD, Yao, N, Fukunaga, M, Hashimoto, R, Okada, N, Yamamori, H, Bustillo, JR, Clark, VP, Agartz, I, Mueller, BA, Cahn, W, de Zwarte, SMC, Hulshoff Pol, HE, Kahn, RS, Ophoff, RA, van Haren, NEM, Andreassen, OA, Dale, AM, Doan, NT, Gurholt, TP, Hartberg, CB, Haukvik, UK, Jørgensen, KN, Lagerberg, TV, Melle, I, Westlye, LT, Gruber, O, Kraemer, B, Richter, A, Zilles, D, Calhoun, VD, Crespo-Facorro, B, Roiz-Santiañez, R, Tordesillas-Gutiérrez, D, Loughland, C, Carr, VJ, Catts, S, Cropley, VL, Fullerton, JM, Green, MJ, Henskens, FA, Jablensky, A, Lenroot, RK, Mowry, BJ, Michie, PT, Pantelis, C, Quidé, Y, Schall, U, Scott, RJ, Cairns, MJ, Seal, M, Tooney, PA, Rasser, PE, Cooper, G, Shannon Weickert, C, Weickert, TW, Morris, DW, Hong, E, Kochunov, P, Beard, LM, Gur, RE, Gur, RC, Satterthwaite, TD, Wolf, DH, Belger, A, Brown, GG, Ford, JM, Macciardi, F, Mathalon, DH, O'Leary, DS, Potkin, SG, Preda, A, Voyvodic, J, Lim, KO, McEwen, S, Yang, F, Tan, Y, Tan, S, Wang, Z, Fan, F, Chen, J, Xiang, H, Tang, S, Guo, H, Wan, P, Wei, D, Bockholt, HJ, Ehrlich, S, Wolthusen, RPF, King, MD, Shoemaker, JM, Sponheim, SR, De Haan, L, Koenders, L, van Erp, TGM, Walton, E, Hibar, DP, Schmaal, L, Jiang, W, Glahn, DC, Pearlson, GD, Yao, N, Fukunaga, M, Hashimoto, R, Okada, N, Yamamori, H, Bustillo, JR, Clark, VP, Agartz, I, Mueller, BA, Cahn, W, de Zwarte, SMC, Hulshoff Pol, HE, Kahn, RS, Ophoff, RA, van Haren, NEM, Andreassen, OA, Dale, AM, Doan, NT, Gurholt, TP, Hartberg, CB, Haukvik, UK, Jørgensen, KN, Lagerberg, TV, Melle, I, Westlye, LT, Gruber, O, Kraemer, B, Richter, A, Zilles, D, Calhoun, VD, Crespo-Facorro, B, Roiz-Santiañez, R, Tordesillas-Gutiérrez, D, Loughland, C, Carr, VJ, Catts, S, Cropley, VL, Fullerton, JM, Green, MJ, Henskens, FA, Jablensky, A, Lenroot, RK, Mowry, BJ, Michie, PT, Pantelis, C, Quidé, Y, Schall, U, Scott, RJ, Cairns, MJ, Seal, M, Tooney, PA, Rasser, PE, Cooper, G, Shannon Weickert, C, Weickert, TW, Morris, DW, Hong, E, Kochunov, P, Beard, LM, Gur, RE, Gur, RC, Satterthwaite, TD, Wolf, DH, Belger, A, Brown, GG, Ford, JM, Macciardi, F, Mathalon, DH, O'Leary, DS, Potkin, SG, Preda, A, Voyvodic, J, Lim, KO, McEwen, S, Yang, F, Tan, Y, Tan, S, Wang, Z, Fan, F, Chen, J, Xiang, H, Tang, S, Guo, H, Wan, P, Wei, D, Bockholt, HJ, Ehrlich, S, Wolthusen, RPF, King, MD, Shoemaker, JM, Sponheim, SR, De Haan, L, and Koenders, L

Abstract

Background: The profile of cortical neuroanatomical abnormalities in schizophrenia is not fully understood, despite hundreds of published structural brain imaging studies. This study presents the first meta-analysis of cortical thickness and surface area abnormalities in schizophrenia conducted by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Schizophrenia Working Group. Methods: The study included data from 4474 individuals with schizophrenia (mean age, 32.3 years; range, 11–78 years; 66% male) and 5098 healthy volunteers (mean age, 32.8 years; range, 10–87 years; 53% male) assessed with standardized methods at 39 centers worldwide. Results: Compared with healthy volunteers, individuals with schizophrenia have widespread thinner cortex (left/right hemisphere: Cohen's d = −0.530/−0.516) and smaller surface area (left/right hemisphere: Cohen's d = −0.251/−0.254), with the largest effect sizes for both in frontal and temporal lobe regions. Regional group differences in cortical thickness remained significant when statistically controlling for global cortical thickness, suggesting regional specificity. In contrast, effects for cortical surface area appear global. Case-control, negative, cortical thickness effect sizes were two to three times larger in individuals receiving antipsychotic medication relative to unmedicated individuals. Negative correlations between age and bilateral temporal pole thickness were stronger in individuals with schizophrenia than in healthy volunteers. Regional cortical thickness showed significant negative correlations with normalized medication dose, symptom severity, and duration of illness and positive correlations with age at onset. Conclusions: The findings indicate that the ENIGMA meta-analysis approach can achieve robust findings in clinical neuroscience studies; also, medication effects should be taken into account in future genetic association studies of cortical thickness in schizophrenia.

Published
2018

32. Trait aspects of auditory mismatch negativity predict response to auditory training in individuals with early illness schizophrenia

Author

Biagianti, B, Roach, B, Fisher, M, Loewy, R, Ford, J, Vinogradov, S, Mathalon, D, Roach, BJ, Ford, JM, Mathalon, DH, Biagianti, B, Roach, B, Fisher, M, Loewy, R, Ford, J, Vinogradov, S, Mathalon, D, Roach, BJ, Ford, JM, and Mathalon, DH

Abstract

Background: Individuals with schizophrenia have heterogeneous impairments of the auditory processing system that likely mediate differences in the cognitive gains induced by auditory training (AT). Mismatch negativity (MMN) is an event-related potential component reflecting auditory echoic memory, and its amplitude reduction in schizophrenia has been linked to cognitive deficits. Therefore, MMN may predict response to AT and identify individuals with schizophrenia who have the most to gain from AT. Furthermore, to the extent that AT strengthens auditory deviance processing, MMN may also serve as a readout of the underlying changes in the auditory system induced by AT. Methods: Fifty-six individuals early in the course of a schizophrenia-spectrum illness (ESZ) were randomly assigned to 40 h of AT or Computer Games (CG). Cognitive assessments and EEG recordings during a multi-deviant MMN paradigm were obtained before and after AT and CG. Changes in these measures were compared between the treatment groups. Baseline and trait-like MMN data were evaluated as predictors of treatment response. MMN data collected with the same paradigm from a sample of Healthy Controls (HC; n = 105) were compared to baseline MMN data from the ESZ group. Results: Compared to HC, ESZ individuals showed significant MMN reductions at baseline (p = .003). Reduced Double-Deviant MMN was associated with greater general cognitive impairment in ESZ individuals (p = .020). Neither ESZ intervention group showed significant change in MMN. We found high correlations in all MMN deviant types (rs = .59-.68, all ps < .001) between baseline and post-intervention amplitudes irrespective of treatment group, suggesting trait-like stability of the MMN signal. Greater deficits in trait-like Double-Deviant MMN predicted greater cognitive improvements in the AT group (p = .02), but not in the CG group. Conclusions: In this sample of ESZ individuals, AT had no effect on auditory deviance processing as assessed

Published
2017

33. Abstract P6-09-09: Evaluation of tumor infiltrating lymphocytes (TILs) and their association with homologous recombination deficiency and BRCA1/2 mutation status in triple-negative breast cancer (TNBC): A pooled analysis

Author

Telli, ML, primary, Badve, S, additional, Vinayak, S, additional, Silver, DP, additional, Isakoff, SJ, additional, Kaklamani, VG, additional, Gradishar, WJ, additional, Stearns, V, additional, Connolly, RM, additional, Ford, JM, additional, Adams, S, additional, Garber, JE, additional, Evans, B, additional, Timms, K, additional, Wenstrup, R, additional, and Richardson, AL, additional

Published
2017
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36. Visual hallucinations are associated with hyperconnectivity between the amygdala and visual cortex in people with a diagnosis of schizophrenia

Author

Ford, JM, Palzes, VA, Roach, BJ, Potkin, SG, Van Erp, TGM, Turner, JA, Mueller, BA, Calhoun, VD, Voyvodic, J, Belger, A, Bustillo, J, Vaidya, JG, Preda, A, McEwen, SC, and Mathalon, DH

Abstract

© The Author 2014. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved.Introduction: While auditory verbal hallucinations (AH) are a cardinal symptom of schizophrenia, people with a diagnosis of schizophrenia (SZ) may also experience visual hallucinations (VH). In a retrospective analysis of a large sample of SZ and healthy controls (HC) studied as part of the functional magnetic resonance imaging (fMRI) Biomedical Informatics Research Network (FBIRN), we asked if SZ who endorsed experiencing VH during clinical interviews had greater connectivity between visual cortex and limbic structures than SZ who did not endorse experiencing VH. Methods: We analyzed resting state fMRI data from 162 SZ and 178 age- and gender-matched HC. SZ were sorted into groups according to clinical ratings on AH and VH: SZ with VH (VH-SZ; n = 45), SZ with AH but no VH (AH-SZ; n = 50), and SZ with neither AH nor VH (NoH-SZ; n = 67). Our primary analysis was seed based, extracting connectivity between visual cortex and the amygdala (because of its role in fear and negative emotion) and visual cortex and the hippocampus (because of its role in memory). Results: Compared with the other groups, VH-SZ showed hyperconnectivity between the amygdala and visual cortex, specifically BA18, with no differences in connectivity among the other groups. In a voxel-wise, whole brain analysis comparing VH-SZ with AH-SZ, the amygdala was hyperconnected to left temporal pole and inferior frontal gyrus in VH-SZ, likely due to their more severe thought broadcasting. Conclusions: VH-SZ have hyperconnectivity between subcortical areas subserving emotion and cortical areas subserving higher order visual processing, providing biological support for distressing VH in schizophrenia.

Published
2015

38. Self-initiated actions result in suppressed auditory but amplified visual evoked components in healthy participants

Author

Mifsud, NG, Oestreich, LKL, Jack, BN, Ford, JM, Roach, BJ, Mathalon, DH, Whitford, TJ, Mifsud, NG, Oestreich, LKL, Jack, BN, Ford, JM, Roach, BJ, Mathalon, DH, and Whitford, TJ

Abstract

Self-suppression refers to the phenomenon that sensations initiated by our own movements are typically less salient, and elicit an attenuated neural response, compared to sensations resulting from changes in the external world. Evidence for self-suppression is provided by previous ERP studies in the auditory modality, which have found that healthy participants typically exhibit a reduced auditory N1 component when auditory stimuli are self-initiated as opposed to externally initiated. However, the literature investigating self-suppression in the visual modality is sparse, with mixed findings and experimental protocols. An EEG study was conducted to expand our understanding of self-suppression across different sensory modalities. Healthy participants experienced either an auditory (tone) or visual (pattern-reversal) stimulus following a willed button press (self-initiated), a random interval (externally initiated, unpredictable onset), or a visual countdown (externally initiated, predictable onset-to match the intrinsic predictability of self-initiated stimuli), while EEG was continuously recorded. Reduced N1 amplitudes for self- versus externally initiated tones indicated that self-suppression occurred in the auditory domain. In contrast, the visual N145 component was amplified for self- versus externally initiated pattern reversals. Externally initiated conditions did not differ as a function of their predictability. These findings highlight a difference in sensory processing of self-initiated stimuli across modalities, and may have implications for clinical disorders that are ostensibly associated with abnormal self-suppression.

Published
2016

40. Abstract OT2-05-04: The Talazoparib Beyond BRCA (TBB) trial: A phase II clinical trial of talazoparib (BMN 673) in BRCA1 and BRCA2 wild-type patients with (i) advanced triple-negative breast cancer (TNBC) and homologous recombination deficiency (HRD) as assessed by myriad genetics HRD assay, and (ii) advanced HER2-negative breast cancer (BC) with either a germline or somatic mutation in homologous recombination (HR) pathway genes

Author

Afghahi, A, primary, Chang, P-J, additional, Ford, JM, additional, and Telli, ML, additional

Published
2016
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41. Abstract PD7-01: Interim analysis of multiplex gene panel testing for inherited susceptibility to breast cancer

Author

Idos, GE, primary, Kurian, AW, additional, Mcdonnell, KJ, additional, Ricker, CN, additional, Sturgeon, DY, additional, Culver, JO, additional, Lowstuter, K, additional, Hartman, A-R, additional, Allen, B, additional, Teeter, C-R, additional, Kingham, KE, additional, Koff, R, additional, Lebensohn, A, additional, Chun, NM, additional, Mills, MA, additional, Petrovchich, I, additional, Hong, C, additional, Ladabaum, U, additional, Ford, JM, additional, and Gruber, SB, additional

Published
2016
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42. Abstract P3-07-12: Homologous recombination deficiency (HRD) as a predictive biomarker of response to neoadjuvant platinum-based therapy in patients with triple negative breast cancer (TNBC): A pooled analysis

Author

Telli, ML, primary, McMillan, A, additional, Ford, JM, additional, Richardson, AL, additional, Silver, DP, additional, Isakoff, SJ, additional, Kaklamani, VG, additional, Gradishar, W, additional, Stearns, V, additional, Connolly, RM, additional, Loibl, S, additional, Elkin, EP, additional, Timms, K, additional, Hartman, A-R, additional, and von Minckwitz, G, additional

Published
2016
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43. Abstract P2-09-07: The patient experience in a prospective trial of multiplex gene panel testing for cancer risk

Author

Kurian, AW, primary, Idos, G, additional, McDonnell, K, additional, Ricker, C, additional, Sturgeon, D, additional, Culver, J, additional, Lowstuter, K, additional, Hartman, A-R, additional, Allen, B, additional, Rowe-Teeter, C, additional, Kingham, KE, additional, Koff, RB, additional, Lebensohn, A, additional, Chun, NM, additional, Petrovchich, IM, additional, Mills, MA, additional, Hong, C, additional, Ladabaum, U, additional, Ford, JM, additional, and Gruber, SB, additional

Published
2016
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44. Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers

Author

van der Post, RS, Vogelaar, IP, Carneiro, F, Guilford, P, Huntsman, D, Hoogerbrugge, N, Caldas, C, Schreiber, KEC, Hardwick, RH, Ausems, MGEM, Bardram, L, Benusiglio, PR, Bisseling, TM, Blair, V, Bleiker, E, Boussioutas, A, Cats, A, Coit, D, DeGregorio, L, Figueiredo, J, Ford, JM, Heijkoop, E, Hermens, R, Humar, B, Kaurah, P, Keller, G, Lai, J, Ligtenberg, MJL, O'Donovan, M, Oliveira, C, Pinheiro, H, Ragunath, K, Rasenberg, E, Richardson, S, Roviello, F, Schackert, H, Seruca, R, Taylor, A, ter Huurne, A, Tischkowitz, M, Joe, STA, van Dijck, B, van Grieken, NCT, van Hillegersberg, R, van Sandick, JW, Vehof, R, van Krieken, JH, Fitzgerald, RC, van der Post, RS, Vogelaar, IP, Carneiro, F, Guilford, P, Huntsman, D, Hoogerbrugge, N, Caldas, C, Schreiber, KEC, Hardwick, RH, Ausems, MGEM, Bardram, L, Benusiglio, PR, Bisseling, TM, Blair, V, Bleiker, E, Boussioutas, A, Cats, A, Coit, D, DeGregorio, L, Figueiredo, J, Ford, JM, Heijkoop, E, Hermens, R, Humar, B, Kaurah, P, Keller, G, Lai, J, Ligtenberg, MJL, O'Donovan, M, Oliveira, C, Pinheiro, H, Ragunath, K, Rasenberg, E, Richardson, S, Roviello, F, Schackert, H, Seruca, R, Taylor, A, ter Huurne, A, Tischkowitz, M, Joe, STA, van Dijck, B, van Grieken, NCT, van Hillegersberg, R, van Sandick, JW, Vehof, R, van Krieken, JH, and Fitzgerald, RC

Abstract

Germline CDH1 mutations confer a high lifetime risk of developing diffuse gastric (DGC) and lobular breast cancer (LBC). A multidisciplinary workshop was organised to discuss genetic testing, surgery, surveillance strategies, pathology reporting and the patient's perspective on multiple aspects, including diet post gastrectomy. The updated guidelines include revised CDH1 testing criteria (taking into account first-degree and second-degree relatives): (1) families with two or more patients with gastric cancer at any age, one confirmed DGC; (2) individuals with DGC before the age of 40 and (3) families with diagnoses of both DGC and LBC (one diagnosis before the age of 50). Additionally, CDH1 testing could be considered in patients with bilateral or familial LBC before the age of 50, patients with DGC and cleft lip/palate, and those with precursor lesions for signet ring cell carcinoma. Given the high mortality associated with invasive disease, prophylactic total gastrectomy at a centre of expertise is advised for individuals with pathogenic CDH1 mutations. Breast cancer surveillance with annual breast MRI starting at age 30 for women with a CDH1 mutation is recommended. Standardised endoscopic surveillance in experienced centres is recommended for those opting not to have gastrectomy at the current time, those with CDH1 variants of uncertain significance and those that fulfil hereditary DGC criteria without germline CDH1 mutations. Expert histopathological confirmation of (early) signet ring cell carcinoma is recommended. The impact of gastrectomy and mastectomy should not be underestimated; these can have severe consequences on a psychological, physiological and metabolic level. Nutritional problems should be carefully monitored.

Published
2015

45. Converging evidence for gamma synchrony deficits in schizophrenia

Author

Roach, BJ, Ford, JM, Hoffman, RE, and Mathalon, DH

Subjects
Psychiatric Status Rating Scales, Adult, Male, Brain Mapping, Analysis of Variance, Time Factors, Auditory Perceptual Disorders, Electroencephalography, Middle Aged, Serious Mental Illness, Brain Waves, Brain Disorders, Young Adult, Mental Health, Acoustic Stimulation, Case-Control Studies, Reaction Time, Schizophrenia, Humans, Female, Evoked Potentials, Auditory, Psychoacoustics
Abstract

BackgroundIn electroencephalogram (EEG) studies of auditory steady-state responses (ASSRs), patients with schizophrenia show a deficit in power and/or phase-locking, particularly at the 40 Hz frequency where these responses resonate. In addition, studies of the transient gamma-band response (GBR) elicited by single tones have revealed deficits in gamma power and phase-locking in schizophrenia. We examined the degree to which the 40 Hz ASSR and the transient GBR to single tones are correlated and whether they assess overlapping or distinct gamma-band abnormalities in schizophrenia.MethodsEEG was recorded during 40 Hz ASSR and auditory oddball paradigms from 28 patients with schizophrenia or schizoaffective disorder (SZ) and 25 age- and gender-matched healthy controls (HC). The ASSR was elicited by 500 ms click trains, and the transient GBR was elicited by the standard tones from the oddball paradigm. Gamma phase and magnitude values, calculated using Morlet wavelet transformations, were used to derive total power and phase-locking measures.ResultsRelative to HC, SZ patients had significant deficits in total gamma power and phase-locking for both ASSR- and GBR-based measures. Within both groups, the 40 Hz ASSR and GBR phase-locking measures were significantly correlated, with a similar trend evident for the total power measures. Moreover, co-varying for GBR substantially reduced 40 Hz ASSR power and phase-locking differences between the groups.Conclusions40 Hz ASSR and transient GBR measures provide very similar information about auditory gamma abnormalities in schizophrenia, despite the overall enhancement of 40 Hz ASSR total power and phase-locking values relative to the corresponding GBR values.

Published
2013

46. A multi-site resting state fMRI study on the amplitude of low frequency fluctuations in schizophrenia

Author

Turner, JA, Damaraju, E, Van Erp, TGM, Mathalon, DH, Ford, JM, Voyvodic, J, Mueller, BA, Belger, A, Bustillo, J, McEwen, S, Potkin, SG, and Calhoun, VD

Abstract

Background: This multi-site study compares resting state fMRI amplitude of low frequency fluctuations (ALFF) and fractional ALFF (fALFF) between patients with schizophrenia (SZ) and healthy controls (HC).Methods: Eyes-closed resting fMRI scans (5:38 min; n = 306, 146 SZ) were collected from 6 Siemens 3T scanners and one GE 3T scanner. Imaging data were pre-processed using an SPM pipeline. Power in the low frequency band (0.01-0.08 Hz) was calculated both for the original pre-processed data as well as for the pre-processed data after regressing out the six rigid-body motion parameters, mean white matter (WM) and cerebral spinal fluid (CSF) signals. Both original and regressed ALFF and fALFF measures were modeled with site, diagnosis, age, and diagnosis × age interactions. Results: Regressing out motion and non-gray matter signals significantly decreased fALFF throughout the brain as well as ALFF in the cortical edge, but significantly increased ALFF in subcortical regions. Regression had little effect on site, age, and diagnosis effects on ALFF, other than to reduce diagnosis effects in subcortical regions. There were significant effects of site across the brain in all the analyses, largely due to vendor differences. HC showed greater ALFF in the occipital, posterior parietal, and superior temporal lobe, while SZ showed smaller clusters of greater ALFF in the frontal and temporal/insular regions as well as in the caudate, putamen, and hippocampus. HC showed greater fALFF compared with SZ in all regions, though subcortical differences were only significant for original fALFF. Conclusions: SZ show greater eyes-closed resting state low frequency power in frontal cortex, and less power in posterior lobes than do HC; fALFF, however, is lower in SZ than HC throughout the cortex. These effects are robust to multi-site variability. Regressing out physiological noise signals significantly affects both total and fALFF measures, but does not affect the pattern of case/control differences. © 2013 Turner, Damaraju, van Erp, Mathalon, Ford, Voyvodic, Mueller, Belger, Bustillo, McEwen, Potkin, FBIRN and Calhoun.

Published
2013

47. Function biomedical informatics research network recommendations for prospective multicenter functional MRI studies

Author

Glover, GH, Mueller, BA, Turner, JA, Van Erp, TGM, Liu, TT, Greve, DN, Voyvodic, JT, Rasmussen, J, Brown, GG, Keator, DB, Calhoun, VD, Lee, HJ, Ford, JM, Mathalon, DH, Diaz, M, O'Leary, DS, Gadde, S, Preda, A, Lim, KO, Wible, CG, Stern, HS, Belger, A, McCarthy, G, Ozyurt, B, and Potkin, SG

Abstract

This report provides practical recommendations for the design and execution of multicenter functional MRI (MC-fMRI) studies based on the collective experience of the Function Biomedical Informatics Research Network (FBIRN). The study was inspired by many requests from the fMRI community to FBIRN group members for advice on how to conduct MC-fMRI studies. The introduction briefly discusses the advantages and complexities of MC-fMRI studies. Prerequisites for MC-fMRI studies are addressed before delving into the practical aspects of carefully and efficiently setting up a MC-fMRI study. Practical multisite aspects include: (i) establishing and verifying scan parameters including scanner types and magnetic fields, (ii) establishing and monitoring of a scanner quality program, (iii) developing task paradigms and scan session documentation, (iv) establishing clinical and scanner training to ensure consistency over time, (v) developing means for uploading, storing, and monitoring of imaging and other data, (vi) the use of a traveling fMRI expert, and (vii) collectively analyzing imaging data and disseminating results. We conclude that when MC-fMRI studies are organized well with careful attention to unification of hardware, software and procedural aspects, the process can be a highly effective means for accessing a desired participant demographics while accelerating scientific discovery. © 2012 Wiley Periodicals, Inc.

Published
2012

48. Metastatic tumor evolution and organoid modeling implicate TGFBR2 as a cancer driver in diffuse gastric cancer

Author

Nadauld, LD, Garcia, S, Natsoulis, G, Bell, JM, Miotke, L, Hopmans, ES, Xu, H, Pai, RK, Palm, C, Regan, JF, Chen, H, Flaherty, P, Ootani, A, Zhang, NR, Ford, JM, Kuo, CJ, Ji, HP, Nadauld, LD, Garcia, S, Natsoulis, G, Bell, JM, Miotke, L, Hopmans, ES, Xu, H, Pai, RK, Palm, C, Regan, JF, Chen, H, Flaherty, P, Ootani, A, Zhang, NR, Ford, JM, Kuo, CJ, and Ji, HP

Abstract

BACKGROUND: Gastric cancer is the second-leading cause of global cancer deaths, with metastatic disease representing the primary cause of mortality. To identify candidate drivers involved in oncogenesis and tumor evolution, we conduct an extensive genome sequencing analysis of metastatic progression in a diffuse gastric cancer. This involves a comparison between a primary tumor from a hereditary diffuse gastric cancer syndrome proband and its recurrence as an ovarian metastasis.

Published
2014

49. Pion-nucleon partial-wave analysis to 2 GeV

Author

L. D. Roper, Ron L. Workman, Ford Jm, Zhujun Li, and R. A. Arndt

Subjects
Elastic scattering, Nuclear physics, Physics, Particle physics, Pion, Partial wave analysis, Particle Data Group, Nuclear Experiment, Polarization (waves), Nucleon, Kinetic energy
Abstract

We have analyzed the available pion-nucleon elastic-scattering data with laboratory kinetic energies below 2 GeV. We present the results of several energy-dependent and energy-independent analyses performed over this energy range. Pole positions and the corresponding residues are reported for resonances. We compare our results to those from our previous analyses and to values reported by the Particle Data Group.

Published
1991

50. Schizophrenia, Myelination, and Delayed Corollary Discharges: A Hypothesis

Author

Whitford, TJ, Ford, JM, Mathalon, DH, Kubicki, M, Shenton, ME, Whitford, TJ, Ford, JM, Mathalon, DH, Kubicki, M, and Shenton, ME

Abstract

Any etiological theory of schizophrenia must account for at least 3 distinctive features of the disorder, namely its excessive dopamine neurotransmission, its frequent periadolescent onset, and its bizarre, pathognomonic symptoms. In this article, we theorize that each of these features could arise from a single underlying cause--namely abnormal myelination of late-developing frontal white matter fasciculi. Specifically, we suggest that abnormalities in frontal myelination result in conduction delays in the efference copies initiated by willed actions. These conduction delays cause the resulting corollary discharges to be generated too late to suppress the sensory consequences of the willed actions. The resulting ambiguity as to the origins of these actions represents a phenomenologically and neurophysiologically significant prediction error. On a phenomenological level, the perception of salience in a self-generated action leads to confusion as to its origins and, consequently, passivity experiences and auditory hallucinations. On a neurophysiological level, this prediction error leads to the increased activity of dopaminergic neurons in the midbrain. This dopaminergic activity causes previously insignificant events to be perceived as salient, which exacerbates the budding hallucinations and passivity experiences and triggers additional first-rank symptoms such as delusions of reference. The article concludes with a discussion of the implications of the theory and some testable predictions which may form a worthwhile basis for future research.

Published
2012

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