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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, Biomedical Imaging, 1.1 Normal biological development and functioning, 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. Prefrontal cortical thinning links to negative symptoms in schizophrenia via the ENIGMA consortium.

Author

Walton, E, Hibar, DP, van Erp, TGM, Potkin, SG, Roiz-Santiañez, R, Crespo-Facorro, B, Suarez-Pinilla, P, van Haren, NEM, de Zwarte, SMC, Kahn, RS, Cahn, W, Doan, NT, Jørgensen, KN, Gurholt, TP, Agartz, I, Andreassen, OA, Westlye, LT, Melle, I, Berg, AO, Morch-Johnsen, L, Færden, A, Flyckt, L, Fatouros-Bergman, H, Karolinska Schizophrenia Project Consortium (KaSP), Jönsson, EG, Hashimoto, R, Yamamori, H, Fukunaga, M, Jahanshad, N, De Rossi, P, Piras, F, Banaj, N, Spalletta, G, Gur, RE, Gur, RC, Wolf, DH, Satterthwaite, TD, Beard, LM, Sommer, IE, Koops, S, Gruber, O, Richter, A, Krämer, B, Kelly, S, Donohoe, G, McDonald, C, Cannon, DM, Corvin, A, Gill, M, Di Giorgio, A, Bertolino, A, Lawrie, S, Nickson, T, Whalley, HC, Neilson, E, Calhoun, VD, Thompson, PM, Turner, JA, and Ehrlich, S

Subjects
Karolinska Schizophrenia Project Consortium, Prefrontal Cortex, Humans, Magnetic Resonance Imaging, Linear Models, Schizophrenia, Psychiatric Status Rating Scales, Schizophrenic Psychology, Internationality, Image Processing, Computer-Assisted, Adult, Female, Male, Functional Laterality, Cortical thickness, ENIGMA, FreeSurfer, MRI, PANSS, SANS, medial orbitofrontal cortex, negative symptoms, schizophrenia, Image Processing, Computer-Assisted, Psychiatry, Psychology, Public Health and Health Services, Neurosciences
Abstract

BackgroundOur understanding of the complex relationship between schizophrenia symptomatology and etiological factors can be improved by studying brain-based correlates of schizophrenia. Research showed that impairments in value processing and executive functioning, which have been associated with prefrontal brain areas [particularly the medial orbitofrontal cortex (MOFC)], are linked to negative symptoms. Here we tested the hypothesis that MOFC thickness is associated with negative symptom severity.MethodsThis study included 1985 individuals with schizophrenia from 17 research groups around the world contributing to the ENIGMA Schizophrenia Working Group. Cortical thickness values were obtained from T1-weighted structural brain scans using FreeSurfer. A meta-analysis across sites was conducted over effect sizes from a model predicting cortical thickness by negative symptom score (harmonized Scale for the Assessment of Negative Symptoms or Positive and Negative Syndrome Scale scores).ResultsMeta-analytical results showed that left, but not right, MOFC thickness was significantly associated with negative symptom severity (β std = -0.075; p = 0.019) after accounting for age, gender, and site. This effect remained significant (p = 0.036) in a model including overall illness severity. Covarying for duration of illness, age of onset, antipsychotic medication or handedness weakened the association of negative symptoms with left MOFC thickness. As part of a secondary analysis including 10 other prefrontal regions further associations in the left lateral orbitofrontal gyrus and pars opercularis emerged.ConclusionsUsing an unusually large cohort and a meta-analytical approach, our findings point towards a link between prefrontal thinning and negative symptom severity in schizophrenia. This finding provides further insight into the relationship between structural brain abnormalities and negative symptoms in schizophrenia.

Published
2018

5. Newborn insula gray matter volume is prospectively associated with early life adiposity gain

Author

Rasmussen, JM, Entringer, S, Kruggel, F, Cooper, DM, Styner, M, Gilmore, JH, Potkin, SG, Wadhwa, PD, and Buss, C

Subjects
Paediatrics, Biomedical and Clinical Sciences, Prevention, Clinical Research, Neurosciences, Obesity, Brain Disorders, Nutrition, Biomedical Imaging, Pediatric, Absorptiometry, Photon, Adiposity, Cerebral Cortex, Energy Metabolism, Female, Gray Matter, Humans, Infant, Newborn, Longitudinal Studies, Male, Pediatric Obesity, Prospective Studies, Signal Transduction, Weight Gain, Medical and Health Sciences, Education, Endocrinology & Metabolism, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundThe importance of energy homeostasis brain circuitry in the context of obesity is well established, however, the developmental ontogeny of this circuitry in humans is currently unknown. Here, we investigate the prospective association between newborn gray matter (GM) volume in the insula, a key brain region underlying energy homeostasis, and change in percent body fat accrual over the first six months of postnatal life, an outcome that represents among the most reliable infant predictors of childhood obesity risk.MethodsA total of 52 infants (29 male, 23 female, gestational age at birth=39(1.5) weeks) were assessed using structural MRI shortly after birth (postnatal age at MRI scan=25.9(12.2) days), and serial Dual X-Ray Absorptiometry shortly after birth (postnatal age at DXA scan 1=24.6(11.4) days) and at six months of age (postnatal age at DXA scan 2=26.7(3.3) weeks).ResultsInsula GM volume was inversely associated with change in percent body fat from birth to six-months postnatal age and accounted for 19% of its variance (β=-3.6%/S.D., P=0.001). This association was driven by the central-posterior portion of the insula, a region of particular importance for gustation and interoception. The direction of this effect is in concordance with observations in adults, and the results remained statistically significant after adjusting for relevant covariates and potential confounding variables.ConclusionsAltogether, these findings suggest an underlying neural basis of childhood obesity that precedes the influence of the postnatal environment. The identification of plausible brain-related biomarkers of childhood obesity risk that predate the influence of the postnatal obesogenic environment may contribute to an improved understanding of propensity for obesity, early identification of at-risk individuals, and intervention targets for primary prevention.

Published
2017

6. Positive symptoms associate with cortical thinning in the superior temporal gyrus via the ENIGMA Schizophrenia consortium

Author

Walton, E, Hibar, DP, Erp, TGM, Potkin, SG, Roiz‐Santiañez, R, Crespo‐Facorro, B, Suarez‐Pinilla, P, Van Haren, NEM, Zwarte, SMC, Kahn, RS, Cahn, W, Doan, NT, Jørgensen, KN, Gurholt, TP, Agartz, I, Andreassen, OA, Westlye, LT, Melle, I, Berg, AO, Mørch‐Johnsen, L, Færden, A, Flyckt, L, Fatouros‐Bergman, H, Consortium, Karolinska Schizophrenia Project, Jönsson, EG, Hashimoto, R, Yamamori, H, Fukunaga, M, Preda, A, De Rossi, P, Piras, F, Banaj, N, Ciullo, V, Spalletta, G, Gur, RE, Gur, RC, Wolf, DH, Satterthwaite, TD, Beard, LM, Sommer, IE, Koops, S, Gruber, O, Richter, A, Krämer, B, Kelly, S, Donohoe, G, McDonald, C, Cannon, DM, Corvin, A, Gill, M, Di Giorgio, A, Bertolino, A, Lawrie, S, Nickson, T, Whalley, HC, Neilson, E, Calhoun, VD, Thompson, PM, Turner, JA, and Ehrlich, S

Subjects
Schizophrenia, Mental Health, Brain Disorders, Mental health, Good Health and Well Being, Adult, Brain Mapping, Female, Humans, Magnetic Resonance Imaging, Male, Prospective Studies, Psychiatric Status Rating Scales, Schizophrenic Psychology, Temporal Lobe, schizophrenia, positive symptoms, superior temporal gyrus, cortical thickness, ENIGMA, FreeSurfer, MRI, scale for the assessment of positive symptoms, positive and negative syndrome scale, Karolinska Schizophrenia Project Consortium, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

ObjectiveBased on the role of the superior temporal gyrus (STG) in auditory processing, language comprehension and self-monitoring, this study aimed to investigate the relationship between STG cortical thickness and positive symptom severity in schizophrenia.MethodThis prospective meta-analysis includes data from 1987 individuals with schizophrenia collected at seventeen centres around the world that contribute to the ENIGMA Schizophrenia Working Group. STG thickness measures were extracted from T1-weighted brain scans using FreeSurfer. The study performed a meta-analysis of effect sizes across sites generated by a model predicting left or right STG thickness with a positive symptom severity score (harmonized SAPS or PANSS-positive scores), while controlling for age, sex and site. Secondary models investigated relationships between antipsychotic medication, duration of illness, overall illness severity, handedness and STG thickness.ResultsPositive symptom severity was negatively related to STG thickness in both hemispheres (left: βstd = -0.052; P = 0.021; right: βstd = -0.073; P = 0.001) when statistically controlling for age, sex and site. This effect remained stable in models including duration of illness, antipsychotic medication or handedness.ConclusionOur findings further underline the important role of the STG in hallmark symptoms in schizophrenia. These findings can assist in advancing insight into symptom-relevant pathophysiological mechanisms in schizophrenia.

Published
2017

7. Subcortical brain volume abnormalities in 2028 individuals with schizophrenia and 2540 healthy controls via the ENIGMA consortium

Author

van Erp, TGM, Hibar, DP, Rasmussen, JM, Glahn, DC, Pearlson, GD, Andreassen, OA, Agartz, I, Westlye, LT, Haukvik, UK, Dale, AM, Melle, I, Hartberg, CB, Gruber, O, Kraemer, B, Zilles, D, Donohoe, G, Kelly, S, McDonald, C, Morris, DW, Cannon, DM, Corvin, A, Machielsen, MWJ, Koenders, L, de Haan, L, Veltman, DJ, Satterthwaite, TD, Wolf, DH, Gur, RC, Gur, RE, Potkin, SG, Mathalon, DH, Mueller, BA, Preda, A, Macciardi, F, Ehrlich, S, Walton, E, Hass, J, Calhoun, VD, Bockholt, HJ, Sponheim, SR, Shoemaker, JM, van Haren, NEM, Pol, HEH, Ophoff, RA, Kahn, RS, Roiz-Santiañez, R, Crespo-Facorro, B, Wang, L, Alpert, KI, Jönsson, EG, Dimitrova, R, Bois, C, Whalley, HC, McIntosh, AM, Lawrie, SM, Hashimoto, R, Thompson, PM, and Turner, JA

Subjects
Biological Psychology, Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Psychology, Serious Mental Illness, Brain Disorders, Schizophrenia, Clinical Research, Neurosciences, Mental Health, Biomedical Imaging, Rare Diseases, Aetiology, 2.1 Biological and endogenous factors, Mental health, Good Health and Well Being, Adult, Brain, Brain Mapping, Case-Control Studies, Female, Functional Laterality, Humans, Image Processing, Computer-Assisted, Longitudinal Studies, Magnetic Resonance Imaging, Male, Middle Aged, Neuroimaging, Prospective Studies, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Clinical sciences, Biological psychology, Clinical and health psychology
Abstract

The profile of brain structural abnormalities in schizophrenia is still not fully understood, despite decades of research using brain scans. To validate a prospective meta-analysis approach to analyzing multicenter neuroimaging data, we analyzed brain MRI scans from 2028 schizophrenia patients and 2540 healthy controls, assessed with standardized methods at 15 centers worldwide. We identified subcortical brain volumes that differentiated patients from controls, and ranked them according to their effect sizes. Compared with healthy controls, patients with schizophrenia had smaller hippocampus (Cohen's d=-0.46), amygdala (d=-0.31), thalamus (d=-0.31), accumbens (d=-0.25) and intracranial volumes (d=-0.12), as well as larger pallidum (d=0.21) and lateral ventricle volumes (d=0.37). Putamen and pallidum volume augmentations were positively associated with duration of illness and hippocampal deficits scaled with the proportion of unmedicated patients. Worldwide cooperative analyses of brain imaging data support a profile of subcortical abnormalities in schizophrenia, which is consistent with that based on traditional meta-analytic approaches. This first ENIGMA Schizophrenia Working Group study validates that collaborative data analyses can readily be used across brain phenotypes and disorders and encourages analysis and data sharing efforts to further our understanding of severe mental illness.

Published
2016

8. Huntington’s disease cerebrospinal fluid seeds aggregation of mutant huntingtin

Author

Tan, Z, Dai, W, van Erp, TGM, Overman, J, Demuro, A, Digman, MA, Hatami, A, Albay, R, Sontag, EM, Potkin, KT, Ling, S, Macciardi, F, Bunney, WE, Long, JD, Paulsen, JS, Ringman, JM, Parker, I, Glabe, C, Thompson, LM, Chiu, W, and Potkin, SG

Subjects
Biomedical and Clinical Sciences, Biological Psychology, Clinical and Health Psychology, Clinical Sciences, Psychology, Rare Diseases, Neurodegenerative, Acquired Cognitive Impairment, Brain Disorders, Huntington's Disease, Orphan Drug, Neurosciences, 2.1 Biological and endogenous factors, Neurological, Animals, Cells, Cultured, Female, Humans, Huntingtin Protein, Huntington Disease, Male, Microscopy, Electron, Mutation, Nerve Tissue Proteins, Peptides, Protein Aggregation, Pathological, Rats, Rats, Transgenic, Transfection, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Clinical sciences, Biological psychology, Clinical and health psychology
Abstract

Huntington's disease (HD), a progressive neurodegenerative disease, is caused by an expanded CAG triplet repeat producing a mutant huntingtin protein (mHTT) with a polyglutamine-repeat expansion. Onset of symptoms in mutant huntingtin gene-carrying individuals remains unpredictable. We report that synthetic polyglutamine oligomers and cerebrospinal fluid (CSF) from BACHD transgenic rats and from human HD subjects can seed mutant huntingtin aggregation in a cell model and its cell lysate. Our studies demonstrate that seeding requires the mutant huntingtin template and may reflect an underlying prion-like protein propagation mechanism. Light and cryo-electron microscopy show that synthetic seeds nucleate and enhance mutant huntingtin aggregation. This seeding assay distinguishes HD subjects from healthy and non-HD dementia controls without overlap (blinded samples). Ultimately, this seeding property in HD patient CSF may form the basis of a molecular biomarker assay to monitor HD and evaluate therapies that target mHTT.

Published
2015

10. 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

11. P50 and phase response of 40-Hz EEG

Author

Jin, Y, Potkin, SG, Sandman, CA, Patterson, JV, and Bunney, WE

Subjects
Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Published
1999

12. Does P50 measure clinical sensory gating?

Author

Jin, Y, Bunney, WE, Sandman, CA, Patterson, JV, Fleming, K, Moenter, JR, Kalali, AH, Hetrick, WP, and Potkin, SG

Subjects
Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Published
1999

13. Structured Interview for Assessing Perceptual Anomalies (SIAPA).

Author

Bunney, WE, Hetrick, WP, Bunney, BG, Patterson, JV, Jin, Y, Potkin, SG, and Sandman, CA

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Brain Disorders, Serious Mental Illness, Schizophrenia, Mental Health, Neurosciences, Clinical Research, Mental health, Adult, Attention, California, Case-Control Studies, Cognition Disorders, Female, Humans, Interview, Psychological, Male, Matched-Pair Analysis, Perceptual Disorders, Perceptual Distortion, Prevalence, Psychometrics, Psychotic Disorders, Reproducibility of Results, Schizophrenic Psychology, Sensation Disorders, perceptual abnormalities, sensory gating, structured interview scale, psychosis, schizophrenia, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Clinical sciences
Abstract

Clinical descriptions of perceptual and attentional anomalies in schizophrenia emphasize phenomena such as flooding, or inundation, by sensory stimuli. A failure of sensory "gating" mechanisms in the brain is hypothesized to account for these symptoms, and this hypothesis has led to a marked interest in their putative psychophysiological substrates. However, there are no systematic analyses of the phenomenology of these perceptual experiences, nor has the hypothesized connection between the clinical phenomena and their reported psychophysiological substrates been tested. In this investigation, a structured interview instrument was developed to measure perceptual anomalies as distinct from hallucinations and to determine their prevalence across sensory modalities in schizophrenia in 67 schizophrenia subjects and 98 normal controls. The instrument includes Likert ratings of hypersensitivity, inundation, and selective attention to external sensory stimuli. Good interrater agreement, determined from interviews, was obtained. Schizophrenia subjects had significantly higher auditory, visual, and combined scores (i.e., across all modalities) than normal controls did, indicating significantly more perceptual anomalies. For the schizophrenia group, the prevalence of auditory and visual anomalies was significantly greater than the other sensory modalities. The data indicate that the putative phenomenological correlates of sensory gating may be reliably measured and tested with the Structured Interview for Assessing Perceptual Anomalies.

Published
1999

14. Is P50 suppression a measure of sensory gating in schizophrenia?

Author

Jin, Y, Bunney, WE, Sandman, CA, Patterson, JV, Fleming, K, Moenter, JR, Kalali, AH, Hetrick, WP, and Potkin, SG

Subjects
Humans, Hallucinations, Acoustic Stimulation, Schizophrenia, Schizophrenic Psychology, Evoked Potentials, Auditory, Adult, Female, Male, Reflex, Startle, schizophrenia, sensory gating, P50, perceptual anomaly, Evoked Potentials, Auditory, Reflex, Startle, Startle Reaction, Biological Sciences, Psychology and Cognitive Sciences, Medical and Health Sciences, Psychiatry
Abstract

BackgroundAbnormal P50 response has been hypothesized to reflect the sensory gating deficit in schizophrenia. Despite the extensive literature concerning the sensory filtering or gating deficit in schizophrenia, no evidence has been provided to test the relationship of the P50 phenomenon with patients' experiences of perceptual anomalies.MethodsSixteen drug-free DSM-IV diagnosed schizophrenic patients who reported moderate to severe perceptual anomalies in the auditory or visual modality were examined as compared to 16 schizophrenic patients who did not report perceptual anomalies, and 16 normal subjects. Both control groups were age- and gender-matched with the study group.ResultsPatients reporting perceptual anomalies exhibited P50 patterns that did not differ from normal subjects. In contrast, patients who did not report perceptual anomalies showed the abnormal P50 ratios previously found to be associated with schizophrenia.ConclusionsThese paradoxical findings do not support the hypothetical relationship between the P50 and behavioral measures of sensory gating, suggesting that additional studies are needed to further explore the clinical correlates of the P50.

Published
1998

15. Effects of P50 temporal variability on sensory gating in schizophrenia.

Author

Jin, Y, Potkin, SG, Patterson, JV, Sandman, CA, Hetrick, WP, and Bunney, WE

Subjects
Cerebral Cortex, Humans, Electroencephalography, Arousal, Attention, Reaction Time, Schizophrenia, Evoked Potentials, Auditory, Reference Values, Signal Processing, Computer-Assisted, Adult, Female, Male, P50, latency, variability, jitter, schizophrenia, gating, Evoked Potentials, Auditory, Signal Processing, Computer-Assisted, Psychiatry, Medical and Health Sciences, Psychology and Cognitive Sciences
Abstract

The conditioning-testing (S1-S2) P50 auditory evoked potential (EP) has been well-documented and accepted as an important tool for measuring sensory gating in schizophrenia research. However, the physiological mechanism of the phenomenon is not known. In this study a single-trial analysis was used to determine the influence of the latency variability of the responses in the formation of the averaged P50. Ten schizophrenic patients and 10 normal controls were tested in the dual-click EP paradigm. Using ensemble averaging analysis, we replicated the previous finding of a lower S1 P50 amplitude and higher S2/S1 ratio in schizophrenics compared with normal controls. The single-trial analysis revealed that patients had significantly higher trial-to-trial latency variability in S1 responses than normal subjects, while the S2 showed the same variability as in controls. Measured by the single-trial procedure, the arithmetic mean amplitudes of P50 responses to S1 and S2 were similar between normal and schizophrenic subjects. The same measure also eliminated the difference in averaged P50 amplitude between S1 and S2 for both groups. Temporal variability appears to be an important factor in the assessment of averaged EPs and thus contribute to the change of P50 amplitude observed in schizophrenia.

Published
1997

16. Electroencephalographic photic driving in patients with schizophrenia and depression.

Author

Jin, Y, Potkin, SG, Sandman, CA, and Bunney, WE

Subjects
Humans, Electroencephalography, Alpha Rhythm, Photic Stimulation, Depressive Disorder, Schizophrenia, Schizophrenic Psychology, Adult, Middle Aged, Female, Male, electroencephalography, photic driving, harmonic, schizophrenia, depression, normal, Biological Sciences, Psychology and Cognitive Sciences, Medical and Health Sciences, Psychiatry
Published
1997

17. Gender differences in gating of the auditory evoked potential in normal subjects.

Author

Hetrick, WP, Sandman, CA, Bunney, WE, Jin, Y, Potkin, SG, and White, MH

Subjects
Cerebral Cortex, Humans, Electroencephalography, Attention, Reaction Time, Sex Factors, Evoked Potentials, Auditory, Neural Inhibition, Reference Values, Signal Processing, Computer-Assisted, Adolescent, Adult, Female, Male, auditory gating, gender, P50, event-related potentials, Evoked Potentials, Auditory, Signal Processing, Computer-Assisted, Psychiatry, Biological Sciences, Psychology and Cognitive Sciences, Medical and Health Sciences
Abstract

Central nervous system (CNS) inhibitory mechanisms hypothesized to "gate" repetitive sensory inputs have been implicated in the pathology of schizophrenia. The present study investigated gender differences in inhibitory gating of evoked brain responses to repeated stimuli in normal subjects (30 women and 30 men) using an auditory conditioning-testing paradigm. Pairs of click stimuli (S1 and S2) were presented with a 0.5 s intrapair and a 10 s interpair interval. The amplitudes and latencies of the P50, N100, P180 components of the auditory evoked response to the conditioning (S1) and test response (S2) were measured, and the gating ratios were computed (T/C ratio = S2/S1 * 100). The amplitudes to S1 were not significantly different between men and women at P50, N100, or P180. However, women had significantly higher amplitudes to S2 at P50 (p = 0.03) and N100 (p = 0.04). The T/C ratios for women were higher (i.e., less suppression of response to S2) for P50 (p = 0.08) and N100 (p = 0.04) compared to men. The results suggested that differences in auditory gating between men and women were not due to biological differences in the P50 and N100 generators but possibly to differential influence of inhibitory mechanisms acting on the generator substrates of these evoked responses.

Published
1996

18. 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, Hulshoff Pol, HE, Kahn, RS, Ayesa-Arriola, R, Ortiz-García de la Foz, V, Tordesillas-Gutierrez, D, Vázquez-Bourgon, J, Crespo-Facorro, B, Alnæs, D, Dahl, A, Westlye, LT, Agartz, I, Andreassen, OA, Jönsson, EG, Kochunov, P, Bruggemann, JM, Catts, SV, Michie, PT, Mowry, BJ, Quidé, Y, Rasser, PE, Schall, U, Scott, RJ, Carr, VJ ; https://orcid.org/0000-0002-8907-5804, Green, MJ ; https://orcid.org/0000-0002-9361-4874, Henskens, FA, Loughland, CM, Pantelis, C, Weickert, CS ; https://orcid.org/0000-0002-4560-0259, Weickert, TW, de Haan, L, Brosch, K, Pfarr, JK, Ringwald, KG, Stein, F, Jansen, A, Kircher, TTJ, Nenadić, I, Krämer, 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, Sarró, 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, WS, Chung, YC, 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, Quide, Yann ; https://orcid.org/0000-0002-8569-7139, Schijven, D, Postema, MC, Fukunaga, M, Matsumoto, J, Miura, K, de Zwarte, SMC, van Haren, NEM, Cahn, W, Hulshoff Pol, HE, Kahn, RS, Ayesa-Arriola, R, Ortiz-García de la Foz, V, Tordesillas-Gutierrez, D, Vázquez-Bourgon, J, Crespo-Facorro, B, Alnæs, D, Dahl, A, Westlye, LT, Agartz, I, Andreassen, OA, Jönsson, EG, Kochunov, P, Bruggemann, JM, Catts, SV, Michie, PT, Mowry, BJ, Quidé, Y, Rasser, PE, Schall, U, Scott, RJ, Carr, VJ ; https://orcid.org/0000-0002-8907-5804, Green, MJ ; https://orcid.org/0000-0002-9361-4874, Henskens, FA, Loughland, CM, Pantelis, C, Weickert, CS ; https://orcid.org/0000-0002-4560-0259, Weickert, TW, de Haan, L, Brosch, K, Pfarr, JK, Ringwald, KG, Stein, F, Jansen, A, Kircher, TTJ, Nenadić, I, Krämer, 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, Sarró, 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, WS, Chung, YC, 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, and Quide, Yann ; https://orcid.org/0000-0002-8569-7139

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

19. Clozapine increases EEG photic driving in clinical responders.

Author

Jin, Y, Potkin, SG, and Sandman, C

Subjects
Thalamus, Cerebral Cortex, Humans, Clozapine, Electroencephalography, Alpha Rhythm, Photic Stimulation, Arousal, Schizophrenia, Psychiatric Status Rating Scales, Schizophrenic Psychology, Evoked Potentials, Visual, Dose-Response Relationship, Drug, Adult, Female, Male, Evoked Potentials, Visual, Dose-Response Relationship, Drug, Mental Health, Neurosciences, Brain Disorders, Psychiatry, Medical and Health Sciences, Psychology and Cognitive Sciences
Abstract

Photically driven electroencephalography was tested in 17 chronic schizophrenia patients who were treated with clozapine for 5 weeks. Eight of the 17 patients showed clinical improvement on the Brief Psychiatric Rating Scale (delta BPRS > 30%) while the other 9 patients remained unchanged (delta BPRS < 15%). In comparison with the nonresponders, clozapine responders had a significantly greater increase in photic driving in the electroencephalogram (EEG), primarily in the low-frequency range of alpha band (7.2 hertz [Hz], 8.3 Hz, 9.0 Hz, and 9.6 Hz, but not 12.0 Hz). The difference in the resting EEG between the responders and nonresponders did not reach statistical significance. These findings suggested that EEG photic driving might be more sensitive than the resting EEG in detecting the central nervous system drug effect. Further analysis revealed that the increase of EEG photic driving was positively correlated with patients' clinical improvement. Combined with our previous observation in the drug-free schizophrenia patients who had lower EEG photic driving, present results supported the hypothesis that the amount of EEG alpha activity, particularly its synchronization to the external stimuli, could reflect the thalamic function in sensory information processing in schizophrenia.

Published
1995

20. Abnormal EEG responses to photic stimulation in schizophrenic patients.

Author

Jin, Y, Potkin, SG, Rice, D, Sramek, J, Costa, J, Isenhart, R, Heh, C, and Sandman, CA

Subjects
Medical Physiology, Biomedical and Clinical Sciences, Mental Health, Neurodegenerative, Adult, Arousal, Cerebral Cortex, Electroencephalography, Evoked Potentials, Visual, Humans, Male, Photic Stimulation, Schizophrenia, Schizophrenic Psychology, Signal Processing, Computer-Assisted, Visual Perception, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Clinical sciences
Abstract

Numerous studies have differentiated schizophrenic patients and normal controls in electroencephalography (EEG) spectral patterns recorded at rest. We replicated the resting EEG spectral differences between these groups and observed significant differences in periodic photic stimuli on the EEG spectra. Drug-free schizophrenic male patients (n = 8, mean age = 23.9) and normal male controls (n = 11, mean age = 24.3) were studied. Eighty seconds of EEG were collected from each subject for each of four experimental conditions: one resting and three photic-driving conditions (2.38, 4.54, and 8.33 Hz). Eye movement and other movement artifacts were minimized by use of an automatic amplitude threshold filter. Although large eye movements could be excluded as confounding factors, the filter could not for certain exclude small eye movements. Subjects were instructed to keep their eyes closed throughout. A significant difference was found between the groups both at rest and following photic stimulation in EEG activity. This result was characterized by increased delta activity and decreased alpha activity in schizophrenic patients at rest. The EEG activity following the photic driving also differentiated the groups. Schizophrenic patients had decreased sensitivity to the photic stimulation in the alpha range for spectra derived from both fundamental and harmonic analysis.

Published
1990

21. Subcortical volumes across the lifespan: Data from 18,605 healthy individuals aged 3-90 years

Author

Dima, D, Modabbernia, A, Papachristou, E, Doucet, GE, Agartz, I, Aghajani, M, Akudjedu, TN, Albajes-Eizagirre, A, Alnaes, D, Alpert, K, Andersson, M, Andreasen, NC, Andreassen, OA, Asherson, P, Banaschewski, T, Bargallo, N, Baumeister, S, Baur-Streubel, R, Bertolino, A, Bonvino, A, Boomsma, D, Borgwardt, S, Bourque, J, Brandeis, D, Breier, A, Brodaty, H, Brouwer, RM, Buitelaar, JK, Busatto, GF, Buckner, RL, Calhoun, V, Canales-Rodriguez, EJ, Cannon, DM, Caseras, X, Castellanos, FX, Cervenka, S, Chaim-Avancini, TM, Ching, CRK, Chubar, V, Clark, VP, Conrod, P, Conzelmann, A, Crespo-Facorro, B, Crivello, F, Crone, EA, Dale, AM, Davey, C, de Geus, EJC, de Haan, L, de Zubicaray, G, den Braber, A, Dickie, EW, Di Giorgio, A, Nhat, TD, Dorum, ES, Ehrlich, S, Erk, S, Espeseth, T, Fatouros-Bergman, H, Fisher, SE, Fouche, J-P, Franke, B, Frodl, T, Fuentes-Claramonte, P, Glahn, DC, Gotlib, IH, Grabe, H-J, Grimm, O, Groenewold, NA, Grotegerd, D, Gruber, O, Gruner, P, Gur, RE, Gur, RC, Harrison, BJ, Hartman, CA, Hatton, SN, Heinz, A, Heslenfeld, DJ, Hibar, DP, Hickie, IB, Ho, B-C, Hoekstra, PJ, Hohmann, S, Holmes, AJ, Hoogman, M, Hosten, N, Howells, FM, Pol, HEH, Huyser, C, Jahanshad, N, James, A, Jernigan, TL, Jiang, J, Jonsson, EG, Joska, JA, Kahn, R, Kalnin, A, Kanai, R, Klein, M, Klyushnik, TP, Koenders, L, Koops, S, Kraemer, B, Kuntsi, J, Lagopoulos, J, Lazaro, L, Lebedeva, I, Lee, WH, Lesch, K-P, Lochner, C, Machielsen, MWJ, Maingault, S, Martin, NG, Martinez-Zalacain, I, Mataix-Cols, D, Mazoyer, B, McDonald, C, McDonald, BC, McIntosh, AM, McMahon, KL, McPhilemy, G, Menchon, JM, Medland, SE, Meyer-Lindenberg, A, Naaijen, J, Najt, P, Nakao, T, Nordvik, JE, Nyberg, L, Oosterlaan, J, Ortiz-Garcia De la Foz, V, Paloyelis, Y, Pauli, P, Pergola, G, Pomarol-Clotet, E, Portella, MJ, Potkin, SG, Radua, J, Reif, A, Rinker, DA, Roffman, JL, Rosa, PGP, Sacchet, MD, Sachdev, PS, Salvador, R, Sanchez-Juan, P, Sarro, S, Satterthwaite, TD, Saykin, AJ, Serpa, MH, Schmaal, L, Schnell, K, Schumann, G, Sim, K, Smoller, JW, Sommer, I, Soriano-Mas, C, Stein, DJ, Strike, LT, Swagerman, SC, Tamnes, CK, Temmingh, HS, Thomopoulos, S, Tomyshev, AS, Tordesillas-Gutierrez, D, Trollor, JN, Turner, JA, Uhlmann, A, van den Heuvel, OA, van den Meer, D, van der Wee, NJA, van Haren, NEM, Van't Ent, D, van Erp, TGM, Veer, IM, Veltman, DJ, Voineskos, A, Voelzke, H, Walter, H, Walton, E, Wang, L, Wang, Y, Wassink, TH, Weber, B, Wen, W, West, JD, Westlye, LT, Whalley, H, Wierenga, LM, Williams, SCR, Wittfeld, K, Wolf, DH, Worker, A, Wright, MJ, Yang, K, Yoncheva, Y, Zanetti, M, Ziegler, GC, Thompson, PM, Frangou, S, Dima, D, Modabbernia, A, Papachristou, E, Doucet, GE, Agartz, I, Aghajani, M, Akudjedu, TN, Albajes-Eizagirre, A, Alnaes, D, Alpert, K, Andersson, M, Andreasen, NC, Andreassen, OA, Asherson, P, Banaschewski, T, Bargallo, N, Baumeister, S, Baur-Streubel, R, Bertolino, A, Bonvino, A, Boomsma, D, Borgwardt, S, Bourque, J, Brandeis, D, Breier, A, Brodaty, H, Brouwer, RM, Buitelaar, JK, Busatto, GF, Buckner, RL, Calhoun, V, Canales-Rodriguez, EJ, Cannon, DM, Caseras, X, Castellanos, FX, Cervenka, S, Chaim-Avancini, TM, Ching, CRK, Chubar, V, Clark, VP, Conrod, P, Conzelmann, A, Crespo-Facorro, B, Crivello, F, Crone, EA, Dale, AM, Davey, C, de Geus, EJC, de Haan, L, de Zubicaray, G, den Braber, A, Dickie, EW, Di Giorgio, A, Nhat, TD, Dorum, ES, Ehrlich, S, Erk, S, Espeseth, T, Fatouros-Bergman, H, Fisher, SE, Fouche, J-P, Franke, B, Frodl, T, Fuentes-Claramonte, P, Glahn, DC, Gotlib, IH, Grabe, H-J, Grimm, O, Groenewold, NA, Grotegerd, D, Gruber, O, Gruner, P, Gur, RE, Gur, RC, Harrison, BJ, Hartman, CA, Hatton, SN, Heinz, A, Heslenfeld, DJ, Hibar, DP, Hickie, IB, Ho, B-C, Hoekstra, PJ, Hohmann, S, Holmes, AJ, Hoogman, M, Hosten, N, Howells, FM, Pol, HEH, Huyser, C, Jahanshad, N, James, A, Jernigan, TL, Jiang, J, Jonsson, EG, Joska, JA, Kahn, R, Kalnin, A, Kanai, R, Klein, M, Klyushnik, TP, Koenders, L, Koops, S, Kraemer, B, Kuntsi, J, Lagopoulos, J, Lazaro, L, Lebedeva, I, Lee, WH, Lesch, K-P, Lochner, C, Machielsen, MWJ, Maingault, S, Martin, NG, Martinez-Zalacain, I, Mataix-Cols, D, Mazoyer, B, McDonald, C, McDonald, BC, McIntosh, AM, McMahon, KL, McPhilemy, G, Menchon, JM, Medland, SE, Meyer-Lindenberg, A, Naaijen, J, Najt, P, Nakao, T, Nordvik, JE, Nyberg, L, Oosterlaan, J, Ortiz-Garcia De la Foz, V, Paloyelis, Y, Pauli, P, Pergola, G, Pomarol-Clotet, E, Portella, MJ, Potkin, SG, Radua, J, Reif, A, Rinker, DA, Roffman, JL, Rosa, PGP, Sacchet, MD, Sachdev, PS, Salvador, R, Sanchez-Juan, P, Sarro, S, Satterthwaite, TD, Saykin, AJ, Serpa, MH, Schmaal, L, Schnell, K, Schumann, G, Sim, K, Smoller, JW, Sommer, I, Soriano-Mas, C, Stein, DJ, Strike, LT, Swagerman, SC, Tamnes, CK, Temmingh, HS, Thomopoulos, S, Tomyshev, AS, Tordesillas-Gutierrez, D, Trollor, JN, Turner, JA, Uhlmann, A, van den Heuvel, OA, van den Meer, D, van der Wee, NJA, van Haren, NEM, Van't Ent, D, van Erp, TGM, Veer, IM, Veltman, DJ, Voineskos, A, Voelzke, H, Walter, H, Walton, E, Wang, L, Wang, Y, Wassink, TH, Weber, B, Wen, W, West, JD, Westlye, LT, Whalley, H, Wierenga, LM, Williams, SCR, Wittfeld, K, Wolf, DH, Worker, A, Wright, MJ, Yang, K, Yoncheva, Y, Zanetti, M, Ziegler, GC, Thompson, PM, and Frangou, S

Abstract

Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resources of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to examine age-related trajectories inferred from cross-sectional measures of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3-90 years. All subcortical structure volumes were at their maximum value early in life. The volume of the basal ganglia showed a monotonic negative association with age thereafter; there was no significant association between age and the volumes of the thalamus, amygdala and the hippocampus (with some degree of decline in thalamus) until the sixth decade of life after which they also showed a steep negative association with age. The lateral ventricles showed continuous enlargement throughout the lifespan. Age was positively associated with inter-individual variability in the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to examine the functional significance of deviations from typical age-related morphometric patterns.

Published
2022

22. Cortical thickness across the lifespan: Data from 17,075 healthy individuals aged 3-90 years

Author

Frangou, S, Modabbernia, A, Williams, SCR, Papachristou, E, Doucet, GE, Agartz, I, Aghajani, M, Akudjedu, TN, Albajes-Eizagirre, A, Alnaes, D, Alpert, K, Andersson, M, Andreasen, NC, Andreassen, OA, Asherson, P, Banaschewski, T, Bargallo, N, Baumeister, S, Baur-Streubel, R, Bertolino, A, Bonvino, A, Boomsma, D, Borgwardt, S, Bourque, J, Brandeis, D, Breier, A, Brodaty, H, Brouwer, RM, Buitelaar, JK, Busatto, GF, Buckner, RL, Calhoun, V, Canales-Rodriguez, EJ, Cannon, DM, Caseras, X, Castellanos, FX, Cervenka, S, Chaim-Avancini, TM, Ching, CRK, Chubar, V, Clark, VP, Conrod, P, Conzelmann, A, Crespo-Facorro, B, Crivello, F, Crone, EA, Dale, AM, Davey, C, de Geus, EJC, de Haan, L, de Zubicaray, G, den Braber, A, Dickie, EW, Di Giorgio, A, Nhat, TD, Dorum, ES, Ehrlich, S, Erk, S, Espeseth, T, Fatouros-Bergman, H, Fisher, SE, Fouche, J-P, Franke, B, Frodl, T, Fuentes-Claramonte, P, Glahn, DC, Gotlib, IH, Grabe, H-J, Grimm, O, Groenewold, NA, Grotegerd, D, Gruber, O, Gruner, P, Gur, RE, Gur, RC, Harrison, BJ, Hartman, CA, Hatton, SN, Heinz, A, Heslenfeld, DJ, Hibar, DP, Hickie, IB, Ho, B-C, Hoekstra, PJ, Hohmann, S, Holmes, AJ, Hoogman, M, Hosten, N, Howells, FM, Pol, HEH, Huyser, C, Jahanshad, N, James, A, Jernigan, TL, Jiang, J, Jonsson, EG, Joska, JA, Kahn, R, Kalnin, A, Kanai, R, Klein, M, Klyushnik, TP, Koenders, L, Koops, S, Kraemer, B, Kuntsi, J, Lagopoulos, J, Lazaro, L, Lebedeva, I, Lee, WH, Lesch, K-P, Lochner, C, Machielsen, MWJ, Maingault, S, Martin, NG, Martinez-Zalacain, I, Mataix-Cols, D, Mazoyer, B, McDonald, C, McDonald, BC, McIntosh, AM, McMahon, KL, McPhilemy, G, Menchon, JM, Medland, SE, Meyer-Lindenberg, A, Naaijen, J, Najt, P, Nakao, T, Nordvik, JE, Nyberg, L, Oosterlaan, J, de la Foz, VO-G, Paloyelis, Y, Pauli, P, Pergola, G, Pomarol-Clotet, E, Portella, MJ, Potkin, SG, Radua, J, Reif, A, Rinker, DA, Roffman, JL, Rosa, PGP, Sacchet, MD, Sachdev, PS, Salvador, R, Sanchez-Juan, P, Sarro, S, Satterthwaite, TD, Saykin, AJ, Serpa, MH, Schmaal, L, Schnell, K, Schumann, G, Sim, K, Smoller, JW, Sommer, I, Soriano-Mas, C, Stein, DJ, Strike, LT, Swagerman, SC, Tamnes, CK, Temmingh, HS, Thomopoulos, S, Tomyshev, AS, Tordesillas-Gutierrez, D, Trollor, JN, Turner, JA, Uhlmann, A, van den Heuvel, OA, van den Meer, D, van der Wee, NJA, van Haren, NEM, van't Ent, D, van Erp, TGM, Veer, IM, Veltman, DJ, Voineskos, A, Voelzke, H, Walter, H, Walton, E, Wang, L, Wang, Y, Wassink, TH, Weber, B, Wen, W, West, JD, Westlye, LT, Whalley, H, Wierenga, LM, Wittfeld, K, Wolf, DH, Worker, A, Wright, MJ, Yang, K, Yoncheva, Y, Zanetti, M, Ziegler, GC, Thompson, PM, Dima, D, Frangou, S, Modabbernia, A, Williams, SCR, Papachristou, E, Doucet, GE, Agartz, I, Aghajani, M, Akudjedu, TN, Albajes-Eizagirre, A, Alnaes, D, Alpert, K, Andersson, M, Andreasen, NC, Andreassen, OA, Asherson, P, Banaschewski, T, Bargallo, N, Baumeister, S, Baur-Streubel, R, Bertolino, A, Bonvino, A, Boomsma, D, Borgwardt, S, Bourque, J, Brandeis, D, Breier, A, Brodaty, H, Brouwer, RM, Buitelaar, JK, Busatto, GF, Buckner, RL, Calhoun, V, Canales-Rodriguez, EJ, Cannon, DM, Caseras, X, Castellanos, FX, Cervenka, S, Chaim-Avancini, TM, Ching, CRK, Chubar, V, Clark, VP, Conrod, P, Conzelmann, A, Crespo-Facorro, B, Crivello, F, Crone, EA, Dale, AM, Davey, C, de Geus, EJC, de Haan, L, de Zubicaray, G, den Braber, A, Dickie, EW, Di Giorgio, A, Nhat, TD, Dorum, ES, Ehrlich, S, Erk, S, Espeseth, T, Fatouros-Bergman, H, Fisher, SE, Fouche, J-P, Franke, B, Frodl, T, Fuentes-Claramonte, P, Glahn, DC, Gotlib, IH, Grabe, H-J, Grimm, O, Groenewold, NA, Grotegerd, D, Gruber, O, Gruner, P, Gur, RE, Gur, RC, Harrison, BJ, Hartman, CA, Hatton, SN, Heinz, A, Heslenfeld, DJ, Hibar, DP, Hickie, IB, Ho, B-C, Hoekstra, PJ, Hohmann, S, Holmes, AJ, Hoogman, M, Hosten, N, Howells, FM, Pol, HEH, Huyser, C, Jahanshad, N, James, A, Jernigan, TL, Jiang, J, Jonsson, EG, Joska, JA, Kahn, R, Kalnin, A, Kanai, R, Klein, M, Klyushnik, TP, Koenders, L, Koops, S, Kraemer, B, Kuntsi, J, Lagopoulos, J, Lazaro, L, Lebedeva, I, Lee, WH, Lesch, K-P, Lochner, C, Machielsen, MWJ, Maingault, S, Martin, NG, Martinez-Zalacain, I, Mataix-Cols, D, Mazoyer, B, McDonald, C, McDonald, BC, McIntosh, AM, McMahon, KL, McPhilemy, G, Menchon, JM, Medland, SE, Meyer-Lindenberg, A, Naaijen, J, Najt, P, Nakao, T, Nordvik, JE, Nyberg, L, Oosterlaan, J, de la Foz, VO-G, Paloyelis, Y, Pauli, P, Pergola, G, Pomarol-Clotet, E, Portella, MJ, Potkin, SG, Radua, J, Reif, A, Rinker, DA, Roffman, JL, Rosa, PGP, Sacchet, MD, Sachdev, PS, Salvador, R, Sanchez-Juan, P, Sarro, S, Satterthwaite, TD, Saykin, AJ, Serpa, MH, Schmaal, L, Schnell, K, Schumann, G, Sim, K, Smoller, JW, Sommer, I, Soriano-Mas, C, Stein, DJ, Strike, LT, Swagerman, SC, Tamnes, CK, Temmingh, HS, Thomopoulos, S, Tomyshev, AS, Tordesillas-Gutierrez, D, Trollor, JN, Turner, JA, Uhlmann, A, van den Heuvel, OA, van den Meer, D, van der Wee, NJA, van Haren, NEM, van't Ent, D, van Erp, TGM, Veer, IM, Veltman, DJ, Voineskos, A, Voelzke, H, Walter, H, Walton, E, Wang, L, Wang, Y, Wassink, TH, Weber, B, Wen, W, West, JD, Westlye, LT, Whalley, H, Wierenga, LM, Wittfeld, K, Wolf, DH, Worker, A, Wright, MJ, Yang, K, Yoncheva, Y, Zanetti, M, Ziegler, GC, Thompson, PM, and Dima, D

Abstract

Delineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large-scale studies. In response, we used cross-sectional data from 17,075 individuals aged 3-90 years from the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to infer age-related changes in cortical thickness. We used fractional polynomial (FP) regression to quantify the association between age and cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma method. Interindividual variability was estimated using meta-analysis and one-way analysis of variance. For most regions, their highest cortical thickness value was observed in childhood. Age and cortical thickness showed a negative association; the slope was steeper up to the third decade of life and more gradual thereafter; notable exceptions to this general pattern were entorhinal, temporopolar, and anterior cingulate cortices. Interindividual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results may form the basis of further investigation on normative deviation in cortical thickness and its significance for behavioral and cognitive outcomes.

Published
2022

23. EEG alpha photic driving abnormalities in chronic schizophrenia.

Author

Rice, DM, Potkin, SG, Jin, Y, Isenhart, R, Heh, CW, Sramek, J, Costa, J, and Sandman, CA

Subjects
Thalamic Nuclei, Cerebral Cortex, Humans, Chronic Disease, Electroencephalography, Alpha Rhythm, Photic Stimulation, Visual Perception, Arousal, Schizophrenia, Schizophrenic Psychology, Signal Processing, Computer-Assisted, Adult, Male, Signal Processing, Computer-Assisted, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

Periodic photic stimuli across the entire electroencephalographic (EEG) frequency range were used in an attempt to assess EEG functional differences between chronic schizophrenic patients and control subjects. The EEG responses to these photic stimuli were significantly attenuated in the schizophrenic patients, specifically at the frequencies within the EEG alpha range. The schizophrenic patients also showed an alpha range attenuation in the "no stimulus" EEG alpha measure, such that there was a significant correlation across subjects between the "stimulus" and "no stimulus" EEG alpha range abnormalities. These abnormalities are discussed with reference to possible dysfunctional thalamic mechanisms involved in the pacing of EEG alpha activity and the gating of information through the cerebral cortex.

Published
1989

24. 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 ; https://orcid.org/0000-0003-4014-4490, Green, MJ ; https://orcid.org/0000-0002-9361-4874, 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 ; https://orcid.org/0000-0002-4560-0259, Weickert, TW ; https://orcid.org/0000-0002-6408-718X, 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, Quide, Yann ; https://orcid.org/0000-0002-8569-7139, 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 ; https://orcid.org/0000-0003-4014-4490, Green, MJ ; https://orcid.org/0000-0002-9361-4874, 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 ; https://orcid.org/0000-0002-4560-0259, Weickert, TW ; https://orcid.org/0000-0002-6408-718X, 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, and Quide, Yann ; https://orcid.org/0000-0002-8569-7139

Published
2019

25. y Long-term effectiveness of aripiprazole once-monthly for schizophrenia is maintained in the QUALIFY extension study

Author

Naber, D, Baker, RA, Eramo, A, Forray, C, Hansen, K, Sapin, C, Peters-Strickland, T, Nylander, A-G, Hertel, P, Schmidt, SN, Loze, J-Y, and Potkin, SG

Subjects
Quality of life, Maintenance treatment, Schizophrenia, Aripiprazole once-monthly
Abstract

To evaluate long-term safety and effectiveness of continued treatment with aripiprazole once-monthly 400mg (AOM 400) in patients with schizophrenia.Patients who completed the QUALIFY study (NCT01795547) in the AOM 400 arm were eligible for 6 additional once-monthly injections of AOM 400 during an open-label, 24-week extension (NCT01959035). Safety data were collected at each visit. Effectiveness measures included change from baseline in health-related qualify of life and functioning on the Heinrichs-Carpenter Quality of Life scale (QLS) and Clinical Global Impression - Severity (CGI-S) scale.Of the 88 patients enrolled, 77 (88%) completed the extension study. Most common treatment-emergent adverse events (incidence ≥2%) were weight increased (6/88, 7%), toothache (3/88, 3%) and headache (3/88, 3%). Effectiveness was maintained during the extension study, with small but continued improvements from baseline: the least squares mean (LSM) change (95% CI) from baseline to week 24 was 2.32 (-1.21 to 5.85) for the QLS total score and -0.10 (-0.26 to 0.06) for the CGI-S score. The aggregated LSM change (95% CI) from baseline of the lead-in study to week 24 of the extension study was 11.54 (7.45 to 15.64) for the QLS total score and -0.98 (-1.18 to -0.79) for the CGI-S score.AOM 400 was well tolerated in patients continuing AOM treatment during the extension phase of the QUALIFY study. Robust and clinically meaningful improvements in health-related quality of life and functioning were maintained, further supporting the long-term clinical benefits of AOM 400 for the treatment of patients with schizophrenia.

Published
2018
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26. 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 ; https://orcid.org/0000-0002-8907-5804, Catts, S, Cropley, VL, Fullerton, JM ; https://orcid.org/0000-0003-4014-4490, Green, MJ ; https://orcid.org/0000-0002-9361-4874, Henskens, FA, Jablensky, A, Lenroot, RK ; https://orcid.org/0000-0002-0949-5121, 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 ; https://orcid.org/0000-0002-4560-0259, Weickert, TW ; https://orcid.org/0000-0002-6408-718X, 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, Quide, Yann ; https://orcid.org/0000-0002-8569-7139, 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 ; https://orcid.org/0000-0002-8907-5804, Catts, S, Cropley, VL, Fullerton, JM ; https://orcid.org/0000-0003-4014-4490, Green, MJ ; https://orcid.org/0000-0002-9361-4874, Henskens, FA, Jablensky, A, Lenroot, RK ; https://orcid.org/0000-0002-0949-5121, 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 ; https://orcid.org/0000-0002-4560-0259, Weickert, TW ; https://orcid.org/0000-0002-6408-718X, 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, and Quide, Yann ; https://orcid.org/0000-0002-8569-7139

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

27. 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, KK, 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, Pol, HEH, Hyde, CL, Isaev, D, Jablensky, A, Jansen, PR, Janssen, J, Jonsson, EG, Jung, LA, Kahn, RS, Kikinis, Z, Liu, K, Klauser, P, Knoechel, 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, R, Michie, PT, Mowry, B, Mueller, BA, Newell, DT, O'Donnell, P, Oertel-Knoechel, V, Oestreich, L, Paciga, SA, Pantelis, C, Pasternak, O, Pearlson, G, Pellicano, GR, Pereira, A, Zapata, JP, Piras, F, Potkin, SG, Preda, A, Rasser, PE, Roalf, DR, Roiz, R, Roos, A, Rotenberg, D, Satterthwaite, TD, Savadjiev, P, Schall, U, Scott, RJ, Seal, ML, Seidman, LJ, Weickert, CS, Whelan, CD, Shenton, ME, Kwon, JS, Spalletta, G, Spaniel, F, Sprooten, E, Stablein, M, Stein, DJ, Sundram, S, Tan, Y, Tan, S, Tang, S, Temmingh, HS, Westlye, LT, Tonnesen, S, Tordesillas-Gutierrez, D, Doan, NT, Vaidya, J, van Haren, NEM, Vargas, CD, Vecchio, D, Velakoulis, D, Voineskos, A, Voyvodic, JQ, Wang, Z, Wan, P, Wei, D, Weickert, TW, Whalley, H, White, T, Whitford, TJ, Wojcik, JD, Xiang, H, Xie, Z, Yamamori, H, Yang, F, Yao, N, Zhang, G, Zhao, J, van Erp, TGM, Turner, J, Thompson, PM, Donohoe, G, 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, KK, 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, Pol, HEH, Hyde, CL, Isaev, D, Jablensky, A, Jansen, PR, Janssen, J, Jonsson, EG, Jung, LA, Kahn, RS, Kikinis, Z, Liu, K, Klauser, P, Knoechel, 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, R, Michie, PT, Mowry, B, Mueller, BA, Newell, DT, O'Donnell, P, Oertel-Knoechel, V, Oestreich, L, Paciga, SA, Pantelis, C, Pasternak, O, Pearlson, G, Pellicano, GR, Pereira, A, Zapata, JP, Piras, F, Potkin, SG, Preda, A, Rasser, PE, Roalf, DR, Roiz, R, Roos, A, Rotenberg, D, Satterthwaite, TD, Savadjiev, P, Schall, U, Scott, RJ, Seal, ML, Seidman, LJ, Weickert, CS, Whelan, CD, Shenton, ME, Kwon, JS, Spalletta, G, Spaniel, F, Sprooten, E, Stablein, M, Stein, DJ, Sundram, S, Tan, Y, Tan, S, Tang, S, Temmingh, HS, Westlye, LT, Tonnesen, S, Tordesillas-Gutierrez, D, Doan, NT, Vaidya, J, van Haren, NEM, Vargas, CD, Vecchio, D, Velakoulis, D, Voineskos, A, Voyvodic, JQ, Wang, Z, Wan, P, Wei, D, Weickert, TW, Whalley, H, White, T, Whitford, TJ, Wojcik, JD, Xiang, H, Xie, Z, Yamamori, H, Yang, F, Yao, N, Zhang, G, Zhao, J, van Erp, TGM, Turner, J, Thompson, PM, and Donohoe, G

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

28. Go/No Go task performance predicts cortical thickness in the caudal inferior frontal gyrus in young adults with and without ADHD

Author

Newman, E, Jernigan, TL, Lisdahl, KM, Tamm, L, Tapert, SF, Potkin, SG, Mathalon, D, Molina, B, Bjork, J, Castellanos, FX, Swanson, J, Kuperman, JM, Bartsch, H, Chen, CH, Dale, AM, and Epstein, JN

Abstract

© 2015, Springer Science+Business Media New York. Response inhibition deficits are widely believed to be at the core of Attention-Deficit Hyperactivity Disorder (ADHD). Several studies have examined neural architectural correlates of ADHD, but research directly examining structural correlates of response inhibition is lacking. Here we examine the relationship between response inhibition as measured by a Go/No Go task, and cortical surface area and thickness of the caudal inferior frontal gyrus (cIFG), a region implicated in functional imaging studies of response inhibition, in a sample of 114 young adults with and without ADHD diagnosed initially during childhood. We used multiple linear regression models to test the hypothesis that Go/No Go performance would be associated with cIFG surface area or thickness. Results showed that poorer Go/No Go performance was associated with thicker cIFG cortex, and this effect was not mediated by ADHD status or history of substance use. However, independent of Go/No Go performance, persistence of ADHD symptoms and more frequent cannabis use were associated with thinner cIFG. Go/No Go performance was not associated with cortical surface area. The association between poor inhibitory functioning and thicker cIFG suggests that maturation of this region may differ in low performing participants. An independent association of persistent ADHD symptoms and frequent cannabis use with thinner cIFG cortex suggests that distinct neural mechanisms within this region may play a role in inhibitory function, broader ADHD symptomatology, and cannabis use. These results contribute to Research Domain Criteria (RDoC) by revealing novel associations between neural architectural phenotypes and basic neurobehavioral processes measured dimensionally.

Published
2016
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29. Erratum: Subcortical brain volume abnormalities in 2028 individuals with schizophrenia and 2540 healthy controls via the ENIGMA consortium (Molecular Psychiatry (2015) DOI:10.1038/mp.2015.63)

Author

Van Erp, TGM, Hibar, DP, Rasmussen, JM, Glahn, DC, Pearlson, GD, Andreassen, OA, Agartz, I, Westlye, LT, Haukvik, UK, Dale, AM, Melle, I, Hartberg, CB, Gruber, O, Kraemer, B, Zilles, D, Donohoe, G, Kelly, S, Mcdonald, C, Morris, DW, Cannon, DM, Corvin, A, Machielsen, MWJ, Koenders, L, De Haan, L, Veltman, DJ, Satterthwaite, TD, Wolf, DH, Gur, RC, Gur, RE, Potkin, SG, Mathalon, DH, Mueller, BA, Preda, A, Macciardi, F, Ehrlich, S, Walton, E, Hass, J, Calhoun, VD, Bockholt, HJ, Sponheim, SR, Shoemaker, JM, Van Haren, NEM, Pol, HEH, Ophoff, RA, Kahn, RS, Roiz-Santiañez, R, Crespo-Facorro, B, Wang, L, Alpert, KI, Jönsson, EG, Dimitrova, R, Bois, C, Whalley, HC, Mcintosh, AM, Lawrie, SM, Hashimoto, R, Thompson, PM, and Turner, JA

Published
2016
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30. Novel genetic loci associated with hippocampal volume

Author

Hibar, DP, Adams, HHH, Jahanshad, N, Chauhan, G, Stein, JL, Hofer, E, Renteria, ME, Bis, JC, Arias-Vasquez, A, Ikram, MK, Desrivieres, S, Vernooij, MW, Abramovic, L, Alhusaini, S, Amin, N, Andersson, M, Arfanakis, K, Aribisala, BS, Armstrong, NJ, Athanasiu, L, Axelsson, T, Beecham, AH, Beiser, A, Bernard, M, Blanton, SH, Bohlken, MM, Boks, MP, Bralten, J, Brickman, AM, Carmichael, O, Chakravarty, MM, Chen, Q, Ching, CRK, Chouraki, V, Cuellar-Partida, G, Crivello, F, Den Braber, A, Nhat, TD, Ehrlich, S, Giddaluru, S, Goldman, AL, Gottesman, RF, Grimm, O, Griswold, ME, Guadalupe, T, Gutman, BA, Hass, J, Haukvik, UK, Hoehn, D, Holmes, AJ, Hoogman, M, Janowitz, D, Jia, T, Jorgensen, KN, Karbalai, N, Kasperaviciute, D, Kim, S, Klein, M, Kraemer, B, Lee, PH, Liewald, DCM, Lopez, LM, Luciano, M, Macare, C, Marquand, AF, Matarin, M, Mather, KA, Mattheisen, M, McKay, DR, Milaneschi, Y, Maniega, SM, Nho, K, Nugent, AC, Nyquist, P, Loohuis, LMO, Oosterlaan, J, Papmeyer, M, Pirpamer, L, Puetz, B, Ramasamy, A, Richards, JS, Risacher, SL, Roiz-Santianez, R, Rommelse, N, Ropele, S, Rose, EJ, Royle, NA, Rundek, T, Saemann, PG, Saremi, A, Satizabal, CL, Schmaal, L, Schork, AJ, Shen, L, Shin, J, Shumskaya, E, Smith, AV, Sprooten, E, Strike, LT, Teumer, A, Tordesillas-Gutierrez, D, Toro, R, Trabzuni, D, Trompet, S, Vaidya, D, Van der Grond, J, Van der Lee, SJ, Van der Meer, D, Van Donkelaar, MMJ, Van Eijk, KR, Van Erp, TGM, Van Rooij, D, Walton, E, Westlye, LT, Whelan, CD, Windham, BG, Winkler, AM, Wittfeld, K, Woldehawariat, G, Wolf, C, Wolfers, T, Yanek, LR, Yang, J, Zijdenbos, A, Zwiers, MP, Agartz, I, Almasy, L, Ames, D, Amouyel, P, Andreassen, OA, Arepalli, S, Assareh, AA, Barral, S, Bastin, ME, Becker, DM, Becker, JT, Bennett, DA, Blangero, J, van Bokhoven, H, Boomsma, DI, Brodaty, H, Brouwer, RM, Brunner, HG, Buckner, RL, Buitelaar, JK, Bulayeva, KB, Cahn, W, Calhoun, VD, Cannon, DM, Cavalleri, GL, Cheng, C-Y, Cichon, S, Cookson, MR, Corvin, A, Crespo-Facorro, B, Curran, JE, Czisch, M, Dale, AM, Davies, GE, De Craen, AJM, De Geus, EJC, De Jager, PL, De Zubicaray, GI, Deary, IJ, Debette, S, DeCarli, C, Delanty, N, Depondt, C, DeStefano, A, Dillman, A, Djurovic, S, Donohoe, G, Drevets, WC, Duggirala, R, Dyer, TD, Enzinger, C, Erk, S, Espeseth, T, Fedko, IO, Fernandez, G, Ferrucci, L, Fisher, SE, Fleischman, DA, Ford, I, Fornage, M, Foroud, TM, Fox, PT, Francks, C, Fukunaga, M, Gibbs, JR, Glahn, DC, Gollub, RL, Goring, HHH, Green, RC, Gruber, O, Gudnason, V, Guelfi, S, Haberg, AK, Hansell, NK, Hardy, J, Hartman, CA, Hashimoto, R, Hegenscheid, K, Heinz, A, Le Hellard, S, Hernandez, DG, Heslenfeld, DJ, Ho, B-C, Hoekstra, PJ, Hoffmann, W, Hofman, A, Holsboer, F, Homuth, G, Hosten, N, Hottenga, J-J, Huentelman, M, Pol, HEH, Ikeda, M, Jack, CR, Jenkinson, M, Johnson, R, Joensson, EG, Jukema, JW, Kahn, RS, Kanai, R, Kloszewska, I, Knopman, DS, Kochunov, P, Kwok, JB, Lawrie, SM, Lemaitre, H, Liu, X, Longo, DL, Lopez, OL, Lovestone, S, Martinez, O, Martinot, J-L, Mattay, VS, McDonald, C, McIntosh, AM, McMahon, FJ, McMahon, KL, Mecocci, P, Melle, I, Meyer-Lindenberg, A, Mohnke, S, Montgomery, GW, Morris, DW, Mosley, TH, Muhleisen, TW, Mueller-Myhsok, B, Nalls, MA, Nauck, M, Nichols, TE, Niessen, WJ, Nothen, MM, Nyberg, L, Ohi, K, Olvera, RL, Ophoff, RA, Pandolfo, M, Paus, T, Pausova, Z, Penninx, BWJH, Pike, GB, Potkin, SG, Psaty, BM, Reppermund, S, Rietschel, M, Roffman, JL, Romanczuk-Seiferth, N, Rotter, JI, Ryten, M, Sacco, RL, Sachdev, PS, Saykin, AJ, Schmidt, R, Schmidt, H, Schofield, PR, Sigursson, S, Simmons, A, Singleton, A, Sisodiya, SM, Smith, C, Smoller, JW, Soininen, H, Steen, VM, Stott, DJ, Sussmann, JE, Thalamuthu, A, Toga, AW, Traynor, BJ, Troncoso, J, Tsolaki, M, Tzourio, C, Uitterlinden, AG, Hernandez, MCV, Van der Brug, M, van der Lugt, A, van der Wee, NJA, Van Haren, NEM, van't Ent, D, Van Tol, M-J, Vardarajan, BN, Vellas, B, Veltman, DJ, Voelzke, H, Walter, H, Wardlaw, JM, Wassink, TH, Weale, ME, Weinberger, DR, Weiner, MW, Wen, W, Westman, E, White, T, Wong, TY, Wright, CB, Zielke, RH, Zonderman, AB, Martin, NG, Van Duijn, CM, Wright, MJ, Longstreth, WT, Schumann, G, Grabe, HJ, Franke, B, Launer, LJ, Medland, SE, Seshadri, S, Thompson, PM, Ikram, MA, Hibar, DP, Adams, HHH, Jahanshad, N, Chauhan, G, Stein, JL, Hofer, E, Renteria, ME, Bis, JC, Arias-Vasquez, A, Ikram, MK, Desrivieres, S, Vernooij, MW, Abramovic, L, Alhusaini, S, Amin, N, Andersson, M, Arfanakis, K, Aribisala, BS, Armstrong, NJ, Athanasiu, L, Axelsson, T, Beecham, AH, Beiser, A, Bernard, M, Blanton, SH, Bohlken, MM, Boks, MP, Bralten, J, Brickman, AM, Carmichael, O, Chakravarty, MM, Chen, Q, Ching, CRK, Chouraki, V, Cuellar-Partida, G, Crivello, F, Den Braber, A, Nhat, TD, Ehrlich, S, Giddaluru, S, Goldman, AL, Gottesman, RF, Grimm, O, Griswold, ME, Guadalupe, T, Gutman, BA, Hass, J, Haukvik, UK, Hoehn, D, Holmes, AJ, Hoogman, M, Janowitz, D, Jia, T, Jorgensen, KN, Karbalai, N, Kasperaviciute, D, Kim, S, Klein, M, Kraemer, B, Lee, PH, Liewald, DCM, Lopez, LM, Luciano, M, Macare, C, Marquand, AF, Matarin, M, Mather, KA, Mattheisen, M, McKay, DR, Milaneschi, Y, Maniega, SM, Nho, K, Nugent, AC, Nyquist, P, Loohuis, LMO, Oosterlaan, J, Papmeyer, M, Pirpamer, L, Puetz, B, Ramasamy, A, Richards, JS, Risacher, SL, Roiz-Santianez, R, Rommelse, N, Ropele, S, Rose, EJ, Royle, NA, Rundek, T, Saemann, PG, Saremi, A, Satizabal, CL, Schmaal, L, Schork, AJ, Shen, L, Shin, J, Shumskaya, E, Smith, AV, Sprooten, E, Strike, LT, Teumer, A, Tordesillas-Gutierrez, D, Toro, R, Trabzuni, D, Trompet, S, Vaidya, D, Van der Grond, J, Van der Lee, SJ, Van der Meer, D, Van Donkelaar, MMJ, Van Eijk, KR, Van Erp, TGM, Van Rooij, D, Walton, E, Westlye, LT, Whelan, CD, Windham, BG, Winkler, AM, Wittfeld, K, Woldehawariat, G, Wolf, C, Wolfers, T, Yanek, LR, Yang, J, Zijdenbos, A, Zwiers, MP, Agartz, I, Almasy, L, Ames, D, Amouyel, P, Andreassen, OA, Arepalli, S, Assareh, AA, Barral, S, Bastin, ME, Becker, DM, Becker, JT, Bennett, DA, Blangero, J, van Bokhoven, H, Boomsma, DI, Brodaty, H, Brouwer, RM, Brunner, HG, Buckner, RL, Buitelaar, JK, Bulayeva, KB, Cahn, W, Calhoun, VD, Cannon, DM, Cavalleri, GL, Cheng, C-Y, Cichon, S, Cookson, MR, Corvin, A, Crespo-Facorro, B, Curran, JE, Czisch, M, Dale, AM, Davies, GE, De Craen, AJM, De Geus, EJC, De Jager, PL, De Zubicaray, GI, Deary, IJ, Debette, S, DeCarli, C, Delanty, N, Depondt, C, DeStefano, A, Dillman, A, Djurovic, S, Donohoe, G, Drevets, WC, Duggirala, R, Dyer, TD, Enzinger, C, Erk, S, Espeseth, T, Fedko, IO, Fernandez, G, Ferrucci, L, Fisher, SE, Fleischman, DA, Ford, I, Fornage, M, Foroud, TM, Fox, PT, Francks, C, Fukunaga, M, Gibbs, JR, Glahn, DC, Gollub, RL, Goring, HHH, Green, RC, Gruber, O, Gudnason, V, Guelfi, S, Haberg, AK, Hansell, NK, Hardy, J, Hartman, CA, Hashimoto, R, Hegenscheid, K, Heinz, A, Le Hellard, S, Hernandez, DG, Heslenfeld, DJ, Ho, B-C, Hoekstra, PJ, Hoffmann, W, Hofman, A, Holsboer, F, Homuth, G, Hosten, N, Hottenga, J-J, Huentelman, M, Pol, HEH, Ikeda, M, Jack, CR, Jenkinson, M, Johnson, R, Joensson, EG, Jukema, JW, Kahn, RS, Kanai, R, Kloszewska, I, Knopman, DS, Kochunov, P, Kwok, JB, Lawrie, SM, Lemaitre, H, Liu, X, Longo, DL, Lopez, OL, Lovestone, S, Martinez, O, Martinot, J-L, Mattay, VS, McDonald, C, McIntosh, AM, McMahon, FJ, McMahon, KL, Mecocci, P, Melle, I, Meyer-Lindenberg, A, Mohnke, S, Montgomery, GW, Morris, DW, Mosley, TH, Muhleisen, TW, Mueller-Myhsok, B, Nalls, MA, Nauck, M, Nichols, TE, Niessen, WJ, Nothen, MM, Nyberg, L, Ohi, K, Olvera, RL, Ophoff, RA, Pandolfo, M, Paus, T, Pausova, Z, Penninx, BWJH, Pike, GB, Potkin, SG, Psaty, BM, Reppermund, S, Rietschel, M, Roffman, JL, Romanczuk-Seiferth, N, Rotter, JI, Ryten, M, Sacco, RL, Sachdev, PS, Saykin, AJ, Schmidt, R, Schmidt, H, Schofield, PR, Sigursson, S, Simmons, A, Singleton, A, Sisodiya, SM, Smith, C, Smoller, JW, Soininen, H, Steen, VM, Stott, DJ, Sussmann, JE, Thalamuthu, A, Toga, AW, Traynor, BJ, Troncoso, J, Tsolaki, M, Tzourio, C, Uitterlinden, AG, Hernandez, MCV, Van der Brug, M, van der Lugt, A, van der Wee, NJA, Van Haren, NEM, van't Ent, D, Van Tol, M-J, Vardarajan, BN, Vellas, B, Veltman, DJ, Voelzke, H, Walter, H, Wardlaw, JM, Wassink, TH, Weale, ME, Weinberger, DR, Weiner, MW, Wen, W, Westman, E, White, T, Wong, TY, Wright, CB, Zielke, RH, Zonderman, AB, Martin, NG, Van Duijn, CM, Wright, MJ, Longstreth, WT, Schumann, G, Grabe, HJ, Franke, B, Launer, LJ, Medland, SE, Seshadri, S, Thompson, PM, and Ikram, MA

Abstract

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg=-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.

Published
2017

31. 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
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32. D2 receptor occupancy following lurasidone treatment in patients with schizophrenia or schizoaffective disorder

Author

Potkin, SG, Keator, DB, Kesler-West, ML, Nguyen, DD, Van Erp, TGM, Mukherjee, J, Shah, N, and Preda, A

Abstract

Objective/Introduction Lurasidone is an atypical antipsychotic medication approved for the treatment of schizophrenia over a dose range of 40-160 mg/day. This study examined D2 receptor occupancy and its association with clinical improvement and side effects in patients with schizophrenia or schizoaffective disorder following repeated doses of 80, 120, or 160 mg/day of lurasidone. Methods Twenty-five patients with The Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) diagnoses of schizophrenia or schizoaffective disorder were washed out of their antipsychotic medications (5 half-lives) and randomly assigned to 80, 120, or 160 mg/day of lurasidone. Subjects were imaged with 18F-fallypride at baseline and at steady-state lurasidone treatment to determine D2 receptor occupancy. Results Blood lurasidone concentration (plus major metabolite), but not dose, significantly correlated with D2 receptor occupancy. D2 receptor occupancy in several subcortical structures is associated with positive but not negative symptom improvement or the presence of movement symptoms. Discussion Blood concentrations greater than 70 ng/mL may be required to achieve a 65% occupancy level in subcortical areas. Intersubject blood concentrations at fixed dose were highly variable and may account for the lack of dose correlations. Conclusions Positron emission tomography (PET) occupancy data suggest that greater than 65% occupancy can be achieved across the dose range of 80-160 mg/day and that some patients require higher doses to achieve antipsychotic efficacy; this finding supports prior randomized clinical trial results. © Cambridge University Press 2013.

Published
2014
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33. 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
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34. 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
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35. Association of common genetic variants in GPCPD1 with scaling of visual cortical surface area in humans

Author

Bakken, TE, Roddey, JC, Djurovic, S, Akshoomoff, N, Amaral, DG, Bloss, CS, Casey, BJ, Chang, L, Ernst, TM, Gruen, JR, Jernigan, TL, Kaufmann, WE, Kenet, T, Kennedy, DN, Kuperman, JM, Murray, SS, Sowell, ER, Rimol, LM, Mattingsdal, M, Melle, I, Agartz, I, Andreassen, OA, Schork, NJ, Dale, AM, Alzheimer’s Disease Neuroimaging Initiative, Pediatric Imaging, Neurocognition, Genetics Study, Weiner, M, Aisen, P, Petersen, R, Jack, CR, Jr, Jagust, W, Trojanowki, JQ, Toga, AW, Beckett, L, Green, RC, Saykin, AJ, Morris, J, Liu, E, Montine, T, Gamst, A, Thomas, RG, Donohue, M, Walter, S, Gessert, D, Sather, T, Harvey, D, Kornak, J, Dale, A, Bernstein, M, Felmlee, J, Fox, N, Thompson, P, Schuff, N, Alexander, G, DeCarli, C, Bandy, D, Koeppe, RA, Foster, N, Reiman, EM, Chen, K, Mathis, C, Cairns, NJ, Taylor-Reinwald, L, Shaw, L, Lee, VM, Korecka, M, Crawford, K, Neu, S, Foroud, TM, Potkin, S, Shen, L, Kachaturian, Z, Frank, R, Snyder, PJ, Molchan, S, Kaye, J, Quinn, J, Lind, B, Dolen, S, Schneider, LS, Pawluczyk, S, Spann, BM, Brewer, J, Vanderswag, H, Heidebrink, JL, Lord, JL, Johnson, K, Doody, RS, Villanueva-Meyer, J, Chowdhury, M, Stern, Yaakov, Honig, LS, Bell, KL, Morris, JC, Ances, B, Carroll, M, Leon, S, Mintun, MA, Schneider, S, Marson, D, Griffith, R, Clark, D, Grossman, H, Mitsis, E, Romirowsky, A, deToledo-Morrell, L, Shah, RC, Duara, R, Varon, D, Roberts, P, Albert, M, Onyike, C, Kielb, S, Rusinek, H, de, Leon, MJ, Glodzik, L, De, Santi, S, Doraiswamy, PM, Petrella, JR, Coleman, RE, Arnold, SE, Karlawish, JH, Wolk, D, Smith, CD, Jicha, G, Hardy, P, Lopez, OL, Oakley, M, Simpson, DM, Porsteinsson, AP, Goldstein, BS, Martin, K, Makino, KM, Ismail, MS, Brand, C, Mulnard, RA, Thai, G, Mc-Adams-Ortiz, C, Womack, K, Mathews, D, Quiceno, M, Diaz-Arrastia, R, King, R, Martin-Cook, K, DeVous, M, Levey, AI, Lah, JJ, Cellar, JS, Burns, JM, Anderson, HS, Swerdlow, RH, Apostolova, L, Lu, PH, Bartzokis, G, Silverman, DH, Graff-Radford, NR, Parfitt, F, Johnson, H, Farlow, MR, Hake, AM, Matthews, BR, Herring, S, van, Dyck, CH, Carson, RE, MacAvoy, MG, Chertkow, H, Bergman, H, Hosein, C, Black, S, Stefanovic, B, Caldwell, C, Ging-Yuek, Hsiung, R, Feldman, H, Mudge, B, Assaly, M, Kertesz, A, Rogers, J, Trost, D, Bernick, C, Munic, D, Kerwin, D, Mesulam, MM, Lipowski, K, Wu, CK, Johnson, N, Sadowsky, C, Martinez, W, Villena, T, Turner, RS, Reynolds, B, Sperling, RA, Johnson, KA, Marshall, G, Frey, M, Yesavage, J, Taylor, JL, Lane, B, Rosen, A, Tinklenberg, J, Sabbagh, M, Belden, C, Jacobson, S, Kowall, N, Killiany, R, Budson, AE, Norbash, A, Johnson, PL, Obisesan, TO, Wolday, S, Bwayo, SK, Lerner, A, Hudson, L, Ogrocki, P, Fletcher, E, Carmichael, O, Olichney, J, Kittur, S, Borrie, M, Lee, TY, Bartha, R, Johnson, S, Asthana, S, Carlsson, CM, Potkin, SG, Preda, A, Nguyen, D, Tariot, P, Fleisher, A, Reeder, S, Bates, V, Capote, H, Rainka, M, Scharre, DW, Kataki, M, Zimmerman, EA, Celmins, D, Brown, AD, Pearlson, GD, Blank, K, Anderson, K, Santulli, RB, Schwartz, ES, Sink, KM, Williamson, JD, Garg, P, Watkins, F, Ott, BR, Querfurth, H, Tremont, G, Salloway, S, Malloy, P, Correia, S, Rosen, HJ, Miller, BL, Mintzer, J, Longmire, CF, Spicer, K, Finger, E, Rachinsky, I, Drost, D, Jernigan, T, McCabe, C, Grant, E, Ernst, T, Kuperman, J, Chung, Y, Murray, S, Bloss, C, Darst, B, Pritchett, L, Saito, A, Amaral, D, DiNino, M, Eyngorina, B, Sowell, E, Houston, S, Soderberg, L, Kaufmann, W, van, Zijl, P, Rizzo-Busack, H, Javid, M, Mehta, N, Ruberry, E, Powers, A, Rosen, B, Gebhard, N, Manigan, H, Frazier, J, Kennedy, D, Yakutis, L, Hill, M, Gruen, J, Bosson-Heenan, J, and Carlson, H

Subjects
anatomy & histology, pathology [Visual Cortex], Adult, Diagnostic Imaging, Male, Linkage disequilibrium, Visual perception, genetic structures, Adolescent, Genotype, Imaging genetics, methods [Diagnostic Imaging], Single-nucleotide polymorphism, Genome-wide association study, Saccharomyces cerevisiae, Biology, Polymorphism, Single Nucleotide, Cohort Studies, methods [Brain Mapping], pathology [Brain], Cortex (anatomy), Genetic variation, Medicine and Health Sciences, medicine, Humans, genetics [Phosphoric Diester Hydrolases], Aged, Visual Cortex, Genetics, Brain Mapping, Multidisciplinary, Models, Genetic, Phosphoric Diester Hydrolases, metabolism [Saccharomyces cerevisiae], Brain, Genetic Variation, Genomics, Middle Aged, Biological Sciences, Visual cortex, medicine.anatomical_structure, Female, Genome-Wide Association Study
Abstract

Visual cortical surface area varies two- to threefold between human individuals, is highly heritable, and has been correlated with visual acuity and visual perception. However, it is still largely unknown what specific genetic and environmental factors contribute to normal variation in the area of visual cortex. To identify SNPs associated with the proportional surface area of visual cortex, we performed a genome-wide association study followed by replication in two independent cohorts. We identified one SNP (rs6116869) that replicated in both cohorts and had genome-wide significant association ( P combined = 3.2 × 10 −8 ). Furthermore, a metaanalysis of imputed SNPs in this genomic region identified a more significantly associated SNP (rs238295; P = 6.5 × 10 −9 ) that was in strong linkage disequilibrium with rs6116869. These SNPs are located within 4 kb of the 5′ UTR of GPCPD1 , glycerophosphocholine phosphodiesterase GDE1 homolog ( Saccharomyces cerevisiae ), which in humans, is more highly expressed in occipital cortex compared with the remainder of cortex than 99.9% of genes genome-wide. Based on these findings, we conclude that this common genetic variation contributes to the proportional area of human visual cortex. We suggest that identifying genes that contribute to normal cortical architecture provides a first step to understanding genetic mechanisms that underlie visual perception.

Published
2012

36. The ENIGMA Consortium: large-scale collaborative analyses of neuroimaging and genetic data

Author

Thompson, PM, Stein, JL, Medland, SE, Hibar, DP, Vasquez, AA, Renteria, ME, Toro, R, Jahanshad, N, Schumann, G, Franke, B, Wright, MJ, Martin, NG, Agartz, I, Alda, M, Alhusaini, S, Almasy, L, Almeida, J, Alpert, K, Andreasen, NC, Andreassen, OA, Apostolova, LG, Appel, K, Armstrong, NJ, Aribisala, B, Bastin, ME, Bauer, M, Bearden, CE, Bergmann, O, Binder, EB, Blangero, J, Bockholt, HJ, Boen, E, Bois, C, Boomsma, DI, Booth, T, Bowman, IJ, Bralten, J, Brouwer, RM, Brunner, HG, Brohawn, DG, Buckner, RL, Buitelaar, J, Bulayeva, K, Bustillo, JR, Calhoun, VD, Cannon, DM, Cantor, RM, Carless, MA, Caseras, X, Cavalleri, GL, Chakravarty, MM, Chang, KD, Ching, CRK, Christoforou, A, Cichon, S, Clark, VP, Conrod, P, Coppola, G, Crespo-Facorro, B, Curran, JE, Czisch, M, Deary, IJ, de Geus, EJC, den Braber, A, Delvecchio, G, Depondt, C, de Haan, L, de Zubicaray, GI, Dima, D, Dimitrova, R, Djurovic, S, Dong, H, Donohoe, G, Duggirala, R, Dyer, TD, Ehrlich, S, Ekman, CJ, Elvsashagen, T, Emsell, L, Erk, S, Espeseth, T, Fagerness, J, Fears, S, Fedko, I, Fernandez, G, Fisher, SE, Foroud, T, Fox, PT, Francks, C, Frangou, S, Frey, EM, Frodl, T, Frouin, V, Garavan, H, Giddaluru, S, Glahn, DC, Godlewska, B, Goldstein, RZ, Gollub, RL, Grabe, HJ, Grimm, O, Gruber, O, Guadalupe, T, Gur, RE, Gur, RC, Goering, HHH, Hagenaars, S, Hajek, T, Hall, GB, Hall, J, Hardy, J, Hartman, CA, Hass, J, Hatton, SN, Haukvik, UK, Hegenscheid, K, Heinz, A, Hickie, IB, Ho, B-C, Hoehn, D, Hoekstra, PJ, Hollinshead, M, Holmes, AJ, Homuth, G, Hoogman, M, Hong, LE, Hosten, N, Hottenga, J-J, Pol, HEH, Hwang, KS, Jack, CR, Jenkinson, M, Johnston, C, Joensson, EG, Kahn, RS, Kasperaviciute, D, Kelly, S, Kim, S, Kochunov, P, Koenders, L, Kraemer, B, Kwok, JBJ, Lagopoulos, J, Laje, G, Landen, M, Landman, BA, Lauriello, J, Lawrie, SM, Lee, PH, Le Hellard, S, Lemaitre, H, Leonardo, CD, Li, C-S, Liberg, B, Liewald, DC, Liu, X, Lopez, LM, Loth, E, Lourdusamy, A, Luciano, M, Macciardi, F, Machielsen, MWJ, MacQueen, GM, Malt, UF, Mandl, R, Manoach, DS, Martinot, J-L, Matarin, M, Mather, KA, Mattheisen, M, Mattingsdal, M, Meyer-Lindenberg, A, McDonald, C, McIntosh, AM, McMahon, FJ, McMahon, KL, Meisenzahl, E, Melle, I, Milaneschi, Y, Mohnke, S, Montgomery, GW, Morris, DW, Moses, EK, Mueller, BA, Munoz Maniega, S, Muehleisen, TW, Mueller-Myhsok, B, Mwangi, B, Nauck, M, Nho, K, Nichols, TE, Nilsson, L-G, Nugent, AC, Nyberg, L, Olvera, RL, Oosterlaan, J, Ophoff, RA, Pandolfo, M, Papalampropoulou-Tsiridou, M, Papmeyer, M, Paus, T, Pausova, Z, Pearlson, GD, Penninx, BW, Peterson, CP, Pfennig, A, Phillips, M, Pike, GB, Poline, J-B, Potkin, SG, Puetz, B, Ramasamy, A, Rasmussen, J, Rietschel, M, Rijpkema, M, Risacher, SL, Roffman, JL, Roiz-Santianez, R, Romanczuk-Seiferth, N, Rose, EJ, Royle, NA, Rujescu, D, Ryten, M, Sachdev, PS, Salami, A, Satterthwaite, TD, Savitz, J, Saykin, AJ, Scanlon, C, Schmaal, L, Schnack, HG, Schork, AJ, Schulz, SC, Schuer, R, Seidman, L, Shen, L, Shoemaker, JM, Simmons, A, Sisodiya, SM, Smith, C, Smoller, JW, Soares, JC, Sponheim, SR, Sprooten, E, Starr, JM, Steen, VM, Strakowski, S, Strike, L, Sussmann, J, Saemann, PG, Teumer, A, Toga, AW, Tordesillas-Gutierrez, D, Trabzuni, D, Trost, S, Turner, J, Van den Heuvel, M, van der Wee, NJ, van Eijk, K, van Erp, TGM, van Haren, NEM, van 't Ent, D, van Tol, M-J, Hernandez, MCV, Veltman, DJ, Versace, A, Voelzke, H, Walker, R, Walter, H, Wang, L, Wardlaw, JM, Weale, ME, Weiner, MW, Wen, W, Westlye, LT, Whalley, HC, Whelan, CD, White, T, Winkler, AM, Wittfeld, K, Woldehawariat, G, Wolf, C, Zilles, D, Zwiers, MP, Thalamuthu, A, Schofield, PR, Freimer, NB, Lawrence, NS, Drevets, W, Thompson, PM, Stein, JL, Medland, SE, Hibar, DP, Vasquez, AA, Renteria, ME, Toro, R, Jahanshad, N, Schumann, G, Franke, B, Wright, MJ, Martin, NG, Agartz, I, Alda, M, Alhusaini, S, Almasy, L, Almeida, J, Alpert, K, Andreasen, NC, Andreassen, OA, Apostolova, LG, Appel, K, Armstrong, NJ, Aribisala, B, Bastin, ME, Bauer, M, Bearden, CE, Bergmann, O, Binder, EB, Blangero, J, Bockholt, HJ, Boen, E, Bois, C, Boomsma, DI, Booth, T, Bowman, IJ, Bralten, J, Brouwer, RM, Brunner, HG, Brohawn, DG, Buckner, RL, Buitelaar, J, Bulayeva, K, Bustillo, JR, Calhoun, VD, Cannon, DM, Cantor, RM, Carless, MA, Caseras, X, Cavalleri, GL, Chakravarty, MM, Chang, KD, Ching, CRK, Christoforou, A, Cichon, S, Clark, VP, Conrod, P, Coppola, G, Crespo-Facorro, B, Curran, JE, Czisch, M, Deary, IJ, de Geus, EJC, den Braber, A, Delvecchio, G, Depondt, C, de Haan, L, de Zubicaray, GI, Dima, D, Dimitrova, R, Djurovic, S, Dong, H, Donohoe, G, Duggirala, R, Dyer, TD, Ehrlich, S, Ekman, CJ, Elvsashagen, T, Emsell, L, Erk, S, Espeseth, T, Fagerness, J, Fears, S, Fedko, I, Fernandez, G, Fisher, SE, Foroud, T, Fox, PT, Francks, C, Frangou, S, Frey, EM, Frodl, T, Frouin, V, Garavan, H, Giddaluru, S, Glahn, DC, Godlewska, B, Goldstein, RZ, Gollub, RL, Grabe, HJ, Grimm, O, Gruber, O, Guadalupe, T, Gur, RE, Gur, RC, Goering, HHH, Hagenaars, S, Hajek, T, Hall, GB, Hall, J, Hardy, J, Hartman, CA, Hass, J, Hatton, SN, Haukvik, UK, Hegenscheid, K, Heinz, A, Hickie, IB, Ho, B-C, Hoehn, D, Hoekstra, PJ, Hollinshead, M, Holmes, AJ, Homuth, G, Hoogman, M, Hong, LE, Hosten, N, Hottenga, J-J, Pol, HEH, Hwang, KS, Jack, CR, Jenkinson, M, Johnston, C, Joensson, EG, Kahn, RS, Kasperaviciute, D, Kelly, S, Kim, S, Kochunov, P, Koenders, L, Kraemer, B, Kwok, JBJ, Lagopoulos, J, Laje, G, Landen, M, Landman, BA, Lauriello, J, Lawrie, SM, Lee, PH, Le Hellard, S, Lemaitre, H, Leonardo, CD, Li, C-S, Liberg, B, Liewald, DC, Liu, X, Lopez, LM, Loth, E, Lourdusamy, A, Luciano, M, Macciardi, F, Machielsen, MWJ, MacQueen, GM, Malt, UF, Mandl, R, Manoach, DS, Martinot, J-L, Matarin, M, Mather, KA, Mattheisen, M, Mattingsdal, M, Meyer-Lindenberg, A, McDonald, C, McIntosh, AM, McMahon, FJ, McMahon, KL, Meisenzahl, E, Melle, I, Milaneschi, Y, Mohnke, S, Montgomery, GW, Morris, DW, Moses, EK, Mueller, BA, Munoz Maniega, S, Muehleisen, TW, Mueller-Myhsok, B, Mwangi, B, Nauck, M, Nho, K, Nichols, TE, Nilsson, L-G, Nugent, AC, Nyberg, L, Olvera, RL, Oosterlaan, J, Ophoff, RA, Pandolfo, M, Papalampropoulou-Tsiridou, M, Papmeyer, M, Paus, T, Pausova, Z, Pearlson, GD, Penninx, BW, Peterson, CP, Pfennig, A, Phillips, M, Pike, GB, Poline, J-B, Potkin, SG, Puetz, B, Ramasamy, A, Rasmussen, J, Rietschel, M, Rijpkema, M, Risacher, SL, Roffman, JL, Roiz-Santianez, R, Romanczuk-Seiferth, N, Rose, EJ, Royle, NA, Rujescu, D, Ryten, M, Sachdev, PS, Salami, A, Satterthwaite, TD, Savitz, J, Saykin, AJ, Scanlon, C, Schmaal, L, Schnack, HG, Schork, AJ, Schulz, SC, Schuer, R, Seidman, L, Shen, L, Shoemaker, JM, Simmons, A, Sisodiya, SM, Smith, C, Smoller, JW, Soares, JC, Sponheim, SR, Sprooten, E, Starr, JM, Steen, VM, Strakowski, S, Strike, L, Sussmann, J, Saemann, PG, Teumer, A, Toga, AW, Tordesillas-Gutierrez, D, Trabzuni, D, Trost, S, Turner, J, Van den Heuvel, M, van der Wee, NJ, van Eijk, K, van Erp, TGM, van Haren, NEM, van 't Ent, D, van Tol, M-J, Hernandez, MCV, Veltman, DJ, Versace, A, Voelzke, H, Walker, R, Walter, H, Wang, L, Wardlaw, JM, Weale, ME, Weiner, MW, Wen, W, Westlye, LT, Whalley, HC, Whelan, CD, White, T, Winkler, AM, Wittfeld, K, Woldehawariat, G, Wolf, C, Zilles, D, Zwiers, MP, Thalamuthu, A, Schofield, PR, Freimer, NB, Lawrence, NS, and Drevets, W

Abstract

The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA's first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way.

Published
2014

37. Generative FDG-PET and MRI model of aging and disease progression in Alzheimer's disease.

Author

Alzheimer's Disease Neuroimaging Initiative, Weiner, M., Aisen, P., Petersen, R., Jack CR.<Suffix>Jr</Suffix>, Jagust, W., Trojanowki, JQ., Toga, AW., Beckett, L., Green, RC., Saykin, AJ., Morris, J., Liu, E., Montine, T., Gamst, A., Thomas, RG., Donohue, M., Walter, S., Gessert, D., Sather, T., Harvey, D., Kornak, J., Dale, A., Bernstein, M., Felmlee, J., Fox, N., Thompson, P., Schuff, N., DeCarli, C., Bandy, D., Koeppe, RA., Foster, N., Reiman, EM., Chen, K., Mathis, C., Cairns, NJ., Taylor-Reinwald, L., Shaw, L., Lee, VM., Korecka, M., Crawford, K., Neu, S., Foroud, TM., Potkin, S., Shen, L., Kachaturian, Z., Frank, R., Snyder, PJ., Molchan, S., Kaye, J., Quinn, J., Lind, B., Dolen, S., Schneider, LS., Pawluczyk, S., Spann, BM., Brewer, J., Vanderswag, H., Heidebrink, JL., Lord, JL., Johnson, K., Doody, RS., Villanueva-Meyer, J., Chowdhury, M., Stern, Y., Honig, LS., Bell, KL., Morris, JC., Ances, B., Carroll, M., Leon, S., Mintun, MA., Schneider, S., Marson, D., Griffith, R., Clark, D., Grossman, H., Mitsis, E., Romirowsky, A., deToledo-Morrell, L., Shah, RC., Duara, R., Varon, D., Roberts, P., Albert, M., Onyike, C., Kielb, S., Rusinek, H., de Leon MJ., Glodzik, L., De Santi, S., Doraiswamy, P., Petrella, JR., Coleman, R., Arnold, SE., Karlawish, JH., Wolk, D., Smith, CD., Jicha, G., Hardy, P., Lopez, OL., Oakley, M., Simpson, DM., Porsteinsson, AP., Goldstein, BS., Martin, K., Makino, KM., Ismail, M., Brand, C., Mulnard, RA., Thai, G., Mc-Adams-Ortiz, C., Womack, K., Mathews, D., Quiceno, M., Diaz-Arrastia, R., King, R., Martin-Cook, K., DeVous, M., Levey, AI., Lah, JJ., Cellar, JS., Burns, JM., Anderson, HS., Swerdlow, RH., Apostolova, L., Lu, PH., Bartzokis, G., Silverman, DH., Graff-Radford, NR., Parfitt, F., Johnson, H., Farlow, MR., Hake, AM., Matthews, BR., Herring, S., van Dyck CH., Carson, RE., MacAvoy, MG., Chertkow, H., Bergman, H., Hosein, C., Black, S., Stefanovic, B., Caldwell, C., Hsiung, GY., Feldman, H., Mudge, B., Assaly, M., Kertesz, A., Rogers, J., Trost, D., Bernick, C., Munic, D., Kerwin, D., Mesulam, MM., Lipowski, K., Wu, CK., Johnson, N., Sadowsky, C., Martinez, W., Villena, T., Turner, RS., Reynolds, B., Sperling, RA., Johnson, KA., Marshall, G., Frey, M., Yesavage, J., Taylor, JL., Lane, B., Rosen, A., Tinklenberg, J., Sabbagh, M., Belden, C., Jacobson, S., Kowall, N., Killiany, R., Budson, AE., Norbash, A., Johnson, PL., Obisesan, TO., Wolday, S., Bwayo, SK., Lerner, A., Hudson, L., Ogrocki, P., Fletcher, E., Carmichael, O., Olichney, J., Kittur, S., Borrie, M., Lee, TY., Bartha, R., Johnson, S., Asthana, S., Carlsson, CM., Potkin, SG., Preda, A., Nguyen, D., Tariot, P., Fleisher, A., Reeder, S., Bates, V., Capote, H., Rainka, M., Scharre, DW., Kataki, M., Zimmerman, EA., Celmins, D., Brown, AD., Pearlson, GD., Blank, K., Anderson, K., Santulli, RB., Schwartz, ES., Sink, KM., Williamson, JD., Garg, P., Watkins, F., Ott, BR., Querfurth, H., Tremont, G., Salloway, S., Malloy, P., Correia, S., Rosen, HJ., Miller, BL., Mintzer, J., Longmire, CF., Spicer, K., Finger, E., Rachinsky, I., Drost, D., Dukart, J., Kherif, F., Mueller, K., Adaszewski, S., Schroeter, M.L., Frackowiak, R.S., Draganski, B., Alzheimer's Disease Neuroimaging Initiative, Weiner, M., Aisen, P., Petersen, R., Jack CR.<Suffix>Jr</Suffix>, Jagust, W., Trojanowki, JQ., Toga, AW., Beckett, L., Green, RC., Saykin, AJ., Morris, J., Liu, E., Montine, T., Gamst, A., Thomas, RG., Donohue, M., Walter, S., Gessert, D., Sather, T., Harvey, D., Kornak, J., Dale, A., Bernstein, M., Felmlee, J., Fox, N., Thompson, P., Schuff, N., DeCarli, C., Bandy, D., Koeppe, RA., Foster, N., Reiman, EM., Chen, K., Mathis, C., Cairns, NJ., Taylor-Reinwald, L., Shaw, L., Lee, VM., Korecka, M., Crawford, K., Neu, S., Foroud, TM., Potkin, S., Shen, L., Kachaturian, Z., Frank, R., Snyder, PJ., Molchan, S., Kaye, J., Quinn, J., Lind, B., Dolen, S., Schneider, LS., Pawluczyk, S., Spann, BM., Brewer, J., Vanderswag, H., Heidebrink, JL., Lord, JL., Johnson, K., Doody, RS., Villanueva-Meyer, J., Chowdhury, M., Stern, Y., Honig, LS., Bell, KL., Morris, JC., Ances, B., Carroll, M., Leon, S., Mintun, MA., Schneider, S., Marson, D., Griffith, R., Clark, D., Grossman, H., Mitsis, E., Romirowsky, A., deToledo-Morrell, L., Shah, RC., Duara, R., Varon, D., Roberts, P., Albert, M., Onyike, C., Kielb, S., Rusinek, H., de Leon MJ., Glodzik, L., De Santi, S., Doraiswamy, P., Petrella, JR., Coleman, R., Arnold, SE., Karlawish, JH., Wolk, D., Smith, CD., Jicha, G., Hardy, P., Lopez, OL., Oakley, M., Simpson, DM., Porsteinsson, AP., Goldstein, BS., Martin, K., Makino, KM., Ismail, M., Brand, C., Mulnard, RA., Thai, G., Mc-Adams-Ortiz, C., Womack, K., Mathews, D., Quiceno, M., Diaz-Arrastia, R., King, R., Martin-Cook, K., DeVous, M., Levey, AI., Lah, JJ., Cellar, JS., Burns, JM., Anderson, HS., Swerdlow, RH., Apostolova, L., Lu, PH., Bartzokis, G., Silverman, DH., Graff-Radford, NR., Parfitt, F., Johnson, H., Farlow, MR., Hake, AM., Matthews, BR., Herring, S., van Dyck CH., Carson, RE., MacAvoy, MG., Chertkow, H., Bergman, H., Hosein, C., Black, S., Stefanovic, B., Caldwell, C., Hsiung, GY., Feldman, H., Mudge, B., Assaly, M., Kertesz, A., Rogers, J., Trost, D., Bernick, C., Munic, D., Kerwin, D., Mesulam, MM., Lipowski, K., Wu, CK., Johnson, N., Sadowsky, C., Martinez, W., Villena, T., Turner, RS., Reynolds, B., Sperling, RA., Johnson, KA., Marshall, G., Frey, M., Yesavage, J., Taylor, JL., Lane, B., Rosen, A., Tinklenberg, J., Sabbagh, M., Belden, C., Jacobson, S., Kowall, N., Killiany, R., Budson, AE., Norbash, A., Johnson, PL., Obisesan, TO., Wolday, S., Bwayo, SK., Lerner, A., Hudson, L., Ogrocki, P., Fletcher, E., Carmichael, O., Olichney, J., Kittur, S., Borrie, M., Lee, TY., Bartha, R., Johnson, S., Asthana, S., Carlsson, CM., Potkin, SG., Preda, A., Nguyen, D., Tariot, P., Fleisher, A., Reeder, S., Bates, V., Capote, H., Rainka, M., Scharre, DW., Kataki, M., Zimmerman, EA., Celmins, D., Brown, AD., Pearlson, GD., Blank, K., Anderson, K., Santulli, RB., Schwartz, ES., Sink, KM., Williamson, JD., Garg, P., Watkins, F., Ott, BR., Querfurth, H., Tremont, G., Salloway, S., Malloy, P., Correia, S., Rosen, HJ., Miller, BL., Mintzer, J., Longmire, CF., Spicer, K., Finger, E., Rachinsky, I., Drost, D., Dukart, J., Kherif, F., Mueller, K., Adaszewski, S., Schroeter, M.L., Frackowiak, R.S., and Draganski, B.

Abstract

The failure of current strategies to provide an explanation for controversial findings on the pattern of pathophysiological changes in Alzheimer's Disease (AD) motivates the necessity to develop new integrative approaches based on multi-modal neuroimaging data that captures various aspects of disease pathology. Previous studies using [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) and structural magnetic resonance imaging (sMRI) report controversial results about time-line, spatial extent and magnitude of glucose hypometabolism and atrophy in AD that depend on clinical and demographic characteristics of the studied populations. Here, we provide and validate at a group level a generative anatomical model of glucose hypo-metabolism and atrophy progression in AD based on FDG-PET and sMRI data of 80 patients and 79 healthy controls to describe expected age and symptom severity related changes in AD relative to a baseline provided by healthy aging. We demonstrate a high level of anatomical accuracy for both modalities yielding strongly age- and symptom-severity- dependant glucose hypometabolism in temporal, parietal and precuneal regions and a more extensive network of atrophy in hippocampal, temporal, parietal, occipital and posterior caudate regions. The model suggests greater and more consistent changes in FDG-PET compared to sMRI at earlier and the inversion of this pattern at more advanced AD stages. Our model describes, integrates and predicts characteristic patterns of AD related pathology, uncontaminated by normal age effects, derived from multi-modal data. It further provides an integrative explanation for findings suggesting a dissociation between early- and late-onset AD. The generative model offers a basis for further development of individualized biomarkers allowing accurate early diagnosis and treatment evaluation.

Published
2013

38. Assessing the impact of fMRI data quality on group level analyses in the FBIRN multi-site study of schizophrenia patients and healthy controls

Author

Jorgensen, KW, primary, Bischoff-Grethe, A, additional, Brown, GG, additional, Fennema-Notestine, C, additional, Gadde, S, additional, Greve, DN, additional, Mueller, BA, additional, Notestine, R, additional, Ozyort, B, additional, Potkin, SG, additional, Turner, JA, additional, and Mathalon, DH, additional

Published
2009
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43. Amyloid pathway-based candidate gene analysis of [(11)C]PiB-PET in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort.

Author

Swaminathan S, Shen L, Risacher SL, Yoder KK, West JD, Kim S, Nho K, Foroud T, Inlow M, Potkin SG, Huentelman MJ, Craig DW, Jagust WJ, Koeppe RA, Mathis CA, Jack CR Jr, Weiner MW, Saykin AJ, Alzheimer's Disease Neuroimaging Initiative, and Swaminathan, Shanker

Abstract

Amyloid imaging with [(11)C]Pittsburgh Compound-B (PiB) provides in vivo data on plaque deposition in those with, or at risk for, Alzheimer's disease (AD). We performed a gene-based association analysis of 15 quality-controlled amyloid-pathway associated candidate genes in 103 Alzheimer's Disease Neuroimaging Initiative participants. The mean normalized PiB uptake value across four brain regions known to have amyloid deposition in AD was used as a quantitative phenotype. The minor allele of an intronic SNP within DHCR24 was identified and associated with a lower average PiB uptake. Further investigation at whole-brain voxel-wise level indicated that non-carriers of the minor allele had higher PiB uptake in frontal regions compared to carriers. DHCR24 has been previously shown to confer resistance against beta-amyloid and oxidative stress-induced apoptosis, thus our findings support a neuroprotective role. Pathway-based genetic analysis of targeted molecular imaging phenotypes appears promising to help elucidate disease pathophysiology and identify potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Published
2012
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45. Effect of dopamine D3 receptor gene polymorphisms and clozapine treatment response: exploratory analysis of nine polymorphisms and meta-analysis of the Ser9Gly variant.

Author

Hwang, R, Zai, C, Tiwari, A, Müller, DJ, Arranz, MJ, Morris, AG, McKenna, PJ, Munro, J, Potkin, SG, Lieberman, JA, Kennedy, JL, and Meltzer, HY

Subjects
DOPAMINE, ANTIPSYCHOTIC agents, CLOZAPINE, PHARMACOGENOMICS, ANTIDEPRESSANTS, META-analysis
Abstract

D2 blockade has been implicated in having a central role in antipsychotic response. However, treatment refractoriness, in spite of complete D2 blockade, as well as the efficacy of clozapine (CLZ) in a portion of this patient population, indicates the involvement of other factors as well. Several lines of evidence suggest a role for D3. Furthermore, an earlier meta-analysis by Jönsson et al. (2003) (n=233) suggested a role for genetic variation in the D3 gene. Relevant to this study, Jönsson et al. found the Ser allele of the D3 serine-to-glycine substitution at amino acid position 9 (Ser9Gly) polymorphism to be associated with worse CLZ response compared with the Gly allele. In this study, we attempt to validate these findings by performing a meta-analysis in a much larger sample (n=758). Eight other variants were also tested in our own sample to explore the possible effect of other regions of the gene. We report a negative but consistent trend across individual studies in our meta-analysis for the DRD3 Ser allele and poor CLZ response. A possible minor role for this single-nucleotide polymorphism cannot be disregarded, as our sample size may have been insufficient. Other DRD3 variants and haplotypes of possible interest were also identified for replication in future studies. [ABSTRACT FROM AUTHOR]

Published
2010
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46. Tuning in to the voices: a multisite FMRI study of auditory hallucinations.

Author

Ford JM, Roach BJ, Jorgensen KW, Turner JA, Brown GG, Notestine R, Bischoff-Grethe A, Greve D, Wible C, Lauriello J, Belger A, Mueller BA, Calhoun V, Preda A, Keator D, O'Leary DS, Lim KO, Glover G, Potkin SG, and Mathalon DH

Abstract

Introduction: Auditory hallucinations or voices are experienced by 75% of people diagnosed with schizophrenia. We presumed that auditory cortex of schizophrenia patients who experience hallucinations is tonically “tuned” to internal auditory channels, at the cost of processing external sounds, both speech and nonspeech. Accordingly, we predicted that patients who hallucinate would show less auditory cortical activation to external acoustic stimuli than patients who did not. Methods: At 9 Functional Imaging Biomedical Informatics Research Network (FBIRN) sites, whole-brain images from 106 patients and 111 healthy comparison subjects were collected while subjects performed an auditory target detection task. Data were processed with the FBIRN processing stream. A region of interest analysis extracted activation values from primary (BA41) and secondary auditory cortex (BA42), auditory association cortex (BA22), and middle temporal gyrus (BA21). Patients were sorted into hallucinators (n = 66) and nonhallucinators (n = 40) based on symptom ratings done during the previous week. Results: Hallucinators had less activation to probe tones in left primary auditory cortex (BA41) than nonhallucinators. This effect was not seen on the right. Discussion: Although “voices” are the anticipated sensory experience, it appears that even primary auditory cortex is “turned on” and “tuned in” to process internal acoustic information at the cost of processing external sounds. Although this study was not designed to probe cortical competition for auditory resources, we were able to take advantage of the data and find significant effects, perhaps because of the power afforded by such a large sample. [ABSTRACT FROM PUBLISHER]

Published
2009
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47. fMRI activity correlated with auditory hallucinations during performance of a working memory task: data from the FBIRN consortium study.

Author

Wible CG, Lee K, Molina I, Hashimoto R, Preus AP, Roach BJ, Ford JM, Mathalon DH, McCarthey G, Turner JA, Potkin SG, O'Leary D, Belger A, Diaz M, Voyvodic J, Brown GG, Notestine R, Greve D, Lauriello J, and FBIRN

Abstract

Introduction: Auditory hallucinations are a hallmark symptom of schizophrenia. The neural basis of auditory hallucinations was examined using data from a working memory task. Data were acquired within a multisite consortium and this unique dataset provided the opportunity to analyze data from a large number of subjects who had been tested on the same procedures across sites. We hypothesized that regions involved in verbal working memory and language processing would show activity that was associated with levels of hallucinations during a condition where subjects were rehearsing the stimuli. Methods: Data from the Sternberg Item Recognition Paradigm, a working memory task, were acquired during functional magnetic resonance imaging procedures. The data were collected and preprocessed by the functional imaging biomedical informatics research network consortium. Schizophrenic subjects were split into nonhallucinating and hallucinating subgroups and activity during the probe condition (in which subjects rehearsed stimuli) was examined. Levels of activation from contrast images for the probe phase (collapsed over levels of memory load) of the working memory task were also correlated with levels of auditory hallucinations from the Scale for the Assessment of Positive Symptoms scores. Results: Patients with auditory hallucinations (relative to nonhallucinating subjects) showed decreased activity during the probe condition in verbal working memory/language processing regions, including the superior temporal and inferior parietal regions. These regions also showed associations between activity and levels of hallucinations in a correlation analysis. Discussion: The association between activation and hallucinations scores in the left hemisphere language/working memory regions replicates the findings of previous studies and provides converging evidence for the association between superior temporal abnormalities and auditory hallucinations. [ABSTRACT FROM PUBLISHER]

Published
2009
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48. Working memory and DLPFC inefficiency in schizophrenia: the FBIRN study.

Author

Potkin SG, Turner JA, Brown GG, McCarthy G, Greve DN, Glover GH, Manoach DS, Belger A, Diaz M, Wible CG, Ford JM, Mathalon DH, Gollub R, Lauriello J, O'Leary D, van Erp TGM, Toga AW, Preda A, Lim KO, and FBIRN

Abstract

Background: The Functional Imaging Biomedical Informatics Network is a consortium developing methods for multisite functional imaging studies. Both prefrontal hyper- or hypoactivity in chronic schizophrenia have been found in previous studies of working memory. Methods: In this functional magnetic resonance imaging (fMRI) study of working memory, 128 subjects with chronic schizophrenia and 128 age- and gender-matched controls were recruited from 10 universities around the United States. Subjects performed the Sternberg Item Recognition Paradigm1,2 with memory loads of 1, 3, or 5 items. A region of interest analysis examined the mean BOLD signal change in an atlas-based demarcation of the dorsolateral prefrontal cortex (DLPFC), in both groups, during both the encoding and retrieval phases of the experiment over the various memory loads. Results: Subjects with schizophrenia performed slightly but significantly worse than the healthy volunteers and showed a greater decrease in accuracy and increase in reaction time with increasing memory load. The mean BOLD signal in the DLPFC was significantly greater in the schizophrenic group than the healthy group, particularly in the intermediate load condition. A secondary analysis matched subjects for mean accuracy and found the same BOLD signal hyperresponse in schizophrenics. Conclusions: The increase in BOLD signal change from minimal to moderate memory loads was greater in the schizophrenic subjects than in controls. This effect remained when age, gender, run, hemisphere, and performance were considered, consistent with inefficient DLPFC function during working memory. These findings from a large multisite sample support the concept not of hyper- or hypofrontality in schizophrenia, but rather DLPFC inefficiency that may be manifested in either direction depending on task demands. This redirects the focus of research from direction of difference to neural mechanisms of inefficiency. [ABSTRACT FROM PUBLISHER]

Published
2009
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50. Butyrycholinesterase: a target in the cholinergic treatment of Alzheimer's disease.

Author

Potkin SG

Abstract

In the 1990s, the first drugs to be licensed specifically for the treatment of Alzheimer's disease (AD) became available. These drugs, the cholinesterase inhibitors (ChEIs), have been shown in numerous studies to be safe and effective in improving, stabilizing, or slowing deterioration in AD patients across a variety of symptoms. The success of ChEIs in the treatment of AD supports the validity of the cholinergic hypothesis, which states that decreased levels of acetylcholine (ACh) are associated with the deficits in learning, memory and behavior seen in AD patients. ChEIs enhance and maintain ACh levels by inhibiting ACh degradation. Originally, acetylcholinesterase (AChE) was thought to be the sole target cholinesterase, but continued research revealed an important new candidate enzyme -- butyrylcholinesterase (BuChE). Growing experimental and clinical evidence suggests that both AChE and BuChE are involved in normal brain function and in the development and symptoms of AD. The inhibition of BuChE may, therefore, offer efficacy beyond that of AChE inhibition alone in maintaining the functions of mental processes, behaviour and independent living which deteriorate in patients with AD. This paper reviews the original rationale for developing the ChEIs and provides further information on new, clinically relevant discoveries relating to the cholinergic hypothesis. [ABSTRACT FROM AUTHOR]

Published
2004
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